Pharmacotherapy Principles & Practice PDF

PHARMACOTHERAPY
PRINCIPLES & PRACTICE

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PHARMACOTHERAPY
PRINCIPLES & PRACTICE
EDITORS JILL M. KOLESAR, PHARMD, BCPS, FCCP
Associate Professor
MARIE A. CHISHOLM-BURNS, PHARMD, FCCP, FASHP University of Wisconsin School of Pharmacy
Professor and Head Faculty Supervisor
Department of Pharmacy Practice and Science Analytical Instrumentation Laboratory
The University of Arizona College of Pharmacy Madison, Wisconsin
Tucson, Arizona
JOHN C. ROTSCHAFER, PHARMD, FCCP
BARBARA G. WELLS, PHARMD, FASHP, FCCP, BCPP Professor
Professor and Dean Department of Experimental and Clinical Pharmacology
Executive Director, Research Institute of Pharmaceutical Sciences College of Pharmacy
School of Pharmacy University of Minnesota
The University of Mississippi Minneapolis, Minnesota
University, Mississippi
JOSEPH T. DIPIRO, PHARMD, FCCP
TERRY L. SCHWINGHAMMER, PHARMD, FCCP, FASHP, Professor and Executive Dean
BCPS South Carolina College of Pharmacy
Professor and Chair University of South Carolina, Columbia
Department of Clinical Pharmacy Medical University of South Carolina
West Virginia University Charleston, South Carolina
School of Pharmacy
Morgantown, West Virginia
PATRICK M. MALONE, PHARMD, FASHP

Professor and Assistant Dean, Internal Affairs
School of Pharmacy
University of Findlay
Findlay, Ohio
New York Chicago San Francisco Lisbon London Madrid Mexico City
Milan New Delhi San Juan Seoul Singapore Sydney Toronto
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DOI: 10.1036/0071448802
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CONTENTS
Contributors ix Section 2. Respiratory Disorders 209

Reviewers xxi
Preface xxxix 11. Asthma 209
W. Greg Leader
PART ONE. BASIC CONCEPTS 12. Chronic Obstructive Pulmonary Disease 231
OF PHARMACOTHERAPY PRINCIPLES Tara R. Whetsel and Nicole D. Verkleeren
AND PRACTICE 1
13. Cystic Fibrosis 245
1. Introduction 3 Kimberly J. Novak
Jack E. Fincham
Section 3. Gastrointestinal Disorders 257
PART TWO. DISORDERS OF ORGAN 14. Gastroesophageal Reux Disease 257

SYSTEMS 7 Dianne B. Williams and Marie A. Chisholm-Burns
Section 1. Cardiovascular Disorders 9 15. Peptic Ulcer Disease 269

Jeffrey J. Fong and John W. Devlin
2. Hypertension 9
Robert J. Straka, R. Todd Burkhardt, and David Parra 16. Inammatory Bowel Disease 281
Brian A. Hemstreet
3. Heart Failure 33
Orly Vardeny and Tien M. H. Ng 17. Nausea and Vomiting 295
Sheila Wilhelm
4. Ischemic Heart Disease 63
Larisa H. Cavallari and Robert J. DiDomenico 18. Constipation, Diarrhea, and Irritable
Bowel Syndrome 307
5. Acute Coronary Syndromes 83 Beverly C. Mims and Clarence E. Curry, Jr.
Sarah A. Spinler and Simon de Denus
19. Portal Hypertension and Cirrhosis 323
6. Arrhythmias 107 Laurajo Ryan
James E. Tisdale
20. Pancreatitis 337
7. Venous Thromboembolism 133 Joseph J. Kishel
Stuart T. Haines and Edith A. Nutescu
21. Viral Hepatitis 345
8. Stroke 161 Juliana Chan
Susan R. Winkler
Section 4. Renal Disorders 361
9. Hyperlipidemia 175
Matthew K. Ito 22. Acute Renal Failure 361
Mary K. Stamatakis
10. Hypovolemic Shock 195
Bradley A. Boucher and G. Christopher Wood
v
vi CONTENTS
23. Chronic and End-Stage Renal Disease 373 39. Attention-Decit Hyperactivity Disorder 633
Kristine S. Schonder Kevin W. Cleveland and John Erramouspe
24. Fluids and Electrolytes 403 Section 7. Endocrinologic Disorders

Mark A. Malesker and Lee E. Morrow
40. Diabetes Mellitus 643
25. Acid-Base Disturbances 419 Christopher L. Cook, John T. Johnson,
Lee E. Morrow and Mark A. Malesker and William E. Wade
Section 5. Neurologic Disorders 41. Thyroid Disorders 667

Michael D. Katz
26. Multiple Sclerosis 431
Melody Ryan 42. Adrenal Gland Disorders 685
Devra K. Dang, Judy T. Chen, Frank Pucino, Jr.,
27. Epilepsy 443 and Karim Anton Calis
Timothy E. Welty and Edward Faught
43. Pituitary Gland Disorders 701
28. Status Epilepticus 461 Judy T. Chen, Devra K. Dang, Frank Pucino, Jr.,
Gretchen M. Brophy and Eljim P. Tesoro and Karim Anton Calis
29. Parkinsons Disease 473 Section 8. Gynecologic and Obstetric Disorders

Mary L. Wagner
44. Pregnancy and Lactation: Therapeutic
30. Pain Management 487 Considerations 721
Christine K. ONeil Deborah Sturpe and Kari Alperovitz-Bichell
31. Headache 501 45. Contraception 737

Leigh Ann Ross and Brendan S. Ross Julie M. Koehler and Kathleen B. Haynes
Section 6. Psychiatric Disorders 46. Menstruation-Related Disorders 751

Elena M. Umland, Lara C. Weinstein,
32. Alzheimers Disease 513 and Abby Morris
Gary M. Levin, Toya M. Bowles, and Megan J. Ehret
47. Hormone-Replacement Therapy in Menopause 765
33. Substance-Related Disorders 525 Nicole S. Culhane and Melissa A. Somma
Sally K. Guthrie, Kirk J. Brower,
and Maher Karam-Hage Section 9. Urologic Disorders
34. Schizophrenia 549 48. Erectile Dysfunction 779

Deanna L. Kelly and Elaine Weiner Cara Liday and Catherine Heyneman
35. Major Depressive Disorder 569 49. Benign Prostatic Hyperplasia 791
Marshall Cates, Angela Ann Boggs, Mary Lee and Roohollah Shari
and Jacqueline Feldman
50. Urinary Incontinence and Pediatric Enuresis 803
36. Bipolar Disorder 585 David R.P. Guay
Brian L. Crabtree and Martha J. Faulkner
Section 10. Immunologic Disorders
37. Generalized Anxiety Disorder, Panic Disorder,
and Social Anxiety Disorder 605 51. Allergic and Pseudoallergic Drug Reactions 819
Sheila Botts, Tawny Bettinger, and Brian Greenlee J. Russell May and Philip H. Smith
38. Sleep Disorders 621 52. Solid-Organ Transplantation 829

John M. Dopp and Bradley G. Phillips Steven Gabardi and Ali J. Olyaei
CONTENTS vii
Section 11. Bone and Joint Disorders 853 68. Lower Respiratory Tract Infections 1049
Diane M. Cappelletty
53. Osteoporosis 853
Beth Bryles Phillips 69. Upper Respiratory Tract Infections 1061
Heather L. VandenBussche
54. Rheumatoid Arthritis 867
Susan P. Bruce 70. Skin and Soft Tissue Infections 1075
A. Christie Graham and Randy Wesnitzer
55. Osteoarthritis 879
Benjamin J. Epstein, John G. Gums, and Karen Hall 71. Infective Endocarditis 1089
Ronda L. Akins
56. Gout and Hyperuricemia 891
Geoffrey C. Wall 72. Tuberculosis 1105
Charles A. Peloquin and Rocsanna Namdar
57. Musculoskeletal Disorders 899
Jill S. Burkiewicz 73. Gastrointestinal Infections 1117
Elizabeth D. Hermsen and Ziba Jalali
Section 12. Disorders of the Eyes, Ears, Nose, and Throat 909
74. Intraabdominal Infections 1129
58. Glaucoma 909 Joseph T. DiPiro and Thomas R. Howdieshell
Mikael D. Jones
75. Parasitic Diseases 1139
59. Allergic Rhinitis 925 J.V. Anandan
Kristi N. Hofer and Michelle W. McCarthy
76. Urinary Tract Infection 1151
60. Minor Ophthalmic Disorders 935 Brian A. Potoski
Kendra J. Grande
77. Sexually Transmitted Infections 1159
Section 13. Dermatologic Disorders 949 Marlon Honeywell and Michael Thompson
61. Psoriasis 949 78. Osteomyelitis 1177

Rebecca M.T. Law Melinda M. Neuhauser and Susan L. Pendland
62. Common Skin Disorders 959 79. Sepsis and Septic Shock 1185
Angie L. Goeser S. Scott Sutton
Section 14. Hematologic Disorders 975 80. Supercial Fungal Infections 1199
Lauren S. Schlesselman
63. Anemia 975
Edward C. Li and James M. Hoffman 81. Invasive Fungal Infections 1211
Russell E. Lewis and P. David Rogers
64. Coagulation Disorders 987
Alma Hamidovic 82. Antimicrobial Prophylaxis in Surgery 1231
Jeremy A. Schafer and John C. Rotschafer
65. Sickle Cell Disease 1003
Tracy M. Hagemann and Teresa V. Lewis 83. Vaccines and Toxoids 1239
Marianne Billeter
Section 15. Diseases of Infectious Origin 1019
84. Human Immunodeciency Virus Infection 1253
66. Antimicrobial Regimen Selection 1019 Amanda Corbett, Rosa Yeh, Julie Dumond,
Catherine M. Oliphant and Karl Madaras-Kelly and Angela D.M. Kashuba
67. Central Nervous System Infections 1033

S. Diane Goodwin and Charles E. Hartis
viii CONTENTS
Section 16. Oncologic Disorders 1277 95. Hematopoietic Cell Transplantation 1447
Jeannine S. McCune
85. Cancer Chemotherapy and Treatment 1277
Dianne Brundage 96. Oncologic Emergencies 1467
Brad L. Stanford
86. Breast Cancer 1303
Kristine Hahn and Laura Boehnke Michaud Section 17. Nutrition and Nutritional Disorders 1493
87. Lung Cancer 1323 97. Parenteral Nutrition 1493

Val Adams and Justin Balko Michael D. Kraft and Imad F. Btaiche
88. Colorectal Cancer 1341 98. Enteral Nutrition 1511

Patrick J. Medina Sarah J. Miller
89. Prostate Cancer 1357 99. Overweight and Obesity 1529

Jill M. Kolesar Maqual R. Graham and Cameron C. Lindsey
90. Malignant Lymphomas 1371 Appendices 1541

Chris Fausel
Appendix A: Conversion Factors
91. Ovarian Cancer 1385 and Anthropometrics 1541
Judith A. Smith
Appendix B: Common Laboratory Tests 1545
92. Acute Leukemias 1397
Nancy Heideman Appendix C: Common Medical Abbreviations 1553
93. Chronic Leukemias and Multiple Myeloma 1415 Appendix D: Glossary 1559
Amy M. Pick and Timothy R. McGuire
94. Skin Cancer 1425 Index 1581

Trinh Pham
CONTRIBUTORS
Val R. Adams, PharmD Marianne Billeter, PharmD, BCPS

Associate Professor Clinical Pharmacy Specialist
University of Kentucky Infectious Diseases
Oncology Clinical Specialist Ochsner Clinic Foundation
Markey Cancer Center New Orleans, Louisiana
Lexington, Kentucky Chapter 83: Vaccines and Toxoids
Chapter 87: Lung Cancer
Angela Ann Boggs, PharmD
Ronda L. Akins, PharmD Clinical Pharmacist
Assistant ProfessorInfectious Diseases University of Maryland
University of Louisiana at Monroe Baltimore, Maryland
College of Pharmacy Chapter 35: Major Depressive Disorder
Monroe, Louisiana
Chapter 71: Infective Endocarditis Sheila R. Botts, PharmD, BCPP
Assistant Professor
Kari Alperovitz-Bichell, MD, MPH University of Kentucky College of Pharmacy
Assistant Professor Clinical Pharmacy Specialist
Family Medicine Psychiatry
University of Maryland School of Medicine Lexington Veterans Affairs Medical Center
University of Maryland Medical System Lexington, Kentucky
Baltimore, Maryland Chapter 37: Generalized Anxiety Disorder, Panic Disorder,
Chapter 44: Pregnancy and Lactation: Therapeutic Considerations and Social Anxiety Disorder
J. V. Anandan, PharmD Bradley A. Boucher, PharmD, FCCP, FCCM

Adjunct Associate Professor of Pharmacy Professor of Pharmacy
Eugene Applebaum College of Pharmacy and Health Sciences Department of Pharmacy
Wayne State University University of Tennessee Health Science Center
Pharmacy Specialist Clinical Pharmacist
Henry Ford Hospital Regional Medical Center at Memphis
Detroit, Michigan Memphis, Tennessee
Chapter 75: Parasitic Diseases Chapter 10: Hypovolemic Shock
Justin M. Balko, PharmD Toya M. Bowles, PharmD, BCPP

Graduate Student Senior Medical Science Manager
University of Kentucky Organon USA
Pharmacist Hallandale Beach, Florida
UK Chandler Medical Center Chapter 32: Alzheimers Disease
Lexington, Kentucky
Chapter 87: Lung Cancer Gretchen M. Brophy, PharmD, BCPS, FCCP, FCCM
Associate Professor of Pharmacy and Neurosurgery
Tawny L. Bettinger, PharmD Clinical Specialist
Assistant Professor Neuroscience Intensive Care Unit
University of Texas at Austin Virginia Commonwealth University
College of Pharmacy Medical College of Virginia Campus
Austin, Texas Richmond, Virginia
Chapter 37: Generalized Anxiety Disorder, Panic Disorder, Chapter 28: Status Epilepticus
and Social Anxiety Disorder
ix
Copyright 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use.
x CONTRIBUTORS
Kirk J. Brower, MD Diane M. Cappelletty, PharmD

Associate Professor of Psychiatry Associate Professor of Pharmacy Practice
University of Michigan Medical School The University of Toledo
Executive Director Adjunct Assistant Professor
Chelsea Arbor Addiction Treatment Center Department of Medicine
Ann Arbor, Michigan Medical University of Ohio
Chapter 33: Substance-Related Disorders Toledo, Ohio
Chapter 68: Lower Respiratory Tract Infections
Susan P. Bruce, PharmD, BCPS
Associate Professor of Pharmacy Practice Marshall E. Cates, PharmD, BCPP, FASHP
Albany College of Pharmacy Professor of Pharmacy Practice
Clinical Pharmacist Samford University McWhorter School of Pharmacy
The Center for Rheumatology Clinical Pharmacist
Albany, New York Department of Psychiatry and Behavorial Neurobiology
Chapter 54: Rheumatoid Arthritis University of Alabama at Birmingham
Birmingham, Alabama
Dianne Brundage, PharmD, FCCP, BCPS, BCOP Chapter 35: Major Depressive Disorder
Oncology Clinical Pharmacy Specialist
Methodist Hospital/Park Nicollet Health Services Larisa H. Cavallari, PharmD
Minneapolis, Minnesota Assistant Professor
Chapter 85: Cancer Chemotherapy and Treatment Department of Pharmacy Practice
University of Illinois at Chicago College of Pharmacy
Imad F. Btaiche, BS, PharmD, BCNSP Chicago, Illinois
Clinical Associate Professor of Pharmacy Chapter 4: Ischemic Heart Disease
Department of Clinical Sciences
University of Michigan College of Pharmacy Juliana Chan, PharmD
Clinical Pharmacist Clinical Assistant Professor
University of Michigan Hospitals and Health Centers Department of Pharmacy Practice
Ann Arbor, Michigan College of Pharmacy
Chapter 97: Parenteral Nutrition Department of Medicine
Sections of Digestive Diseases and Nutrition
R. Todd Burkhardt, PharmD Section of Hepatology
Research Fellow University of Illinois at Chicago
Cardiovascular Pharmacotherapy Chicago, Illinois
Experimental and Clinical Pharmacology Department Chapter 21: Viral Hepatitis
University of Minnesota
Minneapolis, Minnesota Judy T. Chen, PharmD, BCPS
Chapter 2: Hypertension Assistant Professor of Pharmacy Practice
Purdue University
Jill S. Burkiewicz, PharmD, BCPS School of Pharmacy and Pharmaceutical Sciences
Associate Professor and Director Pharmacotherapist
Primary Care Residency Program Tippecanoe Community Health Clinic
Midwestern University Chicago College of Pharmacy West Lafayette, Indiana
Clinical Pharmacist Chapter 42: Adrenal Gland Disorders
Mercy Family Health CenterChicago Chapter 43: Pituitary Gland Disorders
Chicago, Illinois
Chapter 57: Musculoskeletal Disorders Marie A. Chisholm-Burns, PharmD, FCCP, FASHP
Professor and Head
Karim Anton Calis, PharmD, MPH, BCPS, BCNSP, FASHP, FCCP Department of Pharmacy Practice and Science
Professor The University of Arizona College of Pharmacy
Virginia Commonwealth University Tucson, Arizona
Clinical Professor Chapter 14: Gastroesophageal Reux Disease
University of Maryland and Shenandoah University
Clinical Specialist, Endocrinology and Womens Health Kevin W. Cleveland, PharmD
Director, Drug Information Service, NIH Clinical Center Clinical Assistant Professor
National Institutes of Health College of Pharmacy
Bethesda, Maryland Idaho State University
Chapter 42: Adrenal Gland Disorders Pocatello, Idaho
Chapter 43: Pituitary Gland Disorders Chapter 39: Attention-Decit Hyperactivity Disorder
CONTRIBUTORS xi
Christopher L. Cook, PharmD, PhD Simon de Denus, BPharm, MSc

Clinical Assistant Professor Assistant Professor
University of Georgia College of Pharmacy Faculty of Pharmacy
Athens, Georgia University of Montreal Pharmacy Department
Chapter 40: Diabetes Mellitus Fellow in Cardiovascular Research
Montreal Heart Institute
Amanda H. Corbett, PharmD, BCPS Montreal
Clinical Assistant Professor Quebec, Canada
School of Pharmacy Chapter 5: Acute Coronary Syndromes
University of North Carolina
Clinical Pharmacist John W. Devlin, PharmD, BCPS, FCCM
University of North Carolina Health Care Associate Professor
Infectious Disease Clinic Northeastern University School of Pharmacy
Chapel Hill, North Carolina Clinical Pharmacist
Chapter 84: Human Immunodeciency Virus Infection Medical Intensive Care Unit
Tufts-New England Medical Center
Brian L. Crabtree, PharmD, BCPP Boston, Massachusetts
Associate Professor of Pharmacy Practice Chapter 15: Peptic Ulcer Disease
Clinical Associate Professor of Psychiatry,
University of Mississippi School of Pharmacy Robert J. DiDomenico, PharmD
University of Mississippi Medical Center Clinical Associate Professor
School of Medicine Department of Pharmacy Practice
Psychopharmacologist University of Illinois
Mississippi State Hospital Cardiovascular Clinical Pharmacist
Whiteld, Mississippi University of Illinois Medical Center at Chicago
Chapter 36: Bipolar Disorder Chicago, Illinois
Chapter 4: Ischemic Heart Disease
Nicole S. Culhane, PharmD, BCPS
Associate Professor Joseph T. DiPiro, PharmD, FCCP
Pharmacy Practice Professor and Executive Dean
Wilkes University South Carolina College of Pharmacy
Nesbitt College of Pharmacy and Nursing University of South Carolina
Clinical Pharmacist Faculty Columbia
Wyoming Valley Family Practice Residency Medical University of South Carolina
Wilkes-Barre, Pennsylvania Charleston, South Carolina
Chapter 47: Hormone Replacement Therapy in Menopause Chapter 74: Intraabdominal Infections
Clarence E. Curry, Jr., PharmD John M. Dopp, PharmD

Associate Professor Assistant Professor
School of Pharmacy University of Wisconsin-Madison School of Medicine
CPNAHS Clinical Pharmacist
Howard University University of Wisconsin Sleep Disorders Center
Clinical Pharmacist Madison, Wisconsin
Ambulatory Care Chapter 38: Sleep Disorders
Howard University Hospital Clinics
Washington, DC Julie Dumond, PharmD
Chapter 18: Constipation, Diarrhea, and Irritable Bowel Syndrome University of North CarolinaChapel Hill
School of Pharmacy
Devra K. Dang, PharmD Chapel Hill, North Carolina
Assistant Clinical Professor Chapter 84: Human Immunodeciency Virus Infection
University of Connecticut School of Pharmacy
Clinical Faculty Megan J. Ehret, PharmD
St. Francis Hospital/UCONN Primary Care Center Assistant Professor
at Burgdorf Health Center University of Connecticut
Instructor School of Pharmacy
Department of Medicine Storrs, Connecticut
University of Connecticut School of Medicine Chapter 32: Alzheimers Disease
Hartford, Connecticut
Chapter 42: Adrenal Gland Disorders
Chapter 43: Pituitary Gland Disorders
xii CONTRIBUTORS
Benjamin J. Epstein, PharmD, BCPS Steven Gabardi, PharmD, BCPS

Clinical Assistant Professor Renal Transplant Clinical Specialist
Departments of Pharmacy Practice and Internal Medicine Department of Pharmacy Services
Colleges of Pharmacy and Medicine Brigham and Womens Hospital
University of Florida Assistant Professor
Gainesville, Florida Northeastern University
Chapter 55: Osteoarthritis Boston, Massachusetts
Chapter 52: Solid Organ Transplantation
John Erramouspe, PharmD, MS
Professor Angie L. Goeser, PharmD
Idaho State University College of Pharmacy Assistant Professor
Pocatello, Idaho Department of Pharmacy Practice
Chapter 39: Attention-Decit Hyperactivity Disorder Creighton University School of Pharmacy and Health Professions
Omaha, Nebraska
Edward Faught, MD Chapter 62: Common Skin Disorders
Professor of Neurology
University of Alabama School of Medicine S. Diane Goodwin, PharmD, FCCP
Director Clinical Pharmacist
University of Alabama at Birmingham Epilepsy Center Rex Healthcare
Birmingham, Alabama Raleigh, North Carolina
Chapter 27: Epilepsy Chapter 67: Central Nervous System Infections
Martha J. Faulkner, BSN, MSW, MSN, LISW, CNP A. Christie Graham, PharmD
Nurse Practitioner Clinical Assistant Professor
University of New Mexico University of Wyoming School of Pharmacy
Albuquerque, New Mexico Laramie, Wyoming
Chapter 36: Bipolar Disorder Chapter 70: Skin and Soft Tissue Infections
Christopher A. Fausel, PharmD, BCOP Maqual R. Graham, PharmD

Adjunct Associate Professor of Medicine Associate Professor of Pharmacy Practice
Indiana University Cancer Center University of MissouriKansas City
Indianapolis, Indiana Clinical Pharmacy Specialist
Chapter 90: Malignant Lymphomas Veterans Affairs Medical CenterKansas City
Kansas City, Missouri
Jacqueline Maus Feldman, MD Chapter 99: Overweight and Obesity
Patrick H. Linton Professor
University of Alabama School of Medicine Kendra J. Grande, RPh
Director Consultant Pharmacist
Division of Public Psychiatry Abelian Consulting
Community Psychiatry Program Stevensville, Maryland
Birmingham, Alabama Chapter 60: Minor Ophthalmic Disorders
Chapter 35: Major Depressive Disorder
Brian A. Greenlee, MD
Jack E. Fincham, BS, PhD Assistant Professor of Psychiatry
Professor of Pharmacy Practice Neuropsychiatry Clinic Director
School of Pharmacy University of Kentucky
University of Missouri-Kansas City Lexington, Kentucky
Kansas City, Missouri Chapter 37: Generalized Anxiety Disorder, Panic Disorder, and Social
Chapter 1: Introduction Anxiety Disorder
Jeffrey J. Fong, PharmD

Critical Care Fellow
Northeastern University School of Pharmacy
Tufts-New England Medical Center
Boston, Massachusetts
Chapter 15: Peptic Ulcer Disease
CONTRIBUTORS xiii
David R. P. Guay, PharmD, FCCP Charles Hartis, PharmD

Professor Antibiotic Management/Clinical Improvement Pharmacist
Department of Experimental and Clinical Pharmacology Forsyth Medical Center
College of Pharmacy Winston-Salem, North Carolina
University of Minnesota Chapter 67: Central Nervous System Infections
Consultant
Division of Geriatrics Kathleen B. Haynes, PharmD, BCPS
HealthPartners Inc. Disease Management Pharmacist
Minneapolis, Minnesota VEI/Community Health Network
Chapter 50: Urinary Incontinence and Pediatric Enuresis Carmel, Indiana
Chapter 45: Contraception
John G. Gums, PharmD
Professor of Pharmacy and Medicine Nancy Heideman, PharmD, BCPS
Departments of Pharmacy Practice and Community Health Assistant Professor of Pharmacy Practice
and Family Medicine University of New Mexico College of Pharmacy
University of Florida Albuquerque, New Mexico
Gainesville, Florida Chapter 92: Acute Leukemias
Chapter 55: Osteoarthritis
Brian A. Hemstreet, PharmD, BCPS
Sally K. Guthrie, PharmD Assistant Professor
Associate Professor of Pharmacy University of Colorado School of Pharmacy
College of Pharmacy and Department of Psychiatry Denver, Colorado
The University of Michigan Chapter 16: Inammatory Bowel Disease
The University of Michigan Hospitals
Ann Arbor, Michigan Elizabeth D. Hermsen, PharmD, MBA
Chapter 33: Substance-Related Disorders Antimicrobial Specialist
The Nebraska Medical Center
Tracy M. Hagemann, PharmD Adjunct Assistant Professor
Associate Professor of Pharmacy Practice University of Nebraska Medical Center College of Pharmacy
University of Oklahoma College of Pharmacy Omaha, Nebraska
Clinical Pediatric Specialist Chapter 73: Gastrointestinal Infections
Oklahoma City, Oklahoma
Chapter 65: Sickle Cell Disease Catherine A. Heyneman, MS, PharmD
Associate Professor of Pharmacy Practice
Kristine Hahn, PharmD Idaho State University College of Pharmacy
Postdoctoral Fellow Director of Idaho Drug Information Service
University of Wisconsin Comprehensive Cancer Center Pocatello, Idaho
Madison, Wisconsin Chapter 48: Erectile Dysfunction
Chapter 86: Breast Cancer
Kristi N. Hofer, PharmD
Stuart T. Haines, PharmD, FCCP, FASHP Scientic Project Manager
Professor and Vice Chair ASHP Advantage
Pharmacotherapy Specialist Charlottesville, Virginia
University of Maryland Department of Pharmacy Practice and Science Chapter 59: Allergic Rhinitis
University of Maryland Medical Center-Antithrombosis Services
Baltimore, Maryland James M. Hoffman, PharmD, MS
Chapter 7: Venous Thromboembolism Medication Outcomes Coordinator
Pharmaceutical Department
Karen L. Hall, MD St. Jude Childrens Research Hospital
Associate Professor and Residency Program Director Memphis, Tennessee
Department of Community Health and Family Medicine Chapter 63: Anemias
University of Florida
Gainesville, Florida Marlon Honeywell, PharmD
Chapter 55: Osteoarthritis Associate Professor of Pharmacy Practice
Florida A&M University
Alma Hamidovic, PharmD Clinical Pharmacist
Postdoctoral Oncology Fellow Bond Community Health Center
University of Wisconsin Comprehensive Cancer Center Tallahassee, Florida
Madison, Wisconsin Chapter 77: Sexually Transmitted Infections
Chapter 64: Coagulation Disorders
xiv CONTRIBUTORS
Thomas R. Howdieshell, MD, FACS, FCCP Deanna L. Kelly, PharmD, BCPP

Associate Professor of Surgery Associate Professor
Department of Surgery University of Maryland
University of New Mexico Health Science Center Maryland Psychiatric Research Center
Division of Trauma/Surgical Critical Care Baltimore, Maryland
Albuquerque, New Mexico Chapter 34: Schizophrenia
Chapter 74: Intraabdominal Infections
Joseph J. Kishel, Jr., PharmD, BCPS
Matthew K. Ito, PharmD, FCCP, BCPS Adjunct Instructor of Pharmacology
Chair, Department of Pharmacy Practice Penn State College of Medicine
Professor of Pharmacy Practice Clinical Pharmacy SpecialistInfectious Diseases
College of Pharmacy M.S. Hershey Medical Center
Oregon State University Hershey, Pennsylvania
Portland, Oregon Chapter 20: Pancreatitis
Chapter 9: Hyperlipidemia
Julie M. Koehler, PharmD
Ziba Jalali, MD Associate Professor and Chair of Pharmacy Practice
Assistant Professor Butler University College of Pharmacy and Health Sciences
University of Nebraska Medical Center Clinical Pharmacist
College of Medicine Family Medicine
Omaha, Nebraska Clarian Health Partner and the Indiana University-Methodist
Chapter 73: Gastrointestinal Infections Family Residency Program
Indiana University School of Medicine
John T. Johnson, PharmD, CDE Indianapolis, Indiana
Clinical Associate Professor Chapter 45: Contraception
University of Georgia College of Pharmacy
Athens Primary Care Jill M. Kolesar, PharmD, BCPS, FCCP
Mercy Health Center Associate Professor
Athens, Georgia School of Pharmacy
Chapter 40 : Diabetes Mellitus University of Wisconsin
Madison, Wisconsin
Mikael D. Jones, PharmD, BCPS Chapter 89: Prostate Cancer
Assistant Professor
College of Pharmacy and Nursing Michael D. Kraft, PharmD
University of Kentucky Clinial Assistant Professor
Lexington, Kentucky University of Michigan College of Pharmacy
Chapter 58: Glaucoma Clincial Coordinator and Clinical Pharmacist-Surgery/Nutrition
Support
Maher Karam-Hage, MD University of Michigan Health System
Assistant Professor, Addiction Psychiatrist Ann Arbor, Michigan
Medical Director Tobacco Treatment Program (TTP) Chapter 97: Parenteral Nutrition
University of Texas
MD Anderson Cancer Center Rebecca M. T. Law, BScPharm, PharmD
Houston, Texas Associate Professor
Chapter 33: Substance-Related Disorders School of Pharmacy
Memorial University of Newfoundland
Angela D. M. Kashuba, BScPharm, PharmD, DABCP Newfoundland, Canada
Associate Professor Chapter 61: Psoriasis
School of Pharmacy
University of North Carolina at Chapel Hill Cara Lawless-Liday, PharmD
Chapel Hill, North Carolina Associate Professor
Chapter 84: Human Immunodeciency Virus Infection Idaho State University
Intermountain Medical Clinic
Michael D. Katz, PharmD Pocatello, Idaho
Associate Professor and Coordinator, International Education Chapter 48: Erectile Dysfunction
University of Arizona College of Pharmacy
Department of Pharmacy Practice and Science
Tucson, Arizona
Chapter 41: Thyroid Disorders
CONTRIBUTORS xv
W. Greg Leader, PharmD Mark A. Malesker, PharmD, FCCP

Associate Dean Associate Professor of Pharmacy Practice and Medicine
Academic Affairs Clinical Pharmacy Specialist
University of Louisiana Monroe Creighton University Medical Center
College of Pharmacy Omaha, Nebraska
Monroe, Louisiana Chapter 24: Fluids and Electrolytes
Chapter 11: Asthma Chapter 25: Acid-Base Disturbances
Mary Lee, PharmD, BCPS, FCCP J. Russell May, PharmD, FASHP

Dean and Professor Clinical Professor
Midwestern University Chicago College of Pharmacy University of Georgia College of Pharmacy
Chicago, Illinois Clinical Pharmacist
Chapter 49: Benign Prostatic Hyperplasia Medical College of Georgia Health System
Augusta, Georgia
Gary M. Levin, PharmD, BCPP, FCCP Chapter 51: Allergic and Pseudoallergic Drug Reactions
Dean and Professor
LECOM-Bradenton Michelle W. McCarthy, PharmD
School of Pharmacy Drug Information Specialist
Bradenton, Florida University of Virginia Health System
Chapter 32: Alzheimers Disease Charlottesville, Virginia
Chapter 59: Allergic Rhinitis
Russell E. Lewis, PharmD
Associate Professor Jeannine S. McCune, PharmD
University of Houston College of Pharmacy Associate Professor
Clinical Pharmacy Specialist University of Washington
Infectious Diseases Afliate Investigator
Department of Infectious Diseases Fred Hutchinson Cancer Research Center
The University of Texas M.D. Anderson Cancer Center Seattle, Washington
Houston, Texas Chapter 95: Hematopoietic Cell Transplantation
Chapter 81: Invasive Fungal Infections
Timothy R. McGuire, BS, PharmD, FCCP
Teresa V. Lewis, PharmD Associate Professor
Pediatric Pharmacotherapy Fellow Pharmacy Practice
University of Oklahoma College of Pharmacy University of Nebraska Medical Center
Oklahoma City, Oklahoma College of Pharmacy
Chapter 65: Sickle Cell Disease Omaha, Nebraska
Chapter 93: Chronic Leukemias and Multiple Myeloma
Edward C. Li, PharmD
Assistant Professor Patrick J. Medina, PharmD, BCOP
Wilkes University Associate Professor
Nesbitt College of Pharmacy and Nursing University of Oklahoma College of Pharmacy
Wilkes-Barre, Pennsylvania Oklahoma City, Oklahoma
Chapter 63: Anemias Chapter 88: Colorectal Cancer
Cameron C. Lindsey, PharmD, BC-ADM Laura Boehnke Michaud, PharmD

Associate Professor of Pharmacy Practice Clinical Pharmacy Specialist
University of MissouriKansas City School of Pharmacy The University of Texas M.D. Anderson Cancer Center
Clinical Pharmacy Specialist Houston, Texas
Veterans Affairs Medical CenterKansas City Chapter 86: Breast Cancer
Kansas City, Missouri
Chapter 99: Overweight and Obesity Sarah J. Miller, PharmD, BCNSP
Professor, Pharmacy Practice
Karl Madaras-Kelly, PharmD, MPH University of Montana Skaggs School of Pharmacy
Associate Professor Pharmacy Clinical Coordinator
College of Pharmacy Saint Patrick Hospital
Idaho State University Missoula, Montana
Boise, Idaho Chapter 98: Enteral Nutrition
Chapter 66: Antimicrobial Regimen Selection
xvi CONTRIBUTORS
Beverly Mims, PharmD Edith A. Nutescu, PharmD

Associate Professor of Pharmacy Practice Clinical Associate Professor
Howard University School of Pharmacy Department of Pharmacy Practice
Clinical Pharmacist Director
Howard University Hospital Antithrombosis Center
Washington, DC University of Illinois at Chicago College of Pharmacy
Chapter 18: Constipation, Diarrhea, and Irritable Chicago, Illinois
Bowel Syndrome Chapter 7: Venous Thromboembolism
Abby Morris, MD Catherine M. Oliphant, PharmD

Family Medicine Resident Associate Professor of Pharmacy Practice
Thomas Jefferson University Hospital Idaho State University College of Pharmacy
Philadelphia, Pennsylvania Clinical Pharmacist
Chapter 46: Menstruation-Related Disorders St. Lukes Internal Medicine
Boise, Idaho
Lee E. Morrow, MD, MS Chapter 66: Antimicrobial Regimen Selection
Assistant Professor of Medicine
Creighton University Medical Center Ali J. Olyaei, PharmD, BCPS
Omaha, Nebraska Associate Professor
Chapter 24: Fluids and Electrolytes Nephrology and Hypertension
Chapter 25: Acid-Base Disturbances Oregon Health and Sciences University
Clinical Pharamcotherapist
Rocsanna Namdar, PharmD University Hospital
Assistant Professor Portland, Oregon
University of New Mexico Chapter 52: Solid Organ Transplantation
College of Pharmacy
Albuquerque, New Mexico Christine K. ONeil, PharmD, BCPS, CGP, FCCP
Chapter 72: Tuberculosis Associate Professor
Duquesne University
Melinda Margaret Neuhauser, PharmD Mylan School of Pharmacy
Clinical Pharmacy Specialist Director
Infectious Diseases Center for Pharmacy Care
U.S. Department of Veterans Affairs Pittsburgh, Pennsylvania
Pharmacy Benets Management Strategic Health Care Group Chapter 30: Pain Management
Hines, Illinois
Chapter 78: Osteomyelitis David Parra, PharmD, BCPS
Clinical Pharmacy Specialist in Cardiology
Tien M. H. Ng, PharmD, BCPS Department of Cardiology
Assistant Professor of Clinical Pharmacy and Pharmaceutical Veterans Affairs Medical Center
Economics and Policy Clinical Assistant Professor
Department of Pharmacy Experimental and Clinical Pharmacology Department
University of Southern California University of Minnesota
Los Angeles, California Minneapolis, Minnesota
Chapter 3: Heart Failure Chapter 2: Hypertension
Kimberly J. Novak, PharmD Charles A. Peloquin, PharmD

Adjunct Clinical Assistant Professor Clinical Professor of Pharmacy and Medicine
The Ohio State University College of Pharmacy University of Colorado
Clinical Pharmacy Specialist/Pediatric Director
Pulmonary Medicine Infectious Disease Pharmacokinetics Laboratory
Childrens Hospital National Jewish Medical and Research Center
Columbus, Ohio Denver, Colorado
Adjunct Assistant Professor Chapter 72: Tuberculosis
West Virginia University School of Pharmacy
Morgantown, West Virginia
Chapter 13: Cystic Fibrosis
CONTRIBUTORS xvii
Susan L. Pendland, MS, PharmD Phillip David Rogers, PharmD, PhD, FCCP
Adjunct Associate Professor of Pharmacy Practice First Tennessee Chair of Excellence in Pediatric Clinical Pharmacy
University of Illinois at Chicago Associate Professor and Vice Chair for Research
Chicago, Illinois Department of Clinical Pharmacy
Chapter 78: Osteomyelitis Associate Professor, Departments of Pharmaceutical Sciences,
Molecular Sciences, and Pediatrics
Trinh Pham, PharmD, BCOP University of Tennessee Health Science Center
Assistant Clinical Professor Memphis, Tennessee
University of Connecticut, School of Pharmacy Chapter 81: Invasive Fungal Infections
Assistant Clinical Professor
Yale New Haven Hospital Leigh Ann Ross, PharmD, BCPS, CDE
New Haven, Connecticut Assistant Professor
Chapter 94: Skin Cancer University of Mississippi School of Pharmacy
Director
Beth Bryles Phillips, PharmD, BCPS Pharmaceutical Care Services
Assistant Professor (Clinical) University of Mississippi Medical Center
University of Iowa College of Pharmacy Jackson, Mississippi
Clinical Pharmacy Specialist Chapter 31: Headache
Ambulatory Care
University of Iowa Hospitals and Clinics Brendan S. Ross, MD
Iowa City, Iowa Assistant Professor
Chapter 53: Osteoporosis University of Mississippi School of Pharmacy
Staff Physician
Bradley G. Phillips, PharmD G. V. (Sonny) Montgomery Veterans Affairs Medical Center
Associate Professor Jackson, Mississippi
University of Iowa Chapter 31: Headache
College of Pharmacy
Iowa City, Iowa John C. Rotschafer, PharmD, FCCP
Chapter 38: Sleep Disorders Professor
Department of Experimental and Clinical Pharmacology
Amy M. Pick, PharmD College of Pharmacy
Assistant Professor of Pharmacy Practice University of Minnesota
Creighton University Minneapolis, Minnesota
Oncology Clinical Pharmacist Chapter 82: Antimicrobial Prophylaxis in Surgery
Nebraska Methodist Hospital
Omaha, Nebraska Laurajo Ryan, PharmD, BCPS, CDE
Chapter 93: Chronic Leukemias and Multiple Myeloma Clinical Assistant Professor
University of Texas at Austin
Brian A. Potoski, PharmD University of Texas Health Science Center San Antonio
Assistant Professor San Antonio, Texas
Department of Pharmacy and Therapeutics Chapter 19: Portal Hypertension and Cirrhosis
University of Pittsburgh School of Pharmacy
Clinical Specialist Melody Ryan, PharmD
Antibiotic Management Program Associate Professor
University of Pittsburgh Medical Center University of Kentucky College of Pharmacy
Presbyterian University Hospital Clinical Specialist in Neurology
Pittsburgh, Pennsylvania Veterans Affairs Medical Center
Chapter 76: Urinary Tract Infection Lexington, Kentucky
Chapter 26: Multiple Sclerosis
Frank Pucino, Jr., PharmD, BCPS, FASHP, FDPGEC
Ambulatory Care Clinical Pharmacy Team Leader
National Institutes of Health Clinical Center
Bethesda, Maryland
Chapter 42: Adrenal Gland Disorders
Chapter 43: Pituitary Gland Disorders
xviii CONTRIBUTORS
Jeremy A. Schafer, PharmD Sarah A. Spinler, PharmD, FCCP

Senior Clinical Pharmacist Professor of Clinical Pharmacy
Prime Therapeutics Residency and Fellowship Program Coordinator
Eagan, Minnesota Philadelphia College of Pharmacy
Chapter 82: Antimicrobial Prophylaxis in Surgery University of the Sciences in Philadelphia
Philadelphia, Pennsylvania
Lauren S. Schlesselman, PharmD Chapter 5: Acute Coronary Syndromes
Assistant Clinical Professor
University of Connecticut School of Pharmacy Mary K. Stamatakis, BS, PharmD
Department of Pharmacy Practice Associate Dean and Associate Professor
Storrs, Connecticut West Virginia University School of Pharmacy
Chapter 80: Supercial Fungal Infections Morgantown, West Virginia
Chapter 22: Acute Renal Failure
Kristine S. Schonder, PharmD
Assistant Professor Brad L. Stanford, PharmD, BCOP
University of Pittsburgh School of Pharmacy Assistant Professor of Pharmacy Practice
Clinical Specialist Texas Tech University Health Sciences Center
Thomas E. Starzl Transplantation Institute School of Pharmacy
Pittsburgh, Pennsylvania Lubbock, Texas
Chapter 23: Chronic and End-Stage Renal Disease Chapter 96: Oncologic Emergencies
Roohollah Shari, MD, FACS Robert J. Straka, PharmD, FCCP

Professor of Urology Associate Professor
University of Illinois at Chicago Department of Experimental and Clinical Pharmacology
College of Medicine College of Pharmacy
Section Chief of Urology University of Minnesota
Westside Veterans Administration Hospital Minneapolis, Minnesota
Chicago, Illinois Chapter 2: Hypertension
Chapter 49: Benign Prostatic Hyperplasia
Deborah Sturpe, PharmD, BCPS
Judith A. Smith, PharmD, BCOP Assistant Professor
Assistant Professor University of Maryland School of Pharmacy
University of Texas M.D. Anderson Cancer Center Baltimore, Maryland
Houston, Texas Chapter 44: Pregnancy and Lactation: Therapeutic Considerations
Chapter 91: Ovarian Cancer
S. Scott Sutton, PharmD, BCPS
Philip H. Smith, MD, FAAAAI, FACAAI Associate Clinical Professor
Assistant Professor of Medicine South Carolina College of Pharmacy
Allergy and Immunology University of South Carolina
Medical College of Georgia Clinical Pharmacist
Assistant Professor WJB Dorn Veterans Affairs Medical Center
Medical College of Georgia Columbia, South Carolina
Childrens Medical Center Chapter 79: Sepsis and Septic Shock
Augusta, Georgia
Chapter 51: Allergic and Pseudoallergic Drug Reactions Eljim P. Tesoro, PharmD
Clinical Assistant Professor
Melissa A. Somma, PharmD, CDE University of Illinois at Chicago
Assistant Professor of Pharmacy and Family Medicine Pharmacotherapist
University of Pittsburgh Schools of Pharmacy and Medicine Department of Neurosurgery
Director University of Illinois at Chicago Medical Center
University of Pittsburgh/Rite Aid Patient Care Initiative Chicago, Illinois
Rite Aid Corporation Chapter 28: Status Epilepticus
Pittsburgh, Pennsylvania
Chapter 47: Hormone Replacement Therapy in Menopause
CONTRIBUTORS xix
Michael D. Thompson, PharmD, BCNSP William E. Wade, PharmD

Assistant Dean for Clinical Affairs and Professor Professor and Associate Head
Florida A&M University College of Pharmacy
Residency Coordinator and Clinical Pharmacy Director University of Georgia
American Home Patient Clinical Pharmacist
Tallahassee, Florida Saint Marys Health Care Systems
Chapter 77: Sexually Transmitted Infections Athens, Georgia
Chapter 40: Diabetes Mellitus
James E. Tisdale, PharmD
Professor Mary Louise Wagner, MS, PharmD
School of Pharmacy and Pharmaceutical Sciences Associate Professor
Purdue University Ernest Mario School of Pharmacy
Adjunct Professor RutgersState University of New Jersey
School of Medicine Piscataway, New Jersey
Indiana University Chapter 29: Parkinsons Disease
Indianapolis, Indiana
Chapter 6: Arrhythmias Geoffrey C. Wall, PharmD, BCPS
Associate Professor of Pharmacy Practice
Elena M. Umland, BS, PharmD Drake University
Associate Dean for Academic Affairs College of Pharmacy and Health Sciences
Associate Professor of Clinical Pharmacy Internal Medicine Clinical Pharmacist
Jefferson School of Pharmacy Iowa Methodist Medical Center
Jefferson College of Health Professions Des Moines, Iowa
Thomas Jefferson University Chapter 56: Gout and Hyperuricemia
Chapter 46: Menstruation-Related Disorders Elaine Weiner, MD
Assistant Professor
Heather L. VandenBussche, PharmD University of Maryland Medical School
Associate Professor of Pharmacy Practice Medical Director
Ferris State University College of Pharmacy Maryland Psychiatric Research Center
Kalamazoo, Michigan Outpatient Research Program
Chapter 69: Upper Respiratory Tract Infections Catonsville, Maryland
Chapter 34: Schizophrenia
Orly Vardeny, PharmD
Assistant Professor Lara Carson Weinstein, MD
Pharmacy Practice Division Instructor
University of WisconsinMadison Department of Family and Community Medicine
School of Pharmacy Jefferson Medical College
Madison, Wisconsin Thomas Jefferson University
Chapter 3: Heart Failure Jefferson Family Medicine
Nicole D. Verkleeren, PharmD Chapter 46: Menstruation-Related Disorders
Adjunct Clinical Professor
West Virginia University School of Pharmacy Timothy E. Welty, PSPharm, MA, PharmD
Pharmacy Practice Resident Professor
West Virginia University Hospitals McWhorter School of Pharmacy
Morgantown, West Virginia Samford University
Clinical Pharmacist Adjunct Associate Research Professor
The Western Pennsylvania Hospital Department of Neurology
Forbes Regional Campus University of Alabama Birmingham
Monroeville, Pennsylvania Birmingham, Alabama
Chapter 12: Chronic Obstructive Pulmonary Disease Chapter 27: Epilepsy
xx CONTRIBUTORS
Randy Wesnitzer, BS Pharm, PharmD Susan R. Winkler, PharmD, BCPS

Clinical Coordinator Clinical Associate Professor
Wyoming Medical Center Pharmacy Practice
Department of Pharmacy Assistant Director
Casper, Wyoming Ambulatory Clinical Services
Chapter 70: Skin and Soft Tissue Infections Department of Pharmacy Practice
Tara Whetsel, PharmD Chicago, Illinois
Clinical Assistant Professor Chapter 8: Stroke
West Virginia University School of Pharmacy
Morgantown, West Virginia G. Christopher Wood, PharmD
Chapter 12: Chronic Obstructive Pulmonary Disease Associate Professor of Pharmacy
University of Tennessee Health Science Center
Sheila Wilhelm, PharmD Clinical Pharmacist
Assistant Professor Regional Medical Center at Memphis
Wayne State University Memphis, Tennessee
Clinical Pharmacy Specialist Chapter 10: Hypovolemic Shock
Internal Medicine
Harper University Hospital Rosa F. Yeh, PharmD
Detroit, Michigan Assistant Professor
Chapter 17: Nausea and Vomiting University of Houston College of Pharmacy
Houston, Texas
Dianne B. Williams, PharmD, BCPS Chapter 84: Human Immunodeciency Virus Infection
Clinical Assistant Professor
University of Georgia College of Pharmacy
Drug Information and Formulary Coordinator
MCG Health, Inc.
Augusta, Georgia
Chapter 14: Gastroesophageal Reux Disease
REVIEWERS
Beth Alexander, PharmD, BCPS Kathleen L. Becker, MS, CRNP

Associate Professor of Physician Assistant Studies Assistant Professor and Coordinator
Augsburg College Adult Nurse Practitioner Program
Minneapolis, Minnesota The Johns Hopkins University School of Nursing
Adult Nurse Practitioner
Rita Alloway, PharmD, BCPS Health Care for the Homeless
Research Professor Baltimore, Maryland
University of Cincinnati College of Medicine
Cincinnati, Ohio Judith L. Beizer, PharmD, CGP, FASCP
Clinical Professor
Buge Apampa, PhD, BPharm, MRPharmS St. Johns University College of Pharmacy & Allied Health Professions
Clinical Lecturer Jamaica, New York
Pharmacy Practice
Universities of Kent and Greenwich at Medway Renee Bellanger, PharmD, BSPharm
Chatham Maritime Assistant Professor
Kent, United Kingdom Pharmacy Practice
The University of the Incarnate Word
Laurel Ashworth, PharmD San Antonio, Texas
Professor of Clinical and Administrative Sciences & Director
Drug Information Center Mary Mescher Benbenek, MS, RN, CFNP, CPNP
Mercer University School of Pharmacy and Allied Health Sciences Teaching Specialist
Atlanta, Georgia University of Minnesota
Minneapolis, Minnesota
Sara Augustin, PharmD, BCPP
Clinical Pharmacist Marialice Bennett, RPh, FAPhA
Dekalb Regional Crisis Center Professor of Clinical Pharmacy
Decatur, Georgia The Ohio State University
Columbus, Ohio
Ebrahim A. Balbisi, PharmD
Assistant Clinical Professor Heather K.T. Bidinger, MMS, PA-C
St. Johns University College of Pharmacy & Allied Health Professions Clinical Coordinator and Assistant Professor
Jamaica, New York Department of Physician Assistant Education
Augsburg College
Phyllis Barks, PA, MPH Minneapolis, Minnesota
Assistant Professor & Technology Development Coordinator
Oregon Health & Science University School of Medicine Sarah Bland, RPh
Division of Physician Assistant Education Clinical Instructor
Portland, Oregon University of Wisconsin-Madison
Madison, Wisconsin
Bonnie Bata-Jones, MS, RN, FNP
Instructor Patricia J. Blumi, MSN, ARNP
University of Minnesota Advanced Registered Nurse PractitionerRadiation Therapy
Excelsior, Minnesota Via-Christi Cancer Center
Wichita, Kansas
Kathryn R. Bauer, MA, MS, APRN
Instructor
University of Texas Health Science Center at San Antonio
San Antonio, Texas
xxi
xxii REVIEWERS
John A. Bosso, PharmD, FCCP, BCPS Cynthia Carnes, PharmD, PhD

Professor and Chair Associate Professor of Pharmacy and Biophysics
South Carolina College of Pharmacy The Ohio State University
Clinical Specialist in Infectious Diseases Columbus, Ohio
Medical University of South Carolina Hospital
Charleston, South Carolina Barry L. Carter, PharmD
Professor
Margaret Bowers, MSN, APRN, BC Colleges of Pharmacy and Medicine
Assistant Clinical Professor The University of Iowa
Duke University School of Nursing Iowa City, Iowa
Durham, North Carolina
Nina Cheigh, PharmD
Cleopatra Branch, BSc, PharmD, MRPharmS Contributing Editor, The Medical Letter, Inc.
Teacher & Practitioner New Rochelle, New York
Medway School of Pharmacy Clinical Associate Professor
Universities of Kent and Greenwich at Medway University of Illinois College of Pharmacy
Chatham Maritime Chicago, Illinois
Kent, United Kingdom
Deborah Chyun, PhD, RN, FAHA
Joyce Brewer, PhD, CNM, CFNP Associate Professor and Director
Associate Professor Adult Advanced Practice Nursing
University of Mississippi Medical Center Yale University School of Nursing
Jackson, Mississippi New Haven, Connecticut
David M. Brissette, MMSc, PA-C Lorraine Cicero, MS, PharmD

Assistant Professor Associate Professor
Yale University School of Medicine Pharmacy Practice
Physician Associate Program Long Island University College of Pharmacy and Health Sciences
Physician Assistant Brooklyn, New York
Internal Medicine
Yale New Haven Hospital Donald Coerver, PhD, PA-C
New Haven, Connecticut Acting Instructor
MEDEX Northwest Division of Physician Assistant Studies
Cori M. Brock, PharmD Spokane, Washington
Clinical Assistant Professor of Pharmacy Practice
Xavier University College of Pharmacy Carmita A. Coleman, PharmD
New Orleans, Louisiana Assistant Dean for Student Affairs and Associate Professor
of Pharmacy Practice
Denise Buonocore, MSN, APRN, CCRN Feik School of Pharmacy
Acute Care Nurse Practitioner University of the Incarnate Word
Bridgeport Hospital, Bridgeport San Antonio, Texas
Connecticut, and Yale University School of Nursing
New Haven, Connecticut Lynn Convery, RN, MS, CNP
Gerontological Nurse Practitioner
Reamer L. Bushardt, PharmD, PA-C HealthPartners Partnering Care Senior Services
Program Director and Assistant Professor Minneapolis, Minnesota
Department of Clinical Services
College of Health Professions Keely L. Cook, MPAS, PA-C
Medical University of South Carolina Assistant Professor
Charleston, South Carolina Doisy College of Health Sciences
Saint Louis University
Wesley G. Byerly, PharmD St. Louis, Missouri
Executive Director for Research Regulatory Affairs
and Adjunct Assistant Professor Sarah Corlett, PhD, MRPharmS
Wake Forest University School of Medicine University of Greenwich
Winston-Salem, North Carolina Medway School of Pharmacy
Chatham Maritime
Kent, United Kingdom
REVIEWERS xxiii
Joseph E. Crea, DO, MHA Jennifer Fair, PharmD

Assistant Professor Clinical Pharmacy Program
The University of Findlay School of Pharmacy University of Georgia
Findlay, Ohio College of Pharmacy
Medical College of Georgia
Patricia Cunningham, DNSc, APRN, BC Augusta, Georgia
Assistant Professor
University of Tennessee Health Science Center Jingyang Fan, PharmD, BCPS
College of Nursing Assistant Professor of Pharmacy Practice
Memphis, Tennessee University of Southern Nevada College of Pharmacy
Henderson, Nevada
Petra Czarniak, BPharm, MPS
Lecturer in Pharmaceutics Carl E. Fasser, PA
Division of Health Sciences Associate Professor of Family & Community Medicine
Murcoch University School of Pharmacy and Physician Assistant
Murdoch Baylor College of Medicine
Western Australia, Australia Houston, Texas
Bonnie A. Dadig, EdD, PA-C Maisha Kelly Freeman, PharmD, BCPS

Chair, Physician Assistant Department Assistant Professor and Drug Information Specialist
Medical College of Georgia Samford University McWhorter School of Pharmacy
Director Birmingham, Alabama
Physician Assistant Program
Medical College of Georgia Hospitals and Clinics Mark Garrison, PharmD
Augusta, Georgia Associate Professor of Pharmacotherapy & Assistant Dean
of Student Services
Larry Danziger, PharmD Washington State University-Spokane
Professor of Pharmacy Practice Spokane, Washington
Chicago, Illinois Margit B. Gerardi, MS, MSA, MSN, RN-WHNP
Clinical Instructor
Lawrence Davidow, PhD, RPh University of Texas Health Science Center at San Antonio
Clinical Assistant Professor San Antonio, Texas
University of Kansas School of Pharmacy
Lawrence, Kansas Stuart Gill-Banham, MRPharmS, MCMHP
Teacher Practitioner
Jillian H. Davis, PhD Universities of Kent and Greenwich at Medway
Assistant Professor Medway School of Pharmacy
Hampton University School of Pharmacy Chatham Maritime
Hampton, Virginia Kent, United Kingdom
Michelle Devereaux, MA, RN, CNP Sveinbjrn Gizurarson, PhD

Partnering Care Senior Services Professor of Pharmaceutics
Bloomington, Minnesota Biopharmaceutics and Clinical Therapeutics
University of Iceland
Thomas C. Dowling, PharmD, PhD Reykjavk, Iceland
Associate Professor
University of Maryland Nancy Goldstein, MSN, CRNP, RNC
Baltimore, Maryland Instructor
The Johns Hopkins University School of Nursing
Allan Ellsworth, PharmD, PA-C Baltimore, Maryland
Professor of Pharmacy and Family Medicine
University of Washington Schools of Pharmacy and Medicine Justine Schuller Gortney, PharmD, BCPS
Seattle, Washington Clinical Assistant Professor
Mercer University
Katherine Erdman, MPAS, PA-C Atlanta, Georgia
Assistant Director
Baylor College of Medicine
Houston, Texas
xxiv REVIEWERS
Erich J. Grant, MMS, PA-C Michael K. Jensen, BSPharm, MS

Instructor Clinical Adjunct Associate Professor of Pharmacy
Physician Assistant Program University of Utah College of Pharmacy
Wake Forest University School of Medicine Clinical Specialist Ophthalmology
Winston-Salem, North Carolina University of Utah Health Sciences Center
John A. Moran Eye Center
Hillary Wall Grillo, PharmD Salt Lake City, Utah
Adjunct Assistant Professor
Shenandoah University School of Pharmacy Jill T. Johnson, PharmD, BCPS
Winchester, Virginia Associate Professor
University of Arkansas for Medical Sciences College
Sara Haddow, MSA, PA-C of Pharmacy
Instructor Little Rock, Arkansas
Physician Assistant Department
Medical College of Georgia June Felice Johnson, PharmD, BCPS, FASHP, CDM-diabetes
Augusta, Georgia Associate Professor of Pharmacy Practice & Director of Faculty
& Site Development
Robert Hadley, PhD, PA-C Drake University College of Pharmacy & Health Sciences
Associate Professor Des Moines, Iowa
University of Kentucky Physician Assistant Program
Lexington, Kentucky Nikki L. Katalanos, PhD, PA-C
Assistant Professor and Physician Assistant
David Hawkins, PharmD Physician Assistant Program
Senior Associate Dean Department of Family & Community Medicine
Professor of Pharmacy Practice The University of New Mexico School of Medicine
South University School of Pharmacy Albuquerque, New Mexico
Savannah, Georgia
Nancy Kawahara, PharmD, MSEd
Mary S. Hayney, PharmD, BCPS, FCCP Associate Professor and Chair
Associate Professor of Pharmacy Department of Pharmacy Practice
University of Wisconsin School of Pharmacy Loma Linda University School of Pharmacy
Madison, Wisconsin Loma Linda, California
Mark A. Heisler, PharmD, BCPS Michael Kelsch, PharmD, BCPS

Adjunct Faculty Assistant Professor
Grand Canyon University College of Nursing North Dakota State University College of Pharmacy
Phoenix, Arizona Fargo, North Dakota
Adjunct Faculty
Arizona State University College of Nursing Lynn G. Kirkland, DNSc, WHNP, CNM
Tempe, Arizona Assistant Professor
Clinical Pharmacist University of Tennessee Health Science Center
Banner Desert Medical Center Womens Health Nurse Practitioner/Certied Nurse Midwife
Mesa, Arizona Memphis Obstetrics and Gynecological Association P.C.
Bartlett, Tennessee
Pamela Helms, RN, MN, FNP-C
Assistant Professor & Clinical Director Julie Kissack, PharmD, BCCP
UNACARE Health Center Associate Professor
University of Mississippi School of Nursing Mercer University
Ridgeland, Mississippi Southern School of Pharmacy
Atlanta, Georgia
Elizabeth Hermsen, PharmD, MBA
Antimicrobial Specialist Michael E. Klepser, PharmD, FCCP
The Nebraska Medical Center Professor of Pharmacy
Adjunct Assistant Professor Ferris State University College of Pharmacy
University of Nebraska Medical Center College and Borgess Medical Center
of Pharmacy Kalamazoo, Michigan
Omaha, Nebraska
REVIEWERS xxv
Carrie Foust Koenigsfeld, PharmD Henry J. Mann, PharmD, FASHP, FCCM, FCCP
Associate Professor of Pharmacy Practice Professor
Drake College of Pharmacy and Health Sciences University of Minnesota College of Pharmacy
Des Moines, Iowa Department of Experimental and Clinical Pharmacology
Director
Annette C. Larson, MSPAS Center for Excellence in Critical Care
Assistant Professor University of Minnesota
University of North Dakota School of Medicine Academic Health Center
Physician Assistant Minneapolis, Minnesota
Altru Health Care System
Grand Forks, North Dakota Karen F. Marlowe, PharmD, BCPS
Associate Professor
Esther M. Law, BScPhm Auburn University Harrison School of Pharmacy
Director, Pharmaceuticals Adjunct Assistant Professor
Shoppers Drug Mart University of South Alabama School of Medicine
North York, Ontario Mobile, Alabama
Canada
Phyllis Mason, MS, RN, CRNP
Rebecca M. T. Law, BScPhm, PharmD Instructor
Associate Professor The Johns Hopkins University School of Nursing
School of Pharmacy Baltimore, Maryland
Memorial University of Newfoundland
St. Johns, Newfoundland, Canada Jeanie McHugo, MS, PA-C
Assistant Professor
Helen Leather, BPharm, Grad Dip Hosp Pharm (Dist) University of North Dakota Physician Assistant Program
Clinical Pharmacy Specialist Grand Forks, North Dakota
Hematopoietic Stem Cell Transplantation/Leukemia Shands
at the University of Florida Kimberly Ann Meyer, MPAS
Clinical Assistant Professor Infectious Diseases Physician Assistant
University of Florida College of Pharmacy University of Nebraska Medical Center
Gainesville, Florida Omaha, Nebraska
Thomas L. Lenz, PharmD, MA Candis M. Morello, PharmD, CDE, FCSHP

Assistant Professor of Pharmacy Practice Assistant Professor of Clinical Pharmacy
Creighton University Skaggs School of Pharmacy and Pharmaceutical Sciences
Omaha, Nebraska University of California
San Diego
Sonia Lin, PharmD, BCPS La Jolla, California
Clinical Associate Professor
University of Rhode Island Carla Moschella, PA-C, MS, RD
Kingston, Rhode Island Assistant Professor and Academic Coordinator
Department of Physician Assistant Studies
Michael Mancano, PharmD Massachusetts College of Pharmacy and Health Sciences
Associate Chair Boston, Massachusetts
Department of Pharmacy Practice, and
Clinical Associate Professor Dana N. Nadolo, MHS, PA-C
Temple University School of Pharmacy Physician Assistant
Philadelphia, Pennsylvania Academic Faculty, Physician Assistant Program
Instructor, Allied Health Sciences
Donald Maner, PharmD, MHSc, PA-C Baylor College of Medicine
Assistant Professor Houston, Texas
Medical College of Georgia
Physician Assistant Department Jadwiga Najib, BS, PharmD
Evans, Georgia Associate Professor of Pharmacy Practice
Arnold & Marie Schwartz College of Pharmacy
Harold J. Manley, PharmD, FASN, FCCP, BCPS and Health Sciences
Associate Professor Long Island University
Department of Pharmacy Practice Brooklyn, New York
Albany College of Pharmacy
Albany, New York
xxvi REVIEWERS
Jacquelin S. Neatherlin, RN, PhD, CNRN Jane Pruemer, PharmD, BCOP, FASHP
Associate Professor Associate Professor of Clinical Pharmacy Practice
Baylor University University of Cincinnati College of Pharmacy
Dallas, Texas Cincinnati, Ohio
Robert Nelson, PharmD, BCPS Edward W. Randell, PhD, DCC, FCACB

Assistant Professor Chief
North Dakota State University College of Pharmacy Division of Biochemical Pathology Health Sciences Centre
Nursing, and Allied Sciences Associate Professor
Clinical Pharmacy Manager Laboratory Medicine
MeritCare Health System Faculty of Medicine
Fargo, North Dakota Memorial University of Newfoundland
St. Johns, Newfoundland, Canada
Christopher Nemergut, PharmD
Clinical Pharmacist Mette Rasmussen, PhD
Center for Drug Policy Professor
University of Wisconsin Hospital and Clinics Faculty of Pharmaceutical Sciences
Madison, Wisconsin Department of Pharmacology and Pharmacotherapy
Section of Clinical pharmacy
Ayman Noreddin, PhD, RPh University of Copenhagen
Associate Professor Copenhagen, Denmark
University of Minnesota College of Pharmacy
Duluth, Minnesota Michael D. Reed, PharmD, FCCP, FCP
Director
Deborah A. Opacic, EdD, PA-C Pediatric Clinical Pharmacology and Toxicology
Assistant Professor Rainbow Babies and Childrens Hospital and Professor of Pediatrics
Rangos School of Health Sciences School of Medicine
Duquesne University Case Western Reserve University
Pittsburgh, Pennsylvania Cleveland, Ohio
Victor A. Padron, RPh, PhD Kathleen Reeve, DrPH, AOCN, ANP

Associate Professor Associate Professor of Clinical Nursing
Department of Pharmacy Sciences The University of Texas Health Science Center at Houston
Creighton University Houston, Texas
Omaha, Nebraska
Suzanne Reich, PA-C, MPAS
Amy Pakyz, PharmD, MS Assistant Professor
Assistant Professor Department of Physician Assistant Studies
Virginia Commonwealth University School Wake Forest University School of Medicine
of Pharmacy/Medical College of Virginia Campus Winston-Salem, North Carolina
Richmond, Virginia
Warren Richards, BSPharm, MBA, PhD
Cynthia Pentz, EdD, PA-C Associate Professor
Director Lloyd L. Gregory School of Pharmacy
Physician Assistant Program Palm Beach Atlantic University School of Pharmacy
University of Findlay West Palm Beach, Florida
Findlay, Ohio
Keith A. Rodvold, PharmD
Todd Pillen, PA-C/SA, MPAS Professor of Pharmacy Practice & Associate Professor
Manager of Medicine in Pharmacy
Solid Organ Transplant University of Illinois at Chicago
Childrens Healthcare of Atlanta-Egleston Chicago, Illinois
and Emory University Hospital
Atlanta, Georgia Carol J. Rollins, MS, RD, PharmD, BCNSP
Program Director: Nutrition Support Pharmacy Practice
Therese I. Poirier, PharmD, MPH, BCPS, FASHP, FCCP Arizona Health Sciences Center
Professor and Associate Dean Clinical Associate Professor
Academic Affairs College of Pharmacy
Southern Illinois University-Edwardsville University of Arizona
Edwardsville, IIllinois Tucson, Arizona
REVIEWERS xxvii
Wendella Rose-Facey, APRN, CCRN, FNP, MSN Catherine Shull, PA-C, MPAS
Adjunct Professor Instructor
Adelphi University Department of Physician Assistant Studies
Critical Care Specialist at Kingsbrook Jewish Medical Center Wake Forest University School of Medicine
Brooklyn, New York Winston-Salem, North Carolina
Elaine Rosenblatt, MSN, APRN, BC Susan M. Stein, MS, RPh

Clinical Professor Assistant Dean for Clinical Education and Student Development
University of Wisconsin Pacic University School of Pharmacy
Director of Health Services and Quality Improvement Hillsboro, Oregon
University of Wisconsin Medical Foundation
Madison, Wisconsin Henry Stoll, PA-C
Senior Lecturer
Polly Royal, MS, RN-BC University of Washington School of Medicine
Clinical Assistant Professor Seattle, Washington
Purdue University School of Nursing
West Lafayette, Indiana Marc A. Sweeney, RPh, MDiv, PharmD
Chair & Associate Professor
Michael Rybak, PharmD, MPH Pharmacy Practice
Associate Dean for Research & Professor of Pharmacy and Medicine The University of Findlay School of Pharmacy
Director of Anti-Infective Research Laboratory Findlay, Ohio
Wayne State University College of Pharmacy & Health Sciences
Detroit, Michigan Mohammad J. Tafreshi, PharmD, BCPS
Associate Professor
Kiranpal S. Sangha, PharmD Midwestern University College of Pharmacy-Glendale
Clinical Pharmacy Specialist-CNS Glendale, Arizona
The University Hospital
Cincinnati, Ohio Brenda J. J. Talarico, MPAS, PA-C
Adjunct Assistant Professor of Clinical Pharmacy Assistant Professor
The University of Cincinnati College of Pharmacy Department of Physician Assistant Studies
Cincinnati, Ohio Augsburg College
Minneapolis, Minnesota
JoAnne M. Saxe, RN, MS, ANP
Clinical Professor & Director of the Adult Nurse Candace Smith, PharmD
Practitioner Program Associate Clnical Professor
University of California St. Johns University College of Pharmacy
San Francisco School of Nursing & Allied Health Professions
San Francisco, California Jamaica, New York
Dana Sayre-Stanhope, EdD, PA-C Christopher J. Sullivan, MD, FACP

Associate Professor Adjunct Professor of Pharmacy
Saint Louis University University of Minnesota
Doisy College of Health Sciences Birchwood Village, Minnesota
St. Louis, Missouri
Damary Castanheira Torres, PharmD, BCOP
Sarah L. Scarpace, PharmD, BCOP Associate Clinical Professor
Assistant Professor St. Johns University College of Pharmacy
Albany College of Pharmacy & Allied Health Professions
Albany, New York Jamaica, New York
Denise Schentrup, MN, ARNP, BC Mary Fran Tracy, PhD, RN, CCRN, CCNS, FAAN
Clinical Assistant Professor Critical Care Clinical Nurse Specialist
University of Florida University of Minnesota Medical Center
College of Nursing Fairview
Gainesville, Florida Minneapolis, Minnesota
Karin Schurrer-Erickson, MA, RN, CNP Marianne Vail, MS, PA-C

Teaching Specialist Department of Physician Assistant Studies
University of Minnesota School of Nursing Massachusetts College of Pharmacy & Health Sciences
Minneapolis, Minnesota Boston, Massachusetts
xxviii REVIEWERS
Lee Vermeulen, RPh, MS, FCCP Siu-Fun Wong, PharmD, FASHP, FCSHP
Director Associate Professor of Pharmacy Practice
Center for Drug Policy Western University of Health Sciences
University of Wisconsin Hospital and Clinics Faculty-in-Residence
Madison, Wisconsin Hematology-Oncology Medical Group of Orange County, Inc.
Pomona, California
Angie Veverka, BS, PharmD
Assistant Professor of Pharmacy Daniel Wood, MPAS, PA-C
Wingate University School of Pharmacy Clinical Assistant Professor
Wingate, North Carolina University of Texas Health Science Center at San Antonio
San Antonio, Texas
Heather Vezina, PharmD
Assistant Professor Kathleen Woodruff, MS, CRNP
University of Minnesota School of Medicine & College of Pharmacy Instructor
Minneapolis, Minnesota The Johns Hopkins University School of Nursing
Baltimore, Maryland
Vicki Waters, MS, PA-C
Assistant Director for Experiential Learning Monty Yoder, PharmD, BCPS
Physician Assistant Program Pharmaceutical Care Coordinator
School of Allied Health Sciences Wake Forest University Baptist Medical Center
Baylor College of Medicine Winston-Salem, North Carolina
Houston, Texas
Dawn Zwick, MSN, CRNP
Christine Werner, PA-C, PhD Lecturer
Assistant Professor College of Nursing
Saint Louis University Kent State University
Doisy College of Health Sciences Kent, Ohio
St. Louis, Missouri
Thomas White, JD, PA-C

Academic Coordinator
University of New Mexico School of Medicine
Albuquerque, New Mexico
CONTINUING EDUCATION CREDITS
Chap. 1 Introduction Chap. 7 Venous Thromboembolism

Universal Program Number:
Chap. 2 Hypertension 014-999-07-019-H04
Universal Program Number: Three and half (3.5) contact hours
014-999-07-014-H04 (0.35 CEUs) will be awarded and statements
Three (3.0) contact hours (0.30 CEUs) will issued for successful program completion
be awarded and statements issued for and request for continuing education.
successful program completion and request
for continuing education.
Chap. 8 Stroke
Chap. 3 Heart Failure 014-999-07-020-H04
Universal Program Number: Two (2.0) contact hours (0.20 CEUs) will be
014-999-07-015-H04 awarded and statements issued for
Four (4.0) contact hours (0.40 CEUs) will successful program completion and request
be awarded and statements issued for for continuing education.
Chap. 9 Hyperlipidemia
Chap. 4 Ischemic Heart Disease
014-999-07-021-H04
Two and half (2.5) contact hours (0.25 CEUs)
014-999-07-016-H06
will be awarded and statements issued for
Three (3.0) contact hours (0.30 CEUs) will
be awarded and statements issued for
Chap. 5 Acute Coronary Syndromes Chap. 10 Hypovolemic Shock

Universal Program Number: Universal Program Number:
014-999-07-017-H04 014-999-07-022-H04
Two and half (2.5) contact hours (0.25 CEUs) One and half (1.5) contact hours (0.15 CEUs) will
will be awarded and statements issued for be awarded and statements issued for
successful program completion and request successful program completion and request for
for continuing education. continuing education.
Chap. 6 Arrhythmias Chap. 11 Asthma

014-999-07-018-H04 014-999-07-025-H04
Three and half (3.5) contact hours Three (3.0) contact hours (0.30 CEUs) will be
(0.35 CEUs) will be awarded and statements awarded and statements issued for
issued for successful program completion successful program completion and request for
and request for continuing education. continuing education.
xxix
xxx CONTINUING EDUCATION CREDITS
Chap. 12 Chronic Obstructive Chap. 18 Constipation, Diarrhea,

Pulmonary Disease and Irritable Bowel Syndrome
014-999-07-026-H04 014-999-07-032-H04
Two (2.0) contact hours (0.20 CEUs) will be Two and half (2.5) contact hours (0.25 CEUs) will
awarded and statements issued for be awarded and statements issued for
successful program completion and request for successful program completion and request for
continuing education. continuing education.
Chap. 13 Cystic Fibrosis Chap. 19 Portal Hypertension

Universal Program Number: and Cirrhosis
014-999-07-027-H04 Universal Program Number:
Two (2.0) contact hours (0.20 CEUs) will be 014-999-07-033-H04
awarded and statements issued for Two (2.0) contact hours (0.20 CEUs) will be
successful program completion and request for awarded and statements issued for
continuing education. successful program completion and request for
continuing education.
Chap. 14 Gastroesophageal Reux
Disease Chap. 20 Pancreatitis
014-999-07-028-H04 014-999-07-034-H04
One and half (1.5) contact hours (0.15 CEUs) will One (1.0) contact hours (0.10 CEUs) will be
be awarded and statements issued for awarded and statements issued for
Chap. 15 Peptic Ulcer Disease Chap. 21 Viral Hepatitis

014-999-07-029-H04 014-999-07-035-H04
One and half (1.5) contact hours (0.15 CEUs) will Two (2.0) contact hours (0.20 CEUs) will be
Chap. 22 Acute Renal Failure

Chap. 16 Inammatory Bowel Disease Universal Program Number:
Universal Program Number: 014-999-07-036-H04
014-999-07-030-H04 Two (2.0) contact hours (0.20 CEUs) will be
Two (2.0) contact hours (0.20 CEUs) will be awarded and statements issued for
awarded and statements issued for successful program completion and request for
successful program completion and request for continuing education.
Chap. 23 Chronic and End-Stage
Chap. 17 Nausea and Vomiting Renal Disease
014-999-07-031-H04 014-999-07-037-H04
One and half (1.5) contact hours (0.15 CEUs) will Four (4.0) contact hours (0.40 CEUs) will be
CONTINUING EDUCATION CREDITS xxxi
Chap. 24 Fluids and Electrolytes Chap. 30 Pain Management

014-999-07-038-H01 014-999-07-044-H04
Two (2.0) contact hours (0.20 CEUs) will be Two (2.0) contact hours (0.20 CEUs) will be
awarded and statements issued for awarded and statements issued for successful
successful program completion and request for program completion and request for
Chap. 25 Acid-Base Disturbances Chap. 31 Headache

014-999-07-039-H04 014-999-07-047-H04
One and half (1.5) contact hours (0.15 CEUs) will Two (2.0) contact hours (0.20 CEUs) will be
be awarded and statements issued for awarded and statements issued for successful
successful program completion and request for program completion and request for
Chap. 26 Multiple Sclerosis Chap. 32 Alzheimers Disease

014-999-07-040-H04 014-999-07-048-H04
One and half (1.5) contact hours (0.15 CEUs) will One and half (1.5) contact hours (0.15 CEUs)
be awarded and statements issued for will be awarded and statements issued for
successful program completion and request for successful program completion and request
continuing education. for continuing education.
Chap. 27 Epilepsy Chap. 33 Substance-Related Disorders

014-999-07-041-H04 014-999-07-049-H04
Two (2.0) contact hours (0.20 CEUs) will be Three (3.0) contact hours (0.30 CEUs) will
awarded and statements issued for be awarded and statements issued for
successful program completion and request for successful program completion and request
Chap. 28 Status Epilepticus Chap. 34 Schizophrenia

014-999-07-042-H04 014-999-07-050-H04
One and half (1.5) contact hours (0.15 CEUs) Two and half (2.5) contact hours (0.25 CEUs)
will be awarded and statements issued for will be awarded and statements issued for
successful program completion and request successful program completion and request
for continuing education. for continuing education.
Chap. 29 Parkinsons Disease Chap. 35 Major Depressive Disorder

014-999-07-043-H04 014-999-07-051-H04
Two (2.0) contact hours (0.20 CEUs) will be One and half (1.5) contact hours (0.15 CEUs)
awarded and statements issued for successful will be awarded and statements issued for
program completion and request for successful program completion and request
xxxii CONTINUING EDUCATION CREDITS
Chap. 36 Bipolar Disorder Chap. 42 Adrenal Gland Disorders

014-999-07-052-H04 014-999-07-058-H04
Two and half (2.5) contact hours (0.25 CEUs) One (1.0) contact hours (0.10 CEUs) will be
will be awarded and statements issued for awarded and statements issued for successful
successful program completion and request program completion and request for
for continuing education. continuing education.
Chap. 37 Generalized Anxiety Chap. 43 Pituitary Gland Disorder

Disorder, Panic Disorder, Universal Program Number:
and Social Anxiety Disorder 014-999-07-123-H04
Universal Program Number: One and half (1.5) contact hours (0.15 CEUs)
014-999-07-053-H04 will be awarded and statements issued for
One and half (1.5) contact hours (0.15 CEUs) successful program completion and request
will be awarded and statements issued for for continuing education.
Chap. 44 Pregnancy and Lactation:
Therapeutic Considerations
Chap. 38 Sleep Disorders Universal Program Number:
014-999-07-054-H04 One and half (1.5) contact hours (0.15 CEUs)
One (1.0) contact hours (0.10 CEUs) will be will be awarded and statements issued for
awarded and statements issued for successful program completion and request
Chap. 45 Contraception
Chap. 39 Attention-Decit Hyperactivity Disorder Universal Program Number:
Half (0.5) contact hours (0.05 CEUs) will be will be awarded and statements issued for
awarded and statements issued for successful successful program completion and request
program completion and request for for continuing education.
Chap. 46 Menstruation-Related Disorders
Chap. 40 Diabetes Mellitus Universal Program Number:
Two (2.0) contact hours (0.20 CEUs) will be will be awarded and statements issued for
awarded and statements issued for successful successful program completion and request
program completion and request for for continuing education.
Chap. 47 Hormone-Replacement
Chap. 41 Thyroid Disorders Therapy in Menopause
014-999-07-057-H04 014-999-07-062-H04
Two (2.0) contact hours (0.20 CEUs) will be One and half (1.5) contact hours (0.15 CEUs)
awarded and statements issued for successful will be awarded and statements issued for
program completion and request for successful program completion and request
CONTINUING EDUCATION CREDITS xxxiii
Chap. 48 Erectile Dysfunction Chap. 54 Rheumatoid Arthritis

014-999-07-063-H04 014-999-07-069-H04
One (1.0) contact hours (0.10 CEUs) will be One (1.0) contact hours (0.10 CEUs) will be
awarded and statements issued for awarded and statements issued for
Chap. 49 Benign Prostatic Hyperplasia

Chap. 55 Osteoarthritis
014-999-07-064-H04
014-999-07-070-H04
One and half (1.5) contact hours (0.15 CEUs)
One (1.0) contact hours (0.10 CEUs) will be
awarded and statements issued for
Chap. 50 Urinary Incontinence

and Pediatric Enuresis Chap. 56 Gout and Hyperuricemia
014-999-07-065-H04 014-999-07-071-H04
Two (2.0) contact hours (0.20 CEUs) will be Half (0.5) contact hours (0.05 CEUs) will be
Chap. 51 Allergic and Pseudoallergic Chap. 57 Musculoskeletal Disorders

Drug Reactions Universal Program Number:
014-999-07-066-H04 One (1.0) contact hours (0.10 CEUs) will be
One (1.0) contact hours (0.10 CEUs) will be awarded and statements issued for
Chap. 52 Solid-Organ Transplantation Chap. 58 Glaucoma

014-999-07-067-H04 014-999-07-073-H04
Two and half (2.5) contact hours (0.25 CEUs) Two (2.0) contact hours (0.20 CEUs) will be
will be awarded and statements issued for awarded and statements issued for
Chap. 53 Osteoporosis Chap. 59 Allergic Rhinitis

014-999-07-068-H04 014-999-07-074-H04
xxxiv CONTINUING EDUCATION CREDITS
Chap. 60 Minor Ophthalmic Disorders Chap. 66 Antimicrobial Regimen Selection

014-999-07-075-H04 014-999-07-081-H04
One and half (1.5) contact hours (0.15 CEUs) One and half (1.5) contact hours (0.15 CEUs)
Chap. 61 Psoriasis Chap. 67 Central Nervous System Infections

014-999-07-076-H04 014-999-07-082-H04
One and half (1.5) contact hours (0.15 CEUs) One (1.0) contact hours (0.10 CEUs) will be
Chap. 62 Common Skin Disorders Chap. 68 Lower Respiratory Tract Infections

014-999-07-077-H04 014-999-07-083-H04
One and half (1.5) contact hours (0.15 CEUs) One and half (1.5) contact hours (0.15 CEUs)
Chap. 63 Anemia Chap. 69 Upper Respiratory Tract Infections

014-999-07-078-H04 014-999-07-084-H04
Chap. 64 Coagulation Disorders Chap. 70 Skin and Soft Tissue Infections

014-999-07-079-H04 014-999-07-085-H04
Chap. 65 Sickle Cell Disease Chap. 71 Infective Endocarditis

014-999-07-080-H04 014-999-07-086-H04
CONTINUING EDUCATION CREDITS xxxv
Chap. 72 Tuberculosis Chap. 78 Osteomyelitis

014-999-07-087-H04 014-999-07-093-H04
Chap. 73 Gastrointestinal Infections Chap. 79 Sepsis and Septic Shock

014-999-07-088-H04 014-999-07-094-H04
One (1.0) contact hours (0.10 CEUs) will be Two (2.0) contact hours (0.20 CEUs) will be
Chap. 74 Intraabdominal Infections Chap. 80 Supercial Fungal Infections

014-999-07-089-H04 014-999-07-095-H04
One (1.0) contact hours (0.10 CEUs) will be One and half (1.5) contact hours (0.15 CEUs)
awarded and statements issued for will be awarded and statements issued for
Chap. 81 Invasive Fungal Infections

Chap. 75 Parasitic Diseases
014-999-07-096-H04
014-999-07-090-H04
Two and half (2.5) contact hours (0.25 CEUs)
Two (2.0) contact hours (0.20 CEUs) will be
awarded and statements issued for
Chap. 82 Antimicrobial Prophylaxis

Chap. 76 Urinary Tract Infection in Surgery
014-999-07-091-H04 014-999-07-097-H01
Chap. 77 Sexually Transmitted Infections Chap. 83 Vaccines and Toxoids

014-999-07-092-H04 014-999-07-098-H01
Two and half (2.5) contact hours (0.25 CEUs) Two (2.0) contact hours (0.20 CEUs) will be
xxxvi CONTINUING EDUCATION CREDITS
Chap. 84 Human Immunodeciency Chap. 90 Malignant Lymphomas

Virus Infection Universal Program Number:
014-999-07-099-H04 One (1.0) contact hours (0.10 CEUs) will be
Two (2.0) contact hours (0.20 CEUs) will be awarded and statements issued for
Chap. 91 Ovarian Cancer

Chap. 85 Cancer Chemotherapy Universal Program Number:
and Treatment 014-999-07-106-H04
Universal Program Number: Half (0.5) contact hours (0.05 CEUs) will be
014-999-07-100-H01 awarded and statements issued for
Three (3.0) contact hours (0.30 CEUs) will successful program completion and request
be awarded and statements issued for for continuing education.
Chap. 92 Acute Leukemias
Chap. 86 Breast Cancer 014-999-07-107-H04
Universal Program Number: One and half (1.5) contact hours (0.15 CEUs)
014-999-07-101-H04 will be awarded and statements issued for
Two (2.0) contact hours (0.20 CEUs) will be successful program completion and request
awarded and statements issued for for continuing education.
Chap. 93 Chronic Leukemias and
Chap. 87 Lung Cancer Multiple Myeloma
014-999-07-102-H04 014-999-07-108-H04
Chap. 88 Colorectal Cancer Chap. 94 Skin Cancer

014-999-07-103-H04 014-999-07-109-H04
One and half (1.5) contact hours (0.15 CEUs) Two (2.0) contact hours (0.20 CEUs) will be
Chap. 89 Prostate Cancer Chap. 95 Hematopoietic Cell Transplantation

014-999-07-104-H04 014-999-07-110-H04
One (1.0) contact hours (0.10 CEUs) will be Two (2.0) contact hours (0.20 CEUs) will be
CONTINUING EDUCATION CREDITS xxxvii
Chap. 96 Oncologic Emergencies Chap. 98 Enteral Nutrition

014-999-07-111-H04 014-999-07-113-H04
Two and half (2.5) contact hours (0.25 CEUs) One and half (1.5) contact hours (0.15 CEUs)
Chap. 97 Parenteral Nutrition Chap. 99 Overweight and Obesity

014-999-07-112-H04 014-999-07-114-H04
Two (2.0) contact hours (0.20 CEUs) will be One (1.0) contact hours (0.10 CEUs) will be
Continuing Education
Pharmacists, physicians, physician assistants, and nurse practitioners can earn valuable continuing education credit based on the
content of Pharmacotherapy Principles & Practice. For details visit: www.pharmacotherapyprinciples.com
Accreditation
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council
for Continuing Medical Education through the joint sponsorship of the Medical College of Georgia School of Medicine and The
University of Georgia College of Pharmacy.
The Medical College of Georgia School of Medicine is accredited by the Accreditation Council for Continuing Medical Education
to provide continuing medical education for physicians.
The Medical College of Georgia is an approved provider of continuing nursing education by the Georgia Nurses Association, an
accredited approver by the American Nurses Credentialing Centers Commission on Accreditation.
The University of Georgia College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education
as a provider of continuing pharmacy education.
Designation
The Medical College of Georgia School of Medicine designates this educational activity for a maximum of 170 AMA
PRA Category 1 Credits.TM Physicians (and other qualied participants) should only claim credit commensurate with
the extent of their participation in the activity.
The University of Georgia College of Pharmacy designates this on-line educational series for a maximum of
170 contact hours (17.0 CEUs). A Request for CE must be made for EACH offering and continuing education
credit will be awarded and statements issued on-line for successful completion of materials and assessment.
For details visit: www.pharmacotherapyprinciples.com

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PREFACE
Practitioners who design, implement, monitor, and evaluate Up-to-date literature citations. A comprehensive reference list
medication therapy bear an important responsibility to for each chapter is provided on the Online Learning Center
their patients and society. Development of these abilities to substantiate treatment recommendations.
requires an integration of knowledge, skills, attitudes, and Key references and readings. Placed at the end of each
values that can be acquired only through a structured learning chapter, this list provides a mechanism to acquire a deeper
process that includes classroom work, independent study, understanding of the subject matter.
hands-on practice, and, ultimately, involvement with actual Generous use of tables, gures, text boxes, and algorithms.
patients. These visual features enhance understanding of pathophysio-
Pharmacotherapy Principles & Practice is designed to meet logy, clinical presentation, drug selection, pharmacokinetics,
the classroom and independent study needs of todays learners and patient monitoring.
in the health professions. Chapters are written or reviewed by Medical abbreviations and their meanings. Placed at the end
pharmacists, nurse practitioners, physician assistants, and of each chapter, these lists facilitate learning the accepted
physicians who are authorities in their elds and were sub- shorthand used in real-world medical practice.
jected to rigorous review by experts. The book is written in a Glossary of medical terms. The glossary is one of the appen-
concise style that facilitates an in-depth level of understanding dices at the end of the book; the rst use of each glossary
of the essential concepts. The disease states covered and the term in a chapter appears in bold font.
drugs discussed in the text focus on those disorders most Self-assessment questions and answers for each chapter.
often seen in actual practice. Located in the Online Learning Center, these questions are
Each chapter reviews etiology, epidemiology, pathophysio- designed to evaluate student learning and may be used to
logy, and disease presentation, followed by clear therapeutic obtain approximately 170 hours of continuing education
recommendations for drug selection, dosing, and patient credit for licensed pharmacists, nurse practitioners, physi-
monitoring. The learning features used in Pharmacotherapy cians, and physician assistants.
Principles & Practice were designed in collaboration with edu- Laboratory values expressed as both conventional units and
cational design specialists to enhance learning and retention. System International (SI) units. Including both units of meas-
These features include: urement facilitates use of this book throughout the world.
Appendices useful to students and practitioners. These
Structured learning objectives. These are listed at the begin- appendices include: 1) conversion factors and anthropomet-
ning of each chapter, and information in the text that corre- rics; 2) common laboratory tests and their reference ranges;
sponds to each learning objective is identied by a vertical and 3) common medical abbreviations.
rule in the margin, which allows the reader to nd content
related to each objective quickly. An electronic version of Pharmacotherapy Principles &
Key concepts related to patient assessment and treatment. Practice can be downloaded to a desktop or laptop computer
Designed to help focus learning, these key concepts are listed at using the access number that appears on the card inserted in
the beginning of each chapter. Textual material that develops the middle of this book. The Online Learning Center at
these concepts is easily identied by numbered icons through- www.ChisholmPharmacotherapy.com provides complete
out the chapter. reference lists, self-assessment questions, a testing center that
Patient encounter vignettes. Distributed throughout each chap- has the ability to grade and provide immediate feedback on
ter, these case scenarios facilitate critical thinking skills and the self-assessment questions as well as reporting capabilities,
lend clinical relevance to the scientic foundation provided. and other features designed to support learning.
Patient care and monitoring guidelines. This section, placed Pharmacotherapy Principles & Practice is a valuable and
near the end of each chapter, is designed to assist students in unique learning tool that combines state-of-the-art, compre-
their general approach to assessing, treating, and monitoring hensive, yet concise chapters, unique learning features, and
patients for therapeutic response and adverse events. the Online Learning Center.
xxxix
xl PREFACE
We would like to acknowledge the commitment and dedi- families for their patience and support of this work and of our
cation of the 161 contributing authors and 145 reviewers of goal to improve patient care by enhancing learning of pharma-
the chapters contained in this text (a list of contributors and a list cotherapeutics across the health professions.
of reviewers are included in the frontmatter of this book). We
also extend our thanks to the McGraw-Hill Medical Publishing The Editors
July 2007
Division, especially Michael Brown, Maya Barahona, and Robert
Pancotti, for their dedication to this project. Finally, we thank our
PART ONE
BASIC CONCEPTS
OF PHARMACOTHERAPY
PRINCIPLES AND PRACTICE
1 INTRODUCTION
Jack E. Fincham
The prescribing of a drug is the most common outcome of a traditional channels (community chain and independent
patient visit to a physician; 60% of physician visits result in a pharmacies), from mail order pharmacies, through the
prescription or injection for patients. It is incumbent on Internet, from physicians, from health care institutions, and
health professionals to ensure that this process of receiving elsewhere. Herbal remedies are marketed and sold in numerous
and taking medications benets and does not harm patients. outlets. The monitoring of the positive and negative outcomes
Clinicians are often called upon to identify, resolve, and pre- of the use of these drugs, both prescription and OTC, can be
vent problems that occur due to undertreatment, overtreat- disjointed and incomplete. Clinicians and health professions
ment, or inappropriate treatment. Problems occurring with students need to take ownership of these problems and improve
the use of drugs can include: patient outcomes resulting from drug use.
It is important to realize that although clinicians are the
Suboptimal drug, dose, regimen, dosage form, and duration gatekeepers for patients to obtain prescription drugs, patients
of use; can obtain prescription medications from numerous sources.
Unnecessary drug therapy; Patients may also borrow from friends, relatives, or even casual
Therapeutic duplication; acquaintances. In addition, patients obtain OTC medications
Drug-drug, drug-disease, drug-food, or drug-nutrient from physicians through prescriptions, on advice from phar-
interactions; macists and other health professionals, through self-selection,
Drug allergies; or or through the recommendations of friends or acquaintances.
Adverse drug effects, some of which are preventable. Through all of this, it must be recognized that there are both
formal (structural) and informal (word of mouth) compo-
The readers of this book can help to reverse these problems, nents at play. Health professionals may or may not be con-
improve outcomes of care both clinically and economically, and sulted regarding the use of medications, and in some cases are
enable drug use to meet stated goals and objectives. This text unaware of the drugs patients are taking. In addition, herbal
provides a thorough analysis and summary of treatment options remedies or health supplements may be taken without the
for commonly occurring diseases and the medications or alter- knowledge or input of a health professional.
native therapies used to successfully treat these conditions. External variables may greatly inuence patients and their
The use of drugs as a form of medical treatment in the United drug-taking behaviors. Coverage for prescribed drugs allows
States is an enormously complex process. Individuals can pur- those with coverage to obtain medications with varying cost
chase medications through numerous outlets. Over-the-counter sharing requirements. However, many do not have insurance
(OTC) medications can be purchased in pharmacies, grocery coverage for drugs or other health-related needs. With the
stores, supermarkets, convenience stores, via the Internet, and advent of Medicare coverage for prescription medications,
through any number of additional outlets. OTCs are widely more of the elderly will have access to needed therapymore
used by all age groups. Prescriptions can be purchased through than ever before.1
4 PART 1 / BASIC CONCEPTS OF PHARMACOTHERAPY PRINCIPLES AND PRACTICE
SELF-MEDICATION Compliance Issues

Patient noncompliance with prescription regimens is one of
Self-medication can be broadly dened as a decision made by a
the most understated problems in the health care system. The
patient to consume a drug with or without the approval or
effects of noncompliance have enormous ramications for
direction of a health professional. The self-medication activities
patients, caregivers, and health professionals. Compliance
of patients have increased dramatically in the late twentieth and
with medications is a worldwide problem, and measures that
early twenty-rst centuries. Many factors affecting patients have
are effective in one country may not have work elsewhere.
continued to fuel this increase in self-medication. There are ever
In the recently released book on worldwide compliance
increasing ways to purchase OTC medications. There have been
issues (Adherence to Long-term Therapies, Evidence for Action),7
many prescription items switched to OTC classication in the
published by the World Health Organization, researchers indi-
last 50 years. In addition, patients are increasingly becoming
cate that the problem of noncompliance is worse in countries in
comfortable with self-diagnosing and self-selection of OTC
the developing world than in countries in the industrialized
remedies. The number of switched products is dramatically and
world. Many parts of the United States have similar morbidity
signicantly fueling the rapid expansion of OTC drug usage.
and mortality rates as countries in the Third World.8 Specic
Dean2 noted in the past that in many studies, self-medication
disease states may have signicant additional noncompliance
with nonprescribed therapies exceeds the use of prescription
ramications due to the development of drug-resistant strains
medications.
of bacteria.9 Many times what is necessary is referral to specic
Patients use of self-selected products has the potential to
clinicians for individualized treatment and monitoring to
bring enormous benets to patients, as well as others.3 Through
enhance compliance. The case histories provided in this text will
the rational use of drugs, patients may avoid more costly ther-
allow you to follow what others have done in similar situations
apies or expenditures for other professional services. Self-lim-
to optimally help patients succeed in improving compliance
iting conditions and even some chronic health conditions
rates and subsequent positive health outcomes.
(e.g., allergies and dermatologic conditions), if appropriately
treated through patient self-medication, allow the patient to
have a degree of autonomy in health care decisions. This book DRUG COSTS
provides a thorough analysis of common disease states, dis-
cussion of therapies to treat these conditions, and specic Spending for prescription drugs in the United States has sky-
advice to provide to patients to help them self-medicate when rocketed in the recent past. Between 1990 and 2003, the amount
appropriate and safe to do so. spent on prescription drugs in the United States quadrupled, far
outstripping the increase in cost of other commodities in the
United States health care system.10 This large increase in spend-
COMPLIANCE WITH MEDICATION REGIMENS ing has stressed nancing of the health care system. Americans
pay the highest prices for prescription drugs in the world.11
Both self-medication and patient compliance behaviors are United States prices are 72% higher than those in Canada, and
exceedingly complex. McDonald and colleagues4 point out 102% higher than those in Mexico.11 An increase of 25% in the
that patient interventions to impact compliance are complex, percentage of expenditures for prescription drugs as a percent-
labor intensive, and not particularly effective. McDonald and age of all health care costs has occurred over the past 5 years.
colleagues4 further suggest that more convenient care, Numerous types of marketing have impacted the usage of
reminders, self-monitoring by patients, reinforcement, family prescription drugs, and marketing has come under increasing
therapy, and additional attention may need to be in play for scrutiny as one reason for the use of costly alternatives rather
compliance to improve. Meredith5 notes that a focus on the indi- than less expensive therapies that might be equally efcacious.
vidual, rather than a general approach, is more likely to be suc- More and more of these types of comparisons are appearing in
cessful. Haynes and colleagues6 call for better approaches to the lay press (magazines and newspapers). A good share of the
enhance compliance that are more efcient and more effective. success of the pharmaceutical industry is due to lobbying efforts,
For the most part, with regard to compliance-enhancing which have been substantive and effective. Knowledgeable clini-
strategies, the more things that can be done the better the cians can counter the misleading marketing that sometimes
chances of success. Enhancing compliance is more art than sci- occurs, and in doing so provide a signicant service that improves
ence, and more trial and error than precisely delineated. Success the prescribing and drug use process.
may be frustratingly difcult to achieve, but enhanced and suit-
able patient compliance should be the ultimate goal of the pre-
scribing, dispensing, and therapeutic monitoring process. DRUG USE BY THE ELDERLY
Clinicians can have no more rewarding, yet vexing, opportunity
than trying and succeeding in helping patients comply with Various components of drug use in the elderly are worth noting.
medication regimens and achieve treatment goals. Problems with health literacy (i.e., the understanding of medical
CHAPTER 1 / INTRODUCTION 5
terminology and directions from providers) are more common Health Literacy and Indigent Care
among the elderly.12 The burgeoning population of the elderly
The negative inuence of health illiteracy on all affected patients
coupled with their lack of health literacy means that this issue
has tangible outcomes, namely higher rates of hospitalization
will become even more problematic in the future.12
with lower rates of health literacy.16 Much of the elaborate tech-
Over the next decade, seniors will spend $1.8 trillion on
nology used by the United States health care system is not acces-
prescription medications. Medicare proposals to provide a
sible to the uninsured. It is estimated that $1.1 billion per year in
drug benet for seniors have been suggested to cost $400 billion
additional expenditures are needed to deal with undertreatment
over a 10-year period. Thus, the most elaborate of the current
of myocardial infarction, cataracts, and depression.17 As govern-
drug programs will pay only 22% of seniors drug costs.
mental programs expand to provide drug coverage for more
Enhanced use of pharmacoeconomic tenets to select appro-
seniors in Medicare Part D, and for patients shifted from drug
priate therapy while considering cost and therapeutic bene-
coverage under Medicaid to Medicare coverage, the impacts of
ts for seniors and others will become even more crucial for
health illiteracy and the need for clinicians to provide interven-
clinicians in the future.
tions that will enhance drug use will dramatically increase.
Health professionals are at a crucial juncture as we face
an uncertain, yet promising future. Technological advances,
IMPACTING THE PROBLEMS OF DRUG USE
including electronic prescribing, may stem the tide of med-
ication errors and inappropriate prescribing. Pilot studies
Medication Errors
have implemented these technological enhancements for
Brass,13 commenting on the change from prescription to over- physician order entry (via personal data assistants or through
the-counter status of many medications, notes increasing web access to pharmacies) in order to reduce drug errors.
problems with polypharmacy. This is no surprise to anyone The skills and knowledge that enable effective pharmacother-
considering the several classes of drugs that can cause prob- apy practice have never been more daunting among the
lems. These problem drugs include analgesics, sleep prepara- numerous health professions. Sophisticated computer technol-
tions, pseudoephedrine, caffeine, cough and cold prepara- ogy can further empower health professionals to play an ever
tions, and laxatives. The problems with these drugs have been increasing and effective role in helping patients and fellow
also noted in studies elsewhere.14 Inaccurate self-diagnosis health professionals to practice safe and effective medicine.
leads to suboptimal therapy, high patient cost, and more This book, which incorporates materials written by some
adverse effects and/or drug interactions.13 of the nest minds in pharmacy practice and education, can
Elsewhere, it was found that errors by physicians and oth- enable the reader to play a crucial role in improving the drug
ers is often not reported to patients, and surprisingly, 23% of use process for patients, providers, payers, and society. The
physicians and 11% of patients in one study did not feel that purpose of this book is to help hone your skills so you can
physicians should report such errors to patients.15 Clinicians make a real improvement in the therapies you provide to
in the future will be expected to interact more, and more your patients. Current and future clinicians can rely on the
effectively, with patients. These expectations for improved information laid out here to enhance your knowledge and
interaction with patients will help both clinicians and patients allow you to assist your patients with the sound advice that
to reach their therapeutic goals. The authors of the chapters in they expect you to provide. Use the text, case histories, and
this text have worked through patient care problems that are numerous examples detailed here to expand your therapeutic
commonly seen in practice, and the reader will benet by skills, and to help positively impact your patients in the years
using similar tactics to help their patients. to come.
PART TWO
DISORDERS OF
ORGAN SYSTEMS
Section 1. Cardiovascular Disorders
2 HYPERTENSION
Robert J. Straka, R. Todd Burkhardt, and David Parra
LEARNING OBJECTIVES
UPON COMPLETION OF THE CHAPTER, THE READER WILL BE ABLE TO:
1. Classify blood pressure levels and treatment goals.

2. Recognize the underlying causes and contributing factors in the development of
hypertension.
3. Describe the appropriate measurement of blood pressure.
4. Recommend appropriate lifestyle modications and pharmacotherapy for patients with
hypertension.
5. Identify populations requiring special consideration when designing a treatment plan.
6. Construct an appropriate monitoring plan to assess hypertension treatment.
KEY CONCEPTS An approach to selection of drugs for the treatment of

patients with hypertension should be evidence-based with
Hypertension is widely prevalent and accounts for signicant considerations regarding the individuals co-existing disease
morbidity and mortality, as well as billions of dollars in direct states, co-prescribed medications, and practical patient-specic
and indirect costs. issues including costs.
The cause of hypertension is unknown in the majority of cases While the main goal of antihypertensive therapy is to achieve
(primary hypertension), but for those with secondary hyper- target blood pressures, the selection of agents for an individ-
tension, specic causes are indicated. ual should also account for certain special considerations and
Patients failing to achieve goal blood pressure despite maxi- a patients comorbidities. Specic antihypertensive therapy is
mum doses of three antihypertensives including a diuretic warranted for certain patients with comorbid conditions that
should be carefully screened for resistant hypertension. may elevate their level of risk for cardiovascular disease.
The pathophysiology of primary hypertension is heteroge- The frequency of follow-up visits for patients with hyperten-
neous, but ultimately exerts its effects through the two pri- sion will vary based on individual cases, but will be inuenced
mary determinants of blood pressure: cardiac output and by severity of hypertension, comorbidities, and choice of
peripheral resistance. agent selected.
Appropriate technique in measuring blood pressure is a vital
component to the diagnosis and continued management of National and international trends over the past 15 years depict
hypertension in the outpatient setting. modest improvements in the treatment and/or control of blood
Drug selection for the management of patients with hyperten- pressure (BP) for hypertensive patients. This observation is made
sion should be considered as adjunctive to nonpharmacologic despite efforts to promote awareness, treatment, and the means
approaches for blood pressure lowering, and ultimately the available to aggressively manage high blood pressure. Over
attainment of target blood pressure in many cases may be more 65 million Americans have hypertension, which was listed as the
important than the antihypertensive agent used. primary cause of death for over 261,000 individuals in the United
Implementation of lifestyle modications successfully lowers States in 2002.1 Hypertension is also a signicant cause of end-
blood pressure, often with results similar to those of therapy stage renal disease and heart failure. National and international
with a single antihypertensive agent. organizations continually rene their recommendations of how
10 SECTION 1 / CARDIOVASCULAR DISORDERS
clinicians should approach the management of patients with represent specic conditions for which explicit evidence in the
high blood pressure, including methods of measurement, patient literature exists to document the utility of a particular agent
education, medication adherence, and overall benets of reduced or class of agents. Selection of drug therapy consequently
blood pressure. Although approaches vary to some degree, there involves an iterative process of considering multiple antihy-
are clear themes that emerge regardless of which national or pertensive drugs as needed to achieve target blood pressures
international organizations algorithm is followed. The purpose of less than 140/90 mm Hg for all patients, with more aggres-
of this chapter is to provide a summary of key issues associated sive targets of less than 130/80 mm Hg for patients with dia-
with the management of patients with hypertension. We will dis- betes or chronic kidney disease.3 Treatment with drug therapy
cuss the basic approach to treating patients with hypertension should be done in combination with recommended lifestyle
and provide a functional summary of the currently prevailing modications to manage hypertension and minimize risk.
themes of national guidelines, including their grounding in rele-
vant landmark trials. Finally, we will summarize salient pharma-
cotherapeutic issues essential for clinicians to consider when EPIDEMIOLOGY
managing patients with hypertension.
Various algorithms recommending nonpharmacologic and Hypertension is widely prevalent and accounts for signi-
pharmacologic management for typical and atypical patients are cant morbidity and mortality, as well as billions of dollars in
proposed, with the underlying theme that achievement of blood direct and indirect costs. Worldwide prevalence of hyperten-
pressure targets mitigate end-organ damage, leading to substan- sion is estimated to include 1 billion individuals. There are an
tial reductions in stroke, myocardial infarction, and heart failure. estimated 7 million deaths per year that may be related to the
Although references to other algorithms will be mentioned, this diagnosis of hypertension.4 The prevalence of hypertension in
chapter will focus primarily on the Seventh Report of the Joint the United States is estimated to include 65 million individu-
National Committee on Prevention, Detection, Evaluation and als and accounts for an estimated 59.7 billion dollars annually
Treatment of High Blood Pressure, more commonly referred to as in direct and indirect costs.1
the JNC 7 report.2 The prevalence of hypertension differs based on age, sex, and
The JNC 7 report describes four stages of blood pressure clas- ethnicity. As individuals become older, their risk of high blood
sication and provides guidance on nonpharmacologic and pressure increases. Individuals 55 years of age who do not have
pharmacologic approaches to managing patients with hyperten- hypertension are estimated to have a lifetime risk of 90% of even-
sion. The four stages of blood pressure classication include tually developing hypertension. The National Health and
normal, prehypertension, stage 1 hypertension, and stage 2 Nutrition Examination Survey from 1999 to 2000 indicated that
hypertension (Table 21). These stages are dened as such to hypertension is slightly more prevalent in men (30.1%) than
connote a level of risk and thus the need for varying intensities women (27.1%). However, the prevalence increased by 5.6% in
of intervention with drug therapy (Fig. 21). With the exception women and has remained unchanged in men from 1988 to 2000.5
of individuals with compelling indications, recommendations Hypertension prevalence is highest in African-Americans when
for drug therapy typically begin with one or two (in the case of compared to non-Hispanic whites and Mexican-Americans.1
stage 2) antihypertensive drugs as an initial step. Specic drug Hypertension is strongly associated with type 2 diabetes.6 The
selection is guided by the presence of compelling indications added comorbidity of hypertension in diabetes leads to a higher
specic comorbid conditions. These compelling indications, such risk of cardiovascular disease (CVD), stroke, renal disease, and
as heart failure, diabetes, and chronic kidney disease (CKD), diabetic retinopathy leading to greater health care costs.7
TABLE 21. Classication of Blood Pressure (BP) in Children, Adolescents, and Adults Dened as 18 Years
Old or Greater2,70
Children/Adolescents
BP Classication Adult SBP (mm Hg) Adult DBP (mm Hg) SBP or DBP Percentilea
Normal Less than 120 and less than 80 Less than 90th
Prehypertension 120139 or 8089 9095th or 120/80 mm Hg
Stage 1 hypertension 140159 or 9099 9599th + 5 mm Hgb
Stage 2 hypertension Greater than or equal Greater than or equal Greater than 99th + 5 mm Hgc
to 160 to 100
a
Tables contain the 50th, 90th, and 99th percentiles of systolic blood pressure (SBP) and diastolic blood pressure (DBP)
standards based on percentile height by age and sex, which is used to compare the childs measured blood pressure on
three separate occasions. The difference in blood pressure of the 95th and 99th percentiles are 710 mm Hg which requires
an adjustment of 5 mm Hg to accurately categorize stage 1 or 2 hypertension. If the systolic and diastolic percentile cate-
gories are different, then classify hypertension by the higher blood pressure value.
b
Children and adolescents stage 1 hypertension is classied by blood pressure levels that range from the 95th percentile
to 5 mm Hg above the 99th percentile.
c
Children and adolescents stage 2 hypertension is classied by blood pressure levels that are greater than 5 mm Hg above
the 99th percentile.
CHAPTER 2 / HYPERTENSION 11
FIGURE 21. Algorithm for treatment

Lifestyle modifications of hypertension when patients are
not at their goal blood pressure.
Compelling indications refer to
specic indications where the
Not at goal BP
selection of a particular antihyperten-
sive drug class for a dened high-risk
population is highly recommended.
Initial These recommendations are usually
drug therapy based on results from landmark
choices randomized placebo-controlled
outcome trials or consensus
statements from clinical guidelines
and are usually based on ndings
documenting superior outcomes in
terms of morbidity and mortality.
ACE, angiotensin-converting enzyme;
No ARB, angiotensin receptor blocker;
Compelling
compelling
indications BP, blood pressure; CCB, calcium
indications
channel blocker agent; DBP, diastolic
blood pressure; SBP, systolic blood
pressure. (Adapted from JNC 7;
Modied from Saseen JJ, Carter BL.
Hypertension. In: DiPiro JT, Talbert
Stage 1 Stage 2 RL, Yee GC, et al, (eds.)
Hypertension Hypertension Pharmacotherapy: A Pathophysiologic
(SBP 140159 or DBP 9099 (SBP greater than or equal to Approach. 6th ed. New York:
mm HG) 160 or DBP greater than or McGraw-Hill; 2005: 194, with
equal to 100 mm HG) permission.)
Specific drug(s) for the

Thiazide-type diuretics for Two-drug combination for
compelling indications. Other
most. May consider ACE most. Usually a thiazide-type
antihypertensive drugs
inhibitor, ARB, diuretic with an ACE
(diuretic, ACE inhibitor,
-blocker, CCB, or inhibitor, or ARB, or
ARB, -blocker, CCB) used
combination. -blocker, or CCB.
as needed.
Not at goal BP
Optimize dose or add antihypertensive to reach

blood pressure goal
Goal: less than 140/90 mmHg or less than 130/80 mmHg for patients with diabetes or chronic kidney disease.
ETIOLOGY Pheochromocytoma
Primary aldosteronism and other mineralocorticoid excess states
In the majority of patients, up to 95%, the cause of hyper- Renovascular hypertension
tension is unknown and it is referred to as essential, or more appro- Sleep apnea
priately, as primary hypertension.8 However, in some patients there Thyroid or parathyroid disease
is an identiable cause of which the most common are:2
Hypertension caused by any of these conditions is referred to as
Chronic kidney disease secondary hypertension. Identication of a secondary cause of
Coarctation of the aorta hypertension is often not initially pursued unless suggested by
Cushings syndrome and other glucocorticoid excess states routine clinical and laboratory evaluation of the patient, or
Drug induced/related (Table 22) failure to achieve blood pressure control.
TABLE 22. Causes of Resistant Hypertension2 PATHOPHYSIOLOGY

Improper blood pressure measurement
Volume overload
The pathophysiology of primary hypertension is heteroge-
Excess sodium intake neous, but ultimately exerts its effects through the two primary
Volume retention from kidney disease determinants of blood pressure: cardiac output and peripheral
Inadequate diuretic therapy resistance. The processes inuencing these two determinants
Ineffective cardiac pump function are numerous and complex (Fig. 22).9 The underlying cause
Diastolic dysfunction of primary hypertension is unknown and most likely multi-
Drug-induced
Non-steroidal anti-inammatory drugs; cyclooxygenase factorial. Although several hypotheses exist, we will limit our
2 inhibitors discussion to a few while recognizing that only a minority of
Cocaine, amphetamines, and other illicit drugs patients with hypertension may have an identiable cause. For
Sympathomimetics (decongestants, anorectics, and stimulants) a detailed discussion of the pathophysiology behind these sec-
Oral contraceptive hormones ondary causes, the reader is referred to additional texts.10,11
Adrenal steroid hormones
Cyclosporine and tacrolimus Discussion of the management of patients with select second-
Erythropoietin ary causes are found elsewhere in this chapter.
Licorice (including some chewing tobacco)
Select over-the-counter dietary supplements and non-traditional Genetics
medicines (e.g., ephedra, ma huang, and bitter orange)
Therapeutic circumstances Multiple genetic polymorphisms have been associated with
Failure to receive or take antihypertensive medications hypertension. It is estimated that up to 30% to 50% of vari-
Inadequate doses (sub-therapeutic) ability in blood pressure may have a genetic basis.12 The major-
Improper antihypertensive selection or combination ity of these polymorphisms appear to be involved directly or
Drug-drug or drug-food interactions
Associated conditions
indirectly in renal sodium reabsorption, which may represent
Obesity future therapeutic drug targets.13 In addition, the identication
Excess alcohol intake of genetic factors contributing to variability in response to
drug therapy should allow for specic tailoring of individual
patient therapy, thereby optimizing the effectiveness of antihy-
pertensive therapy while minimizing costs and adverse events.
In addition to primary and secondary hypertension, the
Cardiac Output
clinician may encounter what is referred to as resistant hyper-
tension. Patients failing to achieve goal blood pressure despite Cardiac output is an important determinant of blood pres-
maximum doses of three antihypertensives including a diuretic sure. Factors which elevate cardiac output may, in theory, con-
should be carefully screened for resistant hypertension. Several tribute to the development of primary hypertension. Increases
causes of resistant hypertension are listed in Table 22 and in cardiac output and subsequent blood pressure may arise
should be carefully considered in such patients. from factors that increase preload (uid volume) or contractility
Excess Reduced Stress Genetic Obesity Endothelium FIGURE 22. Factors which are
sodium nephron alteration derived factors involved in the pathogenesis of
intake number hypertension are summarized. Some
of the factors involved in the control
of blood pressure affect the basic
Renal Decreased Sympathetic Renin- Cell Hyper- equation: blood pressure = cardiac
sodium filtration nervous over- angiotensin membrane insulinemia output peripheral resistance. The
retention surface activity excess alteration gure depicts the complex nature of
various factors which may play a
role in the development of hyperten-
Fluid Venous sion. Each of these factors may indi-
volume constriction vidually or collectively modulate
blood pressure through their actions
upon various physiologic systems at
the cellular, organ, and organ system
Preload Contractibility Functional Structural level. CO, cardiac output; PR,
constriction hypertrophy
peripheral resistance. (From Kaplan
NM. Primary hypertension:
Pathogenesis. In: Kaplans Clinical
Blood pressure = Cardiac output X Peripheral resistance Hypertension. 8th ed. Philadelphia:
Hypertension = Increased CO and/or increased PR Lippincott Williams & Wilkins; 2002:
Autoregulation 63, with permission.)
of the heart. Nonetheless, even if increased cardiac output step in the eventual formation of angiotensin II, which is pri-
may be involved in the development of primary hypertension, marily responsible for the pressor effects mediated by the
these increases do not appear to persist over time. As a conse- RAAS (Fig. 23). Evidence indicates that renins pressor
quence, elevated cardiac output is not considered a hemody- effects occur at the cellular level (autocrine), the local environ-
namic hallmark of established primary hypertension. ment (paracrine), and throughout the systemic circulation
(endocrine).16 The role of the RAAS in primary hypertension is
Sodium Regulation supported by the presence of high levels of renin, suggesting
The contribution of sodium to the development of primary that the system is inappropriately activated. Proposed mecha-
hypertension is related to excess sodium intake and/or abnormal nisms behind this inappropriate activation include increased
sodium excretion by the kidneys. It is generally accepted that sympathetic drive, defective regulation of the RAAS (non-
dietary salt is associated with increases in blood pressure that can modulation), and the existence of a sub-population of ischemic
be lowered with reduction of sodium intake.2,14 There appears to nephrons which release excess renin.9 However, there are also
be a threshold effect of sodium intake in the range of 50 to patients with primary hypertension and low levels of renin.
100 mmol/day [1.2 to 2.4 grams of sodium per day is equivalent This observation suggests that alternate mechanisms for hyper-
to 3 to 6 grams of sodium chloride per day (50 to 100 mmol/day)] tension unrelated to renin levels or activity may be in play.17
and its impact on blood pressure. The mean sodium intake per
day is 175 mmol (4.1 grams) for men and 120 mmol (2.7 grams) Sympathetic Overactivity
for women in the United States, with the majority derived from Overactivation of the sympathetic nervous system (SNS) may
processed foods.2 However, not all individuals appear to be sus- also play a role in the development and maintenance of pri-
ceptible to a high sodium intake, with about 50% of hypertensive mary hypertension for some individuals. Among other effects,
patients being classied as sodium-sensitive. The proposed direct activation of the SNS may lead to enhanced sodium
mechanisms behind high sodium intake and blood pressure retention, insulin resistance, and baroreceptor dysfunction.9
include increases in intracellular calcium, insulin resistance, par- Regardless of which mechanism(s) underlie the role the SNS
adoxical rise in atrial natriuretic peptide, and other pressor may play in the development of primary hypertension, the
effects.9 Proposed mechanisms behind salt sensitivity include a SNS remains a target of many antihypertensive agents.
defect in renal sodium excretion and an increased rate of proxi-
mal sodium reabsorption, among others.9 Angiotensinogen
In addition to excess sodium intake, abnormal renal sodium Bradykinin
retention may be the primary event in the development of Renin Substance P
Enkephalins
hypertension, and it includes abnormalities in the pressure- Chymase
Angiotensin I
natriuresis mechanism. In hypertensive individuals, this theory CAGE Non-ACE ACE
proposes a shift in the control mechanism preventing the nor- Cathepsin G
Angiotensin II Inactive fragments
malization of blood pressure. The mechanisms behind the reset-
ting of the pressure-natriuresis curve may include afferent arte-
Angiotensin II
riolar vasoconstriction, decreased glomerular ultraltration, or receptors
an increase in tubular sodium reabsorption.4 Other theories Aldosterone
(Sub-type AT 1)
Sympathetic
supporting abnormal renal sodium retention suggest a con- secretion (sodium activation
Vasoconstriction
genital reduction in the number of nephrons, enhanced renin and water retention)
secretion from nephrons that are ischemic, or an acquired com-
Blood pressure
pensatory mechanism for renal sodium retention.9
Given that the majority of patients with hypertension have CAGE: Chymostatin-sensitive II-generating enzyme
no recognizable etiology for their elevated blood pressure, it is FIGURE 23. Diagram of the renin-angiotensin-aldosterone
important to understand systems involved in blood pressure system. The renin-angiotensin-aldosterone system is a key
regulation as a means to employ drug therapy to affect these system involved in the modulation of blood pressure. The dia-
systems. One such system which is central to the understanding gram depicts the pathways involved in the action of various
of hypertension and drug therapies is the renin-angiotensin- antihypertensives including ACE inhibitors, ARBs, diuretics,
aldosterone system (RAAS). and aldosterone antagonists. By inhibiting the action of
angiotensin-converting enzyme, ACE inhibitors reduce both
Renin-Angiotensin-Aldosterone System the formation of the vasoconstrictor angiotensin II, and the
degradation of vasodilating substances including bradykinin.
Since the discovery of renin over 100 years ago, the RAAS has ARBs primarily act through inhibition of the action of
been extensively studied as a prime target or site of action for angiotensin II on the angiotensin-1 receptors which modulate
many effective antihypertensives.15 Renin is produced and vasoconstriction. Aldosterone antagonists directly inhibit the
stored in the juxtaglomerular cells of the kidney, and its release actions of aldosterone while diuretics affect sodium and water
retention at a renal level. ACE, angiotensin-converting enzyme;
is stimulated by impaired renal perfusion, salt depletion, and 1-
ARB, angiotensin receptor blockers; AT1, angiotensin-1.
adrenergic stimulation. The release of renin is the rate-limiting
Peripheral Resistance well-recognized as a global risk factor for CVD. Given the
rapid increase in the prevalence of obesity worldwide and its
Elevated peripheral arterial resistance is a hallmark of primary
association with insulin resistance, diabetes, and dyslipidemia,
hypertension. The increase in peripheral resistance typically
weight loss should be a prime target of interventions aimed at
observed may be due to a reduction in the arterial lumen size
reducing overall cardiovascular risk.
as a result of vascular remodeling. This remodeling, or change
Many other processes are proposed to contribute to the
in vascular tone, may be modulated by various endothelium-
development of hypertension, including physical inactivity,
derived vasoactive substances, growth factors, and cytokines.
insulin resistance, potassium and magnesium depletion,
This increase in arterial stiffness or reduced compliance results
chronic moderate alcohol consumption, and transient effects
in the observed increase in systolic blood pressure.9
of cigarette smoking and caffeine intake.9 Ultimately, the
management of global cardiovascular risk suggests addressing
Other Contributing Processes and Factors each one of these factors where relevant in all patients while
Obesity appears to promote the development of primary pursuing target blood pressures through nonpharmacologic
hypertension via activation of the SNS and the RAAS and is and pharmacologic means.
CLINICAL PRESENTATION AND CO-EXISTING RISK FACTORS
Presentation of Primary (Essential) Presentation of Hypertension and Co-existing

Hypertension Risk Factors in a Diabetic Patient
General (Not necessarily indicative of hypertension, but
General may be seen in hypertensive patients)
Age: prevalence of hypertension is likely to be highest with Hypertension is a common comorbidity in diabetics.
middle-age or older patients. Insulin resistance (metabolic syndrome)
Sex: men have a higher prevalence of hypertension than Dyslipidemia
women until age 55. Microalbuminuria
Family history
Symptoms The primary hypertension patient may be asympto-
Central obesity
matic or may have major cardiovascular disease risk factors.
Physical inactivity
Signs Adult patients with an average of two or more Tobacco use
previous blood pressure readings (systolic, SBP;
diastolic, DBP) indicating either: Symptoms Many patients who are hypertensive also have
diabetes. The diabetic patient may be asymptomatic or may
SPB (mm Hg) DBP (mm Hg) have ischemic heart disease.
Normal Less than 120 or less than 80
Pre-hypertension 120139 or 8089 Signs Patient has previous blood pressure measurements indi-
Stage 1 hypertension 140159 or 9099 cating SBP greater than 130 or DBP greater than 80 mm Hg
Stage 2 hypertension Greater than or or greater than in clinic, or is currently taking antihypertensive medication(s).
equal to 160 or equal to 100 Laboratory Tests The following tests may indicate additional
Laboratory Tests (Not necessarily indicative of hypertension, cardiovascular risk factors or poor control of diabetes.
but may be seen in hypertensive patients) Elevated fasting lipid panel
Fasting lipid panel Elevated fasting blood glucose
Low-density lipoprotein greater than 160 mg/dL Hemoglobin A1c greater than 7.0%
(4.14 mmol/L) Abnormal test may indicate hypertension related to kidney
Total cholesterol greater than 240 mg/dL (6.22 mmol/L) damage
High-density lipoprotein less than 40 mg/dL (1.04 mmol/L) Elevated blood urea nitrogen
Triglycerides greater than 200 mg/dL (2.26 mmol/L) Elevated serum creatinine
Fasting blood serum or plasma glucose Microalbuminuria/proteinuria
Impaired fasting glucose of 100125 mg/dL Target Organ Damage
(5.556.94 mmol/L) Eyes (retinopathy)
Diagnose diabetes with glucose greater than or equal to Heart (angina, coronary artery disease, myocardial infarc-
126 mg/dL (7 mmol/L) tion, or heart failure)
Abnormal test may indicate hypertension-related damage. Kidney (chronic kidney disease)
Serum creatinine elevated (greater than 1.2 mg/dL Brain (transient ischemic attack, stroke)
[106 mol/L])
Microalbuminuria (protein in urine which is excreted at a
rate of 30300 mg per 24 hours or 20200 mcg/minute)
Regardless of the initiating process or processes leading to vary by more than 5 mm Hg between the two readings, then
the development of hypertension, the ultimate goal is to reduce one or two additional blood pressure measurements are
the risk of cardiovascular events and minimize target organ collected and the multiple readings averaged. Details and
damage. This clearly requires the early identication of risk further recommendations for accurate measurement of
factors and treatment of patients with hypertension. blood pressure in special populations can be reviewed in the
Appropriate technique in measuring blood pressure is a ACC/AHA Blood Pressure Measurement in Humans state-
vital component to the diagnosis and continued management of ment for health care professionals.18
hypertension in the outpatient setting. Accurate measurement of Finally, the measurement of clinic or ofce blood pressures
a patients blood pressure identies and controls for factors is poorly correlated with assessments of blood pressure in
that may inuence the variability in the measure. Failure to other settings. Because of this, the use of a 24-hour ambula-
consider how each of these factors may inuence blood pres- tory blood pressure monitoring device has become more
sure measurement results in signicant variation in measure- common. The device can be useful in identifying patients with
ments, leading to misclassication or inaccurate assessments white coat hypertension or with elevations of blood pressure
of risk. Factors including body position, cuff size, device selec- during the nighttime (non-dippers). Its use has also aided in
tion, auscultatory technique, and dietary intake prior to the the management of refractory hypertensives with minor target
clinic visit may contribute to such inaccuracies. Clinicians organ damage, those with suspected autonomic neuropathy,
should instruct patients to avoid exercise, alcohol, caffeine, or and patients with large differences between home and clinic
nicotine consumption 30 minutes before blood pressure blood pressure measurements. The prognostic signicance of
measurement. Patients should be sitting comfortably with an average level with ambulatory blood pressure monitoring
their back supported and arm free of constrictive clothing may be that this measure is better at predicting cardiovascular
with legs uncrossed for a minimum of 5 minutes before the risk than clinic blood pressure.
rst reading. In addition to these important positions,
patients should have their feet uncrossed and at on the oor.
The selection of blood pressure cuff size based on a patients
TREATMENT
arm circumference is crucial for the accurate measurement of
blood pressure. Systolic and diastolic blood pressure tend to
Desired Outcomes
increase when the cuff size is too small relative to the patients Hypertension management by nonpharmacologic and phar-
arm circumference. This circumstance is important due to the macologic therapies has proven useful in reducing the risk of
increasing prevalence of obesity in developed nations. Currently, heart attack, heart failure, stroke, and kidney disease morbidity
the guidelines of the American College of Cardiology/American and mortality. For every 20 mm Hg systolic or 10 mm Hg dias-
Heart Association (ACC/AHA) Blood Pressure Measurement tolic increase in blood pressure, there is a doubling of mortality
in Humans recommends cuff sizes for small, standard, and for both ischemic heart disease and stroke.19 The goal of blood
large adults with an optimal 2:1 ratio of cuff length/width pressure management is to reduce the risk of cardiovascular
based on arm circumference.18 disease and target organ damage.
Mercury sphygmomanometers are recommended for routine
ofce measurements, but concerns of patient exposure and envi-
ronmental contamination of mercury has fostered the develop-
General Approach to Treatment
ment of other devices to measure blood pressure. However, there As is the case with dyslipidemia and other cardiovascu-
is no general concensus among health care providers as to an lar conditions, drug selection for the management of patients
acceptable replacement for mercury sphygmomanometers. with hypertension should be considered as adjunctive to non-
To reduce deviations in blood pressure measurement in pharmacologic approaches for blood pressure lowering.
the clinic, the patient and clinician should not talk during Previous clinical research has established the relative value of
blood pressure readings. The measurement arm is sup- using individual antihypertensive drugs versus placebo to
ported and positioned at heart level with the blood pressure achieve reduction in morbidity and mortality by lowering
cuff encircling at least 80% of arm circumference. If a mer- blood pressure. However, as newer antihypertensive agents are
cury or aneroid device is used, then the palpatory method developed by pharmaceutical companies, it is difficult to
must be used rst to estimate the systolic blood pressure.18 ethically justify the comparison of newer agents to placebo.
If an automated device is used, this is not necessary. After Consequently, there have been attempts to conduct large
the patients cuff is inated above the systolic pressure, the outcome-based, multi-center trials comparing one specic agent
mercury column should drop at a rate of 2 to 3 mm per sec- versus another antihypertensive pharmacologic agent. These
ond. A stethoscope placed over the brachial artery in the head-to-head comparisons and meta-analyses of multidrug
antecubital fossa identifies the first and last audible regimen trials have provided convincing evidence supporting
Korotkoff sounds, which should be taken as systolic and the position that the overall importance of which drug to ini-
diastolic pressure, respectively. A minimum of two readings tiate therapy with is less important than the achievement of
at least 1 minute apart are then averaged. If measurements targeted blood pressure goals. Inherent in this position is the
realization that nonpharmacologic approaches alone are Physical activity

rarely successful in attaining target blood pressures, and Moderation of alcohol consumption
multidrug therapy (sometimes as many as three or more
agents) is necessary for most patients with hypertension.20 Implementation of these lifestyle modications success-
Furthermore, JNC 7 continues to focus on targeting blood fully lowers blood pressure (Table 23), often with results simi-
pressure goals in contrast to the European Society of lar to those of therapy with a single antihypertensive agent.22
Cardiology, which utilizes a broader approach such as the Combinations of two or more lifestyle modications can
Systematic Coronary Risk Evaluation (SCORE) system.21 In have even greater effects with blood pressure lowering.
spite of global variance in approaches, this chapter will Weight reduction in overweight individuals would ideally
focus on the importance of advocating nonpharmacologic lead to attainment and maintenance of a normal body weight
approaches and provide specic guidance on these steps, and should be encouraged. Blood pressure lowering in over-
keeping in mind the JNC 7 theme that achievement of weight patients may be seen by a weight loss of as few as
blood pressure goals should remain the focus. 10 pounds (4.5 kilograms). The Dietary Approaches to Stop
Hypertension (DASH) trial demonstrated that a diet high in
fruits, vegetables, and low-fat dairy products, along with a
Nonpharmacologic Treatment: Lifestyle reduced intake of total and saturated fat, significantly
Modications reduced blood pressure in as little as 8 weeks.22 Sodium
Therapeutic lifestyle modifications consisting of non- restriction in moderate amounts lowers blood pressure, is
pharmacologic approaches to blood pressure reduction should generally well-accepted, and is free of adverse effects.
be an active part of all treatment plans for patients with hyper- Restriction of sodium intake to 2.4 grams (100 mmol) of
tension. The most widely studied interventions demonstrating elemental sodium [6 grams of sodium chloride (100 mmol)
effectiveness include: or 1 teaspoon of table salt] should be easily achievable in
most patients simply by avoidance of highly salted processed
Weight reduction in overweight or obese individuals foods.23 Simple dietary advice and instructions on reading
Adoption of a diet rich in potassium and calcium packaging labels should be introduced to the patient initially
Dietary sodium restriction and assessed and reinforced at subsequent ofce visits. As is
TABLE 23. Lifestyle Modications to Manage Hypertension2,a,b
Approximate Systolic BP
Modication Recommendation Reduction, Range
Weight reduction Maintain normal body weight (body mass 520 mm Hg/10 kg
index 18.524.9 kg/m2)
Adopt DASH Consume a diet rich in fruits, vegetables, 814 mm Hg
eating plan and low-fat dairy products with
a reduced content of saturated and
total fat
Dietary sodium Reduce dietary sodium intake to no 28 mm Hg
restriction more than 100 mmol per day (2.4 g
sodium or 6 g sodium chloride)
Physical activity Engage in regular aerobic physical 49 mm Hg
activity such as brisk walking (at
least 30 minutes per day, most days
of the week)
Moderation of Limit consumption to no more than 24 mm Hg
alcohol consumption 2 drinks [e.g., 24 oz (710 mL)
beer, 10 oz (296 mL) wine, or
3 oz (89 mL) 80-proof whiskey]
per day in most men and to no more
than 1 drink per day in women and
lighter weight persons
BP, blood pressure; DASH, Dietary Approaches to Stop Hypertension.
a
For overall cardiovascular risk reduction, stop smoking.
b
The effects of implementing these modications are dose- and time-dependent and could be greater for
some individuals.
the case with weight loss, changes in physical activity do not Pharmacologic Treatment
need to be profound in order to have a signicant effect on
blood pressure. It is generally accepted that 30 minutes of
An approach to selection of drugs for the treatment of
patients with hypertension should be evidence-based decision
moderately intense aerobic activity (e.g., brisk walking) most
making with considerations regarding the individuals co-existing
days of the week will lower blood pressure.24 While most
disease states, co-prescribed medications, and practical patient-
patients can safely engage in moderately intense aerobic activ-
specic issues including cost. The current JNC 7 report recom-
ity, individuals with known cardiovascular disease, multiple
mends drug therapy that is largely grounded in the best available
risk factors with symptoms, or selected diabetic patients
evidence for superiority in outcomesspecically morbidity and
should undergo medical examination, possibly including exer-
mortality.2 The approach is often tempered with practical consid-
cise testing, prior to participation.25,26 The effects of alcohol on
erations relating to competing options for specic comorbidities
blood pressure are variable. Initially, acute ingestion leads to a
and practical issues regarding a patients experience or tolerance
fall in blood pressure followed by a rise several hours later,27
for side effects, and in some cases, the cost of medications.
and binge drinking is associated with a higher risk of stroke.
Although landmark trials, such as the Antihypertensive and
Furthermore, abstinence from alcohol in heavy drinkers leads
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALL-
to a reduction in blood pressure.28 Alcohol also attenuates the
HAT), have provided some objective basis for comparisons
effects of antihypertensive therapy, which is mostly reversible
between initiating antihypertensive drug therapy with one class of
within 1 to 2 weeks with moderation of intake.
antihypertensives versus another, there is room for criticism of
In addition to their benecial effects on lowering blood
these studies.20,31,32 Consequently, practical interpretations of their
pressure, lifestyle modications also have a favorable effect on
conclusions must always leave room for individualization based
other risk factors such as dyslipidemia and insulin resistance,
on clinical judgment. Overall, JNC 7 provides a reasonable basis
which are commonly encountered in the hypertensive popula-
for guiding the selection of drug classes for individuals based on
tion, and lifestyle modications should be encouraged for this
their stage of hypertension, comorbidities, and special circum-
reason as well. Smoking cessation should also be encouraged
stances. The following section will summarize key features of spe-
for overall cardiovascular health despite its lack of chronic
cic drug classes and summarize the JNC 7based recommenda-
effects on blood pressure.29,30 Although lifestyle modications
tions for patients with hypertension. Finally, an overview of the
have never been documented to reduce cardiovascular mor-
specic oral antihypertensive drug classes in common use is sum-
bidity and mortality in patients with hypertension, they do
marized in Table 24.
effectively lower blood pressure to some extent in most hyper-
tensive patients. This may obviate the need for drug therapy in
those with mild elevations in blood pressure or minimize the Diuretics
doses or number of antihypertensive agents required in those Many authorities recognize the value of diuretics as rst-line
with greater elevations in blood pressure. agents for the majority of patients with hypertension.
Extensive experience with using diuretics, as well as their
practical attributes (acquisition cost and availability as com-
bination agents), make thiazide-type diuretics a seemingly
Patient Encounter 1 attractive selection as rst-line agents. The endorsement by
JNC 7 as an initial drug therapy selection for stage 1 and stage
2 hypertensive patients without compelling indications is
RS, a 67-year-old Hispanic man, comes to your clinic with based on a litany of placebo-controlled studies, and in no
results from a health fair he attended last week. He is small way, on the results of active controlled outcome studies
concerned because his blood pressure at that time was such as ALLHAT.20 This landmark double-blind study
150/70 mm Hg, and when repeated was 154/68 mm Hg. attempted to test the hypothesis that newer antihypertensive
Upon examination, seated blood pressure is 134/82 mm Hg agents would outperform thiazide-type diuretics when
in the left arm and 136/80 mm Hg in the right arm. Repeat selected as initial drug therapy. After 4.9 years of follow-up in
measurements 5 minutes later are 142/84 and 138/76 mm Hg over 42,000 patients, the primary endpoint of fatal coronary
in the left and right arms, respectively.
heart disease and non-fatal myocardial infarction was indis-
tinguishable between chlorthalidone versus either amlodipine
Based on the above information, should RS be classied
as having hypertension? or lisinopril. A fourth arm examining doxazosin was terminated
What factors may have contributed to the discrepancy early based on a higher risk of heart failure for doxazosin
between the health fair and ofce-based blood pressure compared with chlorthalidone.33 In spite of these ndings for
readings? the primary endpoint, differences in outcomes for select sec-
What additional information do you need to know before ondary endpoints demonstrated superiority of chlorthali-
creating a treatment plan for RS? done over either of the two remaining comparison groups.
These observations, along with perceived cost-effectiveness
18
TABLE 24. Oral Antihypertensive Drugs by Pharmacologic Class2
Drug Name and

Class Oral Dose (mg/day) Compelling Indications2 Clinical Trials Select Adverse Events Comments
Diuretics
Chlorthalidone (Hygroton) Heart failure stage A ALLHAT20 Hypokalemia; Negative effect Monitor electrolytes (e.g.,
6.2525 (chlorthalidone) on glucose and lipids decreased potassium)
High coronary disease ALLHAT20 Chlorthalidone is about
risk (chlorthalidone) twice as potent as
Diabetes (chlorthalidone) ALLHAT20 hydrochlorothiazide
Indapamide (Lozol) Stroke (perindopril + indapamide) PROGRESS53

2.55
Hydrochlorothiazide (Microzide)
12.550
Aldosterone Antagonists
Spironolactone Heart failure (spironolactone) RALES73 Hyperkalemia; Gynecomastia Monitor electrolytes (e.g.,
(Aldactone) 2550 (spironolactone) increased potassium)
Eplerenone (Inspra) Heart failure EPHESUS42 Eplerenone contraindicated
50100 post-MI (eplerenone) in patients with
estimated creatinine
clearance less than
50 mL/minute or serum
creatinine greater than
1.8 mg/dL (159.12
mmol/L) in women or
greater than 2 mg/dL
(176.8 mmol/L) in men
b-Blockers
Metoprolol extended- Heart failure (metoprolol XL, MERIT-HF74 Bradycardia; Heart block; Caution with heart rate
release carvedilol) Fatigue less than 60 bpm
(Toprol XL) 50200 Selectivity of 1 agents is
Carvedilol (Coreg) Heart failure post-MI COPERNICUS75 diminished at higher
12.550 (carvedilol) CAPRICORN76 doses
Propranolol (Inderal) Post-MI (propranolol, BHAT77 Abrupt discontinuation
160480 1-antagonists) may cause rebound
Propranolol long-acting High coronary disease risk hypertension
(Inderal LA, InnoPran
XL) 80320
Metoprolol (Lopressor)
50200
Atenolol (Tenormin) Diabetes (atenolol) UKPDS 3378
25100
Calcium Channel
Blockers
Verapamil sustained- High coronary disease INVEST79 Peripheral edema Caution with heart rate
release (Calan SR, risk (verapamil) (amlodipine) less than 60 bpm
Isoptin SR, Verelan) Diabetes (verapamil, diltiazem)
180480 Extended-release
Amlodipine (Norvasc) formulations are
510 preferred for
Nifedipine long-acting once- or twice-daily
(Adalat CC, Procardia XL) medication
3090 administration
Diltiazem sustained-
release (Cardizem
SR) 180360
Angiotensin-Converting
Enzyme Inhibitors
Benazepril (Lotensin) 1040 Heart failure (enalapril) SOLVD80 Hyperkalemia; Cough Monitor electrolytes (e.g.,
Captopril (Capotan) 12.5150 High coronary disease risk HOPE65 increased potassium)
Enalapril (Vasotec) 540 (ramipril, trandolapril) Monitor rental function
Fosinipril (Monopril) 1040 Heart failure post-MI AIRE81 with serum creatinine
Lisinopril (Priniril, Zestril, (ramipril, trandolapril) TRACE82 Contraindicated in
Various) 1040 Post-MI (captopril) SAVE83 pregnancy, do not use
Moexipril (Univasc) 7.530 Diabetes (captopril) UKPDS 3378
Perindopril (Aceon) 416 Chronic kidney disease Captopril Trial50
Quinapril (Accupril) 1080 (captopril, ramipril)
Ramipril (Altace) 2.510 High coronary disease risk EUROPA64
Trandolapril (Mavik) 14 (perindopril)
Stroke (perindopril + PROGRESS53
indapamide)
Angiotensin
Receptor Blockers
Valsartan (Diovan) Heart failure (valsartan, ValHEFT84 Hyperkalemia Monitor electrolytes (e.g.,
80320 candesartan) CHARM54 increased potassium)
Candesartan (Atacand) Monitor renal function
432 with serum creatinine
Losartan (Cozarr) High coronary disease LIFE58 Contraindicated in
25100 risk (losartan) pregnancy, do not use
Diabetes May use when patient
Irbesartan (Avapro) Chronic kidney disease RENAAL58 develops cough
150300 (irbesartan, losartan) IDNT57 with ACE inhibitor
IRMA-II60
a1-Blockers
Doxazosin (Cardura) No recommendations at Syncope May be used in elderly
Terazosin (Hytrin) this time Dizziness males with prostatism
Prazosin (Minipress) Palpitations
19
20
TABLE 24. Oral Antihypertensive Drugs by Pharmacologic Class2 (Continued )
Drug Name and

Class Oral Dose (mg/day) Compelling Indications2 Clinical Trials Select Adverse Events Comments
Central a2-Agonists
Methyldopa No recommendations Transient sedation initially First-line in pregnancy
Clonidine (Catapres) at this time (methyldopa)
Guanabenz
Guanfacine (Tenex)
Guanadrel
Direct Vasodilators
Isosorbide dinitrate Heart failure (isosorbide A-HeFT66 Edema (minoxidil)
20 mg and dinitrate + hydralazine in Tachycardia
hydralazine 37.5 African-Americans) Lupus-like syndrome
(BiDil) 12 tablets (hydralazine)
three times a day
Minoxidil (Loniten)
Hydralazine
Other Agents
Reserpine No recommendations Mental depression May be used in resistant
at this time hypertension when
combined with a
thiazide
Antihypertensive drug name and dose is associated with compelling indications which are based on benets from outcome studies or clinical guidelines. For example, the drug class aldos-
terone antagonists have eplerenone dosed at 2550 mg per day which is indicated for heart failure patients after an MI and supported by the EPHESUS trial.
A-HeFT, African-American Heart Failure trial; AIRE, Acute Infarction Ramipril Efcacy Study; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial;
BHAT, Beta-Blocker Heart Attack Trial; bpm, beats per minute; CAPRICORN, Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Trial; Captopril Trial, Collaborative Study
Captopril Trial (The Effect of Angiotensin-Converting Enzyme Inhibition on Diabetic Nephropathy); CHARM, Candesartan in Heart Failure Assessment of Reduction in Morbidity and
Mortality Trial; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival Trial; EPHESUS, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efcacy and Survival
Study; EUROPA, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Trial; HOPE, Heart Outcomes Prevention Evaluation Study; IDNT,
Irbesartan Diabetic Nephropathy Trial; INVEST, International Verapamil-Trandolapril Study; IRMA-II, Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria study; ISA, intrinsic
sympathomimetic activity; LIFE, Losartan Intervention For Endpoint reduction in hypertension study; MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure;
MI, myocardial infarction; PROGRESS, Perindopril Protection Against Recurrent Stroke Study; RALES, Randomized Aldactone Evaluation Study; RENAAL, Reduction of Endpoints in NIDDM
with the Angiotensin II Antagonist Losartan study; SAVE, Survival and Ventricular Enlargement trial; SOLVD, Studies of Left Ventricular Dysfunction; TRACE, Trandolapril Cardiac Evaluation;
UKPDS, UK Prospective Diabetes Study; VALUE, Valsartan Antihypertensive Long-term Use Evaluation; ValHEFT, Veterans Affairs Cooperative I study.
(which was not specically evaluated in this study), led the electrolyte-related effects (hypokalemic, hypomagnesemic,
authors and JNC 7 to endorse diuretics as keys to initial drug hyperuricemic, and hypercalcemic) seem to increase with higher
therapy for most patients with hypertension. Nonetheless, doses. This has led to national guidelines2 recommending doses
substantial criticism of this trial has undermined some of the not exceeding 6.25 to 25 mg/day for chlorthalidone versus 12.5
enthusiasm for diuretics in some clinicians minds as well as to 50 mg/day for hydrochlorothiazide. These metabolic effects
international guideline committees.34 Criticism of the differ- may clearly complicate the management of higher-risk patients
ential blood pressures achieved in the various treatment with common comorbidities such as dyslipidemia or diabetes,
groups, the articial construct guiding the use of add-on or even those likely to be sensitive to the potassium- or magne-
drugs to base therapy, and the overrepresentation of African- sium-wasting effects of diuretics (patients with dysrhythmias or
Americans exhibiting select endpoints have weakened the those taking digoxin). While rates of diabetes are higher follow-
interpretability of the authors conclusions. Furthermore, ing administration of thiazides, there is plenty of evidence that
other contemporary studies31,35 have also challenged the sta- this can be greatly minimized by keeping potassium in the high
tus of diuretics as ideal baseline choices for initial antihy- normal range (i.e., above 4.0 mEq/L [4 mmol/L]).39 Nonetheless,
pertensive drug therapy for all patients. Specically, the clinicians should rarely approach the upper limits of these dosage
Australian-New Zealand Blood Pressure-2 (ANBP2) Study35 ranges without careful assessment of their metabolic effects
seemingly demonstrated (in particular for the male cohort) or potential to induce electrolyte disturbances. In this way, opti-
a superior outcome for angiotensin-converting enzyme mization of blood pressure lowering potential may be achieved
(ACE) inhibitorbased therapy versus diuretic-based therapy while minimizing potential adverse outcomes.
in over 6,000 relatively older patients treated for over 4 years. Another key feature of the thiazide-type diuretics is their
Similarly, the Anglo-Scandinavian Cardiac Outcomes Trial- limited efcacy in patients whose estimated renal function is
Blood Pressure Lowering Arm (ASCOT-BPLA)31 study reduced, such as the elderly. For example, patients with esti-
demonstrated in over 19,000 patients treated for approximates of reduced renal function, such as those with a
mately 5 years more favorable outcomes for the dual therapy of glomerular ltration rate (GFR) below 30 mL/minute, should
a calcium channel blocker agent (CCBA)/ACE inhibitorbased be considered for more potent loop type diuretics such as
approach versus a -blocker/ diureticbased approach. Needless furosemide. Clinicians often fail to either reconsider the role
to say, all three of these major trials are subject to signicant of thiazide diuretics prescribed to individuals whose renal
criticism related to study design issues, including inequities function has been declining or fail to recognize the likely
of achievement in blood pressure targets between groups for prevalence of renal compromise in the elderly to begin with.
the ALLHAT and ASCOT-BPLA studies.36 Nonetheless, Renal function is often estimated by formulas that attempt
diuretics continue to receive support for use as baseline to predict GFR. As stated above, when predicted GFR is
initial therapy for most hypertensive patients who do not less than 30 mL/minute, the natural course of action would be
have compelling indications.37 to consider more potent diuretics. The loop diuretics, such as
Key features of diuretics that must be kept in mind, along with furosemide, bumetanide, torsemide, and ethacrynic acid, have
evidence from outcome-based studies, include the diversity a common site of action in the thick ascending limb of the
between the sub-types of diuretics and their corresponding loop of Henle.40 Responsible for reabsorption of over 65% of
diversity of pharmacologic actions. The four sub-types include the ltered sodium, their diuretic activity is clearly greater
thiazides, loop diuretics, potassium-sparing agents, and aldos- than that of the thiazides, potassium-sparing diuretics, and
terone antagonists. The latter will be discussed as a separate mineralocorticoid-acting agents. Practically speaking, furosemide
entity. Each sub-type has clinically based properties which distin- is the most common agent used as a functional alternative for
guish their roles in select patient populations. Thiazide diuretics patients whose renal compromise precludes effective diuresis
are by far the most commonly prescribed sub-type with the great- from thiazide-type agents. In situations in which a patient has
est number of outcome-based studies supporting their use. In the poor renal function, a loop diuretic should be given at least
United States, hydrochlorothiazide and chlorthalidone represent twice a day, with the exception of furosemide to augment blood
the most commonly prescribed thiazide-type diuretics and have pressure control with combination antihypertensive therapy.
been the subject of the majority of large outcome-based studies. Diuretic resistance may result from extended use of loop diuret-
Although subtle differences in pharmacokinetics between these ics. In these circumstances, the addition of a thiazide to a loop
agents exist, practical differences are limited to their relative diuretic may dramatically enhance overall diuresis. The most
diuretic potency. Chlorthalidone is considered approximately signicant adverse effects related to loop diuretic use concern
1.5 to 2 times more potent than hydrochlorothiazide for blood their potential for excessive diuresis leading to hyponatremia
pressure reduction.38 Since the relationship between antihyper- or hypotension. Additionally, hypokalemia, hypomagnesemia,
tensive efcacy and metabolic/electrolyte-related side effects of and hypocalcemia may develop over time and contribute to
thiazide diuretics is considered to be dose-related, attention to the potential for cardiac arrhythmias. Overall relevance of
this differential in potency may be important. Specically, drug-drug interactions and potential for aggravating select
select metabolic effects (hyperlipidemic and hyperglycemic) and conditions (hyperglycemia, dyslipidemias, and hyperuricemia)
should be routinely considered in the monitoring plan for (e.g., potassium supplements) or potassium excretory function
those taking loop diuretics for extended periods of time. (e.g., NSAIDs). The most commonly used potassium-sparing
Potassium-sparing diuretics that do not act through miner- diuretic is spironolactone; however, eplerenone has been
alocorticoid receptors include triamterene and amiloride. increasingly used in patients with heart failure following acute
These agents are often prescribed with potassium-wasting myocardial infarction.42 Although spironolactone is commonly
diuretics in an attempt to mitigate the loss of potassium. When associated with gynecomastia, eplerenone rarely causes this
administered as a single entity or as one component of a com- complication.43 The risk of hyperkalemia is also more com-
bination product, these agents result in moderate diuresis. monly reported with patients on spironolactone.44
Potassium-sparing diuretics act on the late distal tubule and
collecting duct and thereby have limited ability to affect sodium Beta-Blockers
reabsorption, which translates into modest diuresis. The most The JNC 7 identies -blockers as agents appropriate for rst-
important adverse effects associated with these agents are their line therapy for many individuals with hypertension. Based on
potential to contribute to hyperkalemia. This is especially JNC 7, the role of -blockers in patients with select comorbidi-
relevant in the context of those patients receiving other agents ties is extensive (Table 25). Patients with comorbidities such as
with potassium-sparing properties, such as ACE inhibitors, heart failure, recent myocardial infarction, and diabetes represent
angiotensin receptor blockers (ARBs), and potassium supple- opportunities for -blocker use on the basis of proven outcome-
ments, as well nonsteroidal anti-inammatory drugs (NSAIDs), based studies. The role of -blockers for patients with ischemic
in those with mild to moderate renal impairment. conditions including acute myocardial infarction is based on
their hemodynamic effects on heart rate, blood pressure, and
Aldosterone Antagonists cardiac output, as well as their possibly antiarrhythmic proper-
Aldosterone antagonism has recently been recognized as more ties.40 Given their reputation for negative inotropic and
than an alternate means of achieving diuresis. Indeed, spirono- chronotropic effects, any role of -blockers in heart failure
lactone, and more recently eplerenone in the RAAS system would at rst appear counterintuitive. This is based on the fact
(Fig. 23), have been recognized as important modulators of that heart failure patients with systolic dysfunction would seem
vascular tone through a variety of mechanisms. These inhibitors to be poor candidates for therapeutic agents that reduce inotrop-
of aldosterone are commonly used in patients as components of icity or contractility. Nonetheless, in the long run -blockers,
select combination drug therapies to balance the potassium- when judiciously used in patients with heart failure, have con-
wasting effects of more potent diuretics, such as thiazide or loop sistently been shown to reduce morbidity and mortality relative
diuretics, as well as for their direct antihypertensive effects to standard heart failure therapies. Similarly, given their effects
through aldosterone modulation. Patients with resistant hyper- on pancreatic -cell release of insulin and metabolic effects,
tension with and without primary aldosteronism had signicant such as reducing gluconeogenesis and glycogenolysis, their role
additive blood pressure reductions when adding low-dose in managing diabetic patients would also seem illogical.
spironolactone (12.5 to 50 mg/day) to diuretics, ACE inhibitors, However, randomized trials strongly support -blockers in
and ARBs.41 Although functional for these purposes, it is impor- both of these populations. In contrast, a meta-analysis by
tant to recognize their potential to cause hyperkalemia when Lindholm and associates45 has shown a higher risk of stroke
used in conjunction with other select agents or in patients with with -blocker treatment compared to other antihypertensive
comorbidities resulting in reduced renal function. Classic therapy in the treatment of patients with primary hypertension.
examples include co-administration with ACE inhibitors and The drug with the most prominent difference in the increased
ARBs, known for their potassium-sparing effects, as well as risk of stroke between the three -blocker subgroups was
agents that may directly or indirectly alter renal potassium load atenolol. Moreover, Messerli and colleagues46 showed that
TABLE 25. Compelling Indications for Individual Drug Classes
Recommended Drug Class
Compelling Indication Diuretic Ald Ant BB CCBA ACE-I ARB Dir Vaso
Heart failure
Post-myocardial infarction
High coronary disease risk
Diabetes
Chronic kidney disease
Recurrent stroke prevention
ACE-I, angiotensin-converting enzyme inhibitor; Ald Ant, aldosterone antagonist; ARB, angiotensin receptor
blocker; BB, beta-blocker; CCBA, calcium channel blocking agent; Dir Vaso, direct vasodilator.
-blocker therapy was ineffective in preventing coronary heart pulmonary disease, or peripheral vascular disease (intermit-
disease, cardiovascular mortality, and all-cause mortality when tent claudication). A -blocker with relative cardioselectivity
compared to diuretics for elderly patients (60 years of age or to block 1-receptors may be more desirable in such a patient,
greater) treated for primary hypertension. Clearly, the effects of while a nonselective -blocker (Fig. 24) may be potentially
-blockers on blood pressure are complex and difcult to disadvantageous. In such a patient, low doses of cardioselective
ascribe to one or two mechanisms. Rather, the varied effects of -blockers may achieve adequate blockade of 1-receptors in
negative chronotropic and inotropic properties along with the heart and kidneys while minimizing the undesirable
reduced renin levels (Fig. 23) appear to result in an overall effects of 2-receptor blockade on the smooth muscle lining
reduction in cardiac output and/or reduction in peripheral the bronchioles. In doing so, hypertension may be managed
resistance. while avoiding complications of the co-existing reactive airway
The specic pharmacologic properties of various -blockers disease, which is mediated by 2-receptor stimulation. Similarly,
are varied and diverse. An understanding of these properties either because of a reduction in the 2-mediated vascular
may be useful in order to prioritize selection of one agent over blood ow or by enhanced unopposed -agonistmediated
others given a patients specic condition(s). One of these vasoconstriction, a patient with peripheral vascular disease
properties is cardioselectivitythe property of some -block- (intermittent claudication) may experience a worsening of
ers that preferentially block 1- versus 2-receptors. Another symptoms with use of a nonselective -blocker (Fig. 24). It is
property exhibited by some -blockers is membrane stabiliza- important to remember that cardioselectivity is dependent
tion activity, which relates to the propensity of the -blocker upon dose, with diminished selectivity exhibited with higher
to possess some capacity for antiarrhythmic properties, in doses.
addition to -receptor blocking properties. Some -blockers Membrane stabilization activity and ISA are two pharma-
(Fig. 24) possess properties referred to as intrinsic sympatho- cologic properties of some -blockers whose value in the clin-
mimetic activity (ISA). -Blockers possessing this property ical setting is less well established. Generally, membrane stabi-
effectively block the -receptor at higher circulating cate- lization activity may correlate with antiarrhythmic properties,
cholamine levels, such as during exercise, while having modest while -blockers with ISA properties have the theoretical
-blocking activity at times of lower catecholamine levels, such advantage of mitigating reductions in resting heart rate while
as at rest.47 acting as classic -blockers, at higher sympathetic tone.40 Since
Each of these properties may be exploited to some extent neither has directly proven value in the clinical setting, they will
when prescribing a -blocker, while others (membrane not be discussed further other than to point out that -blockers
stabilization activity and ISA) are more of theoretical inter- with ISA are not recommended for use in the postmyocardial
est, with less relative value in clinical practice. For example, infarction patient.48
consider a patient with mild asthma, chronic obstructive A limited number of -blockers possess properties that
block -receptors and antagonize -receptors (Fig. 24).
-Blockers with -receptorblocking activity also have a clini-
cal role that is theoretically benecial, yet somewhat difcult to
prove as a clinical advantage. Such is the case for carvedilol and
Beta blocking agents labetalol. Both these -blockers possess -receptorblocking
activity in addition to their -receptorblocking properties. In
the case of carvedilol, reductions in peripheral resistance
through -receptormediated blockade, in addition to
Non-selective Selective With
-blockade, may be thought of as a benet for patients with
alpha-blocking
activity hypertension. Such a combination should theoretically con-
tribute to enhanced reductions in vascular tone. Nonetheless,
ISA +ISA ISA +ISA
there has been no proven evidence of superior outcome
from the use of -blockers with -blocking activity compared
Nadolol Pindolol Atenolol Acebutolol Labetalol to those with only -blocking activity. Blocked -receptors
Propranolol Carteolol Metoprolol Carvedilol may represent a theoretical disadvantage for carvedilol when
Timolol Penbutolol Esmolol used to manage patients with chronic heart failure. In such
Betaxolol
Bisoprolol patients, when recommended therapy is prescribed,49 there is
Beta-1 Cardioselective
often a risk of lowering peripheral vascular resistance too
ISA = Intrinsic Sympathomimetic Activity
much (through - and -receptor blockade) in such
patients, who may have precious little reserve blood pres-
FIGURE 24. Flowchart listing various -blocking agents sure. Nonetheless, carvedilol has enjoyed considerable clini-
separated by -receptor activity and intrinsic sympathomimetic
activity.
cal and proven success as a mainstay of managing patients
with chronic heart failure.49
The adverse effects of -blockers logically follow their study and favored the ARB-based regimen over the CCBA-
pharmacology. Initiating -blockers for hypertension in all based regimen in the VALUE study.
patients may have the potential to precipitate bradycardia, Often used to augment blood pressure lowering, CCBAs are
various degrees of heart block, or signs and symptoms of most commonly used as add-on therapy for patients who are in
heart failure. The latter is usually limited to those with a sub- need of further blood pressure lowering above and beyond that
clinical diagnosis and should be considered in the elderly or afforded by diuretics or other antihypertensives. Nonetheless,
those with documented reductions in left ventricular function. they have demonstrated their efcacy in select patient popula-
Conversely, abrupt discontinuation of -blockers has been tions as very effective blood pressure lowering agents.
cited as a precipitating factor in the development of ischemic The diversity of pharmacologic properties within the
syndromesespecially for those patients in whom -blockers CCBA class is signicant. Knowledge of their subclass helps
were used for extended periods of time or at higher doses, In the clinician to recognize their predominant effects on the
such cases, the dose of these agents should be reduced cardiovascular system and probable side-effect prole.
(tapered) over a period of several days to perhaps 1 or even 2 Dihydropyridine CCBAs such as amlodipine are commonly
weeks depending on patient-related factors. associated with edema, especially when used at higher doses.
Phenylalkylamine-verapamil and benzothiazepine-diltiazem
Calcium Channel Blocking Agents are more commonly recognized for their effects on the cardiac
Exhibiting considerable interclass diversity, calcium channel conduction system and their propensity to be negative
blocking agents (CCBAs) have been recognized as effective inotropes and negative chronotropes. Many of these pharma-
antihypertensives, for the elderly in particular. Earlier trials cologic properties are exploited for their specic clinical utility.
demonstrated effective event reduction for patients with Given that verapamil and diltiazem (both are nondihydropy-
isolated systolic hypertension and clearly established the ridine CCBAs) effectively block cardiac conduction through
effectiveness of the blood pressurelowering effects of dihy- the atrioventricular node, their value in the management of
dropyridine CCBAs. Comparative data between specic CCBAs patients with atrial brillation in addition to hypertension is
as part of combination drug therapy versus other combina- obvious. In contrast, the dihydropyridine subclass of agents
tion regimens have been forthcoming as of late. Specically, has no utility in managing atrial dysrhythmias. Similarly, all
the Valsartan Antihypertensive Long-term Use Evaluation three subclasses of CCBAs possess some coronary vasodilating
(VALUE) trial compared valsartan-based therapy to amlodipine- properties and hence may be used in select patients for the
based therapy in over 15,000 patients who were at high risk for management of patients with angina, in addition to their anti-
cardiac events. In spite of an attempt to achieve identical hypertensive benets.
blood pressure reductions, differences were noted early and
sustained throughout the 4.2-year length of the study. ACE Inhibitors
Overall the primary endpoint (composite cardiac mortality ACE inhibitors are a key class of antihypertensive agents used
and morbidity) was not statistically signicantly different in a vast array of patients with or without comorbidities
between the groups, but cause-specic outcomes did favor the and/or cardiovascular risk factors. As the target agents of
regimen affording the achievement of lower blood pres- choice for numerous outcome trials, they have been exten-
suresnamely the amlodipine-based therapy. This theme of sively studied across a wide variety of patient types and thus
unequal reductions in BP accounting for differences in cause- have considerable applicability to a wide array of potential
specic outcomes was shared by the ndings of the ASCOT- patients. This broad utility extends to the list of compelling
BPLA study, which compared amlodipine-based therapy ver- indications (Table 25) for patients as described in JNC 7.
sus atenolol-based therapy in over 19,000 hypertensives for These compelling indications include their qualied role in
5.5 years. Again although no statistically signicant reduction managing patients with hypertension who have type 1 dia-
in the primary endpoint was observed, the study was stopped betes,50 heart failure,49 postmyocardial infarction,48 type 2
prematurely because of fewer individuals achieving the pri- diabetes,3 chronic kidney disease,51,52 or recurrent stroke pre-
mary endpoint while receiving the amlodipine-based regimen vention.53 Comparative trials between ACE inhibitors and
compared to those taking the atenolol-based regimen. These various other agents as initial drug therapy have also demon-
observations appear to conrm a critical theme that regardless strated some differences in outcomes for this class. In the case
of the agents used, the overwhelming evidence appears to of ALLHAT,20 ACE inhibitors appeared to perform less well
indicate that the amount of blood pressure lowering achieved than diuretics in terms of incidence of combined cardiovas-
has more to do with event reduction than with the agents or cular disease and heart failure. On the other hand, the ANBP2
combinations of agents used to achieve them. Primary end- trial35 seemed to suggest that ACE inhibitors may be equiva-
points aside, certain secondary endpoints demonstrated dif- lent to diuretics in terms of overall outcomes. Since there are
ferences between regimens. Protection from the development legitimate criticisms of both these trials, it may only be safe to
of new-onset diabetes over the duration of the study was conclude that both diuretics and ACE inhibitors represent
noted for the amlodipine-based therapy in the ASCOT-BPLA formidable agents as either rst- or second-line hypertensive
therapies that effectively achieve a target blood pressure goal Angiotensin Receptor Blockers
for most patients with or without comorbidities. ARBs are another key class of agents whose role in managing
Although generally well-tolerated by most, classic side patients with hypertension has been further dened by recently
effects associated with ACE inhibitors include their potential completed studies. ARBs are inhibitors of the angiotensin-1
to cause hyperkalemia and a persistent dry cough. Modest ele- (AT1) receptors (Fig. 23). AT1 receptor stimulation evokes a
vations in serum potassium should be anticipated. This is par- pressor response via a host of accompanying effects on cate-
ticularly true in patients with compromised renal function, cholamines, aldosterone, and thirst.40 Consequently, inhibition
those receiving concurrent NSAIDs, or those taking potas- of AT1 receptors directly prevents this pressor response and
sium supplementation. The elevations in potassium should be results in up-regulation of the RAAS. Up-regulation of the
anticipated if not prospectively considered when starting or RAAS results in elevated levels of angiotensin II, which have
increasing the dose of an ACE inhibitor. Hyperkalemia is the added effect of stimulating the angiotensin-2 (AT2) receptors.
rarely a reason for discontinuation of this otherwise reason- AT2-receptor stimulation is generally associated with antihy-
ably well-tolerated class of agents. Nonetheless, periodic mon- pertensive activity; however, long-term effects of AT2-receptor
itoring of serum potassium is prudent for patients receiving stimulation that involve cellular growth and repair are relatively
ACE inhibitors. unknown. What is clear is that ARBs differ from ACE inhibitors
Another effect of ACE inhibitors includes their propensity in that the former cause up-regulation of the RAAS while the
to cause a dry cough. This cough is thought to be caused by latter blocks the breakdown of bradykinin. The therapeutic
accumulation of bradykinin resulting from a direct effect of relevance resulting from these pharmacologic differences has
inhibiting ACE. It can be a troubling source of nonadherence yet to be fully evaluated through long-term clinical comparative
to this class of agents. Although mild forms are tolerable, trials.
should cough become the source of poor compliance with the At this point, ARBs have emerged as an effective class of
agent, ARBs should be considered as possible alternative agents. antihypertensives whose low incidence of side effects and
This is particularly true for patients in whom there is a need demonstrated clinical role in patients with specic comor-
for RAAS inhibition. bidities have afforded them an attractive position in the anti-
In general, the effects of ACE inhibitors on diminished renal hypertensive armamentarium. Like ACE inhibitors, the anti-
function and potassium can be predicted given an understand- hypertensive effectiveness of ARBs is greatly enhanced by
ing of their pharmacologic actions (Fig. 23). Inhibition of the combining them with diuretics. Furthermore, they have
generation of angiotensin II through ACE inhibition (or direct proven their value as well-tolerated alternatives to ACE
blockage of the angiotensin II receptor by angiotensin II recep- inhibitors for patients with chronic kidney disease, diabetes
tor blockers) naturally would reduce the efferent renal artery mellitus, and postacute myocardial infarction (AMI)
tone thereby changing the intraglomerular pressure. Although (Table 25). As of late, the addition of ARBs to standard
changes in the afferent renal artery tone also occur, the overall therapy for patients with congestive heart failure (CHF),
effects usually translate into a reduction in GFR52 with resulting including ACE inhibitors, have demonstrated additional
elevations of up to 30% in serum creatinine values. It is impor- incremental benets for patients with systolic dysfunction54 or
tant to recognize that such elevations in serum creatinine are not diastolic dysfunction55 or as alternatives to ACE inhibitors
usually indications to discontinue use of the ACE inhibitor. when ACE inhibitors are not tolerated.56 Comparative studies
Rather, possible dose reduction and continued monitoring for with alternate (non-ACE inhibitors) antihypertensive regi-
further increases in serum creatinine remains prudent. mens in patients with type 2 diabetes57,58 and left ventricular
Alternatively, should elevations in serum creatinine exceed 30%, hypertrophy59 have demonstrated their usefulness as effective
discontinuation is prudent until further evaluation can be made. antihypertensives in these special populations. Studies (the
More rare forms of adverse effects of ACE inhibitors Irbesartan Diabetic Nephropathy Trial [IDNT] and Reduction
include blood dyscrasias, angioedema, and more serious effects of Endpoints in NIDDM with the Angiotensin II Antagonist
of ACE inhibitors on renal function such as acute renal failure Losartan [RENAAL]) have demonstrated superiority of delay-
in those with preexisting kidney dysfunction or renal artery ing progression toward renal dysfunction for ARBs relative to
stenosis. With incidences usually less than 1%, these adverse alternative antihypertensives in type 2 diabetics.57,58 Their use
effects are rarely seen by many clinicians. Nonetheless, given in treatment of diabetic nephropathy and proteinuria in
their potential for serious consequences, they remain impor- patients with type 2 diabetes mellitus and hypertension has
tant to consider given the widespread use of ACE inhibitors for been supported by their Food and Drug Administration
a variety of cardiovascular conditions. Specically, the insidious (FDA) approval for use in this population and inclusion in
nature of the development of neutropenia and agranulocytosis national guidelines.3 The Irbesartan in Patients with Type 2
and the acute effects of lip and tongue swelling accompanying Diabetes and Microalbuminuria (IRMA II)60 study demon-
angioedema or acute renal failure in a patient with bilateral strated the dose dependency of these outcomes in type 2 dia-
renal artery stenosis can have potentially life-threatening betics, while the IDNT study suggested a relative superiority
complications. over alternative antihypertensives, namely CCBAs. Although
of patients with hypertension. Their central 2-adrenergic

Patient Encounter 2 stimulation is thought to reduce sympathetic outow and
enhance parasympathetic activity thereby reducing heart rate,
cardiac output, and total peripheral resistance. Occasionally
used for cases of resistant hypertension, these agents may have
JT, a 55-year-old African-American woman, comes to your
clinic with a recent diagnosis of hypertension. She is 55 a role when other more conventional therapies appear ineffec-
(165 cm) tall and weighs 160 pounds (72.7 kg) with a body tive. The availability of a transdermal clonidine patch that is
mass index (BMI) of 26.6 kg/m2. JT does not use tobacco or applied once weekly may offer an alternative to hypertensive
drink alcohol, and exercises about once a week. Physical patients with adherence problems.
exam was unremarkable, but an electrocardiogram revealed
left ventricular hypertrophy. Baseline laboratory tests were sig-
nicant for fasting blood glucose of 124 mg/dL (6.88 mmol/L), Other Agents
serum creatinine of 1.5 mg/dL (133 mmol/L), total cholesterol Direct vasodilators such as hydralazine and minoxidil rep-
of 200 mg/dL (5.18 mmol/L), high-density lipoprotein choles- resent additional alternative agents used rarely for patients
terol of 40 mg/dL (1.04 mmol/L), triglycerides of 200 mg/dL
with resistant hypertension. Primarily acting to relax
(2.26 mmol/L), and low-density lipoprotein cholesterol of
120 mg/dL (3.11 mmol/L). Urinalysis was positive for
smooth muscles in arterioles and activate baroreceptors, use
microalbuminuria. Blood pressure today was 165/86 mm Hg. of these agents in the absence of concurrently administered
-blockers and diuretics is uncommon. This is due to the
What signs of target organ damage does JT exhibit? need to offset their tendency to cause reex tachycardia and
Is more extensive testing for identiable causes of uid retention. Other more rare adverse effects include
hypertension indicated at this time? hydralazine-induced lupus-like syndrome and hypertri-
Based on the information presented, create a care plan chosis from minoxidil. Finally, reserpine, although slow to
for JTs hypertension. This should include (1) goals of act, represents another rarely used alternative agent for
therapy, (2) a patient-specic therapeutic plan, and (3) a those who are recalcitrant to more standard therapy. This
plan for appropriate monitoring to achieve goals and agent is a long-acting depleter of the catecholamine norep-
avoid adverse effects.
inephrine, which causes reduced sympathetic tone leading
to reductions in peripheral resistance. Reserpines associa-
tion with numerous side effects including gastric ulceration,
depression, and sexual side effects has limited its usefulness
in all but the more rare cases of patients with resistant
better tolerated than ACE inhibitors, ARBs have not been hypertension. However, the Systolic Hypertension in the
shown to demonstrate superiority of outcomes relative to Elderly (SHEP) trial61 demonstrated the blood pressure
ACE inhibitors. This key observation, in addition to their lowering effectiveness of reserpine (0.05 mg per day) when
relatively higher acquisition cost, has mitigated the growth of combined with a diuretic, and similar cardiopulmonary and
ARB use relative to ACE inhibitors. psychosocial side effects between the treatment and placebo
groups.
Alpha-Blockers
Generally, 1-blockers are considered as second-line agents to
be added on to most other agents when hypertension is not
adequately controlled. They may have a specic role in the SPECIAL PATIENT POPULATIONS
antihypertensive regimen for elderly males with prostatism;
however, their use is often curtailed by complaints of syncope, Compelling Indications and Special Considerations
dizziness, or palpitations following the rst dose and ortho-
While the main goal of antihypertensive therapy is to
static hypotension with chronic use. The roles of doxazosin,
achieve target blood pressures, the selection of agents for an indi-
terazosin, and prazosin in the management of patients with
vidual should also account for certain special considerations and
hypertension are limited due to the paucity of outcome data
a patients comorbidities. Specic antihypertensive therapy is
and the absence of a unique role for special populations or
warranted for certain patients with comorbid conditions that
compelling indications from JNC 7.
may elevate their level of risk for cardiovascular disease. Clinical
conditions for which there is compelling evidence supporting
Central Alpha2-Agonists one or more classes of drug therapy include:2
Also limited by their tendency to cause orthostasis, sedation,
dry mouth, and vision disturbances, clonidine, methyldopa, and Ischemic heart disease
guanabenz represent rare choices in contemporary treatment Heart failure
Diabetes prior stroke or transient ischemic attack. This therapy reduces

Chronic kidney disease the risk of recurrent stroke, making it particularly attractive in
Cerebrovascular disease these patients for blood pressure control.53
There are several situations in the management of hyper-
Compelling indications for specific drug therapies are tension requiring special considerations including, but not
summarized in Table 25.62 In patients with hypertension limited to:
and chronic stable angina, -blockers and long-acting cal-
cium channel blockers are indicated due to their antihyper- Hypertensive crisis
tensive and antianginal effects.2,63 In patients at high risk of Elderly populations
ischemic heart disease, such as diabetic patients with addi- Isolated systolic hypertension
tional cardiovascular risk factors or chronic coronary Minority populations
artery or vascular disease, ACE inhibitors are particularly Pregnancy
useful in reducing the risk of cardiovascular events regard- Pediatrics
less of whether the patient carries a concurrent diagnosis of
hypertension.2,64,65
Hypertensive crisis can be divided into hypertensive emergen-
-Blockers and ACE inhibitors are also indicated for
cies and hypertensive urgencies. A hypertensive emergency
postmyocardial infarction for the reduction of cardiovascu-
occurs when severe elevations in blood pressure are accompa-
lar morbidity and mortality, as are aldosterone antagonists, in
nied by acute or life-threatening target organ damage such as
postmyocardial infarction patients with reduced left ventricular
acute myocardial infarction, unstable angina, encephalopathy,
systolic function and diabetes or signs and symptoms of heart
intracerebral hemorrhage, acute left ventricular failure with
failure.2,48
pulmonary edema, dissecting aortic aneurysm, rapidly pro-
Patients with asymptomatic left ventricular systolic dys-
gressive renal failure, accelerated malignant hypertension with
function and hypertension should be treated with -blockers
papilledema, and eclampsia among others. Blood pressure is
and ACE inhibitors. Those with heart failure secondary to left
generally greater than 220/140 mm Hg, although a hypertensive
ventricular dysfunction and hypertension should be treated
emergency can occur at lower levels, particularly in individuals
with drugs proven to also reduce the morbidity and mortal-
without previous hypertension. The goal in a hypertensive
ity of heart failure, including -blockers, ACE inhibitors,
emergency is to reduce mean arterial pressure by up to 25% to
ARBs, aldosterone antagonists, and diuretics for symptom
the range of 160/100 to 110 mm Hg in minutes to hours.2,68
control as well as antihypertensive effect. In African-
Intravenous therapy is generally required and may consist of
Americans with heart failure and left ventricular systolic dys-
the agents listed in Table 26.62 A hypertensive urgency is
function, combination therapy with nitrates and hydralazine
manifested as a severe elevation in blood pressure without evi-
not only affords a morbidity and mortality benet, but may
dence of acute or life-threatening target organ damage. In
also be useful as antihypertensive therapy if needed.66 The
these individuals, blood pressure can usually be managed with
dihydropyridine calcium channel blockers amlodipine or
orally administered short-acting medications (i.e., captopril,
felodipine may also be used in patients with heart failure and
clonidine, or labetalol) and observation in the emergency
left ventricular systolic dysfunction for uncontrolled blood
department over several hours, with subsequent discharge on
pressure, although they have no effect on heart failure mor-
oral medications and follow-up in the outpatient setting
bidity and mortality in these patients.49 For patients with
within 24 hours.2,62
heart failure and preserved ejection fraction, antihyperten-
The treatment of elderly patients with hypertension, as
sive therapies that should be considered include -blockers,
well as those with isolated systolic hypertension, should fol-
ACE inhibitors, ARBs, calcium channel blockers (including
low the same approach as with other populations with the
nondihydropyridine agents), diuretics, and others as needed
exception that lower starting doses may be warranted to
to control blood pressure.2,49
avoid symptoms and with special attention paid to postural
Patients with diabetes and hypertension should initially be
hypotension. This should include a careful assessment of
treated with either -blockers, ACE inhibitors, ARBs, diuret-
orthostatic symptoms, measurement of blood pressure in
ics, or calcium channel blockers. There is a general consensus
the upright position, and caution to avoid volume depletion
that therapy focused on RAAS inhibition by ACE inhibitors or
and rapid titration of antihypertensive therapy.2 In indi-
ARBs may be optimal if the patient has additional cardiovas-
viduals with isolated systolic hypertension, the optimal level
cular risk factors such as left ventricular hypertrophy or
of diastolic pressure is not known, and although treated
chronic kidney disease.2,3,59,67
patients who achieve diastolic pressures less than 60 to
In patients with chronic kidney disease and hypertension,
70 mm Hg had poorer outcomes in a landmark trial, their
ACE inhibitors and ARBs are preferred, usually in combina-
cardiovascular event rate was still lower than those receiving
tion with a diuretic.67 ACE inhibitors in combination with a
placebo.69
thiazide diuretic are also preferred in patients with a history of
TABLE 26. Parenteral Antihypertensive Agents for Hypertensive Emergencya
28
Duration of
Drug Dose Onset of Action Action Adverse Effectsb Special Indications
Vasodilators
Sodium 0.2510 mcg/kg/minute Immediate 12 minutes Nausea, vomiting, muscle Most hypertensive
nitroprusside as IV infusionc twitching, sweating, emergencies; use with
thiocyanate and caution with high
cyanide intoxication intracranial pressure
or azotemia
Nicardipine 515 mg/hour IV 510 minutes 1530 minutes, Tachycardia, headache, Most hypertensive
hydrochloride may exceed ushing, local phlebitis emergencies except
4 hours acute heart failure;
use with caution
with coronary
ischemia
Fenoldopam 0.10.3 mcg/kg/minute Less than 5 minutes 30 minutes Tachycardia, headache, Most hypertensive
mesylate as IV infusionc nausea, ushing emergencies; use with
caution with
glaucoma
Nitroglycerin 5100 mcg/kg/minute 25 minutes 510 minutes Headache, vomiting, Coronary ischemia
as IV infusion methemoglobinemia,
tolerance with
prolonged use
Enalaprilat 1.255 mg 1530 minutes 612 hours Precipitous fall in pressure Acute left ventricular
every 6 hours in high-renin states; failure; avoid in
variable response acute myocardial
infarction
Hydralazine 1020 mg IV 1020 minutes 14 hours IV Tachycardia, ushing, Eclampsia
hydrochloride 1040 mg IM 2030 minutes 46 hours IM headache, vomiting,
aggravation of angina
Adrenergic Inhibitors
Labetalol 2080 mg IV 510 minutes 36 hours Vomiting, scalp tingling, Most hypertensive
hydrochloride bolus every dizziness, emergencies except
10 minutes bronchoconstriction, acute heart failure
nausea, heart block,
orthostatic hypotension
Esmolol 250500 mcg/kg/minute 12 minutes 1030 minutes Hypotension, nausea, Aortic dissection,
hydrochloride IV bolus, then asthma, rst-degree perioperative
50100 mcg/kg/minute heart block, heart failure
by infusion; may
repeat bolus after
5 minutes or increase
infusion to
300 mcg/minute
Phentolamine 515 mg IV bolus 12 minutes 1030 minutes Tachycardia ushing, Catecholamine excess
headache
IM, intramuscular; IV, intravenous.
a
These doses may vary from those in the Physicians Desk Reference (51st ed.).
b
Hypotension may occur with all agents.
c
Requires special delivery system.
Reproduced from Saseen JJ, Carter BL. Hypertension. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:
212, with permission.
TABLE 27. Treatment of Chronic Hypertension in Pregnancy2

Patient Encounter 3
Agent Comments
Methyldopa Preferred rst-line therapy on the basis
of long-term follow-up studies
DW, a 78-year-old Caucasian man, presents to the emer- supporting safety after exposure in
gency room with complaints of a headache persisting over utero. Surveillance data do not sup-
the last 3 days. Repeated blood pressure measurements port an association between drug and
average 200/110 mm Hg. He reports no other symptoms congenital defects when the mother
and physical examination and laboratory tests are unre- took the drug early in the rst
markable as is his past medical history with the exception trimester.
of hypertension diagnosed in his early 60s. DW reports that Labetalol Increasingly preferred to methyldopa
because of reduced side effects. The
he is struggling on a xed retirement income with no pre-
agent does not seem to pose a risk to
scription coverage and takes what I can afford. Blood the fetus, except possibly in the rst
pressure medications are carvedilol 25 mg twice daily, trimester.
amlodipine 10 mg once daily, torsemide (Demadex) -Blockers Generally acceptable on the basis of
10 mg once daily, and valsartan 320 mg once daily. limited data. Reports of intrauterine
growth restriction with atenolol in the
What type of hypertensive crisis is DW experiencing? rst and second trimesters.
What are likely causes of DWs loss of blood pressure Clonidine Limited data; no association between
control? drug and congenital defects when the
Create a care plan for DWs hypertensive crisis. This should mother took the drug early in the rst
trimester, but number of exposures is
include (1) acute goals of therapy, (2) a patient-specic
small.
therapeutic plan to achieve goals, and (3) a plan for Calcium Limited data; nifedipine in the rst
appropriate outpatient follow-up including recommenda- antagonists trimester was not associated with
tions for changes, if any, to current medications. increased rates of major birth
defects, but animal data were associ-
ated with fetal hypoxemia and aci-
dosis. This agent should probably be
limited to mothers with severe
hypertension.
Diuretics Not rst-line agents; probably safe;
available data suggest that throughout
While the treatment approach of hypertension in
gestation a diuretic is not associated
minority populations is similar, special consideration should with an increased risk of major fetal
be paid to socioeconomic and lifestyle factors that may be anomalies or adverse fetal-neonatal
important barriers to blood pressure control. In addition, in events.
patients of African origin, diminished blood pressure Angiotensin- Contraindicated; reported fetal toxicity
converting and death.
responses have been seen with ACE inhibitors and ARBs
enzyme inhibitors
compared to diuretics or calcium channel blockers.2 and angiotensin II
Hypertension in pregnancy is a major cause of maternal, receptor antagonists
fetal, and neonatal morbidity and mortality. There are many
categories of hypertension in pregnancy; however, preexisting
hypertension and preeclampsia are treated differently. The
therapeutic selection of an oral antihypertensive agent and is associated with obesity, sedentary lifestyle, or a positive
(Table 27) in a pregnant patient with chronic hypertension family history, which increases the risk of cardiovascular dis-
is determined with regard to fetal safety. Therapeutic options ease. The clinician should be aware that secondary causes
for acute severe hypertension in pre-eclampsia may be reviewed are common in adolescent hypertension and the identica-
in JNC 7.2 tion and aggressive modication of risk factors with non-
Similar to the JNC 7 criteria (which has four stages for pharmacologic and pharmacologic interventions is paramount
blood pressure classication in adults), the measurement of for risk reduction of target organ damage. The 2004 National
three or more blood pressures in children and adolescents High Blood Pressure Education Program (NHBPEP) Working
are compared to tables listing the 90th, 95th, and 99th per- Group Report on Hypertension in Children and Adolescents
centile blood pressures based on age, height, and gender that has recommendations to modify and treat risk factors.70 The
classify blood pressure as normal, prehypertension, and Nelson Textbook of Pediatrics is also recommended for a
stage 1 and stage 2 hypertension (Table 21).70 The preva- comprehensive review of treatment of congenital and pedi-
lence of hypertension in adolescent populations is increasing atric hypertension.71
PATIENT CARE AND MONITORING

Patient Care and Monitoring
The frequency of follow-up visits for patients with hyperten-
sion will vary based on individual cases, but will be inuenced by
severity of hypertension, comorbidities, and choice of agent 1. Measure patient blood pressure twice, at least 1 minute
selected. However, generally speaking, assessment of response to apart in a sitting position, and then average the readings
medications may be prudent at 1-month intervals.2 For patients to determine if blood pressure is adequately controlled.
with stage 2 hypertension or those with comorbidities (e.g., diabetes, 2. Conduct a medical history. Does the patient have any
vascular disease, CHF, or CKD) shorter time frames of 2 weeks or compelling indications? Is the patient pregnant?
less may be more appropriate.51 Annual or semiannual monitor-
3. Conduct a medication history (prescription, over-the-
ing for changes in serum biochemistries such as serum creati- counter, and dietary supplements) to determine condi-
nine or potassium are recommended.2 However, for patients tions or causes of hypertension. Does the patient take any
with CHF, CKD, or diabetes, more frequent monitoring will be medications, supplements, herbal products, or foods that
necessary to adequately control comorbid conditions. Another may elevate SBP or DBP? Does the patient have drug
aspect to monitoring relates to the importance of medication allergies?
adherence. Conrmation of continued use of antihypertensive 4. Review available laboratory tests to examine electrolyte
medications should be considered in the routine monitoring of balance and renal function.
patients on numerous medications for hypertension. Evaluation 5. Discuss lifestyle modications that may reduce blood
of side effects, lab abnormalities, and/or progression to target pressure with the patient. Determine what non-
organ damage should also be considered at appropriate inter- pharmacologic approaches might be or have been
vals. Given the asymptomatic nature of hypertension, patient helpful to the patient.
motivation to adhere to prescribed medications becomes a key 6. Evaluate the patient if pharmacologic treatment has
tool in controlling hypertension.2 reached the target blood pressure goal. If the patient is
Given the chronic nature of hypertension, parsimony of at the goal, skip to step 8.
medication regimens is a virtue of a good therapeutic plan. 7. If patient is not at goal BP, assess efcacy, safety, and
Minimizing the number of medications a patient is compliance of the antihypertensive regimen to deter-
required to take has the potential to enhance adherence and mine if a dose increase or additional antihypertensive
mitigate cost. Often, control of blood pressure is achieved agent (step 8) is needed to achieve goal blood pressure.
by use of two or even three or more antihypertensives.20,72 8. Select an agent to minimize adverse drug reactions and
Many combination products contain a diuretic as one of interactions when additional drug therapy is needed.
their active components. However, combination therapy Does the patient have prescription coverage or is the
may limit the ability of the clinician to titrate the dose of a recommended agent in the formulary?
specic agent. As such, the number of medications (pill 9. Open a dialogue to address patient concerns about
count) may often be reduced through use of combination hypertension and management of the condition.
products. This inherently simplies the number of medica- 10. Provide a plan to assess the effectiveness and safety of
tions and co-pays a patient may have to endure to achieve therapy. Follow-up in 2 to 4 weeks if the medication
effective blood pressure control. These practicalities, regimen has changed, otherwise semi-annual or annual
although obvious, go a long way to optimize compliance, clinic visits to assess blood pressure, electrolyte bal-
another challenge to maximizing therapy effectiveness. ance, and renal function should occur.
OUTCOME EVALUATION
ABBREVIATIONS
Short-term goals are to safely achieve reduction in blood
pressure through the iterative process of employing ACC/AHA: American College of Cardiology/American Heart
drug therapy, along with non-drug therapy or lifestyle Association
changes. ACE: angiotensin-converting enzyme
Lifestyle changes should address other risk factors for car- A-HeFT: African-American Heart Failure trial
AIRE: Acute Infarction Ramipril Efcacy Study
diovascular disease including obesity, physical inactivity,
ALLHAT: Antihypertensive and Lipid-Lowering Treatment
insulin resistance, dyslipidemia, smoking cessation, and to Prevent Heart Attack Trial
others. AMI: acute myocardial infarction
Monitoring for efcacy, adverse events, and adherence to ANBP2: Australian-New Zealand Blood Pressure-2 study
therapy is key to achieving the long-term goals of reducing ARB: angiotensin receptor blocker
the risk of morbidity and mortality associated with cardio- ASCOT-BPLA: Anglo-Scandinavian Cardiac Outcomes Trial-
vascular disease. Blood Pressure Lowering Arm study
AT1: Angiotensin-1 TRACE: Trandolapril Cardiac Evaluation

AT2: Angiotensin-2 UKPDS: UK Prospective Diabetes Study
BB: beta-blocker VALUE: Valsartan Antihypertensive Long-term Use Evaluation
BHAT: Beta-Blocker Heart Attack Trial ValHEFT: Veterans Affairs Cooperative I study
BP: blood pressure
bpm: beats per minute Reference lists and self-assessment questions and answers are
CAGE: Chymostatin-sensitive II-generating enzyme available at www.ChisholmPharmacotherapy.com.
CAPRICORN: Carvedilol Post-Infarct Survival Control in Left
Ventricular Dysfunction Trial Log into the website: www.pharmacotherapyprinciples.com
Captopril Trial: Collaborative Study Captopril Trial (The Effect of
for information on obtaining continuing education credit for
Angiotensin-Converting Enzyme Inhibition on
Diabetic Nephropathy)
this chapter.
CCBA: calcium channel blocking agents
CHARM: Candesartan in Heart Failure Assessment of KEY REFERENCES AND READINGS
Reduction in Morbidity and Mortality Trial
CHF: congestive heart failure, but the latest recommen- Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines
dations use HF for heart failure for the management of patients with ST-elevation myocardial
CKD: chronic kidney disease infarctionexecutive summary: a report of the American
CO: cardiac output College of Cardiology/American Heart Association Task Force
COPERNICUS: Carvedilol Prospective Randomized Cumulative on Practice Guidelines (Writing Committee to Revise the 1999
Survival Trial Guidelines for the Management of Patients With Acute
CVD: cardiovascular disease Myocardial Infarction). Circulation 2004;110(5):588636.
DASH: Dietary Approaches to Stop Hypertension Arauz-Pacheco C, Parrott MA, Raskin P. Hypertension management
DBP: diastolic blood pressure in adults with diabetes. Diabetes Care 2004;27(Suppl 1):
EPHESUS: Eplerenone Post-Acute Myocardial Infarction S65S67.
Heart Failure Efcacy and Survival Study Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint
EUROPA: European Trial on Reduction of Cardiac Events National Committee on Prevention, Detection, Evaluation, and
with Perindopril in Stable Coronary Artery Disease Treatment of High Blood Pressure. Hypertension 2003; 42(6):
Trial 12061252.
FDA: Food and Drug Administration Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events
GFR: glomerular ltration rate with an antihypertensive regimen of amlodipine adding perindo-
HOPE: Heart Outcomes Prevention Evaluation Study pril as required versus atenolol adding bendroumethiazide as
IDNT: Irbesartan Diabetic Nephropathy Trial required, in the Anglo-Scandinavian Cardiac Outcomes Trial-
IM: intramuscular Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre
INVEST: International Verapamil-Trandolapril Study randomised controlled trial. Lancet 2005;366(9489): 895906.
IRMA-II: Irbesartan in Patients with Type 2 Diabetes and Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline
Microalbuminuria study Update for the Diagnosis and Management of Chronic Heart
ISA: intrinsic sympathomimetic activity Failure in the AdultSummary Article: A Report of the
IV: intravenous American College of Cardiology/American Heart Association
JNC 7: Joint National Committee Seventh Report Task Force on Practice Guidelines (Writing Committee to Update
LIFE: Losartan Intervention For Endpoint reduction in the 2001 Guidelines for the Evaluation and Management of Heart
hypertension study Failure): Developed in Collaboration with the American College
MERIT-HF: Metoprolol CR/XL Randomised Intervention Trial of Chest Physicians and the International Society for Heart and
in Congestive Heart Failure Lung Transplantation: Endorsed by the Heart Rhythm Society.
MI: myocardial infarction Circulation 2005;112(12):18251852.
NHBPEP: National High Blood Pressure Education Program Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive
NIDDM: noninsulin-dependent diabetes mellitus patients at high cardiovascular risk treated with regimens based
NSAID: non-steroidal anti-inammatory drug on valsartan or amlodipine: the VALUE randomised trial.
PR: peripheral resistance Lancet 2004;363(9426):20222231.
PROGRESS Perindopril Protection Against Recurrent Stroke Study K/DOQI clinical practice guidelines on hypertension and antihyper-
RAAS: renin-angiotensin-aldosterone system tensive agents in chronic kidney disease. Am J Kidney Dis 2004;
RALES: Randomized Aldactone Evaluation Study 43(5 Suppl 1):S1S290.
RENAAL: Reduction of Endpoints in NIDDM with the Major outcomes in high-risk hypertensive patients randomized to
Angiotensin II Antagonist Losartan study angiotensin-converting enzyme inhibitor or calcium channel
SAVE: Survival and Ventricular Enlargement Trial blocker vs. diuretic: The Antihypertensive and Lipid-Lowering
SBP: systolic blood pressure Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA
SCORE: Systematic Coronary Risk Evaluation 2002;288(23):29812997.
SHEP: Systolic Hypertension in the Elderly The fourth report on the diagnosis, evaluation, and treatment of
SNS: sympathetic nervous system high blood pressure in children and adolescents. Pediatrics
SOLVD: Studies of Left Ventricular Dysfunction 2004;114(2 Suppl 4th Report):555576.
3 HEART FAILURE
Orly Vardeny and Tien M. H. Ng
LEARNING OBJECTIVES
1. Differentiate between the common underlying etiologies of heart failure, including

ischemic, non-ischemic, and idiopathic causes.
2. Describe the pathophysiology of heart failure as it relates to neurohormonal activation of
the renin-angiotensin-aldosterone system and the sympathetic nervous system.
3. Identify signs and symptoms of heart failure and classify a given patient by the New York
Heart Association Functional Classication and American College of Cardiology/American
Heart Association Heart Failure Staging.
4. Describe the goals of therapy for a patient with acute or chronic heart failure.
5. Develop a nonpharmacologic treatment plan which includes patient education for
managing heart failure.
6. Develop a specic evidence-based pharmacologic treatment plan for a patient with acute
or chronic heart failure based on disease severity and symptoms.
7. Formulate a monitoring plan for the nonpharmacologic and pharmacologic treatment of a
patient with heart failure.
KEY CONCEPTS Nonpharmacologic treatment involves dietary modications

such as sodium and uid restriction, risk factor reduction
The most common causes of heart failure are coronary including smoking cessation, timely immunizations, and super-
artery disease (CAD), hypertension, and dilated cardio- vised regular physical activity.
myopathy. Diuretics are used for relief of acute symptoms of congestion
Development and progression of heart failure involves activa- and maintenance of euvolemia.
tion of neurohormonal pathways, including the sympathetic Agents with proven benets in improving symptoms, slowing
nervous system and the renin-angiotensin-aldosterone system disease progression, and improving survival in chronic heart fail-
(RAAS). ure target neurohormonal blockade; these include angiotensin-
The clinician must identify potential reversible causes of converting enzyme (ACE) inhibitors or angiotensin receptor
heart failure exacerbations including prescription and non- blockers (ARBs), -adrenergic blockers, and aldosterone
prescription drug therapies, dietary indiscretions, and med- antagonists.
ication non-adherence. Combination therapy with hydralazine and isosorbide dini-
Symptoms of left-sided heart failure include dyspnea, orthopnea, trate is an appropriate substitute for angiotensin II antago-
and paroxysmal nocturnal dyspnea (PND), whereas symptoms nism in those unable to tolerate an ACE inhibitor or ARB, or
of right-sided heart failure include uid retention, gastro- as add-on therapy in African-Americans.
intestinal bloating, and fatigue. Treatment of acute heart failure targets relief of congestion
Therapeutic goals focus on alleviating symptoms, slowing or and optimization of cardiac output utilizing oral or intra-
preventing disease progression, maintaining quality of life, venous diuretics, intravenous vasodilators, and when appro-
and improving patient survival. priate, inotropes.
33
Heart failure (HF) is dened as the inadequate ability of the The prognosis for patients hospitalized for AHF remains
heart to pump enough blood to meet the blood ow and poor. Average hospital length of stay is estimated to be between
metabolic demands of the body.1 High-output HF is charac- 4 to 6 days, a number which has remained constant over the
terized by an inordinate increase in the bodys metabolic past decade.3 The in-hospital mortality rate has been estimated
demands, which outpaces an increase in cardiac output (CO) at approximately 4%, but ranges from 2% to 20% depending on
of a generally normally functioning heart. More commonly, the report.4 In-hospital mortality increases to an average of
HF is a result of low CO secondary to impaired cardiac func- 10.6% in patients requiring an intensive care unit admission.
tion. The term heart failure will refer to low-output HF for Readmissions are also high, with up to 30% to 60% of patients
purposes of this chapter. readmitted within 6 months of their initial discharge date.4 The
Heart failure is a clinical syndrome characterized by a his- 5-year mortality rate for chronic HF remains greater than 50%.
tory of specic signs and symptoms related to congestion and Survival strongly correlates with severity of symptoms and
hypoperfusion. As HF can occur in the presence or absence of functional capacity. Sudden cardiac death is the most common
fluid overload, the term heart failure is preferred over the for- cause of death, occurring in approximately 40% of patients
mer term congestive heart failure. Heart failure results from with HF.2 Although therapies targeting the up-regulated neuro-
any structural or functional cardiac disorder that impairs the hormonal response contributing to the pathophysiology of
ability of the ventricle to ll with or eject blood.1 Many disor- HF have clearly impacted morbidity and mortality, long-term
ders such as those of the pericardium, epicardium, endo- survival remains low.
cardium, or great vessels may lead to HF, but most patients
develop symptoms due to impairment in left ventricular (LV)
Etiology
myocardial function.
The phrase acute heart failure (AHF) is used to signify Heart failure is the eventual outcome of numerous cardiac
either an acute decompensation of a patient with a history of diseases or disorders (Table 31).5 Heart failure can be classi-
chronic heart failure or to refer to a patient presenting with ed by the primary underlying etiology as ischemic or non-
new-onset HF symptoms. Terms commonly associated with ischemic, with 70% of HF related to ischemia. The most
HF, such as cardiomyopathy and LV dysfunction, are not common causes of HF are CAD, hypertension, and dilated car-
equivalent to HF but describe possible structural or functional diomyopathy. Coronary artery disease resulting in an acute
reasons for the development of HF. MI and reduced ventricular function is a common presenting
history. Non-ischemic etiologies include hypertension, viral
illness, thyroid disease, excessive alcohol use, illicit drug use,
pregnancy-related heart disease, familial congenital disease,
EPIDEMIOLOGY AND ETIOLOGY and valvular disorders such as mitral or tricuspid valve regur-
gitation or stenosis.
Epidemiology
Heart failure is a major public health concern affecting approxi-
mately ve million people in the United States. An additional
550,000 new cases are diagnosed each year. Heart failure mani- TABLE 31. Causes of Heart Failure
fests most commonly in adults over the age of 60.2 The growing
Systolic Dysfunction (Decreased Contractility)
prevalence of HF corresponds to: (1) better treatment of patients Reduction in muscle mass (e.g., myocardial infarction)
with acute myocardial infarctions (MIs) who will survive to Dilated cardiomyopathies
develop HF later in life, and (2) the increasing proportion of Ventricular hypertrophy
older adults due to the aging baby boomer population. The rel- Pressure overload (e.g., systemic or pulmonary hypertension,
ative incidence of HF is lower in women compared to men, but aortic or pulmonic valve stenosis)
Volume overload (e.g., valvular regurgitation, shunts, high-
there is a greater prevalence in women overall due to their longer output states)
life expectancy. Acute heart failure accounts for 12 to 15 million Diastolic Dysfunction (Restriction in Ventricular Filling)
ofce visits per year and 6.5 million hospitalizations annually.2 Increased ventricular stiffness
According to national registries, patients presenting with AHF Ventricular hypertrophy (e.g., hypertrophic cardiomyopathy,
are older (mean age 75 years) and have numerous comorbidities other examples above)
such as CAD, renal insufciency, and diabetes.2 Inltrative myocardial diseases (e.g., amyloidosis, sarcoidosis,
endomyocardial brosis)
Total estimated direct and indirect costs for managing both Myocardial ischemia and infarction
chronic and acute HF in the United States for 2005 was Mitral or tricuspid valve stenosis
approximately $27.9 billion. Medications account for approx- Pericardial disease (e.g., pericarditis, pericardial tamponade)
imately 10% of that cost.3 Heart failure is the most common
From Parker RB, Patterson JH, Johnson JA. Heart failure. In: DiPiro JT,
hospital discharge diagnosis for Medicare patients and is the Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic
most costly diagnosis in this population. Approach. 6th ed. New York: McGraw-Hill; 2005: 220, with permission.
CHAPTER 3 / HEART FAILURE 35
Heart failure can also be classied based on the main com- muscle incorporating ber shortening and tension develop-
ponent of the cardiac cycle leading to impaired ventricular func- ment. Contractility is inuenced to a large degree by adrenergic
tion. A normal cardiac cycle is dependent on two components: nerve activity and circulating catecholamines such as epineph-
systole and diastole. Expulsion of blood occurs during systole rine and norepinephrine.
or contraction of the ventricles, while diastole relates to lling
of the ventricles. Ejection fraction (EF) is the fraction of the
volume present at the end of diastole that is pushed into the aorta Compensatory Mechanisms
during systole. Abnormal ventricular lling (diastolic dys- In the setting of a sustained loss of myocardium, a number of
function) and/or ventricular contraction (systolic dysfunc- mechanisms aid the heart when faced with an increased hemo-
tion) can result in a similar decrease in CO and cause HF dynamic burden and reduced CO. They include the following:
symptoms. Most HF is associated with evidence of LV systolic the Frank-Starling mechanism, tachycardia and increased after-
dysfunction (evidenced by a reduced EF) with or without a load, and cardiac hypertrophy and remodeling (Table 32).5,7
component of diastolic dysfunction, which coexists in up to
two-thirds of patients. Isolated diastolic dysfunction, occur- Preload and the Frank-Starling Mechanism
ring in approximately one-third of HF patients, is diagnosed In the setting of a sudden decrease in CO, the natural response
when a patient exhibits impaired ventricular lling with or of the body is to decrease blood ow to the periphery in order
without accompanying HF symptoms but normal systolic to maintain perfusion to the vital organs such as the heart and
function. Long-standing hypertension is the leading cause of brain. Therefore, renal perfusion is compromised due to both
diastolic dysfunction. Ventricular dysfunction can also involve the decreased CO, as well as shunting of blood away from
either the left or right chamber of the heart or both. This has peripheral tissues. This results in activation of the renin-
implications for symptomatology, as right-sided failure man- angiotensin-aldosterone system (RAAS). The decrease in renal
ifests as systemic congestion whereas left-sided failure results perfusion is sensed by the juxtaglomerular cells of the kidneys
in pulmonary symptoms. leading to the release of renin and initiation of the cascade for
production of angiotensin II. Angiotensin II stimulates the
synthesis and release of aldosterone, which stimulates sodium
PATHOPHYSIOLOGY and water retention in an attempt to increase intravascular
volume and hence preload. In a healthy heart, a large increase
A basic grasp of normal cardiac function sets the stage for in CO is usually accomplished with just a small change in pre-
understanding the pathophysiologic processes leading to HF load. However, in a failing heart, alterations in the contractile
and selecting appropriate therapy for HF. Cardiac output is laments reduce the ability of cardiomyocytes to adapt to
dened as the volume of blood ejected per unit of time (liters increases in preload. Thus, an increase in preload actually
per minute) and is a major determinant of tissue perfusion. impairs contractile function in the failing heart and results in
Cardiac output is the product of heart rate (HR) and stroke a further decrease in CO.
volume (SV): CO = HR SV. The following describes how
each parameter relates to CO. Tachycardia and Increased Afterload
Heart rate is controlled by the autonomic nervous system, Another mechanism to maintain CO when contractility is low
where sympathetic stimulation of -adrenergic receptors is to increase heart rate. This is achieved through sympathetic
results in an increase in HR and CO. Stroke volume is the vol- nervous system (SNS) activation and the agonist effect of nor-
ume of blood ejected with each systole. Stroke volume is deter- epinephrine on -adrenergic receptors in the heart. Sympathetic
mined by factors regulating preload, afterload, and contractil- activation also enhances contractility by increasing cytosolic
ity. Preload is a measure of ventricular lling pressure, or the calcium concentrations. SV is relatively xed in HF, thus HR
volume of blood in the left ventricle (also known as LV end- becomes the major determinant of CO. Although this mechanism
diastolic volume). Preload is determined by venous return as increases CO acutely, the chronotropic and inotropic responses
well as atrial contraction. An increase in venous return to the to sympathetic activation increase myocardial oxygen demand,
left ventricle results in the stretch of cardiomyocyte sarcomeres worsen underlying ischemia, contribute to proarrhythmia, and
(or contractile units) and a subsequent increase in the number further impair both systolic and diastolic function.
of cross-bridges formed between actin and myosin myola- Activation of both the RAAS and the SNS also contribute
ments. This results in an increase in the force of contraction to vasoconstriction in an attempt to redistribute blood ow
based on the Frank-Starling mechanism.6 Afterload is the from peripheral organs such as the kidneys to coronary and
resistance to ventricular ejection and is regulated by ejection cerebral circulation.7 However, arterial vasoconstriction leads
impedence, wall tension, and regional wall geometry. Thus, to impaired forward ejection of blood from the heart due to
elevated aortic and systemic pressures result in an increase in an increase in afterload. This results in a decrease in CO and
afterload and reduced SV. Contractility, also known as the continued stimulation of compensatory responses, creating a
inotropic state of the heart, is an intrinsic property of cardiac vicious cycle of neurohormonal activation.
TABLE 32. Benecial and Detrimental Effects of the Compensatory Responses in Heart Failure
Compensatory Response Benecial Effects of Compensation Detrimental Effects of Compensation

Increased preload (through Optimize stroke volume via Pulmonary and systemic congestion
sodium and water Frank-Starling mechanism and edema formation
retention) Increased MVO2
Vasoconstriction Maintain blood pressure and Increased MVO2
perfusion in the face of reduced Increased afterload decreases stroke
cardiac output volume and further activates the
compensatory responses
Tachycardia and increased Increase cardiac output Increased MVO2
contractility (due to Shortened diastolic lling time
SNS activation) 1-Receptor down-regulation, decreased
receptor sensitivity
Precipitation of ventricular arrhythmias
Increased risk of myocardial cell death
Ventricular hypertrophy Maintains cardiac output Diastolic dysfunction
and remodeling Reduces myocardial wall stress Systolic dysfunction
Decreases MVO2 Increased risk of myocardial cell death
Increased risk of myocardial
ischemia
Increased arrhythmia risk
MVO2, myocardial oxygen consumption; SNS, sympathetic nervous system.
Cardiac Hypertrophy and Remodeling starts within a few days.5 Chronic remodeling, however, is
Ventricular hypertrophy, an adaptive increase in ventricular what progressively worsens HF and therefore is a major tar-
muscle mass due to growth of existing myocytes, occurs in get of drug therapy.
response to an increased hemodynamic burden such as vol-
ume or pressure overload.5 Hypertrophy can be concentric or
Models of Heart Failure
eccentric. Concentric hypertrophy occurs in response to pres-
sure overload such as in long-standing hypertension or pul- Earlier models of HF focused on the hemodynamic conse-
monary hypertension, whereas eccentric hypertrophy occurs quences of volume overload from excess sodium and water
after an acute myocardial infarction. Eccentric hypertrophy retention, decreased CO secondary to impaired ventricular
involves an increase in myoctye size in a segmental fashion, as function, and vasoconstriction.8 Congestion was a result of
opposed to the global hypertrophy occurring in concentric uid backup due to inadequate pump function. Therefore,
hypertrophy. Although hypertrophy helps to reduce cardiac drug therapy was focused on relieving excess volume using
wall stress in the short term, continued hypertrophy acceler- diuretics, improving pump function with inotropic agents, and
ates myocyte cell death through an overall increase in myocar- alleviating vasoconstriction with vasodilators. Although these
dial oxygen demand. agents improved HF symptoms, they did little to slow the pro-
Cardiac remodeling occurs as a compensatory adaptation gressive decline in cardiac function or to improve survival.
to a change in wall stress and is largely regulated by neuro-
hormonal activation, with angiotensin II and aldosterone Neurohormonal Model
being key stimuli.7 The process entails changes in myocardial Development and progression of HF involves activation of
and extracellular matrix composition and function which neurohormonal pathways including the sympathetic nervous
results in both structural and functional alterations to the system and the renin-angiotensin-aldosterone system (RAAS).
heart. In HF, the changes in cardiac size, shape, and composi- This model begins with an initial precipitating event or
tion are pathologic and detrimental to heart function. In myocardial injury resulting in a decline in CO, followed by the
addition to myocyte size and extracellular matrix changes, compensatory mechanisms previously discussed. This includes
heart geometry shifts from an elliptical to a less efcient activation of neurohormonal pathways with pathologic con-
spherical shape. Even after remodeling occurs, the heart can sequences including the RAAS, SNS, endothelin and vaso-
maintain CO for many years. However, heart function will pressin, and those with counterregulatory properties such as
continue to deteriorate until progression to clinical HF. The the natriuretic peptides and nitric oxide. This model currently
timeline for remodeling varies depending on the cardiac guides our therapy for chronic HF in terms of preventing dis-
insult. For example, in the setting of an acute MI, remodeling ease progression and mortality.
Angiotensin II poorest prognosis. Several mechanisms relate to diminished

Angiotensin II is a key neurohormone in the pathophysiology responsiveness to catecholamines (e.g., norepinephrine) as
of HF. The vasoconstrictive effects of angiotensin II lead to an cardiac function declines.6 Adrenergic receptor desensitiza-
increase in systemic vascular resistance (SVR) and blood pres- tion and down-regulation (decreased receptor number and
sure. The resulting increase in afterload contributes to an post-receptor responses and signaling) occurs under sustained
increase in myocardial oxygen demand and opposes the sympathetic stimulation. The desensitization contributes to
desired increase in SV. In the kidneys, angiotensin II enhances further release of norepinephrine.5 -Adrenergic blocking
renal function acutely by raising intraglomerular pressure agents, although intrinsically negatively inotropic, have
through constriction of the efferent arterioles.6 However, the become an essential therapy for chronic HF.
increase in glomerular ltration pressure may be offset by a
reduction in renal perfusion secondary to angiotensin IIs
Endothelin
inuence over the release of other vasoactive neurohormones
Endothelin-1, one of the most potent physiologic vasocon-
such as vasopressin and endothelin-1 (ET-1). Angiotensin II
strictors, is an important contributor to HF pathophysiology.9
also potentiates the release of aldosterone from the adrenal
Endothelin-1 binds to two G-protein coupled receptors,
glands and norepinephrine from adrenergic nerve terminals.
endothelin-A (ET-A) and endothelin-B (ET-B). Endothelin-A
Additionally, angiotensin II induces vascular hypertrophy and
receptors mediate vasoconstriction and are prevalent in vas-
remodeling in both cardiac and renal cells. Clinical studies
cular smooth muscle and cardiac cells. Endothelin-B recep-
show that blocking the effects of the RAAS in HF is associated
tors are expressed on the endothelium and in vascular
with improved cardiac function and prolonged survival. Thus,
smooth muscle, and receptor stimulation mediates vasodila-
angiotensin-converting enzyme (ACE) inhibitors and
tion. Levels of ET-1 correlate with HF functional class and
angiotensin receptor blockers (ARBs) are the cornerstone of
mortality.
HF treatment.
Arginine Vasopressin
Aldosterone Higher vasopressin concentrations are linked to dilutional
Aldosterones contribution to HF pathophysiology is also hyponatremia and a poor prognosis in HF. Vasopressin exerts
multifaceted. Renally, aldosterone causes sodium and water its effects through vasopressin type 1a (V1a ) and vasopressin
retention in an attempt to enhance intravascular volume and type 2 (V2) receptors.5,7 Vasopressin type 1a stimulation leads
CO. This adaptive mechanism has deleterious consequences to vasoconstriction, while actions on the V2 receptor cause
since excessive sodium and water retention worsen the already free water retention through aquaporin channels in the col-
elevated ventricular lling pressures. Aldosterone also con- lecting duct. Vasopressin increases preload, afterload, and
tributes to electrolyte abnormalities seen in HF patients. myocardial oxygen demand in the failing heart.
Hypokalemia and hypomagnesemia contribute to the increased
risk of arrhythmias. In addition, evidence supports the role of
aldosterone as an etiologic factor for myocardial brosis and Counterregulatory Hormones (Natriuretic Peptides,
cardiac remodeling.6 Elevated aldosterone concentrations Bradykinin, and Nitric Oxide)
have been associated with more severe cardiac disease and a Atrial natriuretic peptide (ANP) and B-type (formerly brain)
poorer prognosis in HF. Thus, aldosterone antagonism has natriuretic peptide (BNP) are endogenous neurohormones
become an important therapeutic target for improvement of that regulate sodium and water balance. Natriuretic peptides
long-term prognosis. decrease sodium reabsorption in the collecting duct of the
kidney.10 Natriuretic peptides also cause vasodilation through
the cyclic guanosine monophosphate (cGMP) pathway. Atrial
Norepinephrine natriuretic peptide is synthesized and stored in the atria, while
Norepinephrine is a classic marker for SNS activation. It plays BNP is produced mainly in the ventricles. Release of ANP and
an adaptive role in the failing heart by stimulating HR and BNP is stimulated by increased cardiac chamber wall stretch
myocardial contractility to augment CO and by producing usually indicative of volume load. Higher concentrations of
vasoconstriction to maintain organ perfusion. However, natriuretic peptides correlate with a more severe HF func-
excess levels are directly cardiotoxic. In addition, sympathetic tional class and prognosis. BNP is sensitive to volume status;
activation increases the risk for arrhythmias, ischemia, and thus, the plasma concentration can be used as a diagnostic
myocyte cell death through increased myocardial workload marker in HF.10
and accelerated apoptosis (i.e., programmed cell death). Bradykinin is part of the kallikrein-kinin system, which
Ventricular hypertrophy and remodeling are also inuenced shares a link to the RAAS through angiotensin-converting
by norepinephrine.8 enzyme. Bradykinin is a vasodilatory peptide that is released in
Plasma norepinephrine concentrations are elevated pro- response to a variety of stimuli, including neurohormonal and
portionally to HF severity, with highest levels correlating to the inammatory mediators known to be activated in HF.9 As a
consequence, bradykinin levels are elevated in HF patients and TABLE 33. Exacerbating or Precipitating Factors in Heart
thought to partially antagonize the vasoconstrictive peptides. Failure
Nitric oxide, a vasodilatory hormone released by the
Cardiac Metabolic Patient-Related
endothelium, is found in higher concentrations in HF
patients and provides two main benets in HF: vasodilation Acute ischemia Anemia Dietary/uid
Arrhythmia Hyperthyroidism/ non-adherence
and neurohormonal antagonism of endothelin.9 Nitric
Endocarditis thyrotoxicosis HF therapy non-adherence
oxides production is affected by the enzyme inducible nitric Myocarditis Infection Use of cardiotoxins
oxide synthetase (iNOS), which is up-regulated in the setting Pulmonary Pregnancy (cocaine, chronic
of HF, likely due to increased levels of angiotensin II, norep- embolus Worsening renal alcohol, amphetamines,
inephrine, and multiple cytokines. In HF, the physiologic Uncontrolled function sympathomimetics)
hypertension Offending medications
response to nitric oxide appears to be blunted, which con-
Valvular (NSAIDs, COX-2
tributes to the imbalance between vasoconstriction and disorders inhibitors, steroids,
vasodilation. lithium, -blockers,
calcium channel
blockers, anti-
Cardiorenal Model arrhythmics, alcohol,
There is growing evidence of a link between renal disease thiazolidinediones)
and HF. 8 Renal insufficiency is present in one-third of HF
COX-2, cyclooxygenase-2; HF, heart failure; NSAID, non-steroidal anti-
patients and is associated with a worse prognosis. In hos- inammatory drug.
pitalized HF patients, the presence of renal insufficiency
is associated with longer lengths of stay, increased in-
hospital morbidity and mortality, and detrimental neu-
rohormonal alterations. Conversely, renal dysfunction is HF medications deserves special attention, as it is the most com-
a common complication of HF or results from its treat- mon cause of acute decompensation and can be prevented. As
ment. Renal failure is also a common cause for HF such, an accurate history regarding diet, food choices, and the
decompensation. patients knowledge regarding sodium and uid intake (including
alcohol) is valuable in assessing dietary indiscretion. Non-
Proinammatory Cytokines adherence with medical recommendations such as laboratory
Inammatory cytokines have been implicated in the patho- and other appointment follow-up can also be indicative of
physiology of HF.9 Several proinflammatory (e.g., tumor non-adherence with diet or medications.
necrosis factor- [TNF-], interleukin-1, interleukin-6,
and interferon-) and anti-inflammatory cytokines (e.g.,
interleukin-10) are overexpressed in the failing heart. The
most is known about TNF-, a pleiotrophic cytokine that
acts as a negative inotrope, stimulates cardiac cell apoptosis, Patient Encounter, Part 1
uncouples -adrenergic receptors from adenylyl cyclase,
and is related to cardiac cachexia. The exact role of
cytokines and inammation in HF pathophysiology contin- BE is a 62-year-old female with a history of known coronary
ues to be studied. artery disease and type 2 diabetes mellitus who presents for a
belated follow-up clinic visit (her last visit was 2 years ago).
She states that she used to be able to walk over one-half
Precipitating and Exacerbating Factors in mile (0.8 km) and two ights of stairs before experiencing
Heart Failure chest pain and becoming short of breath. Since her last
visit, she has had increasing symptoms and has now pro-
Heart failure patients exist in one of two clinical states. When gressed to shortness of breath (SOB) with walking only half
a patients volume status and symptoms are stable, their HF a block and doing chores around the house. She also notes
condition is said to be compensated. In situations of volume her ankles are always swollen and her shoes no longer t,
overload or other worsening symptoms, the patient is consid- therefore she only wears slippers. Additionally, her appetite
ered decompensated. Acute decompensation can be precipi- is decreased, and she often feels bloated. She also feels full
tated by numerous etiologies that can be grouped into cardiac, after eating only a few bites of each meal.
metabolic, or patient-related causes (Table 33).5
What information is suggestive of a diagnosis of heart
The clinician must identify potential reversible causes of failure?
HF exacerbations including prescription and non-prescription What additional information do you need to know before
drug therapies, dietary indiscretions, and medication non- creating a treatment plan for BE?
adherence. Non-adherence with dietary restrictions or chronic
CLINICAL PRESENTATION AND DIAGNOSIS OF

CHRONIC HEART FAILURE Clinical Presentation and Diagnosis of
Heart Failure
In low-output HF, symptoms are generally related to either
congestion behind the failing ventricle(s), or hypoperfusion General
(decreased tissue blood supply), or both. Congestion is the Patient presentation may range from asymptomatic to
most common symptom in HF, followed by symptoms cardiogenic shock.
related to decreased perfusion to peripheral tissues including Symptoms
decreased renal output, mental confusion, and cold extrem- Dyspnea, particularly on exertion
ities. Activation of the compensatory mechanisms occurs in Orthopnea
an effort to increase CO and preserve blood ow to vital Shortness of breath (SOB)
organs. However, the increase in preload and afterload in Paroxysmal nocturnal dyspnea
the setting of a failing ventricle leads to elevated lling pres- Exercise intolerance
sures and further impairment of cardiac function, which Tachypnea
Cough
manifests as systemic and/or pulmonary congestion. It is
Fatigue
important to remember that congestion develops behind Nocturia and/or polyuria
the failing ventricle, caused by the inability of that ventricle Hemoptysis
to eject the blood that it receives from the atria and venous Abdominal pain
return. As such, signs and symptoms may be classied as Anorexia
left-sided or right-sided. Symptoms of left-sided HF Nausea
include dyspnea, orthopnea, and paroxysmal nocturnal dysp- Bloating
Ascites
nea (PND), whereas symptoms of right-sided HF include uid
Mental status changes
retention, gastrointestinal bloating, and fatigue. Although Weakness
most patients initially have left ventricular failure (LVF; pul- Lethargy
monary congestion), the ventricles share a septal wall, and
Signs
because LVF increases the workload of the right ventricle, Pulmonary rales
both ventricles eventually fail and contribute to the HF syn- Pulmonary edema
drome. Because of the complex nature of this syndrome, it has S3 gallop
become exceedingly more difcult to attribute a specic sign Pleural effusion
or symptom as caused by either right ventricular failure Cheyne-Stokes respiration
(RVF; systemic congestion) or LVF. Therefore, the numerous Tachycardia
Cardiomegaly
signs and symptoms associated with this disorder are collec-
Peripheral edema (e.g., pedal edema, which is swelling of
tively attributed to HF rather than to dysfunction of a specic feet and ankles)
ventricle. Jugular venous distension (JVD)
Hepatojugular reex (HJR)
Hepatomegaly
General Signs and Symptoms Cyanosis of the digits
Pallor or cool extremities
Hypoperfusion of skeletal muscles leads to fatigue, weak-
ness, and exercise intolerance. Decreased perfusion of the Laboratory Tests
BNP greater than 100 pg/mL (greater than 100 ng/L) or
central nervous system (CNS) is related to confusion, hallu-
N-terminal proBNP (NT-proBNP) greater than 300 pg/mL
cinations, insomnia, and lethargy. Peripheral vasoconstric- (greater than 300 ng/L or greater than 35.4 pmol/L)
tion due to SNS activity causes pallor, cool extremities, and Electrocardiogram (ECG): May be normal or could show
cyanosis of the digits. Tachycardia is also common in these numerous abnormalities including acute ST-Twave
patients and may reect increased SNS activity. Patients will changes from myocardial ischemia, atrial brillation,
often exhibit polyuria and nocturia. Polyuria is a result of bradycardia, and LV hypertrophy.
increased release of natriuretic peptides caused by volume Serum creatinine: May be increased owing to hypoper-
fusion; preexisting renal dysfunction can contribute to
overload. Nocturia occurs due to increased renal perfusion
volume overload.
as a consequence of reduced SNS renal vasoconstrictive Complete blood count: Useful to determine if heart failure
effects at night. In chronic severe HF, unintentional weight is due to reduced oxygen-carrying capacity.
loss can occur which leads to a syndrome of cardiac Chest x-ray: Useful for detection of cardiac enlargement,
cachexia. This results from several factors, including loss of pulmonary edema, and pleural effusions.
appetite, malabsorption due to gastrointestinal edema, ele- Echocardiogram: Used to assess LV size, valve function,
vated metabolic rate, and elevated levels of proinammatory pericardial effusion, wall motion abnormalities, and ejec-
tion fraction.
cytokines.
Patients can experience a variety of symptoms related to infrequently and is caused by long-term systemic venous conges-
buildup of uid in the lungs. Dyspnea, or shortness of breath, tion. Intestinal or abdominal congestion can also be present, but
can result from pulmonary congestion or systemic hypoper- usually doesnt lead to characteristic signs unless overt ascites is
fusion due to LVF. Exertional dyspnea occurs when patients evident. In advanced RVF, evidence of pulmonary hypertension
describe breathlessness induced by physical activity or a lower may be present (e.g., right ventricular heave).
level of activity than previously known to cause breathless- The most recognized nding of systemic congestion is
ness. Patients often state that activities such as stair climbing, peripheral edema. It usually occurs in dependent areas of the
carrying groceries, or walking a particular distance cause body, such as the ankles (pedal edema) for ambulatory
shortness of breath. Severity of HF is inversely proportional to patients, or the sacral region for bedridden patients. Weight
the amount of activity required to produce dyspnea. In severe gain often precedes signs of overt peripheral edema. Therefore,
HF, dyspnea will be present even at rest. it is crucial for patients to weigh themselves daily even in the
Orthopnea is dyspnea that is positional. Orthopnea is pres- absence of symptoms to assess uid status.
ent if a patient is unable to breathe while lying at on a bed Patients may complain of swelling of their feet and ankles,
(i.e., in the recumbent position). It manifests within minutes which can extend up to their calves or thighs. Abdominal con-
of a patient lying down and is relieved immediately when the gestion may cause a bloated feeling, abdominal pain, early
patient sits upright. Patients can relieve orthopnea by elevat- satiety, nausea, anorexia, and constipation. Often patients may
ing their head and shoulders with pillows. The practitioner have difculty tting into their shoes or pants due to edema.
should inquire as to the number of pillows needed to prevent
dyspnea as a marker of worsening HF. Paroxysmal nocturnal Patient History
dyspnea occurs when patients awaken suddenly with a feeling A thorough history is crucial to identify cardiac and non-car-
of breathlessness and suffocation. Paroxysmal nocturnal dys- diac disorders or behaviors that may lead to or accelerate the
pnea is caused by increased venous return and mobilization of development of HF. Past medical history, family history, and
interstitial uid from the extremities, leading to alveolar social history are important for identifying comorbid illnesses
edema and usually occurs within 1 to 4 hours of sleep. In con- that are risk factors for the development of HF or underlying
trast to orthopnea, PND is not relieved immediately by sitting etiologic factors. A complete medication history (including
upright and often takes up to 30 minutes for symptoms to prescription and non-prescription drugs, herbal therapy, and
subside. vitamin supplements) should be obtained each time a patient is
Pulmonary congestion may also cause a non-productive seen to evaluate adherence, to assess appropriateness of therapy,
cough that occurs at night or with exertion. Cheyne-Stokes to eliminate drugs that may be harmful in HF (Table 34), and
respiration, or periodic breathing, is common in advanced to determine additional monitoring requirements. For newly
HF. It is usually associated with low-output states and may be
perceived by the patient as either severe dyspnea or transient
cessation of breathing. In cases of pulmonary edema, the most TABLE 34. Drugs That May Precipitate or Exacerbate Heart
severe form of pulmonary congestion, patients may produce a Failure
pink, frothy sputum and experience extreme breathlessness
Agents Causing Negative Inotropic Effect
and anxiety due to feelings of suffocation and drowning. If Antiarrhythmics (e.g., disopyramide, ecainide, and others)
not treated aggressively, patients can become cyanotic and aci- -Blockers (e.g., propranolol, metoprolol, atenolol, and others)
dotic. Severe pulmonary edema can progress to respiratory Calcium channel blockers (e.g., verapamil and others)
failure, necessitating mechanical ventilation. Itraconazole
Terbinane
Systemic venous congestion results mainly from right ven-
Rosiglitazone
tricular failure. A clinically validated assessment of the jugular
Cardiotoxic Agents
venous pressure (JVP) is performed by examining the right Doxorubicin
internal jugular vein for distention or elevation of the pulsa- Daunomycin
tion while reclining at a 45 degree angle. A JVP more than 4 cm Cyclophosphamide
above the sternal angle is indicative of elevated right atrial Agents Causing Sodium and Water Retention
pressure. Jugular venous pressure may be normal at rest, but if Non-steroidal anti-inammatory drugs
application of pressure to the abdomen can elicit a sustained COX-2 inhibitors
Glucocorticoids
elevation of JVP, this is dened as hepatojugular reux (HJR).
Androgens
A positive nding of HJR indicates hepatic congestion and Estrogens
results from displacement of volume from the abdomen into Salicylates (high-dose)
the jugular vein because the right atrium is unable to accept Sodium-containing drugs (e.g., carbenicillin disodium, ticarcillin
this additional blood. Hepatic congestion can cause abnormal- disodium)
Thiazolidinediones (e.g., rosiglitazone, pioglitazone)
ities in liver function, which can be evident in liver function
tests and/or clotting times. Development of hepatomegaly occurs COX-2, cyclooxygenase-2.
diagnosed HF, previous use of chemotherapeutic agents as well as classications, patients are placed into stages A through D
current or past use of alcohol and illicit drugs should be assessed. (Table 35).11 Stage A encompasses patients who carry risk fac-
In addition, for patients with a known history of HF, questions tors for the development of HF, such as CAD, hypertension, and
related to symptomatology and exercise tolerance are essential diabetes mellitus. Stage B includes high-risk patients with docu-
for assessing any changes in clinical status that may warrant fur- mented structural heart disease (LV hypertrophy or impaired LV
ther evaluation or adjustment of the medication regimen. function). Stage C denotes patients with current or past symp-
toms of HF and underlying structural heart disease. Stage D is
Heart Failure Classication reserved for those with refractory or end-stage HF in whom spe-
cial interventions may be indicated, such as mechanical circula-
There are two common systems for categorizing patients with
tory support. Since the staging system is related to development
HF. The New York Heart Association (NYHA) Functional
and progression of HF, it also proposes management strategies for
Classication (FC) system is based on the patients activity level
each stage including risk factor modication. The staging system
and exercise tolerance. It divides patients into one of four classes,
is meant to complement the NYHA FC system; however, patients
with functional class I patients exhibiting no symptoms or lim-
can move between NYHA functional classes as symptoms
itations of daily activities, and functional class IV patients who
improve with treatment, whereas HF staging does not allow for
are symptomatic at rest (Table 35). The NYHA FC system
patients to move to a lower stage (e.g., patients cannot be catego-
reects a subjective assessment by a health care provider and can
rized as stage C and move to stage B after treatment). Currently,
change frequently over short periods of time. Functional class
patients are categorized based on both systems. Functional classi-
correlates poorly with EF; however, EF is one of the strongest
cation and staging are useful from a clinicians perspective,
predictors of prognosis. In general, anticipated survival declines
allowing for a longitudinal assessment of a patients risk and
in conjunction with a decline in functional ability.
progress, requirements for nonpharmacologic interventions,
The American College of Cardiology/American Heart
response to medications, and overall prognosis.
Association (ACC/AHA) has proposed another system based
on the development and progression of the disease. Instead of
Patient Encounter, Part 2
TABLE 35. New York Heart Association (NYHA) Functional
Classication and American College of Cardiology/
American Heart Association (ACC/AHA) Staging
BEs Medical History, Physical Exam, and Diagnostic Tests
NYHA ACC/ PMH
Functional AHA Type 2 diabetes mellitus 15 years
Class Stage Description Coronary artery disease 10 years (MIs in 1999 and 2002)
N/A A Patients at high risk for heart failure but Tobacco use
without structural heart disease or History of back surgery in 2001
symptoms of heart failure.
Allergies
I B Patients with cardiac disease but No known drug allergies
without limitations of physical activ-
ity. Ordinary physical activity does Meds
not cause undue fatigue, dyspnea, Diltiazem CD 240 mg once daily
or palpitation. Nitroglycerin 0.4 mg sublingual (SL) as needed (last use
II C Patients with cardiac disease that yesterday after showering)
results in slight limitations of Ibuprofen 600 mg twice daily for arthritis pain
physical activity. Ordinary physical Vitamin B12 once daily
activity results in fatigue, Multivitamin daily
palpitations, dyspnea, or angina. Aspirin 325 mg once daily
III C Patients with cardiac disease that FH
results in marked limitation of physi-
Signicant for early heart disease in father (MI at age 53)
cal activity. Although patients are
comfortable at rest, less than ordi- SH
nary activity will lead to symptoms. She is disabled from a previous accident; she is married, has
IV C, D Patients with cardiac disease that 6 children, and runs her own business; she does not drink
results in an inability to carry on alcohol and smokes one to two packs of cigarettes per day.
physical activity without discomfort.
PE
Symptoms of heart failure are
present at rest. With any physical Blood pressure 126/70 mm Hg, pulse 60 bpm and regular,
activity, increased discomfort is respiratory rate 16/minute, Ht 58 (173 cm), Wt 251 lb
experienced. Stage D refers to (114 kg), body mass index (BMI): 38.2 kg/m2
end-stage heart failure patients. (Continued)
stage D, the goals shift toward quality-of-life related issues.

Patient Encounter, Part 2 (Continued ) Only with aggressive management throughout all the stages
of the disease will the ultimate goal of improving survival be
Lungs are clear to auscultation with a prolonged expiratory realized. The attainment of these goals is based on designing
phase; rales are present bilaterally
a therapeutic approach that encompasses strategies aimed
CV: Regular rate and rhythm with normal S1 and S2; there is at control and treatment of contributing disorders, non-
an S3 and a soft S4 present; there is a 2/6 systolic ejection pharmacologic interventions, and optimal use of pharma-
murmur heard best at the left lower sternal border; point of cologic therapies.12,13
maximal impulse is within normal limits at the midclavicu-
lar line; there is no JVD
Abd: Soft, non-tender, and bowel sounds are present; 2+
Control and Treatment of Contributing Disorders
pitting edema of extremities extending to below the knees All causes of HF must be investigated to determine the etiol-
is observed ogy of cardiac dysfunction in a given patient. Since the most
Chest x-ray: Bilateral pleural effusions and cardiomegaly common etiology of HF in the United States is ischemic heart
disease, coronary angiography is warranted in the majority of
Echocardiogram: EF = 35%
patients with a history suggestive of underlying CAD.
Laboratory Values Revascularization of those with signicant CAD may help
Hct: 41.1% WBC: 5.3 103/L (5.3 109/L) restore some cardiac function in patients with reversible
Sodium: 132 mEq/L Potassium: 3.2 mEq/L
ischemic defects. Aggressive control of hypertension, diabetes,
(132 mmol/L) (3.2 mmol/L)
and obesity is also essential since each of these conditions can
Bicarb: 30 mEq/L Chloride: 90 mEq/L
(30 mmol/L) (90 mmol/L) cause further cardiac damage. Surgical repair of valvular dis-
Magnesium: 1.5 mEq/L Fasting blood sugar: 120 mg/dL ease or congenital malformations may be warranted if
(0.8 mmol/L) (6.7 mmol/L) detected. Since clinical HF is partly dependent on metabolic
Uric acid: 8 mg/dL Blood urea nitrogen (BUN): processes, correction of imbalances such as thyroid disease and
(476 mol/L) 40 mg/dL (14 mmol/L) anemia is required. Other more rare causes such as autoim-
SCr: 0.8 mg/dL Alk Phos: 120 IU/L (2 Kat/L) mune disorders or acquired illnesses may have specic treat-
(71 mol/L) ments. Identifying and discontinuing medications that can
Aspartate aminotransferase: 100 IU/L (1.7 Kat/L) exacerbate HF is also an important intervention.
What other laboratory or other diagnostic tests are required
for assessment of BEs condition? Nonpharmacologic Interventions
How would you classify BEs NYHA functional class and
ACC/AHA heart failure stage? It is imperative that patients recognize the role of self-management
Identify exacerbating or precipitating factors that may in HF. Nonpharmacologic treatment involves dietary modica-
worsen BEs heart failure. tions such as sodium and uid restriction, risk factor reduction
What are your treatment goals for BE? including smoking cessation, timely immunizations, and super-
vised regular physical activity. Patient education regarding moni-
toring symptoms, dietary and medication adherence, exercise and
physical tness, risk factor reduction, and immunizations are
TREATMENT OF CHRONIC HEART FAILURE important for prevention of AHF exacerbations.
Patients should be encouraged to become involved in their
Desired Therapeutic Outcomes own care through several avenues, the rst of which is self-
There is no cure for HF. The general management goals for monitoring. A general explanation of symptoms associated
chronic HF include preventing the onset of clinical symptoms or with HF should be included at the initiation of treatment.
reducing symptoms, preventing or reducing hospitalizations, slow- Home monitoring should include daily assessment of weight
ing progression of the disease, improving quality of life, and pro- and exercise tolerance. Daily weights should be done rst
longing survival. The ACC/AHA staging system described earlier thing in the morning upon arising and before any food intake
provides a guide for application of these goals based on the clin- to maintain consistency. Patients should record their weight
ical progression of HF for a given patient. The goals are additive daily in a journal and bring this log to each clinic or ofce
as one moves from stage A to stage D.1,11 For stage A, risk factor visit. Changes in weight can indicate uid retention and con-
management is the primary goal. Stage B includes the addition gestion prior to onset of peripheral or pulmonary symptoms.
of pharmacologic therapies known to slow the progression of Individuals who have an increase of 2 to 3 pounds (0.91 to
the disease in an attempt to prevent the onset of clinical symp- 1.36 kg) in a single day or 5 pounds (2.27 kg) over 5 days should
toms. Stage C involves the use of additional therapies aimed be referred to their HF care provider. Some patients may be edu-
at controlling symptoms and decreasing morbidity. Finally, in cated about self-adjusting diuretic doses based on daily weights.
In addition to weight changes, a marked decline in exercise tol- tobacco products.1 All HF patients who smoke should be
erance should also be reported to the HF care provider. counseled on the importance of tobacco cessation and offered
Non-adherence is an important issue as it relates to acute a referral to a cessation program. Patients with an alcoholic
exacerbations of HF. Ensuring an understanding of the cardiomyopathy should abstain from alcohol. Whether all
importance of each medication used to treat HF, proper patients with other forms of HF should abstain from any
administration, and potential adverse effects may improve alcohol intake remains controversial. Proponents of modera-
adherence. Stressing the rationale for each medication is tion of alcohol base their rationale on the potential cardio-
important, especially for NYHA FC I or ACC/AHA stage B protective effects. However, opponents to any alcohol intake
patients who are asymptomatic, yet started on drugs that may point out that alcohol is cardiotoxic and should be avoided.
worsen symptoms initially. A clinicians involvement in In general, it is suggested that patients remain up to date on
emphasizing medication adherence, offering adherence sug- standard immunizations. Patients with HF should be coun-
gestions such as optimal timing of medications or use of seled to receive yearly inuenza vaccinations. Additionally, a
weekly pill containers, and providing intensive follow-up care pneumococcal vaccine is recommended. Usually only one
has been shown to reduce AHF hospitalizations. pneumonia vaccination is necessary unless a patient is vacci-
Dietary modications in HF consist of initiation of an AHA nated before age 65. In that case, a booster vaccination is sug-
step II diet as part of cardiac risk factor reduction, sodium gested 5 years after the initial vaccination.
restriction, and sometimes uid restriction. As sodium and
water retention is a compensatory mechanism that contributes
to volume overload in HF, salt and uid restriction is often nec- Pharmacologic Treatment
essary to help avoid or minimize congestion. The normal In addition to determining therapeutic goals, the ACC/AHA
American diet includes 3 to 6 grams of sodium per day. Most staging system delineates specic therapy options based on dis-
patients with HF should limit salt intake to a maximum of ease progression.1,11 For patients in stage A, every effort is made
2 grams per day. Patients should be educated to avoid cooking to minimize the impact of diseases that can injure the heart.
with salt and to limit intake of foods with high salt content, such Antihypertensive and lipid-lowering therapies should be uti-
as fried or processed food (lunchmeats, soups, cheeses, salted lized when appropriate to decrease the risk for stroke, MI, and
snack foods, canned food, and some ethnic food). Salt restric- HF. ACE inhibitors should be considered in high-risk vascular
tion can be challenging for many patients. The clinician should disease patients. For stage B patients, the goal is to prevent or
assess a patients salt consumption habits and counsel to restrict slow disease progression by interfering with neurohormonal
salt slowly over time. Drastic dietary changes may lead to non- pathways that lead to cardiac damage and mediate pathologic
adherence due to an unpalatable diet. Substituting spices to a- remodeling. The goal is to prevent the onset of HF symptoms.
vor food is a useful recommendation. Salt substitutes should be The backbone of therapy in these patients includes ACE
used judiciously, as many contain large amounts of potassium inhibitors or ARBs and -blockers. In stage C patients with
which can increase the risk of hyperkalemia. Fluid restriction symptomatic LV systolic dysfunction (EF less than 40%), the
may not be necessary in many patients. When applicable, a gen- goals focus on alleviating uid retention, minimizing disability,
eral recommendation is to limit uid intake from all sources to slowing disease progression, and reducing long-term risk for
less than 2 liters per day. hospitalizations and death. Treatment entails a strategy that
Exercise, while discouraged when the patient is acutely combines diuretics to control intravascular uid balance with
decompensated to ease cardiac workload, is recommended neurohormonal antagonists to minimize the effects of the RAAS
when patients are stable. The heart is a muscle that requires and SNS. Aldosterone antagonists and digoxin are often added
activity to prevent atrophy. In addition, exercise improves as cardiac function continues to decline. Patients with advanced
peripheral muscle conditioning and efciency, which may con- stage D disease are offered more modest goals, such as improve-
tribute to better exercise tolerance despite the low CO state. ment in quality of life. Enhancing quality of life is often achieved
Regular low intensity, aerobic exercise that includes walking, at the expense of expected survival. Treatment options include
swimming, or riding a bike is encouraged, while heavy weight mechanical support, transplantation, and continuous use of
training is discouraged. The prescribed exercise regimen needs intravenous vasoactive therapies, in addition to maintaining an
to be tailored to the individuals functional ability, and thus it is optimal regimen of chronic oral medications.
suggested that patients participate in cardiac rehabilitation pro-
grams, at least initially. It is important that patients not overex- Diuretics
ert themselves to fatigue or exertional dyspnea. Diuretics have been the mainstay for HF symptom man-
Modication of classic risk factors, such as tobacco and agement for many years. Diuretics are used for relief of acute
alcohol consumption, is important to minimize the potential symptoms of congestion and maintenance of euvolemia. These
for further aggravation of heart function. Data from observa- agents interfere with sodium retention by increasing urinary
tional studies suggest that patients with HF who smoke have a sodium and free water excretion. No prospective data exist on
mortality rate 40% higher than those who do not consume the effects of diuretics on patient outcomes.14 Therefore, the
primary rationale for the use of diuretic therapy is to maintain TABLE 36. Loop Diuretics Used in Heart Failure
euvolemia in symptomatic or stages C and D heart failure.
Furosemide Bumetanide Torsemide
Diuretic therapy is recommended for all patients with clinical
evidence of uid overload retention.15,16 In more mild HF, Usual daily 20160 mg 0.54 mg 1080 mg
diuretics may be used on an as-needed basis. However, once dose (oral)
the development of edema is persistent, regularly scheduled Ceiling dose:
Normal renal 80160 mg 12 mg 2040 mg
doses will be required.
function
Two types of diuretics are used for volume management in CrCL 2050 160 mg 2 mg 40 mg
HF: thiazides and loop diuretics. Thiazide diuretics such as mL/minute
hydrochlorothiazide, chlorthalidone, and metolazone block CrCL less than 400 mg 810 mg 100 mg
sodium and chloride reabsorption in the distal convoluted 20 mL/minute
tubule. Thiazides are weaker than loop diuretics in terms of Bioavailability 10100% 8090% 80100%
effecting an increase in urine output and therefore are not uti- (average 50%)
lized frequently as monotherapy in HF. They are optimally suited Affected by food Yes Yes No
for patients with hypertension who have mild congestion. Half-life 0.33.4 hours 0.31.5 34
Additionally, the action of thiazides is limited in patients with hours hours
renal insufciency (creatinine clearance less than 30 mL/minute) CrCL, creatinine clearance.
due to reduced secretion into their site of action. An exception is
metolazone, which retains its potent action in patients with renal day. Patients with severe volume overload should be managed
dysfunction. Metolazone is often used in combination with loop in an inpatient setting. Once diuretic therapy is initiated,
diuretics when patients exhibit diuretic resistance, dened as dosage adjustments are based on symptomatic improvement
edema unresponsive to loop diuretics alone. and daily body weight. As body weight changes are a sensitive
Loop diuretics are the most widely used diuretics in HF. marker of uid retention or loss, patients should continue to
These agents, including furosemide, bumetanide, and weigh themselves daily. Once a patient reaches a euvolemic
torsemide, exert their action at the thick ascending loop of state, diuretics may be cautiously tapered and then withdrawn
Henle. Loop diuretics are not ltered through the glomerulus, in appropriate patients. In stable, educated, and compliant
but instead undergo active transport into the tubular lumen patients, another option is self-adjusted diuretic dosing. Based
via the organic acid pathway. As a result, drugs that compete on daily body weight, patients may temporarily increase their
for this active transport (e.g., probenecid and organic by- diuretic regimen in order to reduce the incidence of overt
products of uremia) can lower efcacy of loop diuretics. Loop edema. This also avoids overuse of diuretics and possible
diuretics increase sodium and water excretion and induce a complications of over-diuresis such as hypotension, fatigue,
prostaglandin-mediated increase in renal blood ow which and renal impairment.
contributes to their natriuretic effect. Unlike thiazides, they The maximal response to diuretics is reduced in HF, creat-
retain their diuretic ability in patients with poor renal func- ing a ceiling dose above which there is limited added bene-
tion. The various loop diuretics are equally effective when used t. This diuretic resistance is due to a compensatory increase
at equipotent doses, although there are intrinsic differences in in sodium reabsorption in the proximal and distal tubules,
pharmacokinetics and pharmacodynamics (Table 36).5 The which decreases the effect of blocking sodium reabsoption in
choice of which loop diuretic to use and the route of adminis- the loop of Henle.17 In addition, there is a simultaneous
tration depends on clinical factors, such as presence of intes- increase in the reabsorption of sodium from the proximal
tinal edema and rapidity of desired effect. Oral diuretic efcacy tubule, allowing less to reach the site of action for loop diuret-
may vary based on differing bioavailability, which is almost ics. Apart from increasing diuretic doses, strategies to improve
complete for torsemide and bumetanide, but averages only diuretic efcacy include increasing the frequency of dosing to
50% for furosemide. Therefore, oral torsemide can be consid- two or three times daily, utilizing a continuous infusion of a
ered an alternative to the intravenous route of administration loop diuretic, and/or combining a loop diuretic with a thi-
for patients who do not respond to oral furosemide in the set- azide diuretic.17,18 The latter strategy theoretically prevents
ting of profound edema. The onset of effect is slightly delayed sodium and water reabsorption at both the loop of Henle and
after oral administration but occurs within a few minutes with the compensating distal convoluted tubule. Metolazone is
intravenous dosing. Consequently, bioequivalent doses of used most often for this purpose, as it retains its activity in set-
intravenous furosemide are half the oral dose, whereas tings of a low creatinine clearance. Metolazone can be dosed
bumetanide and torsemide intravenous doses are generally daily or as little as once weekly. This combination is usually
equivalent to the oral doses. maintained until the patient reaches his or her baseline weight.
In patients with evidence of mild to moderate volume Diuretics cause numerous adverse effects and metabolic
overload, diuretics should be initiated at a low dose and abnormalities, with severity linked to diuretic potency. A par-
titrated to achieve a weight loss of up to 2 pounds (0.91 kg) per ticularly worrisome adverse effect in the setting of HF is
hypokalemia. Low serum potassium can predispose patients doses and titrated up to target doses over several weeks depend-
to arrhythmias and sudden death. Hypomagnesemia often ing on tolerability (adverse effects and blood pressure). The
occurs concomitantly with diuretic-induced hypokalemia, ACC/AHA 2005 guidelines advocate using the doses that were
and therefore both should be assessed and replaced in patients proven to decrease mortality in clinical trials as the target doses
needing correction of hypokalemia. Magnesium is an essential (Table 37).1 If the target dose cannot be attained in a given
co-factor for movement of potassium intracellularly to restore patient, the highest tolerated dose should be used chronically.
body stores. Patients taking diuretics are also at risk for renal Although there is incremental benet with higher doses of ACE
insufciency due to overdiuresis and reex activation of the inhibitors, it is accepted that lower doses provide substantial if
renin-angiotensin system. The potential reduction in renal not the majority of the effect.22 Since ACE inhibitors are only one
blood ow and glomerular pressure is amplied by concomi- component of a mortality-reducing treatment plan in HF, target-
tant use of ACE inhibitors or ARBs. ing a high ACE inhibitor dose should not interfere with starting
a -blocker or aldosterone antagonist. Specically, higher ACE
Neurohormonal Blocking Agents inhibitor dosing may accentuate the hypotensive effects. Higher
Agents with proven benets in improving symptoms, slow- ACE inhibitor dosing may also limit tolerability of a regimen
ing disease progression, and improving survival in chronic HF which also includes -blockers and aldosterone antagonists.
target neurohormonal blockade. These include ACE inhibitors, Despite their clear benets, ACE inhibitors are still under-
ARBs, b-adrenergic blockers, and aldosterone antagonists. utilized in HF. One reason is undue concern or confusion
regarding absolute versus relative contraindications for their use.
Angiotensin-Converting Enzyme Inhibitors Absolute contraindications include a history of angioedema,
ACE inhibitors are the cornerstone of treatment for HF. ACE bilateral renal artery stenosis, and pregnancy. Relative con-
inhibitors decrease neurohormonal activation by blocking the traindications include unilateral renal artery stenosis, renal
conversion of angiotensin I (AT1) to angiotensin II (AT2), a insufciency, hypotension, hyperkalemia, and cough. Relative
potent mediator of vasoconstriction and cardiac remodeling. contraindications provide a warning that close monitoring is
The breakdown of bradykinin is also reduced. Bradykinin required, but they do not necessarily preclude their use.
enhances the release of vasodilatory prostaglandins and hista- Clinicians are especially concerned about the use of ACE
mines. These effects result in arterial and venous dilatation, inhibitors in patients with renal insufciency. It is important
and a decrease in myocardial workload through reduction of to recognize that ACE inhibitors can potentially contribute to
both preload and afterload. ACE inhibitors demonstrate preservation or decline in renal function depending on the
favorable effects on cardiac hemodynamics, such as long-term clinical scenario. Through preferential efferent arteriole
increases in cardiac index (CI), stroke work index, and SV vasodilation, ACE inhibitors can reduce intraglomerular pres-
index, as well as signicant reductions in LV lling pressure, sure. Reduced glomerular pressures are renoprotective chron-
SVR, mean arterial pressure, and HR. ically; however, in situations of reduced or xed renal blood
There is extensive clinical experience with ACE inhibitors ow, this leads to a reduction in ltration. In general, ACE
in systolic HF. Numerous clinical studies show ACE inhibitor inhibitors can be used in patients with serum creatinine less
therapy is associated with improvements in clinical symp- than 2.5 to 3 mg/dL (221 to 265 mol/L). In HF, their addition
toms, exercise tolerance, NYHA functional class, LV size and can result in improved renal function through an increase in
function, and quality of life as compared with placebo.1821 CO and renal perfusion. Some data suggest that ACE inhibitors
ACE inhibitors signicantly reduce hospitalization rates and are especially benecial in those with renal dysfunction.
mortality regardless of underlying disease severity or etiology. Although a small increase in serum creatinine (less than
ACE inhibitors are also effective in preventing HF develop- 0.5 mg/dL [44 mol/L]) is possible with the addition of an ACE
ment in high-risk patients. Studies in acute MI patients show inhibitor, it is usually transient or becomes the patients new
a reduction in new-onset HF and death with ACE inhibitors serum creatinine baseline level. However, ACE inhibition can
whether they are initiated early (within 36 hours) or started also worsen renal function since glomerular ltration is main-
later. In addition, ACE inhibition decreases the risk of HF tained in the setting of reduced CO through angiotensin IIs
hospitalization and death in patients with asymptomatic LV constriction of the efferent arteriole. Patients most dependent
dysfunction. The exact mechanisms for decreased HF progres- on angiotensin II for maintenance of glomerular ltration pres-
sion and mortality are postulated to involve both the hemody- sure, and hence most susceptible to ACE inhibitor worsening of
namic improvement and the inhibition of angiotensin IIs renal function, include those with hyponatremia, severely
growth promoting and remodeling effects. All patients with depressed LV function, or dehydration. It is important to note
documented LV systolic dysfunction, regardless of existing HF that the most common reason for creatinine elevation in a
symptoms, should receive ACE inhibitors unless a contraindi- patient without a history of renal dysfunction is overdiuresis.
cation or intolerance is present. Therefore, clinicians should consider decreasing or holding
There is no evidence to suggest that one ACE inhibitor is pre- diuretic doses if an elevation in serum creatinine occurs con-
ferred over another. ACE inhibitors should be initiated using low comitantly with a rise in blood urea nitrogen.
TABLE 37. Dosing and Monitoring for Neurohormonal Blocking Agents
Target or
Drug Initial Daily Dose Maximum Daily Dose Monitoring
ACE Inhibitors
Captopril 6.25 mg 3 times 50 mg 3 times BP
Enalapril 2.5 mg twice 1020 mg twice Electrolytes (K+, BUN, SCr)
Fosinopril 510 mg once 40 mg once at baseline, 2 weeks,
Lisinopril 2.55 mg once 2040 mg once and after dose titration,
Perindopril 2 mg once 816 mg once CBC periodically
Quinopril 5 mg once 20 mg twice Adverse effects: cough,
Ramipril 1.252.5 mg once 10 mg once angioedema
Trandolapril 1 mg once 4 mg once
Angiotensin
Receptor Blockers
Candesartan 48 mg once 32 mg once BP
Losartan 2550 mg once 50100 mg once Electrolytes (K+, BUN, SCr)
Valsartan 2040 mg once 160 mg twice at baseline, 2 weeks,
and after dose titration,
CBC periodically
Adverse effects: cough,
angioedema
Aldosterone
Antagonists
Spironolactone 12.525 mg once 25 mg once BP
or twice Electrolytes (K+) at
Eplerenone 25 mg once 50 mg once baseline and within
1 week of initiation
and dose titration
Adverse effects:
gynecomastia or breast
tenderness, menstrual
changes, hirsutism
b-Blockers
Bisoprolol 1.25 mg once 10 mg once BP, HR baseline and after
Carvedilol 3.125 mg twice 25 mg twice each dose titration, ECG
(50 mg twice Adverse effects: worsening
for patients HF symptoms (edema,
greater than 85 kg SOB, fatigue), depression,
or 187 lbs) sexual dysfunction
Metoprolol 12.525 mg once 200 mg once
succinate
BP, blood pressure; BUN, blood urea nitrate; CBC, complete blood cell count; ECG, electrocardiogram; HF, heart
failure; HR, heart rate; K+, potassium; SCr, serum creatinine; SOB, shortness of breath.
Hypotension occurs commonly at the initiation of therapy inhibitors is also increased in HF due to a propensity for
or with dosage increases but may happen anytime during impaired renal function and additive effects with aldosterone
therapy. Hypotension can manifest as dizziness, lightheaded- antagonists. To minimize hyperkalemia, patients should be
ness, presyncope, or syncope. The risk of hypotension due to counseled to avoid foods high in potassium such as certain salt
possible volume depletion increases when ACE inhibitors are substitutes. ACE inhibitor dose may need to be decreased or
initiated or used concomitantly in patients on high diuretic held if serum potassium increases above 5 mEq/L (5 mmol/L).
doses. Therefore, in euvolemic patients, diuretic doses may Persistent hyperkalemia in the setting of renal insufciency
often be decreased or withheld during ACE inhibitor dose may preclude the use of an ACE inhibitor.
titration. Initiating at a low dose and titrating slowly can also Cough is commonly seen with ACE inhibitors (5% to 15%)
minimize hypotension. It may be advisable to initiate therapy and may be related to accumulation of tissue bradykinins.5 It
with a short-acting ACE inhibitor, such as captopril, and sub- can be challenging to distinguish an ACE inhibitorinduced
sequently switch to a longer-acting agent, such as lisinopril or cough from cough caused by pulmonary congestion. A pro-
enalapril, once the patient is stabilized. ductive or wet cough usually signies congestion, whereas a
Hyperkalemia results from reduced angiotensin IIstimulated dry, hacking cough is more indicative of a drug-related etiology.
aldosterone release. The risk of hyperkalemia with ACE If a cough is determined to be ACE inhibitorinduced, its
severity should be evaluated before deciding on a course of including the need for monitoring renal function, blood pres-
action. If the cough is truly bothersome, a trial with a different sure, and potassium. Bilateral renal artery stenosis is an absolute
ACE inhibitor or switching to an ARB is warranted. contraindication to ARB therapy unless it has been corrected.
Neither ACE inhibitors nor ARBs should be used in patients
Angiotensin Receptor Blockers
who are pregnant or actively trying to become pregnant because
Angiotensin receptor blockers selectively antagonize the of associated teratogenicity. In patients truly intolerant or con-
effects of angiotensin II directly at the AT1 receptor. AT1 receptor traindicated to ACE inhibitors or ARBs, the combination of
stimulation is associated with vasoconstriction, release of hydralazine and isosorbide dinitrate should be considered.
aldosterone, and cellular growth promoting effects, while
angiotensin receptor type 2 (AT2) stimulation causes vasodila- Hydralazine and Isosorbide Dinitrate
tion. By selectively blocking AT1 but leaving AT2 unaffected, Complementary hemodynamic actions originally led to the
ARBs block the detrimental AT1 effects on cardiac function combination of nitrates with hydralazine. Nitrates reduce pre-
while allowing AT2-mediated vasodilation and inhibition of load by causing primarily venous vasodilation through activat-
ventricular remodeling. Angiotensin receptor blockers are con- ing guanylate cyclase and a subsequent increase in cyclic guano-
sidered an equally effective replacement for ACE inhibitors in sine monophosphate (cGMP) in vascular smooth muscle.
patients who are intolerant or have a contraindication to an Hydralazine reduces afterload through direct arterial smooth
ACE inhibitor. muscle relaxation via an unknown mechanism. More recently,
It was hoped that the more complete blockade of angiotensin nitric oxide has been implicated in modulating numerous
IIs AT1 effects would confer greater long-term efcacy with pathophysiologic processes in the failing heart, including
ARBs compared to ACE inhibitors. However, prospective, ran- inammation, cardiac remodeling, and oxidative damage.
domized trials suggest that the clinical efcacy of ARBs is sim- Supplementation of nitric oxide via administration of nitrates
ilar to that of ACE inhibitors for reduction of hospitalizations has also been proposed as a mechanism for benet from this
for HF, sudden cardiac death, and all cause mortality.2325 combination therapy. The benecial effect of an external
Despite poorer suppression of AT2, comparable efcacy of nitric oxide source may be more apparent in the African-
ACE inhibitors may be due to the additional effects on the American population, which appears to be predisposed to
kallikrein-kinin system. Although ARBs produce hemody- having an imbalance in nitric oxide production. In addition,
namic and neurohormonal effects similar to those of ACE hydralazine may reduce the development of nitrate tolerance
inhibitors, they are considered second-line therapy due to the when nitrates are given chronically.
overwhelming clinical trial experience with ACE inhibitors. The combination of hydralazine and isosorbide dinitrate
Since the mechanism for long-term benet appears differ- was the rst therapy shown to improve long-term survival in
ent for ACE inhibitors and ARBs, the combination has been patients with systolic HF, but has largely been supplanted by
studied for additive benets. One study evaluated the addition angiotensin II antagonist therapy (ACE inhibitors and
of the ARB candesartan versus placebo in three distinct ARBs).27,28 Therefore, until recently, this combination therapy
groups of HF patients: systolic dysfunction intolerant to an was reserved for patients intolerant to ACE inhibitors or ARBs
ACE inhibitor, systolic dysfunction currently on ACE inhibitor secondary to renal impairment, angioedema, or hyperkalemia.
therapy, and patients with preserved systolic function.25 New insight into the pathophysiologic role of nitric oxide has
Candesartan reduced the combined incidence of cardiovascu- reinvigorated research into this combination therapy.
lar death and hospitalization for HF in all three groups, with The nitrate-hydralazine combination was rst shown to
the greatest benet being seen in those not on an ACE improve survival compared to placebo.27 Subsequently, the
inhibitor. Candesartan signicantly decreased mortality com- combination of isosorbide dinitrate 40 mg and hydralazine
pared to placebo when all three groups were combined. Based 75 mg, both given four times daily, was compared to the ACE
on this study, the addition of an ARB to ACE inhibitor ther- inhibitor enalapril.28 Enalapril produced a 28% greater
apy can be considered in patients with evidence of disease decrease in mortality. Therefore, the combination is consid-
progression despite optimal ACE inhibitor therapy.1 This ered a third-line vasodilatory option for patients truly intoler-
study also demonstrates the importance of having some form ant of ACE inhibitors and ARBs.
of angiotensin II antagonism as part of a treatment regimen. More recently, the value of adding the combination of isosor-
Angiotensin receptor blockers show similar tolerability to bide dinitrate 40 mg and hydralazine 75 mg three times daily to
ACE inhibitors with regard to hypotension and hyperkalemia, therapy including ACE inhibitors, -blockers, digoxin, and
but they do not induce cough since ARBs do not cause an accu- diuretics was evaluated in a prospective, randomized trial.26 The
mulation of bradykinin. Angiotensin receptor blockers can be study enrolled only African-American patients and demon-
considered in patients with ACE inhibitorinduced strated a signicant reduction in mortality, as well as rst hospi-
angioedema, but they should be initiated cautiously, as cross- talization for HF. Quality-of-life scores were also improved over
reactivity has been reported. Many of the other considerations placebo. Combination therapy with hydralazine and isosorbide
for the use of ARBs are similar to those of ACE inhibitors, dinitrate is an appropriate substitute for angiotensin II antagonism
in those unable to tolerate an ACE inhibitor or ARB or as add-on translates into vasodilatory effects and theoretically more
therapy in African-Americans. The ACC/AHA HF guidelines now complete antagonism of sympathetic stimulation, and (2) has
recommend considering the addition of isosorbide dinitrate and in vitro antioxidant activity that could reduce vascular and
hydralazine in African-Americans already on ACE inhibitors or cardiac oxidative damage. Several smaller studies and a meta-
ARBs.1 Combination therapy with isosorbide dinitrate and analysis suggested that carvedilol increased left ventricular
hydralazine should be initiated and titrated as are other neuro- ejection fraction (LVEF), improved cardiac hemodynamics,
hormonal agents such as ACE inhibitors and -blockers. Low and slowed remodeling to a greater extent than metoprolol
doses are used to initiate therapy with subsequent titration of tartrate. To compare their relative effects on patient outcomes,
the dose toward target doses based on tolerability. Adverse one study compared immediate-release metoprolol tartrate to
effects such as hypotension and headache cause frequent dis- carvedilol in 3,000 patients with mild to severe HF.33
continuations in patients taking this combination, and full doses Carvedilol lowered all-cause mortality signicantly more than
often cannot be tolerated. Patients should be monitored for metoprolol tartrate. However, the controversy remains, as
headache, hypotension, and tachycardia. Hydralazine is also proponents for metoprolol question: (1) the validity of using
associated with a dose-dependent risk for lupus. immediate-release metoprolol tartrate as the comparison
The frequent dosing of isosorbide dinitrate (e.g. 34 times agent in this study, and (2) the low average dose of metopro-
daily) is not conducive to patient adherence; therefore, a once- lol tartrate achieved in the study. It also remains controversial
daily isosorbide mononitrate is commonly substituted for as to whether metoprolol tartrate should be used in HF since
isosorbide dinitrate to simplify the dosing regimen. A nitrate- the only trial demonstrating a mortality benet with meto-
free interval is still required when using nitrates for HF. prolol used the sustained-release succinate dosage form.
The key to utilizing -blockers in systolic HF is initiation
Beta-Adrenergic Antagonists with low doses and slow titration to target doses over weeks to
Beta-adrenergic antagonists, or -blockers, competitively months. It is important that the -blocker be initiated when a
block the inuence of the SNS at -adrenergic receptors. As patient is clinically stable and euvolemic. Volume overload at the
recently as 15 years ago, -adrenergic blockers were thought to time of -blocker initiation increases the risk for worsening
be detrimental in HF due to their negative inotropic actions, symptoms. -Blockade should begin with the lowest possible
which could potentially worsen symptoms and cause acute dose (Table 37), after which the dose may be doubled every 2
decompensations. Since then, the benets of inhibiting the to 4 weeks depending on patient tolerability. -Blockers may
SNS have been recognized as far outweighing the acute nega- cause an acute decrease in LVEF and short-term worsening of
tive inotropic effects. Chronic -blockade reduces ventricular HF symptoms upon initiation and at each dosage titration. After
mass, improves ventricular shape, and reduces LV end-systolic each dose titration, if the patient experiences symptomatic
and diastolic volumes.6,8 -Blockers also exhibit antiarrhyth- hypotension, bradycardia, orthostasis, or worsening symptoms,
mic effects, slow or reverse catecholamine-induced ventricular further increases in dose should be withheld until the patient
remodeling, decrease myocyte death from catecholamine- stabilizes. After stabilization, attempts to increase the dose
induced necrosis or apoptosis, and prevent myocardial fetal should be reinstituted. If mild congestion ensues as a result of
gene expression. Consequently, -blockers improve EF, reduce the -blocker, an increase in diuretic dose may be warranted. If
all-cause and HF-related hospitalizations, and decrease all- moderate or severe symptoms of congestion occur, a reduction
cause mortality in patients with systolic HF.2933 in -blocker dose should be considered along with an increase in
The ACC/AHA recommends that -blockers be initiated in diuretic dose. Dose titration should continue until target clinical
all patients with NYHA FC I to IV or ACC/AHA stages B trial doses are achieved (Table 37) or until limited by repeated
through D heart failure if clinically stable.1 To date, only three - hemodynamic or symptomatic intolerance. Patient education
blockers have been shown to reduce mortality in systolic HF, regarding the possibility of acutely worsening symptoms but
including the selective 1-antagonists bisoprolol and metoprolol improved long-term function and survival is essential to ensure
succinate, and the non-selective 1-, 2-, and 1-antagonist adherence.
carvedilol.2933 The positive ndings should not be extrapolated Apart from possible clinical differences between the -block-
to be indicative of a class effect, as bucindolol did not exhibit a ers approved for HF, selection of a -blocker may also be affected
benecial effect on mortality when studied for HF, and there is by pharmacologic differences. Carvedilol exhibits a more pro-
limited information with propranolol and atenolol. nounced blood pressure lowering effect and thus causes more
Controversy surrounds the selection of a -blocker for HF frequent dizziness and hypotension as a consequence of its 1-
management. First, although metoprolol and carvedilol are receptor blocking activity. Therefore, in patients predisposed to
the most commonly used -antagonists in HF, it remains con- symptomatic hypotension, such as those with advanced LV dys-
troversial as to whether one agent should be considered rst- function (LVEF less than 20%) who normally exhibit low systolic
line. Carvedilol exhibits several pharmacologic properties that blood pressures, metoprolol succinate may be the most desirable
theoretically would confer superior efcacy, since carvedilol: rst-line -blocker. In patients with uncontrolled hypertension,
(1) provides blockade at multiple adrenergic receptors, which carvedilol may provide additional antihypertensive efcacy.
-Blockers may be used by those with reactive airway dis- The major risk related to aldosterone antagonists is hyper-
ease or peripheral vascular disease, but should be used with kalemia. Therefore, the decision for use of these agents should
considerable caution or avoided if patients display active res- balance the benet of decreasing death and hospitalization from
piratory symptoms. Care must also be used in interpreting HF and the potential risks of life-threatening hyperkalemia.
shortness of breath in these patients, as the etiology could be Before and within one week of initiating therapy, two parame-
either cardiac or pulmonary. A selective 1-blocker such as ters must be assessed: serum potassium and creatinine clearance
metoprolol is a reasonable option for patients with reactive (or serum creatinine). Aldosterone antagonists should not be
airway disease. The risk versus benet of using any -blocker initiated in patients with potassium concentrations greater than
in peripheral vascular disease must be weighed based on the 5.5 mEq/L (5.5 mmol/L). Likewise, these agents should not be
severity of the peripheral disease. given when creatinine clearance is less than 30 mL/minute or
Both metoprolol and carvedilol are metabolized by the liver serum creatinine is greater than 2.5 mg/dL (221 mol/L).
through cytochrome P-450 (CYP450)2D6 and undergo exten- In patients without contraindications, spironolactone is ini-
sive rst-pass metabolism. Bisoprolol is not as commonly tiated at a dose of 12.5 to 25 mg daily, or occasionally on alter-
used since it is not Food and Drug Administration (FDA)- nate days for patients with baseline renal insufciency.
approved for this use. Eplerenone is used at a dose of 25 mg daily, with the option to
titrate up to 50 mg daily. Doses should be halved or switched
Aldosterone Antagonists to alternate-day dosing if creatinine clearance falls below
Currently, the aldosterone antagonists available are spironolac- 50 mL/minute. Potassium supplementation is often decreased or
tone and eplerenone. Both agents are inhibitors of aldosterone stopped after aldosterone antagonists are initiated, and patients
that produce weak diuretic effects while sparing potassium con- should be counseled to avoid high-potassium foods. At any time
centrations. Eplerenone is selective for the mineralocorticoid after initiation of therapy, if potassium concentrations exceed
receptor and hence does not exhibit the endocrine adverse-effect 5.5 mEq/L (5.5 mmol/L), the dose of the aldosterone antagonist
prole commonly seen with spironolactone. The initial ration- should be reduced or discontinued. Patients receiving concomi-
ale for specically targeting aldosterone for treatment of HF was tant potassium supplements should have these discontinued. In
based on the knowledge that ACE inhibitors do not suppress the addition, worsening renal function dictates consideration for
chronic production and release of aldosterone. Aldosterone is a stopping the aldosterone antagonist. Other adverse effects
key pathologic neurohormone which exerts multiple detrimen- observed mainly with spironolactone include gynecomastia for
tal effects in HF. Through the kidneys, aldosterone promotes men and breast tenderness and menstrual irregularities for
uid retention and electrolyte abnormalities. Aldosterone is women. Gynecomastia leads to discontinuation in up to 10% of
another neurohormone known to mediate pathologic ventricu- patients on spironolactone. Eplerenone is a CYP3A4 substrate and
lar remodeling by causing increased extracellular matrix colla- should not be used concomitantly with strong inhibitors of 3A4.
gen deposition and cardiac brosis. Aldosterone potentially con-
tributes to disease progression via sympathetic potentiation and Digoxin
ventricular remodeling. In addition, the combination of these Digoxin has been used for several decades in the treatment of
multiple effects is likely responsible for the increased risk of sud- HF. Traditionally, it was considered useful for its positive
den cardiac death attributed to aldosterone. Similar to norepi- inotropic effects, but more recently its benets are thought to be
nephrine and angiotensin II, aldosterone levels are increased in related to neurohormonal modulation. Digoxin exerts positive
HF and have been shown to correlate with disease severity and inotropic effects through binding to sodium- and potassium-
patient outcomes. activated adenosine triphosphate (ATP) pumps, leading to
Each agent (spironolactone and eplerenone) has been increased intracellular sodium concentrations and subsequently
studied in a dened population of patients with HF. One more available intracellular calcium during systole. The mecha-
study established efcacy with low-dose spironolactone in nism of digoxins neurohormonal blocking effect is less well
NYHA FC III and IV heart failure patients in reducing HF understood, but may be related to restoration of baroreceptor
hospitalizations, improving functional class, reducing sud- sensitivity and reduced central sympathetic outow.5
den cardiac death, and improving all-cause mortality.34 The exact role of digoxin in therapy remains controversial
Another study investigated the use of eplerenone in patients largely due to disagreement on the risk versus benet of rou-
within 14 days of MI and LVEF less than 40%.35 Eplerenone tinely using this drug in patients with systolic HF. Digoxin was
was found to decrease mortality as well as cardiovascular shown to decrease HF-related hospitalizations but did not
death and related hospitalization, mainly due to reducing decrease HF progression or improve survival.36 Moreover,
occurrence of sudden cardiac death. Based on these two stud- digoxin was associated with an increased risk for concentration
ies, the ACC/AHA guidelines recommend that the addition of related toxicity and numerous adverse effects. Post-hoc study
spironolactone be considered in NYHA FC III and IV analyses demonstrated a clear relationship between digoxin
(ACC/AHA stages C and D) patients, and eplerenone in plasma concentration and outcomes. Concentrations below
directly post-MI patients with evidence of LV dysfunction.1 1.2 mg/dL (1.5 nmol/L) were associated with no apparent
adverse effect on survival, whereas higher concentrations in HF patients to treat uncontrolled hypertension or angina
increased the relative risk of mortality.37,38 once all other appropriate drugs are maximized.
Current recommendations are for the addition of digoxin
for patients who remain symptomatic despite an optimal HF Antiplatelets and Anticoagulation
regimen consisting of an ACE inhibitor or ARB, -blocker, Patients with HF are at an increased risk of thromboembolic
and diuretic. In patients with concomitant atrial brillation, events secondary to a combination of hypercoagulability, rel-
digoxin may be added to slow ventricular rate regardless of ative stasis of blood, and endothelial dysfunction. However,
HF symptomology. the role of antiplatelets and anticoagulants remains debatable
Digoxin is initiated at a dose of 0.125 to 0.25 mg daily due to a lack of prospective clinical trials.
depending on age, renal function, weight, and risk for toxicity. Aspirin is generally used in HF patients with an underlying
The lower dose should be used if the patient satises any of ischemic etiology, a history of ischemic heart disease, or other
the following criteria: over 65 years of age, creatinine clear- compelling indications such as history of embolic stroke.
ance less than 60 mL/minute, or ideal body weight less than Routine use in non-ischemic cardiomyopathy patients is cur-
70 kg (154 lb). The 0.125 mg daily dose is adequate in the rently discouraged because of a lack of data supporting any
majority of patients. The desired concentration range for long-term benet, as well as the potential negative drug-drug
digoxin is 0.5 to 1.2 ng/mL (0.64 to 1.5 nmol/L), preferably with interaction with ACE inhibitors and ARBs. If aspirin is indi-
concentrations at or less than 0.8 ng/mL (1 nmol/L). Routine cated, the preference is to use a low dose (81 mg daily).41
monitoring of serum drug concentrations is not required but Although no data are available with clopidogrel, it may
recommended in those with changes in renal function, suspected become the antiplatelet agent of choice in HF because it has
toxicity, or after addition or subtraction of an interacting drug. not been shown to adversely affect the actions of ACE
Digoxin toxicity may manifest as non-specic ndings such inhibitors or ARBs.
as fatigue or weakness, and other CNS effects such as confusion, Current consensus recommendations support the use of
delirium, and psychosis. Gastrointestinal manifestations include warfarin in patients with reduced LV systolic dysfunction and
nausea, vomiting, or anorexia, and visual disturbances may a compelling indication such as atrial brillation or prosthetic
occur such as halos, photophobia, and color perception problems heart valves.42 In addition, warfarin is empirically used in
(red-green or yellow-green vision). Cardiac ndings include patients with echocardiographic evidence of a mural thrombus
numerous types of arrhythmias related to enhanced automatic- or severely depressed (LVEF less than 20%) LV function.43
ity, slowed or accelerated conduction, or delayed afterdepolar- However, there are no prospective data and only limited
izations. These include ventricular tachycardia and brillation, observational data supporting the use of empiric warfarin
atrioventricular nodal block, and sinus bradycardia. Risk of based on these echocardiographic ndings. Patients with HF
digoxin toxicity, in particular the cardiac manifestations, are often have difculty maintaining a therapeutic International
increased with electrolyte disturbances such as hypokalemia, Normalized Ratio (INR) due to uctuating volume status and
hypercalcemia, and hypomagnesemia. To reduce the proar- varying drug absorption. Therefore, the benet of using war-
rhythmic risk of digoxin, serum potassium and magnesium farin should be evaluated in the context of the risk for major
should be monitored closely to ensure adequate concentrations and minor bleeding.
(potassium greater than 4.0 mEq/L [4.0 mmol/L] and magne-
sium greater than 2.0 mEq/L [1 mmol/L]). In patients with
Heart Failure with Preserved Left Ventricular
life-threatening toxicity due to cardiac or other ndings,
Ejection Fraction
administration of digoxin-specic Fab antibody fragments
usually reverses adverse effects within an hour in most cases. It is now recognized that a signicant number of patients
exhibiting HF symptoms have normal systolic function or
Calcium Channel Blockers preserved LVEF (40% to 60%). It is believed that the primary
Treatment with nondihydropyridine calcium channel blockers defect in these patients is impaired ventricular relaxation and
(diltiazem and verapamil) may worsen HF and increase the lling, commonly referred to as diastolic dysfunction or dias-
risk of death in patients with advanced LV dysfunction due to tolic HF. Heart failure with preserved EF is more prevalent in
their negative inotropic effects. Conversely, dihydropyridine older women and is closely associated with hypertension or
calcium channel blockers, although negative inotropes in diabetes, and to a lesser extent, CAD and atrial brillation.44
vitro, do not appear to decrease contractility in vivo. Morbidity in HF patients with preserved EF is comparable to
Amlodipine and felodipine are the two most extensively stud- those with depressed EF, as both are characterized by frequent,
ied dihydropyridine calcium channel blockers for systolic repeated hospitalizations.44 However, HF with preserved EF is
HF.39,40 These two agents have not been shown to affect associated with better survival. The diagnosis is based on nd-
patient survival, either positively or negatively. As such, they ings of typical signs and symptoms of HF, in conjunction with
are not routinely recommended as part of a standard HF reg- echocardiographic evidence of normal LV systolic function
imen; however, amlodipine and felodipine can safely be used and no valvular disease.
Unlike systolic HF, few prospective trials have evaluated the the advent of pharmacogenomics (the inuence of genetics on
safety and efcacy of various cardiac medications in patients drug response). The application of race and genetics to phar-
with diastolic HF or preserved ejection fraction. The macotherapeutic decision making for HF is in the early stages.
Candesartan in Heart Failure Assessment of Reduction in However, these concepts are being applied to the use of
Mortality and Morbidity (CHARM) study demonstrated that hydralazine and isosorbide dinitrate in African-American
angiotensin receptor blockade with candesartan resulted in patients.26 It is anticipated that further investigation will lead
benecial effects on HF morbidity in patients with preserved to better insight relating to the clinical applicability of genetic
LVEF similar to those seen in depressed LV function.25 variations to drug responses.
In the absence of more landmark clinical studies, the cur-
rent treatment approach for diastolic dysfunction or pre- Peripartum Cardiomyopathy and Pregnancy
served LVEF is: (1) correction or control of underlying etiolo- Peripartum cardiomyopathy (PPCM) is currently dened as
gies (including optimal treatment of hypertension and CAD clinical and echocardiographic evidence for new-onset HF
and maintenance of normal sinus rhythm); (2) reduction occurring during pregnancy and up to 6 months after deliv-
of cardiac lling pressures at rest and during exertion; and ery, with other etiologies excluded. Although PPCM is not
(3) increased diastolic lling time. Diuretics, ACE inhibitors, well understood, it manifests in pregnant women of all ages,
and ARBs are frequently used to control congestion. but the risk is elevated in women older than 30 years of age.45
Angiotensin receptor blockers may also slow disease progres- The true incidence of idiopathic PPCM is debatable, with
sion. -Blockers and calcium channel blockers can theoretically reported rates for peripartum HF at 1 case per 100 to 4,000
improve ventricular relaxation through negative inotropic and deliveries.46 The leading hypothesis for PPCM pathogenesis is
chronotropic effects. Unlike in systolic HF, nondihydropyridine myocarditis caused by a viral infection or an abnormal immune
calcium channel blockers (diltiazem and verapamil) may be response to pregnancy. Heart failure may persist after delivery
especially useful in improving diastolic function by limiting the but can be reversible (with partial or full recovery of cardiac
availability of calcium that mediates contractility. The role of function) in many cases.45
digoxin for symptom management and HR control in these The clinical presentation of peripartum HF is indistinguish-
patients is not well established. able from that of other types of HF. Initial treatment is also
similar, with the exception of ACE inhibitors and ARBs being
contraindicated during the antepartum period. Treatment
Special Populations and Patients with Concomitant includes reducing preload by sodium restriction and diuretics,
Disorders afterload reduction with vasodilators, and sometimes inotropic
support with digoxin. Hydralazine is utilized frequently in preg-
Ethnic and Genetic Considerations
nancy and is classied as FDA pregnancy category C. Labetalol
Heart failure is more prevalent and associated with a worse
is used for acute parenteral control of blood pressure, but long-
prognosis in African-Americans compared to the general
term -blocker use corresponds with low birth weight infants.
population.1 Unfortunately, deciencies in disease prevention,
Management of the cardiomyopathy after delivery includes use
detection, and access to treatment are well documented in
of ACE inhibitors and -blockers, although these treatment
minority populations. African-Americans and other races are
guidelines have been extrapolated from studies in patients with
underrepresented in clinical trials, compromising the extrap-
idiopathic dilated cardiomyopathy rather than specic trials in
olation of results from these studies to ethnic subpopulations.
PPCM. Patients with PPCM also have a high rate of throm-
The inuence of race on efcacy and safety of medications
boembolism. Treatment options during pregnancy are limited
used in HF treatment has received additional attention with
to unfractionated heparin and low-molecular-weight heparin
since warfarin is contraindicated. After delivery, anticoagula-
tion is recommended in patients with LVEF less than 20%.46
OUTCOME EVALUATION OF CHRONIC

HEART FAILURE
Based on the information presented and your problem-
based assessment, create a care plan for BEs heart failure.
The evaluation of therapy is inuenced by the ability of
Your plan should include:
treatment to successfully reduce symptoms, improve quality
Nonpharmacologic treatment options. of life, decrease frequency of hospitalizations for AHF,
Acute and chronic treatment plans to address BEs symp- reduce disease progression, and prolong survival (Fig. 31).
toms and prevent disease deterioration. The major outcome parameters focus on: (1) volume status;
Monitoring plan for acute and chronic treatments. (2) exercise tolerance; (3) overall symptoms/quality of life;
(4) adverse drug reactions; and (5) disease progression and
cardiac function. Assess quality of life by evaluating patients ACUTE AND ADVANCED HEART FAILURE
ability to continue their activities of daily living.
Assess symptoms of HF such as dyspnea on exertion, Clinical Presentation and Diagnosis of
orthopnea, weight gain, and edema, and abdominal manifes- Acute Heart Failure
tations such as nausea, bloating, and loss of appetite.
If diuretic therapy is warranted, monitor for therapeutic Patients with acute heart failure (AHF) present with symp-
response by assessing weight loss and improvement of uid toms of worsening uid retention or decreasing exercise
retention, as well as exercise tolerance and presence of fatigue. tolerance and fatigue (typically worsening of symptoms
Once therapy for preventing disease progression is initiated, presented in the chronic heart failure clinical presentation
monitoring for symptomatic improvement continues. text box). These symptoms reect congestion behind the
It is important to keep in mind that patients symptoms of failing ventricle and/or hypoperfusion. Patients can be cate-
HF can worsen with -blockers, and it may take weeks or gorized into hemodynamic subsets based on assessment of
months before patients notice improvement. physical signs and symptoms of congestion and/or hypoperfu-
Monitor blood pressure to evaluate for hypotension caused sion.47 Patients can be described as wet or dry depending
by drug therapy. on volume status, as well as warm or cool based on ade-
To assess for prevention of disease progression, practitioners quacy of tissue perfusion. Wet refers to patients with vol-
may utilize serial echocardiograms every 6 months to assess ume/uid overload [e.g., edema and jugular venous distention
cardiac function and evaluate the effects of drug therapy. (JVD)], whereas dry refers to euvolemic patients. Warm
Occasional exercise testing is conducted in order to ascertain refers to patients with adequate CO to perfuse peripheral tis-
disease prognosis or suitability for heart transplant. Even sues (and hence the skin will be warm to touch), whereas
though these tests can demonstrate improvement in heart cool refers to patients with evidence of hypoperfusion
function and therefore slowed disease progression, patient (skin cool to touch with diminished pulses). Additionally,
symptoms may not improve. invasive hemodynamic monitoring can be used to provide
FIGURE 31. Treatment algo-

Structural heart Yes Stage B heart rithm for chronic heart failure.
failure Heart failure symptoms?
disease? ACE, angiotensin-converting
Examples:
enzyme; ARB, angiotensin
- Previous MI
- LV remodeling receptor blocker; EF, ejection
No
- Low EF fraction; HF, heart failure; LV,
- Valvular disease Stage C heart failure left ventricular; MI,
Stage A heart failure Patients with known myocardial infarction; SOB:
No Yes structural heart disease
Address risk factors Address risk factors shortness of breath. Table 35
- Treat hypertension and
SOB, fatigue, reduced describes staging of
- Encourage smoking
cessation Drugs: exercise tolerance heart failure.
- Treat lipid disorders - ACE inhibitor or
- Optimize diabetes ARB Treatment plan:
mellitus treatment - Beta blockers - Salt restriction
- Encourage exercise Drugs:
- Discourage excessive - Diuretics for edema
alcohol intake No - ACE inhibitors
Refractory symptoms - Beta blockers
Drugs:
of HF at rest?
ACE inhibitor or ARB if In selected patients:
compelling indication Yes - ARBs
- Digoxin
Stage D heart failure - Aldosterone
Patients with marked antagonists
symptoms at rest despite - Hydralazine/nitrates
maximal medical therapy - Devices
--Biventricular pacing
Treatment plan: -- Implantable
- Continue interventions defibrillators
under Stages A through C
- End of life care/hospice
- Specialized Interventions:
-- Heart transplant
-- Chronic inotropes
-- Mechanical support
objective data for assessing volume status [pulmonary cap- Clinical Assessment and Diagnosis
illary wedge pressure (PCWP)] and perfusion (CO). A CI
Precipitating Factors
below 2.2 L/minute per square meter is consistent with
hypoperfusion and reduced contractility, and a PCWP
It is important for the clinician to identify the cause(s) of
AHF in order to maximize treatment efcacy and reduce future
above 18 mm Hg correlates with congestion and an ele-
disease exacerbations. Cardiovascular, metabolic, and lifestyle
vated preload. The four possible hemodynamic subsets a
factors can all precipitate AHF. The most common precipitat-
patient may fall into are: warm and dry, warm and wet,
ing factors for acute decompensation and how they contribute
cool and dry, or cool and wet.
pathophysiologically are listed in Table 33.
Laboratory Assessment
Routine laboratory testing of patients with AHF includes elec-
trolytes and blood glucose, as well as serum creatinine and
Clinical Presentation of Acute blood urea nitrogen to assess renal function. Complete blood
Heart Failure
cell count is measured to determine if anemia or infection is
present. Creatine kinase and/or troponin concentrations are
Subset I (Warm and Dry) used to diagnose ischemia, and hepatic transaminases are
Cardiac index (CI) greater than 2.2 L/minute per square measured to help rule out hepatic congestion (in other words,
meter, pulmonary capillary wedge pressure (PCWP) less until it is determined that it is not hepatic congestion). Thyroid
than 18 mm Hg function tests are measured to assess hyperthyroidism or
Patients considered well compensated and perfused, hypothyroidism as causes of AHF. A urinalysis is attained in
without evidence of congestion patients with an unknown history of renal disease to rule out
No immediate interventions necessary except nephrotic syndrome. Lastly, a toxicology screen is obtained in
optimizing oral medications and monitoring
patients in whom use of illicit drugs is suspected.
Subset II (Warm and Wet) Assays measuring BNP and its degradation product NT-
CI greater than 2.2 L/minute per square meter, PCWP proBNP have been developed and are being used with greater
greater than or equal to 18 mm Hg frequency in clinical practice.10 B-type natriuretic peptide is
Patients adequately perfused and display signs and symp- synthesized, stored, and released from the ventricles in response
toms of congestion
to increased ventricular lling pressures. Hence, plasma levels
Main goal is to reduce preload (PCWP) carefully with
loop diuretics and vasodilators
of BNP can be used as a marker for volume overload. The most
widely accepted indication for BNP measurement is as an
Subset III (Cool and Dry) adjunctive aid for diagnosing a cardiac etiology for dyspnea.10
CI less than 2.2 L/minute per square meter, PCWP Although there is evidence to support a prognostic role for BNP
less than 18 mm Hg
concentrations in HF and MI, widespread clinical application
Patients are inadequately perfused and not congested
Hypoperfusion leads to increased mortality, elevating
has yet to occur. Current trials are also testing whether serial
death rates four-fold compared to those who are ade- BNP monitoring can be used to guide therapy.
quately perfused The current values for ruling out a cardiac etiology for dyspnea
Treatment focuses on increasing CO with positive are a BNP less than 100 pg/mL (100 ng/L) or an NT-proBNP less
inotropic agents and/or replacing intravascular uids than 300 pg/mL (300 ng/L or 35.4 pmol/L). BNP measurements
Fluid replacement must be performed cautiously, as require cautious interpretation, as numerous conditions can also
patients can rapidly become congested elevate BNP concentrations. These include older age, renal dys-
Subset IV (Cool and Wet) function, pulmonary embolism, and chronic pulmonary disease.
CI less than 2.2 L/minute per square meter, PCWP greater Nesiritide, a recombinant BNP drug, has an identical structure to
than 18 mm Hg native BNP and will interfere with the commercial BNP assay,
Patients are inadequately perfused and congested resulting in a falsely elevated level. Therefore, blood for BNP
Classied as the most complicated clinical presentation determination should be obtained 2 hours after the end of a nesir-
of AHF with the worst prognosis itide infusion, or alternatively the NT-proBNP assay should be
Most challenging to treat; therapy targets alleviating signs utilized.
and symptoms of congestion by increasing CI as well as Other diagnostic tests should also be obtained in order to
reducing PCWP, while maintaining adequate mean
rule out precipitating factors (chest radiograph) and to evalu-
arterial pressure
Treatment involves a delicate balance between diuretics,
ate cardiac function (ECG).
vasodilators, and inotropic agents Invasive hemodynamic monitoring in patients with HF
Use of vasopressors is sometimes necessary to maintain entails placement of a right heart or pulmonary artery catheter
blood pressure (PAC). The catheter is inserted percutaneously through a central
vein and advanced through the right side of the heart to the
TABLE 38. Hemodynamic Monitoring: Normal Values achieve all of these goals will a patients prognosis be improved
and future hospitalizations for acute decompensations prevented.
Hemodynamic Variable Normal Value
Removal or control of precipitating factors is essential for an
Central venous (right atrial) Less than 5 mm Hg optimal response to pharmacologic therapy. Relief of symp-
pressure, mean toms should occur rapidly to minimize length of hospitaliza-
Right ventricular pressure 25/0 mm Hg tion. Although a rapid discharge from the hospital is desirable,
Pulmonary artery pressure 25/10 mm Hg a patient should not be discharged before ensuring that he or
Pulmonary artery pressure, Less than 18 mm Hg she is in a euvolemic, or nearly euvolemic, state with a body
mean weight and functional capacity similar to before the acute
Pulmonary artery occlusion Less than 12 mm Hg decompensation. Oral agents such as -blockers, ACE inhibitors
pressure, mean or ARBs, and aldosterone antagonists should be initiated as
Systemic arterial pressure 120/80 mm Hg soon as possible during the hospitalization. These chronic oral
Mean arterial pressure 90120 mm Hg medications not only improve mortality and prevent readmis-
Cardiac index 2.84.2 L/minute per square meter sions, acutely they also contribute to improvement in hemody-
Stroke volume index 3065 mL/beat per square meter namics. Patient education prior to discharge from the hospital
Systemic vascular resistance 9001.400 dynsm5 is recommended to assist in minimizing adverse effects and
Pulmonary vascular resistance 150250 dynsm5 non-adherence. Dissemination of written information, in addi-
Arterial oxygen content 20 mL/dL tion to verbal information, is helpful for patient comprehension
Mixed venous oxygen content 15 mL/dL
and retention. This can include therapy goals, lifestyle modi-
cations, drug regimen, dosage information, and relevant adverse
Arteriovenous oxygen content 35 mL/dL
difference effects, as well as symptom and diary cards.
Pharmacologic Approaches to Treatment

pulmonary artery. Ination of a balloon proximal to the end port
allows the catheter to wedge, yielding the PCWP, which esti- Treatment of AHF targets relief of congestion and opti-
mates pressures in the left ventricle during diastole. Additionally, mization of CO utilizing oral or intravenous diuretics, intra-
CO can be estimated and SVR calculated (Table 38). venous vasodilators, and when appropriate inotropes, based on
There are no universally accepted guidelines dictating when presenting hemodynamics. Current treatment strategies in AHF
invasive monitoring in HF is required. The use of a PAC remains target improving hemodynamics while preserving organ func-
an essential component of management and monitoring of tion. A specic treatment approach is formulated depending
patients in cardiogenic shock; however, the use of inotropic agents on the patients symptoms (congestion versus hypoperfusion)
does not mandate invasive monitoring. Invasive hemodynamic and hemodynamic indices (CI and PCWP).48,49 If the patient
monitoring is most commonly used to aid in the assessment of primarily exhibits signs and symptoms of congestion, treat-
hemodynamics when there is disagreement between signs and ment entails use of diuretics as rst-line agents to decrease
symptoms and clinical response. In addition, invasive monitoring PCWP. Additionally, intravenous vasodilators are added to
is helpful in guiding ongoing therapy for AHF. Invasive monitor- provide rapid relief of congestion and additional reductions
ing offers the advantage of immediate hemodynamic assessment in PCWP. By reducing congestion in the heart, cardiac con-
of an intervention, allowing for prompt adjustments. Risks with tractile function may improve, which results in an increase in
PACs include infection, bleeding, thrombosis, catheter malfunc- SV and CO, and hence perfusion to vital organs. For patients
tion, and ventricular ectopy. A recent randomized trial of PAC use primarily displaying symptoms of hypoperfusion, treatment
in HF demonstrated a neutral effect on patient mortality. relies on use of agents that increase cardiac contractility,
known as positive inotropes. Some patients display both symp-
toms of congestion as well as hypoperfusion and thus require
TREATMENT OF ACUTE HEART FAILURE
use of combination therapies. One of the current challenges to
the treatment of AHF is achieving hemodynamic improve-
Desired Therapeutic Outcomes
ment without adversely affecting organ function. In the case of
The goals of therapy for AHF are to: (1) correct the underly- inotropes, the increased contractility occurs at the expense of
ing precipitating factor(s); (2) relieve the patients symptoms; an increase in cardiac workload and proarrhythmia. In addi-
(3) improve hemodynamics; (4) optimize a chronic oral med- tion, high-dose diuretic therapy is associated with worsened
ication regimen; and (5) educate the patient, reinforcing adher- renal function and possibly neurohormonal activation.
ence to lifestyle modications and the drug regimen. The ulti-
mate goal for a patient hospitalized for AHF is the return to a Diuretics
compensated HF state and discharge to the outpatient setting on Loop diuretics, including furosemide, bumetanide, and
oral medications. Only through aggressive management to torsemide are the diuretics of choice in the management of
TABLE 39. Intravenous Diuretics Used to Treat Heart FailureRelated Fluid Retention
Onset of Duration of Relative Intermittent Bolus Continuous Infusion

Action (minutes) Action (hours) Potency Dosing (mg) Dosing (bolus/infusion)
Furosemide 25 6 40 20200+ 2040/2.510
Torsemide Less than 10 612 20 10100 20/25
Bumetanide 23 46 0.5 110 14/0.51
Ethacrynic acid 515 27 0.51 mg/kg per
dose up to
100 mg/dose
AHF. Furosemide is the most commonly used agent. of action within the nephron. The most common combina-
Diuretics decrease preload by functional venodilation within tion is the use of a loop diuretic with a thiazide diuretic such
5 to 15 minutes of administration and subsequently by an as metolazone. Combining diuretics should be used with cau-
increase in sodium and water excretion. This provides rapid tion due to an increased risk for cardiovascular collapse due to
improvement in symptoms of pulmonary congestion. rapid intravascular volume depletion. Strict monitoring of
Diuretics reduce PCWP but do not increase CI like positive electrolytes, vital signs, and uid balance is warranted.
inotropes and arterial vasodilators. Patients who have signi- Finally, poor CO may contribute to diuretic resistance. In
cant volume overload often have impaired absorption of oral these patients, it may become necessary to add vasodilators or
loop diuretics because of intestinal edema or altered transit inotropes to enhance perfusion to the kidneys. Care must be
time. Therefore, doses are usually administered via intra- taken, as vasodilators can decrease renal blood ow despite
venous boluses, given either at the same dose as the home oral increasing CO through dilation of central and peripheral vas-
dose for those taking diuretics regularly or at lower doses for cular beds.
diuretic-nave patients (Table 39). Higher doses may be
required for patients with renal insufciency due to decreased Vasodilators
drug delivery to the site of action in the loop of Henle. Intravenous vasodilators cause a rapid decrease in arterial
There is a paucity of clinical trial evidence comparing the tone, resulting in a decrease in SVR and a subsequent increase
benet of diuretics to other therapies for symptom relief or in SV and CO. Additionally, vasodilators reduce ventricular
long-term outcomes. Additionally, excessive preload reduc- lling pressures (PCWP) within 24 to 48 hours, reduce
tion can lead to a decrease in CO resulting in reex increase in myocardial oxygen consumption, and decrease ventricular
sympathetic activation, renin release, and the expected conse- workload. Vasodilators are commonly used in patients present-
quences of vasoconstriction, tachycardia, and increased ing with AHF accompanied by moderate to severe congestion.
myocardial oxygen demand. Careful use of diuretics is recom- This class includes nitroglycerin, nitroprusside, and nesiritide.
mended to avoid overdiuresis. Monitor serum electrolytes Hemodynamic effects and dosages for these agents are
such as potassium, sodium, and magnesium frequently to included in Tables 310 and 311, respectively. Although
identify and correct imbalances. Monitor serum creatinine vasodilators are generally safe and effective, identication of
and blood urea nitrogen daily at a minimum to assess volume the proper patient for use is important to minimize the risk of
depletion and renal function.
Occasionally, patients with HF do not respond to a
diuretic, dened as failure to achieve a weight reduction of at TABLE 310. Usual Hemodynamic Effects of Commonly Used
least 0.5 kg (or negative net uid balance of at least 500 mL) Intravenous Agents for Treatment of Acute or
after several increasing bolus doses.17 Severe Heart Failure
Several strategies are employed to overcome diuretic resist- Drug CO PCWP SVR BP HR
ance. These include using larger oral doses, converting to
intravenous dosing, or increasing the frequency of adminis- Diuretics //0 0
tration. Small studies using low-dose continuous infusions of Nitroglycerin /0
furosemide and torsemide have shown an increase in urine Nitroprusside
output compared to intermittent bolus dosing.50 Continuous Nesiritide 0
infusions may provide a theoretical advantage of continuous Dobutamine /0 /0 /0
presence of high drug levels within the tubular lumen, causing Milrinone
a sustained natriuresis. Most regimens include a bolus dose
BP, blood pressure; CO, cardiac output; HR, heart rate; PCWP, pul-
followed by a maintenance infusion (Table 39).51 Another monary capillary wedge pressure; SVR, systemic vascular resistance; ,
useful strategy is to combine two diuretics with different sites increase; , decrease; 0, no or little change.
TABLE 311. Usual Doses and Monitoring of Commonly Used which can be evident within 12 hours after initiation of con-
Hemodynamic Medications tinuous infusion and necessitate additional titrations to
higher doses.
Drug Dose Monitoring Variablesa
Dopamine 0.510+ mcg/kg BP, HR, urinary output and
Nitroprusside
per minute kidney function, ECG,
extremity perfusion Nitroprusside, like nitroglycerin, causes the formation of nitric
(higher doses only) oxide and vascular smooth muscle relaxation. In contrast to nitro-
Dobutamine 2.520 mcg/kg BP, HR urinary output and glycerin, nitroprusside is both a venous and arterial vasodilator
per minute function, ECG regardless of dosage. Nitroprusside causes a pronounced
Milrinone 0.3750.75 mcg/kg BP, HR, urinary output and decrease in PCWP, SVR, and blood pressure, with a modest
per minute function, ECG, changes increase in CO. Nitroprusside has been studied to a limited
in ischemic symptoms extent in AHF and no studies have evaluated its effects on mor-
(e.g., chest pain),
tality.48 Nitroprusside is initiated at 0.1 to 0.25 mcg/kg per
electrolytes
minute, followed by dose adjustments in 0.1 to 0.2 mcg/kg per
Nitroprusside 0.253 mcg/kg BP, HR, liver and kidney
per minute function, blood cyanide minute increments if necessary to achieve desired effect. Because
and/or thiocyanate of its rapid onset of action and metabolism, nitroprusside is
concentrations if administered as a continuous infusion that is easy to titrate and
toxicity suspected provides predictable hemodynamic effects. Nitroprusside
(nausea, vomiting, requires strict monitoring of blood pressure and HR.
altered mental function)
Nitroprussides use is limited in AHF due to recommended
Nitroglycerin 5200+ mcg/kg BP, HR, ECG, changes in
hemodynamic monitoring with an arterial line and mandatory
per minute ischemic symptoms
intensive care unit admission at many institutions. Abrupt with-
Nesiritide Bolus: 2 mcg/kg; BP, HR, urinary output and
Infusion: kidney function, blood drawal of therapy should be avoided, as rebound neurohor-
0.01 mcg/kg BNP concentrations monal activation may occur. Therefore, the dose should be
per minute tapered slowly. Nitroprusside has the potential to cause cyanide
a and thiocyanate toxicity, especially in patients with renal insuf-
In addition to pulmonary capillary wedge pressure and cardiac output.
ciency. Toxicity is most common with use longer than 3 days and
BNP, B-type natriuretic peptide; BP, blood pressure; ECG, electrocardio-
gram; HR, heart rate. with higher doses. Nitroprusside should be avoided in patients
with active ischemia, because its powerful afterload-reducing
signicant hypotension. In addition, vasodilators are con- effects within the myocardium can steal coronary blood ow
traindicated in patients whose cardiac lling (and hence CO) from myocardial segments that are supplied by epicardial vessels
depends on venous return or intravascular volume, as well as with high-grade lesions.
patients who present with shock.
Nesiritide
Nitroglycerin B-type natriuretic peptide is an endogenous neurohormone
Nitroglycerin acts as a source of nitric oxide, which induces that is synthesized and released from the ventricles in response
smooth muscle relaxation in venous and arterial vascular to chamber wall stretch or increased lling pressures.
beds. Nitroglycerin is primarily a venous vasodilator at lower Recombinant BNP, or nesiritide, is the newest compound
doses, but exerts potent arterial vasodilatory effects at higher developed for AHF. Nesiritide binds to guanylate cyclase
doses. Thus, at lower doses, nitroglycerin causes decreases in receptors in vascular smooth muscle and endothelial cells,
preload (or lling pressures) and improved coronary blood causing an increase in cGMP concentrations leading to
ow. At higher doses (greater than 100 mcg/minute), additional vasodilation (venous and arterial) and natriuresis. Nesiritide
reduction in preload is achieved, along with a decrease in after- also antagonizes the effects of the RAAS and endothelin.
load and subsequent increase in SV and CO. Intravenous nitro- Nesiritide reduces PCWP, right atrial pressure, and SVR.
glycerin is primarily used as a preload reducer for patients Consequently, it also increases SV and CO without affecting
exhibiting pulmonary congestion or in combination with heart rate. Continuous infusions result in sustained effects for
inotropes for congested patients with severely reduced CO.52 24 hours without tachyphylaxis, although experience with its
Continuous infusions of nitroglycerin should be initiated at a use beyond 72 hours is limited.
dose of 5 to 10 mcg/minute and increased every 5 to 10 minutes Nesiritide has been shown to improve symptoms of dysp-
until symptomatic or hemodynamic improvement. Effective nea and fatigue. In a randomized clinical trial, the safety and
doses range from 35 to 200 mcg/minute. The most common efcacy of adding nesiritide to standard care was compared to
adverse events reported are headache, dose-related hypoten- placebo and nitroglycerin.53 Nesiritide was found to signi-
sion, and tachycardia. A limitation to nitroglycerins use is the cantly decrease PCWP more than nitroglycerin and placebo
development of tachyphylaxis, or tolerance to its effects, over 3 hours. Nesiritide improved patients self-reported
dyspnea scores compared to placebo at 3 hours, but there was documenting improved hemodynamics, but large-scale clini-
no difference compared to nitroglycerin. There are no cal trials in AHF are lacking.54
prospective mortality studies with nesiritide in AHF. Dobutamine is initiated at a dose of 2.5 to 5 mcg/kg per
Currently, nesiritide is indicated for patients with AHF minute, which can be gradually titrated to 20 mcg/kg per
exhibiting dyspnea at rest or with minimal activity. The rec- minute based on clinical response. There are several practical
ommended dose regimen is a bolus of 2 mcg/kg, followed by considerations to dobutamine therapy in AHF. First, owing to
a continuous infusion for up to 24 hours of 0.01 mcg/kg per its vasodilatory potential, monotherapy with dobutamine is
minute. Because nesiritides effects are predictable and sus- reserved for patients with systolic blood pressures greater than
tained at the recommended dosage, titration of the infusion 90 mm Hg. However, it is commonly used in combination with
rate (maximum of 0.03 mcg/kg per minute) is not commonly vasopressors in patients with lower systolic blood pressures.
required nor is invasive hemodynamic monitoring. Nesiritide Second, due to down-regulation of 1-receptors or uncoupling
should be avoided in patients with systolic blood pressure less of 2- receptors from adenylate cyclase with prolonged expo-
than 90 mm Hg. Although nesiritides place in AHF therapy is sure to dobutamine, attenuation of hemodynamic effects has
not rmly dened, it is used as one of the rst-line agents (in been reported to occur as early as 48 hours after initiation of a
combination with diuretics) for the majority of patients pre- continuous infusion, although tachyphylaxis is more evident
senting in moderate to severe decompensation, mainly due to with use spanning longer than 72 hours. Full sensitivity to
its proven benets and unique mechanism of action. One dobutamines effects can be restored 7 to 10 days after the
potential disadvantage compared to other vasodilators is its drug is withdrawn. Third, many patients with AHF will be
longer half-life. If hypotension occurs, the effect can be pro- taking -blockers on a chronic basis. Because of -blockers
longed (2 hours). There are also concerns relating to eleva- high afnity for -receptors, the effectiveness of -agonists
tions in serum creatinine observed with nesiritide; however, such as dobutamine will be reduced. In patients on -blocker
whether this effect is clinically relevant remains unanswered. therapy, it is recommended that consideration be given to the
use of phosphodiesterase inhibitors such as milrinone, which
Inotropic Agents are not dependent on -receptors for effect.55,56 Although
Currently available positive inotropic agents act via increasing commonly practiced, use of high doses of dobutamine to
intracellular cyclic adenosine monophosphate (cAMP) con- overcome the -blockade should be discouraged, as this
centrations through different mechanisms. -Agonists acti- negates any of the protective benets of the -blocker.
vate adenylate cyclase through stimulation of -adrenergic
receptors, which subsequently catalyzes the conversion of Dopamine
adenosine triphosphate (ATP) to cAMP. In contrast, phos- Dopamine is most commonly reserved for patients with low
phodiesterase inhibitors reduce degradation of cAMP. The systolic blood pressures and those approaching cardiogenic
resulting elevation in cAMP levels leads to enhanced phos- shock. It may also be used in low doses (less than 3 mcg/kg per
pholipase activity, which then increases the rate and extent of minute) to improve renal function in a patient with inade-
calcium inux during systole, thereby enhancing contractility. quate urine output despite high lling pressures and volume
Additionally, during diastole, cAMP promotes uptake of calcium overload, although this indication is controversial.
by the sarcoplasmic reticulum which improves cardiac relax- Dopamine exerts its effects through direct stimulation of
ation. The inotropes approved for use in AHF are discussed in adrenergic receptors, as well as release of norepinephrine from
the following sections. adrenergic nerve terminals. Dopamine produces hemodynamic
effects that differ based on dosing. At lower doses, dopamine
Dobutamine stimulates dopamine type 1 (D1) receptors and thus increases
Dobutamine has historically been the inotrope of choice for renal perfusion. Positive inotropic effects are more pronounced
AHF. As a synthetic catecholamine, it acts as an agonist mainly at doses of 3 to 10 mcg/kg per minute. Cardiac index is increased
on 1- and 2-receptors and minimally on 1-receptors. The due to increased SV and HR. At doses higher than 10 mcg/kg per
resulting hemodynamic effects are due to both receptor- and minute, chronotropic and 1-mediated vasoconstriction effects
reex-mediated activities. These effects include: increased are evident. This causes an increase in mean arterial pressure due
contractility and HR through 1- (and 2-) receptors and to higher CI and SVR. The ultimate effect on cardiac hemody-
vasodilation through a relatively greater effect on 2- than 1- namics will depend largely on the dosage prescribed and must
receptors. Dobutamine can increase, decrease, or cause little be individually tailored to the patients clinical status. Dopamine
change in mean arterial pressure depending on whether the is generally associated with an increase in CO and blood pres-
resulting increase in CO is enough to offset the modest sure, with a concomitant increase in PCWP. Dopamine increases
vasodilation. Although dobutamine displays a half life of myocardial oxygen demand and may decrease coronary blood
approximately 2 minutes, its positive hemodynamic effects can ow through vasoconstriction and increased wall tension. As
be observed for several days to months after administration. with other inotropes, dopamine is associated with a risk for
The use of dobutamine is supported by several small studies arrhythmias.
Phosphodiesterase Inhibitors
Milrinone and inamrinone work by inhibiting phosphodi- Patient Encounter, Part 4
esterase III, the enzyme responsible for the breakdown of
cAMP. The increase in cAMP levels leads to increased intra-
cellular calcium concentrations and enhanced contractile After 6 months, BE returns to clinic complaining of extreme
force generation. Milrinone has replaced inamrinone as the SOB with any activity, including dressing and showering, as
phosphodiesterase inhibitor of choice due to the higher fre- well as at rest. She sleeps sitting up due to severe orthopnea,
quency of thrombocytopenia seen with inamrinone. is unable to eat without nausea, and states she has gained
Milrinone has both positive inotropic and vasodilating prop- 22 lb (10 kg) from her baseline weight. She also states that
erties and as such is referred to as an inodilator. Its vasodilating she does not feel her furosemide therapy is working, She is
activities are especially prominent on venous capacitance vessels admitted to the cardiology unit.
and pulmonary vascular beds, although a reduction in arterial SH
tone is also noted. Intravenous administration results in an BE admits to resuming smoking after quitting for 2 months;
increase in SV and CO, and usually only minor changes in heart additionally, she has been eating out in restaurants more
rate. Milrinone also lowers PCWP through venodilation. Routine often in the past 2 weeks.
use of milrinone during acute decompensations in NYHA FC II Meds
to IV HF is not recommended, and milrinone use remains lim- Lisinopril 10 mg once daily
ited to patients who require inotropic support.57 Furosemide 80 mg twice daily
Dosing recommendations for milrinone include a loading Nitroglycerin 0.4 mg sublingual (SL) as needed
dose of 50 mcg/kg, followed by an infusion beginning at 0.5 Multivitamin daily
mcg/kg per minute (range 0.23 mcg/kg per minute for patients Aspirin 325 mg daily
with renal failure up to 0.75 mcg/kg per minute). A loading VS: blood pressure 146/94 mm Hg, pulse 102 bpm and
dose is not necessary if immediate hemodynamic effects are regular, respiratory rate 22/minute, temperature 37C
not required or if patients have low systolic blood pressures (98.6F), Wt 271 lb (123 kg), BMI 41.2
(less than 90 mm Hg). Decreases in blood pressure during an Lungs: There are rales present bilaterally
infusion may necessitate dose reductions as well.
CV: Regular rate and rhythm with normal S1 and S2; there is
Milrinone is a good option for patients requiring an
an S3 and an S4; a 4/6 systolic ejection murmur is present and
inotrope who are also chronically receiving -blockers, as the
heard best at the left lower sternal border; point of maximal
inotropic effects are achieved independent of -adrenergic impulse is displaced laterally; jugular veins are distended, JVP
receptors. However, milrinone exhibits a long distribution is 11 cm above sternal angle; a positive HJR is observed
and elimination half-life compared to -agonists, thus requir-
Abd: Hard, tender, and bowel sounds are absent; 3+ pitting
ing a loading dose when an immediate response is desired.
edema of extremities is observed
Potential adverse effects include hypotension, arrhythmias,
and less commonly, thrombocytopenia. Milrinone should not CXR: Bilateral pleural effusions and cardiomegaly
be used in patients in whom vasodilation is contraindicated. Echo: EF = 20%
Pertinent labs
BNP 740 pg/mL (740 ng/L), K: 4.2 mEq/L (4.2 mmol/L),
Mechanical, Surgical, and Device Therapies
BUN 64 mg/dL (23 mmol/L), SCr 2.4 mg/dL (212 mmol/L),
Implantable Cardioverter Debrillators Mg 1.8 mEq/L (0.9 mmol/L)
Implantable cardioverter debrillators (ICDs) are the most A pulmonary catheter is placed, revealing the following:
effective modality for primary and secondary prevention of PCWP 37 mm Hg; cardiac index 2.2 L/minute per square
sudden cardiac death in patients with LV dysfunction. Studies meter
universally demonstrate greater efcacy compared to antiar-
rhythmic therapy and a signicant reduction in mortality What NYHA functional class, ACC/AHA stage, and
compared to placebo.5860 Recent studies have expanded the hemodynamic subset is BE currently in?
eligible patient populations beyond classic indications, such as What are your initial treatment goals?
prior MI and non-sustained ventricular tachycardia or non- What pharmacologic agents are appropriate to use at this
time?
suppressible ventricular tachycardia during an electrophysio-
Identify a monitoring plan to assess for efcacy and toxicity
logic study. A clear advantage of implanting ICDs in all symp-
of the recommended drug therapy.
tomatic patients with LVEF less than 35% regardless of etiology Once BEs symptoms are improved, how would you
or other cardiac parameters has been demonstrated.60 Since optimize her oral medication therapy for heart failure?
ICD implantation and follow-up is associated with a signi-
cant economic burden, the cost-effectiveness of widespread
ICD use continues to be debated. Dening subgroups that
would derive the greatest benet and determining the optimal adverse effects include bleeding, air embolism, device failure,
ICD conguration will aid in improving the potential costs and multiorgan failure.
compared to benets.
Surgical Therapy
Cardiac Resynchronization Therapy Heart transplantation represents the nal option for refrac-
Dyssynchronous contraction, as a reection of intra- and inter- tory, end-stage HF patients who have exhausted medical and
ventricular conduction delays between chambers of the heart, is device therapies. Heart transplantation is not a cure, but should
common in advanced HF patients. Dyssynchrony contributes to be considered a trade between a life-threatening syndrome and
diminished cardiac function and unfavorable myocardial ener- the risks associated with the operation and long-term
getics through altered lling times, valvular dysfunction, and immunosuppression. Assessment of appropriate candidates
wall motion defects. Cardiac resynchronization therapy (CRT) includes comorbid illnesses, psychosocial behavior, available
with biventricular pacing devices improves cardiac function, nancial and social support, and patient willingness to adhere
quality of life, and mortality in patients with NYHA FC III or IV to lifelong therapy and close medical follow-up.1 Overall, the
HF, evidence of intraventricular conduction delay (QRS greater transplant recipients quality of life may be improved, but not
than 120 ms), depressed LV function (LVEF less than 35%), and all patients receive this benet. Posttransplant survival contin-
on an optimal pharmacologic regimen. A recent study also ues to improve due to advances in immunosuppression, treat-
showed that the addition of an ICD to CRT with biventricular ment and prevention of infection, and optimal management
pacing further reduced hospitalizations and mortality.61 of patient comorbidities.
Intra-aortic Balloon Counterpulsation Investigational Therapies

Intra-aortic balloon counterpulsation (IABC) or intra-aortic
balloon pumps (IABPs) are one of the most widely used Clinical trials are currently investigating new agents for the
mechanical circulatory assistance devices for patients with treatment of AHF. These compounds offer unique mecha-
cardiac failure who do not respond to standard therapies. An nisms of action by targeting different neurohormonal recep-
IABP is placed percutaneously into the femoral artery and tors (vasopressin, endothelin, atrial natriuretic peptide, and
advanced to the high descending thoracic aorta. Once in posi- adenosine) or through completely novel pharmacologic pro-
tion, the balloon is programmed to inate during diastole and les (levosimendan). Some agents or drug classes being stud-
deate during systole. Two main benecial mechanisms are: ied include: tolvaptan, a V2-selective vasopressin antagonist;
(1) ination during diastole increases aortic pressure and per- various ET-A selective and non-selective antagonists; and an
fusion of the coronary arteries, and (2) deation just prior to adenosine-1 receptor agonist.
the aortic valve opening reduces arterial impedence (after-
load). As such, IABC increases myocardial oxygen supply and OUTCOME EVALUATION OF ACUTE
decreases oxygen demand. This device has many indications, HEART FAILURE
including cardiogenic shock, high-risk unstable angina in
conjunction with percutaneous interventions, preoperative Focus on: (1) acute improvement of symptoms and hemo-
stabilization of high-risk patients prior to surgery, and in dynamics due to intravenous therapies; (2) criteria for a safe
patients who cannot be weaned from cardiopulmonary discharge from the hospital; and (3) optimization of oral
bypass. Possible complications include infection, bleeding, therapy.
thrombosis, limb ischemia, and device malfunction. The Initially, monitor patients for rapid relief of symptoms related
device is typically useful for short-term therapy due to the to the chief complaint on admission. This includes improve-
invasiveness of the device, the need for limb immobilization, ment of dyspnea, oxygenation, fatigue, JVD, and other mark-
and the requirement for full anticoagulation. ers of congestion or distress.
Monitor for adequate perfusion of vital organs through
Ventricular Assist Device assessment of mental status, creatinine clearance, liver func-
The ventricular assist device (VAD) is a surgically implanted tion tests, and a stable HR between 50 and 100 beats per
pump that reduces or replaces the work of the right, left, or minute. Additionally, adequate skin and muscle blood perfu-
both ventricles. Ventricular assist devices are currently indicated sion and normal pH is desirable.
for short-term support in patients refractory to pharmacologic Monitor changes in hemodynamic variables if available.
therapies, as long-term bridge therapy (a temporary transi- Cardiac index should increase, with a goal to maintain it above
tion treatment) in patients awaiting cardiac transplant, or in 2.2 L/minute per square meter. Pulmonary capillary wedge
some instances, as the destination therapy (treatment for pressure should decrease in volume overloaded patients to a
patients in lieu of cardiac transplant for those who are not goal of less than 18 mm Hg.
appropriate candidates for transplantation).1 The most common Closely monitor blood pressures and renal function while
complications are infection and thromboembolism. Other decreasing preload with diuretics and vasodilators.
Ensure patients are euvolemic or nearly euvolemic prior to ABBREVIATIONS

discharge.
Since oral therapies can both improve symptoms and pro- ACC/AHA: American College of Cardiology/American Heart
long survival, optimizing outpatient HF management is a Association
priority when preparing a patient for hospital discharge. ACE: angiotensin-converting enzyme
Ensure that the patients regimen includes a vasodilator, AHF: acute heart failure
-blocker, a diuretic at an adequate dose to maintain euv- ANP: atrial natriuretic peptide
ARB: angiotensin receptor blocker
olemia, and digoxin or aldosterone antagonist if indicated.
AT1: angiotensin type 1
AT2: angiotensin type 2
ATP: adenosine triphosphate
BMI: body mass index
BNP: B-type natriuretic peptide
BP: blood pressure
1. Assess the severity and duration of the patients symp- bpm: beats per minute
toms including limitations in activity. Rule out potential BUN: blood urea nitrogen
exacerbating factors. CAD: coronary artery disease
cAMP: cyclic adenosine monophosphate
2. Obtain a thorough history of prescription, non- CBC: complete blood cell count
prescription, and herbal medication use. Is the patient cGMP: cyclic guanosine monophosphate
taking any medications that can exacerbate HF? CHARM: Candesartan in Heart Failure Assessment of Reduction
3. Review available diagnostic information from the chest in Mortality and Morbidity
radiograph, ECG, and echocardiogram. CI: cardiac index
4. Review the patients lifestyle habits including salt and CNS: central nervous system
alcohol intake, tobacco product use, and exercise routine. CO: cardiac output
CrCL: creatinine clearance
5. If unknown, investigate the patients underlying etiology
CRT: cardiac resynchronization therapy
of HF. Verify that comorbidities that lead to or worsen HF
CXR: chest x-ray
are optimally managed with appropriate drug therapy.
CYP450: cytochrome P-450 isoenzyme
6. Educate the patient on lifestyle modications such as salt D1: dopamine receptor type 1
restriction (maximum 2 to 4 grams per day), uid restric- ECG: electrocardiogram
tion if appropriate, limitation of alcohol, tobacco cessa- EF: ejection fraction
tion, participation in a cardiac rehabilitation and exercise ET-1: endothelin-1
program, and proper immunizations such as the pneu- ET-A: endothelin-A
mococcal vaccine and yearly inuenza vaccine. ET-B: endothelin-B
7. Develop a treatment plan to alleviate symptoms and FDA: Food and Drug Administration
maintain euvolemia with diuretics. Daily weights to HF: heart failure
assess uid retention are recommended. HJR: hepatojugular reux
8. Develop a medication regimen to slow the progression of HR: heart rate
HF with the use of neurohormonal blockers such as IABC: intra-aortic balloon counterpulsation
vasodilators (ACE inhibitors, ARBs, or hydralazine/ IABP: intra-aortic balloon pump
isosorbide dinitrate), -blockers, and aldosterone antago- ICD: implantable cardioverter debrillator
nists. Utilize digoxin if the patient remains symptomatic iNOS: inducible nitric oxide synthetase
despite optimization of the above therapies. INR: international normalized ratio
Is the patient at goal or maximally tolerated doses of JVD: jugular venous distention
vasodilator and -blocker therapy? JVP: jugular venous pressure
Are aldosterone antagonists utilized in appropriate LV: left ventricular
patients with proper electrolyte and renal function LVEF: left ventricular ejection fraction
monitoring? LVF: left ventricular failure
9. Stress the importance of adherence to the therapeutic MI: myocardial infarction
regimen and lifestyle changes for maintenance of a MVO2: myocardial oxygen consumption
compensated state and slowing of disease progression. NSAID: non-steroidal anti-inammatory drug
NT-proBNP: N-terminal proBNP
10. Evaluate the patient for presence of adverse drug
NYHA FC: New York Heart Association Functional Class
reactions, drug allergies, and drug interactions.
PAC: pulmonary artery catheter
11. Provide patient education with regard to disease state PCWP: pulmonary capillary wedge pressure
and drug therapy, and reinforce self-monitoring for PE: physical exam
symptoms of HF that necessitate follow-up with a PND: paroxysmal nocturnal dyspnea
health care practitioner. PPCM: peripartum cardiomyopathy
QRS: ventricular depolarization
RAAS: renin-angiotensin-aldosterone system Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA Guideline update
RVF: right ventricular failure for the diagnosis and management of chronic heart failure in the
SCr: serum creatinine adultsummary article: a report of the American College of
SL: sublingual Cardiology/American Heart Association Task Force on Practice
SNS: sympathetic nervous system Guidelines (Committee to revise the 2001 Guidelines for the
SOB: shortness of breath Evaluation and Management of Heart Failure). J Am Coll Cardiol
SV: stroke volume 2005;46:11161143.
SVR: systemic vascular resistance Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the
TNF-: tumor necrosis factor- evaluation and management of chronic heart failure in the
V1a: vasopressin type 1a adult: executive summary: a report of the American College of
V2: vasopressin type 2 Cardiology/American Heart Association Task Force on Practice
VAD: ventricular assist device Guidelines (Committee to revise the 1995 Guidelines for the
Evaluation and Management of Heart Failure). J Am Coll
Reference lists and self-assessment questions and answers are Cardiol 2001;38:21012113.
available at www.ChisholmPharmacotherapy.com. Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348:20072018.
Mann DL. Mechanisms and models in heart failurea combinatorial
approach. Circulation 1999;100:9991008.
Log into the website: www.pharmacotherapyprinciples.com
Ng TMH, Carter O, Guillory GS, et al. High-impact articles related to
for information on obtaining continuing education credit for the pharmacotherapeutic management of systolic heart failure.
this chapter. Pharmacotherapy 2004;24:15941633.
Nohria A, Lewis E, Stevenson LW. Medical management of advanced
KEY REFERENCES AND READINGS heart failure. JAMA 2002;287:628640.
DiDomenico RJ, Park HY, Southworth MR, et al. Guidelines for acute
decompensated heart failure treatment. Ann Pharmacother
2004;38:649660.
4 ISCHEMIC HEART DISEASE
Larisa H. Cavallari and Robert J. DiDomenico
LEARNING OBJECTIVES
1. Identify risk factors for the development of ischemic heart disease.

2. Recognize the symptoms and diagnostic criteria of ischemic heart disease in a specic
patient.
3. Differentiate between the pathophysiology of chronic stable angina and acute coronary
syndromes.
4. Identify the treatment goals of ischemic heart disease and appropriate lifestyle modications
and pharmacologic therapy to address each goal.
5. Design an appropriate therapeutic regimen for the management of ischemic heart disease
based on patient-specic information.
6. Formulate a monitoring plan to assess effectiveness and adverse effects of an ischemic heart
disease drug regimen.
KEY CONCEPTS Both 3-hydroxy-3-methylglutaryl coenzyme A reductase

inhibitors (statins) and angiotensin-converting enzyme
Ischemic heart disease results from an imbalance between inhibitors are believed to provide vasculoprotective effects,
myocardial oxygen demand and oxygen supply that is most and in addition to antiplatelet agents, have been shown to
often due to coronary atherosclerosis. Common clinical man- reduce the risk of acute coronary events as well as mortality in
ifestations of ischemic heart disease include chronic stable patients with ischemic heart disease. Angiotensin receptor
angina and the acute coronary syndromes of unstable angina, blockers may be used in patients who cannot tolerate
nonST-segment elevation myocardial infarction, and ST- angiotensin-converting enzyme inhibitors because of side
segment elevation myocardial infarction. effects (e.g., chronic cough). -Blockers have been shown to
Early detection and aggressive modication of risk factors is decrease morbidity and improve survival in patients who have
one of the primary strategies for delaying ischemic heart dis- suffered a myocardial infarction.
ease progression and preventing ischemic heart diseaserelated Antiplatelet therapy with aspirin should be considered for all
events including death. patients without contraindications, particularly in patients with
Patients with chest pressure or heaviness that is provoked by a history of myocardial infarction. Clopidogrel may be consid-
activity and relieved with rest should be assessed for ischemic ered in patients with allergies or intolerance to aspirin. In some
heart disease. Sharp pain is not a typical symptom of ischemic patients, combination antiplatelet therapy with aspirin and
heart disease. Some patients may experience discomfort in the clopidogrel may be used.
neck, jaw, shoulder, or arm rather than, or in addition to, the To control risk factors and prevent major adverse cardiac events,
chest. Pain may be accompanied by nausea, vomiting, or statin therapy should be considered in all patients with ischemic
diaphoresis. heart disease, particularly in those with elevated low-density
The major goals for the treatment of ischemic heart disease lipoprotein cholesterol. In the absence of contraindications,
are to prevent acute coronary syndromes and death, alleviate angiotensin-converting enzyme inhibitors should be considered
acute symptoms of myocardial ischemia, prevent recurrent in ischemic heart disease patients who also have diabetes melli-
symptoms of myocardial ischemia, and avoid or minimize tus, left ventricular dysfunction, history of myocardial infarction,
adverse treatment effects. or any combination of these. Angiotensin receptor blockers
63
may be used in patients who cannot tolerate angiotensin-con- an imbalance between myocardial oxygen supply and oxygen
verting enzyme inhibitors because of side effects. demand (Fig. 41). Common clinical manifestations of IHD
All patients with a history of angina should have sublingual include chronic stable angina and the acute coronary syndromes
nitroglycerin tablets or spray to relieve acute ischemic symp- (ACS) of unstable angina, nonST-segment elevation myocardial
toms. Patients should be instructed to use one dose (tablet or infarction (MI), and ST-segment elevation MI.
spray) every 5 minutes until pain is relieved and to call 911 if Angina pectoris, or simply angina, is the most common
pain is unimproved or worsens 5 minutes after the rst dose. symptom of IHD. Angina is discomfort in the chest that occurs
-Blockers are rst-line therapy for preventing ischemic when the blood supply to the myocardium is compromised.
symptoms, particularly in patients with a history of myocar- Chronic stable angina is dened as a chronic and predictable
dial infarction. Long-acting calcium channel blockers and occurrence of chest discomfort due to transient myocardial
long-acting nitrates may be added for refractory symptoms or ischemia with physical exertion or other conditions that increase
substituted if a -blocker is not tolerated. oxygen demand. The primary focus of this chapter is on the
Patients should be monitored to assess for drug effectiveness, management of chronic stable angina. However, some informa-
adverse drug reactions, and potential drug-drug interactions. tion is also provided related to ACS, given the overlap between
Patients should be assessed for adherence to their pharma- the two disease states. The American College of Cardiology and
cotherapeutic regimens and lifestyle modications. the American Heart Association have jointly published practice
guidelines for the management of patients with chronic stable
Ischemic heart disease (IHD) is also called coronary heart angina, and the reader is referred to these guidelines for further
disease (CHD) or coronary artery disease. The term ischemic information.1
refers to a decreased supply of oxygenated blood, in this case to
the heart muscle. Ischemic heart disease is caused by the narrow-
ing of one or more of the major coronary arteries that supply EPIDEMIOLOGY AND ETIOLOGY
blood to the heart, most commonly by atherosclerotic plaques.
Atherosclerotic plaques may impede coronary blood ow to the Ischemic heart disease affects over 13 million Americans and
extent that cardiac tissue distal to the site of the coronary artery is the leading cause of death for both men and women in the
narrowing is deprived of sufcient oxygen in the face of United States.2 The incidence of IHD is higher in middle-aged
increased oxygen demand. Ischemic heart disease results from men compared to women. However, the rate of IHD increases
/ Heart rate
/ Myocardial contractility
/ Ventricular wall tension
Arterial pO2 Heart rate

Diastolic filling time Myocardial contractility
Coronary blood flow Ventricular wall tension
/ Arterial pO2
/ Diastolic filling time
Coronary blood flow
Oxygen supply = Oxygen demand Oxygen supply / Oxygen demand
= No change = Decreases = Increases
FIGURE 41. This illustration depicts the balance between myocardial oxygen supply and demand and the various factors that affect
each. It should be noted that diastolic lling time is not an independent predictor of myocardial oxygen supply per se, but rather a
determinant of coronary blood ow. On the left is myocardial oxygen supply and demand under normal circumstances. On the
right is the mismatch between oxygen supply and demand in patients with ischemic heart disease. In patients without ischemic
heart disease, coronary blood ow increases in response to increases in myocardial oxygen demand. However, in patients with
ischemic heart disease, coronary blood ow cannot sufciently increase (and may decrease) in response to increased oxygen
demand resulting in angina. IHD, ischemic heart disease; pO2, partial pressure of oxygen.
CHAPTER 4 / ISCHEMIC HEART DISEASE 65
two- to three-fold in women after menopause. Chronic stable Proximal right Left main
angina is the initial manifestation of IHD in about 50% of Proximal
circumflex
patients. In other patients, unstable angina or MI is the rst Proximal left
sign of IHD. Chronic stable angina is associated with consid- anterior descending
erable patient morbidity, with many affected patients eventu- First obtuse
marginal
ally requiring hospitalization for ACS.3 In addition, chronic Second obtuse
stable angina has a major negative impact on health-related marginal
quality of life.4 Thus, in patients with chronic stable angina, it Third obtuse
marginal
is important to optimize pharmacotherapy to reduce symp- Mid right
toms, improve quality of life, slow disease progression, and First
diagonal
prevent ACS. Mid left
anterior
Acute descending
marginal Second
Conditions Associated with Angina Distal right diagonal
First septal
Figure 42 shows the anatomy of the coronary arteries. The Distal left
anterior
major epicardial coronary arteries are the left main, left ante- descending
rior descending, left circumex, and right coronary arteries. Sternocostal aspect
Atherosclerosis involving one or more of the major coronary
arteries or their principal branches is the major cause of
angina. Vasospasm at the site of an atherosclerotic plaque Distal circumflex
may contribute to angina by further restricting blood supply Right posterior
to the distal myocardium. Less commonly, vasospasm in coro- lateral segment
nary arteries with no or minimal atherosclerotic disease can

produce angina and even precipitate ACS. This type of
vasospasm is referred to as variant or Prinzmetals angina.
Non-ischemic cardiac conditions, such as aortic dissection
(tear in the wall of the aorta leading to bleeding into the media Inferior septal
layer of vessel and separation or dissecting of media from the Left

outer layer of the aorta) and pericarditis, can cause chest dis- atrioventricular
comfort that resembles angina. Non-cardiac conditions involv- Third right posterior lateral
ing the pulmonary, gastrointestinal, and psychological systems First left posterior lateral
can also cause angina-like symptoms. Table 41 lists specic Second right posterior lateral
Second left posterior lateral
conditions other than atherosclerosis that can precipitate
Right posterior descending
angina-like symptoms. It is important to differentiate the eti- Left posterior descending
ology of chest discomfort since treatment varies depending on
First right posterior lateral
the underlying disease process. Third left posterior lateral
Diaphragmatic aspect
Risk Factors FIGURE 42. Coronary artery anatomy with sternocostal

and diaphragmatic views. (Reproduced from Talbert RL.
Factors that predispose an individual to IHD are listed in Ischemic heart disease. In: DiPiro JT, Talbert RL, Yee GC,
Table 42. Hypertension, diabetes, dyslipidemia, and cigarette et al, (eds.) Pharmacotherapy: A Pathophysiologic
smoking are associated with endothelial dysfunction and Approach. 6th ed. New York: McGraw-Hill; 2005: 263,
potentiate atherosclerosis of the coronary arteries. The risk for with permission.)
IHD increases two-fold for every 20 mm Hg increment in sys-
tolic blood pressure and up to eight-fold in the presence of
diabetes.5,6 Physical inactivity and obesity independently
increase the risk for IHD, in addition to predisposing individ-
uals to other cardiovascular risk factors (e.g., hypertension, resistance. The risk of developing IHD and related complica-
dyslipidemia, and diabetes). tions is two-fold higher in patients with metabolic syndrome.7
Patients with multiple risk factors, particularly those with Therefore, detection and appropriate management of these
diabetes, are at the greatest risk for IHD. Metabolic syndrome patients is important. While there are several criteria used to
is a constellation of cardiovascular risk factors related to diagnose metabolic syndrome, those endorsed by the National
hypertension, abdominal obesity, dyslipidemia, and insulin Cholesterol Education Program are probably the most widely
TABLE 41. Non-atherosclerotic Conditions that Can Cause oxygen consumption (MVO2). Left ventricular wall tension is
Angina-like Symptoms a function of blood pressure, left ventricular end-diastolic vol-
ume, and ventricular wall thickness. Physical exertion increases
Organ System Condition
heart rate, blood pressure, and cardiac contractility, and com-
Cardiac Aortic dissection, coronary artery vasospasm, monly precipitates ischemia and symptoms of angina in
pericarditis, valvular heart disease
patients with signicant coronary atherosclerosis. Medications
Non-cardiac Anemia, anxiety disorders, carbon monoxide that reduce heart rate, cardiac contractility, and/or ventricular
poisoning, cocaine use, esophageal reux,
peptic ulcer, pleuritis, pneumonia,
wall tension are commonly prescribed to prevent ischemic
pneumothorax, pulmonary embolus, symptoms in patients with chronic stable angina.
pulmonary hypertension, thyrotoxicosis Reductions in coronary blood ow (secondary to athero-
sclerotic plaques, vasospasm, or thrombus formation) and
arterial oxygen content (secondary to hypoxia) decrease
accepted.8 To diagnose metabolic syndrome, patients must myocardial oxygen supply. Because the coronary arteries ll
meet at least three of the following criteria: during diastole, decreases in diastolic lling time (e.g., tachy-
cardia) can also reduce coronary perfusion and myocardial oxy-
Increased waist circumference (greater than 40 inches or 102 gen supply. In chronic stable angina, atherosclerotic plaques are
cm in males and greater than 35 inches or 89 cm in females). the most common cause of coronary artery narrowing and
Triglycerides of 150 mg/dL (1.70 mmol/L) or greater or reductions in coronary blood ow. In contrast, in ACS, disrup-
active treatment to lower triglycerides. tion of an atherosclerotic plaque with subsequent thrombus
Low high-density lipoprotein (HDL) cholesterol (less than (blood clot) formation causes abrupt reductions in coronary
40 mg/dL or 1.04 mmol/L in males and less than 50 mg/dL blood ow and oxygen supply. Anemia, carbon monoxide poi-
or 1.3 mmol/L in females) or active treatment to raise HDL soning, and cyanotic congenital heart disease are examples of
cholesterol. conditions that reduce the oxygen-carrying capacity of the
Blood pressure of 130/85 mm Hg or greater or active treat- blood, potentially causing ischemia in the face of adequate
ment with antihypertensive therapy. coronary perfusion. Interventional procedures to compress or
Fasting blood glucose of 100 mg/dL (5.55 mmol/L) or bypass atherosclerotic plaques are effective methods of improv-
greater or active treatment for diabetes. ing myocardial oxygen supply in patients with IHD.
Early detection and aggressive modication of risk factors

are among the primary strategies for delaying IHD progression Coronary Atherosclerosis
and preventing IHD-related events including death. The normal arterial wall consists of the intima, media, and
adventitia, as illustrated in Fig. 43A. The endothelium is located
in the intima and consists of a layer of endothelial cells that line
PATHOPHYSIOLOGY the lumen of the artery and form a selective barrier between the
vessel wall and blood contents. The internal elastic lamina sepa-
The determinants of oxygen supply and demand are shown in rates the intima and media, where vascular smooth muscle cells
Fig. 41. Increases in heart rate, left ventricular wall tension, are found. The vascular adventitia comprises the arterys outer
and cardiac contractility increase the rate of myocardial layer. Atherosclerotic lesions form in the subendothelial space
between the endothelial cells and internal elastic lamina.
Dysfunction of the endothelium allows lipoproteins, pre-
TABLE 42. Major Risk Factors for Ischemic Heart Disease
dominantly low-density lipoprotein (LDL) cholesterol, and
Modiable Non-modiable inammatory cells, namely monocytes and T lymphocytes,
Cigarette smoking Age 45 years or greater for males,
to migrate from the plasma to the sub-endothelial space.
Dyslipidemia age 55 years or greater for females Monocyte-derived macrophages ingest lipoproteins to form
Elevated LDL or Gender (men and postmenopausal foam cells. Macrophages also secrete growth factors that promote
total cholesterol women) smooth muscle cell migration from the media to the intima. A
Reduced HDL Family history of premature fatty streak consists of lipid-laden macrophages and smooth
cholesterol cardiovascular disease, dened as
Diabetes mellitus cardiovascular disease in a male
muscle cells and is the earliest type of atherosclerotic lesion.
Hypertension rst-degree relative (i.e., father or Lipid-laden macrophages, smooth muscle cells, and necrotic
Physical inactivity brother) younger than 55 years debris from the death of foam cells accumulate in the sub-
Obesity (body mass old or a female rst-degree endothelial space, leading to enlargement of the fatty streak. A
index greater than relative (i.e., mother or sister) collagen matrix forms a brous cap that covers the lipid core of
or equal to 30 kg/m2) younger than 65 years
the lesion to establish a brous plaque called an atherosclerotic
HDL, high-density lipoprotein; LDL, low-density lipoprotein plaque. Initially, the diameter of the coronary artery lumen is
FIGURE 43. Pathophysiology

Chronic stable angina of chronic stable angina versus
acute coronary syndromes.
Panel A depicts the cross-sec-
Normal coronary artery A Smooth muscle cells Stable B tion of a normal coronary
Smooth muscle cells
Atherosclerotic
Endothelial plaque artery. Panel B depicts the
cells cross-section of a coronary
artery with a stable atheroscle-
Endothelium
Coronary artery lumen rotic plaque. Note that the
Coronary artery lumen
Fibrous cap lipid core is relatively small in
size and the brous cap is
Internal elastic lamina made up of several layers of
smooth muscle cells. Panel C
Intima Intima depicts an unstable atheroscle-
Media
Adventitia
Media
Adventitia
rotic plaque with a larger lipid
Lipid core
core, and a thin brous cap
Acute coronary syndrome comprised of a single layer of
smooth muscle cells with a
ssure or rupture. Panel D
D Smooth muscle cells Plaque C Smooth muscle cells
depicts platelet adhesion in
fissure/rupture response to the ssured
plaque. Platelet activation may
Coronary artery ensue leading to platelet
lumen aggregation as brinogen
Platelet Coronary artery lumen
adhesion binds platelets to one another
Platelet
to form a meshlike occlusion in
the coronary lumen (Panel E).
At this stage, patients may
Intima Intima experience symptoms of acute
Media Media coronary syndrome. If endoge-
Lipid core Adventitia Lipid core Adventitia
nous anticoagulant proteins
fail to halt this process, platelet
aggregation continues and b-
rinogen is converted to brin,
E Smooth muscle cells F Smooth muscle cells
resulting in an occlusive
thrombus (Panel F).
Platelet
aggregation Thrombus
formation
Fibrinogen
Intima Intima
Media Media
Lipid core Adventitia Lipid core Adventitia
maintained as the plaque grows outward (external to the lumen) coronary blood ow to the extent that myocardial oxygen sup-
in a process referred to as arterial remodeling.9 However, with ply can no longer meet increases in myocardial oxygen
signicant plaque progression, the atherosclerotic plaque begins demand. Over time, an established plaque may become unsta-
to protrude into the artery lumen and impede blood ow. When ble and rupture, leading to an ACS. Atherosclerotic plaque
the plaque occludes 70% or more of the artery, the patient may rupture with subsequent thrombus formation is the hallmark
begin to experience angina during activities that increase feature in the pathophysiology of unstable angina and MI and
myocardial oxygen demand (i.e., chronic stable angina). is depicted in Fig. 43. Plaque rupture refers to ssuring or
erosion of the brous cap that covers the lipid core and expo-
sure of the plaque contents to elements in the blood. Plaque
Stable versus Unstable Atherosclerotic Plaques
composition, rather than the degree of coronary stenosis,
The hallmark feature in the pathophysiology of chronic stable determines the stability of the plaque and the likelihood of
angina is an established atherosclerotic plaque that impedes plaque rupture and ACS. Specically, a stable lesion consists of
a small lipid core that is surrounded by a thick brous cap

that protects the lesion from the shear stress of blood ow Clinical Presentation and Diagnosis
(Fig. 43B). In contrast, an unstable plaque consists of a thin, of Ischemic Heart Disease
weak cap in combination with a large, rich lipid core that ren-
ders the plaque vulnerable to rupture (Fig. 43C). The trans-
General
formation of a stable plaque into an unstable plaque involves
Patients with chronic stable angina will generally be in no
the degradation of the brous cap by substances released from acute distress. In patients presenting in acute distress, the
macrophages and other inammatory cells. An unstable clinician should be suspicious of ACS.
plaque often produces minimal occlusion of the coronary ves-
Symptoms of Angina Pectoris
sel, and the patient remains asymptomatic until the plaque
Patients typically describe pain as a sensation of pressure,
ruptures. In fact, the majority of MIs arise from vulnerable
heaviness, or squeezing in the anterior chest area. Sharp
plaques that occlude less than 50% of the coronary lumen.10 pain is not a typical symptom of IHD.
As a result, unstable angina or MI is the initial manifestation Pain may radiate to the neck, jaw, shoulder, back, or arm.
of IHD in about one-half of affected patients. Pain may be accompanied by dyspnea, nausea, vomiting,
or diaphoresis.
Symptoms are often provoked by exertion (e.g., walking,
Atherosclerotic Plaque Rupture climbing stairs, and doing yard or house work) or emo-
Following plaque rupture, exposure of the blood to the tional stress and relieved within minutes by rest or nitro-
thrombogenic contents of the plaque stimulates platelet adhe- glycerin. Other precipitating factors include exposure to
sion and activation of the coagulation cascade. Platelets cold temperatures and heavy meals. Pain that occurs at
rest (without provocation) or that is prolonged and unre-
adhere to the site of rupture, aggregate, and generate throm-
lieved by nitroglycerin is indicative of an ACS. Some
bin (Fig. 43D, E, and F). Thrombin converts brinogen to
patients, most commonly women and patients with dia-
brin to form a brin clot. Coronary thrombi extend into the betes, present with atypical symptoms of ischemia includ-
vessel lumen, where they either partially or completely ing indigestion, gastric fullness, and shortness of breath.
occlude blood ow, resulting in unstable angina or MI.
Signs
Findings on the physical exam are often normal in patients
Coronary Artery Vasospasm with chronic stable angina. However, during episodes of
ischemia, patients may present with abnormal heart sounds,
Prinzmetals or variant angina results from spasm (or contraction) such as paradoxical splitting of the second heart sound, a
of a normal or diseased coronary artery. In contrast to chronic sta- third heart sound, or a loud fourth heart sound.
ble angina, diseased arteries in variant angina contain lesions
Laboratory Tests
that do not obstruct blood ow. While vasospasm is generally
Biochemical markers (creatine kinase [CK], CK-MB frac-
transient, in some instances vasospasm may persist long enough tion, troponin I and troponin T) are elevated in MI (ST-
to infarct the myocardium. Variant angina usually occurs at rest, segment elevation MI and nonST-segment elevation MI),
especially in the early morning hours. Patients with variant but normal in chronic stable angina and unstable angina.
angina are typically younger than those with chronic stable
Other Diagnostic Tests
angina and often do not possess the classic risk factors for IHD.
A 12-lead electrocardiogram (ECG) recorded during rest is
The cause of variant angina is unclear but appears to involve often normal in patients with chronic stable angina in the
endothelial dysfunction and paradoxical response to agents that absence of active ischemia. Signicant Q waves indicate
normally cause vasodilation. Precipitants of variant angina prior MI. ST-segment or T-wave changes during symptoms of
include cigarette smoking, cocaine use, hyperventilation, and angina support the diagnosis of IHD. ST-segment depression
exposure to cold temperatures. The management of variant or T-wave inversion is typically observed in chronic stable
angina differs from that of classic angina, and thus it is impor- angina, unstable angina, and nonST-segment elevation MI,
tant to distinguish between the two. whereas ST-segment elevation occurs with ST-segment ele-
vation MI and Prinzmetals (variant) angina.
Treadmill or bicycle exercise ECG, commonly referred to
as a stress test, is considered positive for IHD if the
CLINICAL PRESENTATION AND DIAGNOSIS ECG shows at least a 1 mm deviation of the ST-segment
(depression or elevation).
History Wall motion abnormalities or left ventricular dilation with
stress echocardiography are indicative of IHD.
The evaluation of a patient with suspected IHD begins with a Stress myocardial perfusion imaging with the radionu-
detailed history of anginal symptoms. The ve components clides technetium-99m sestamibi or thallium-201 allows
commonly used to characterize chest pain are quality, loca- for the identication of multivessel disease and assess-
tion, duration of pain, factors that provoke pain, and factors ment of myocardial viability.
(Continued )
TABLE 43. The Canadian Cardiovascular Society

Coronary angiography detects the location and degree of
Classication System of Angina49
coronary atherosclerosis and is used to evaluate the
potential benet from revascularization procedures. Class Description
Stenosis of at least 70% of the diameter of at least one of
the major epicardial arteries on coronary angiography is I Able to perform ordinary physical activity (e.g., walking
and climbing stairs) without symptoms. Strenuous,
indicative of signicant IHD.
rapid, or prolonged exertion causes symptoms.
II Symptoms slightly limit ordinary physical activity.
Walking rapidly or for more than two blocks,
that relieve pain. The classic presentation of angina is climbing stairs rapidly or climbing more than one
described in the Clinical Presentation and Diagnosis box. In ight of stairs causes symptoms.
some cases, ischemia may not produce any symptoms and is III Symptoms markedly limit ordinary physical activity.
termed silent ischemia. Patients with diabetes may experi- Walking less than two blocks or climbing one ight
of stairs causes symptoms.
ence associated symptoms, such as dyspnea and diaphoresis,
without having any of the classic chest pain symptoms. IV Angina may occur at rest. Any physical activity causes
symptoms.
Non-cardiac conditions, such as gastroesophageal reux
disease, may cause chest pain that is difcult to distinguish
from angina. A detailed history and risk factor assessment
Distinguishing Characteristics of Chronic Stable
may help to clarify the diagnosis. For example, pain that is
Angina and Unstable Angina
sharp or stabbing, occurs randomly (not provoked by exertion
or stress), is tender to palpation, changes with position or res- Chronic stable angina should be distinguished from unstable
piration, responds variably to nitroglycerin, or lasts for hours angina since the latter is associated with a greater risk for MI
is atypical of angina and suggestive of a non-cardiac etiology. and death and requires more aggressive treatment. Because
The diagnosis of IHD is also less likely in a patient with atyp- the pathophysiology of chronic stable angina is due primarily
ical symptoms who has no known risk factors for IHD. to increases in oxygen demand, not acute changes in oxygen
supply, symptoms are typically reproducible and reversible.
The Canadian Cardiovascular Society Specically, a patient will generally experience a similar pattern of
Classication System discomfort (i.e., same quality, location, and accompanying symp-
toms) with a similar level of exertion with each angina attack.
The Canadian Cardiovascular Society Classication System Chronic stable angina is usually relieved within minutes by rest
(Table 43) is commonly used to assess the degree of disabil- or sublingual nitroglycerin. In contrast, unstable angina is due to
ity resulting from IHD. Patients are categorized into one of an acute decrease in coronary blood ow leading to insufcient
four classes depending on the extent of activity that produces oxygen supply. Consequently, unstable angina is marked by pro-
angina. Grouping patients according to this or a similar longed symptoms (greater than or equal to 20 minutes) or an
method is commonly used to assess changes in IHD severity escalation in the frequency or severity of angina over a short
over time and the effectiveness of pharmacologic therapy. period of time. Unstable angina frequently occurs at rest without
any precipitating factors, whereas chronic stable angina usually
occurs with exertion. Unstable angina may be less responsive to
Patient Encounter, Part 1 rest or medication. The presentation of unstable angina is
described in greater detail in Table 44.
RJ is a 47-year-old man with a history of hypertension Physical Findings and Laboratory Analysis
who presents to your clinic complaining of chest pain A thorough medical history and physical exam are necessary to
that occurred several times over the past few weeks. RJ
ascertain cardiovascular risk factors and to exclude non-ischemic
describes his chest pain as a heaviness. He states that it
rst occurred while he was mowing the grass. He later felt
the same heavy sensation while raking leaves and again TABLE 44. Presentations of Unstable Angina50
while carrying some boxes. The pain was located in the
substernal area and radiated to his neck. The pain resolved Angina at rest that is prolonged in duration, usually lasting over
after about 5 minutes of rest. 20 minutes.
Angina of recent onset (within 2 months) that markedly limits
Are RJs symptoms consistent with angina? usual activity.
What tests would be benecial in establishing a diagnosis? Angina that increases in severity (i.e., by Canadian Cardiovascular
What additional objective information do you need in Society Classication System Class of one level or greater), fre-
order to create a treatment plan for this patient? quency, or duration, or that occurs with less provocation over a
short time period (i.e., within 2 months).
and non-cardiac conditions that could cause angina-like

symptoms. Cardiac ndings on the physical exam are often Patient Encounter, Part 2: Medical
normal in patients with chronic stable angina. However, nd- History, Physical Exam, and Diagnostic
ings such as carotid bruits or abnormal peripheral pulses Tests
would indicate atherosclerosis in other vessel systems and
PMH
raise the suspicion for IHD.
Hypertension, diagnosed 7 years ago
Laboratory analysis and cardiac testing are other important
components of the evaluation of the patient with chest pain. FH
Usual laboratory tests include hemoglobin, fasting glucose, and Father with coronary artery disease, had a myocardial
infarction at age 50 years
fasting lipid prole (total cholesterol, LDL cholesterol, HDL
Mother alive and well
cholesterol, and triglycerides) to assess for cardiovascular risk
factors and comorbid conditions. Biochemical markers of SH
myocardial necrosis (i.e., cardiac enzymes), including creatine Smokes 1/2 to 1 pack per day
kinase (CK)-MB fraction and cardiac troponin (I or T), are Denies alcohol and illicit drug use
No regular exercise program
acutely elevated after MI but normal in chronic stable angina
and unstable angina. Therefore serial measurements of cardiac Meds
enzymes (usually three measurements within 24 hours) are used Hydrochlorothiazide 25 mg PO once daily
to exclude the diagnosis of MI. Nifedipine XL 60 mg PO once daily
No known drug allergies
PE
Diagnostic Tests VS: Blood pressure = 154/90 mm Hg
A resting ECG is indicated in all patients with angina-like Heart rate = 84 beats per minute, respirations = 16
symptoms. A 12-lead ECG should be done within 10 minutes Temperature = 37C (98.6F)
of presentation to the emergency department in patients with Height = 510 (178 cm), weight = 230 lb (104.6 kg)
Cardiovascular: Regular rate and rhythm, normal S1 and S2,
symptoms of ischemia. Electrocardiographic ndings indica-
no S3 or S4; no murmurs, rubs, gallops
tive of myocardial ischemia include ST-segment elevation, ST-
Lungs: Clear to auscultation and percussion
segment depression, and T-wave abnormalities in two or more Abd: Nontender, nondistended, + bowel sounds
contiguous leads. It is important to promptly identify patients
with ST-segment elevation, as these patients are at the high- Labs
Fasting lipid prole: total cholesterol 233 mg/dL
est risk of death and need interventions to restore blood
(6.03 mmol/L), HDL cholesterol 30 mg/dL (0.78 mmol/L),
ow to the myocardium as quickly as possible. In patients
LDL cholesterol 165 mg/dL (4.27 mmol/L), triglycerides
without ST-segment elevation, biochemical markers are used 188 mg/dL (2.12 mmol/L); other labs within normal limits
to distinguish between unstable angina and nonST-segment
elevation MI. Exercise treadmill test: positive for ischemia
Exercise ECG testing using either a treadmill (most
Identify RJs risk factors for ischemic heart disease.
commonly) or bicycle ergometer is a common non-invasive
How might RJs current drug regimen adversely affect his
test to evaluate the patient with suspected IHD. Stress ischemic heart disease?
testing increases myocardial oxygen demand and often pre- What therapeutic alternatives are available to manage RJs
cipitates angina in patients with IHD. Approximately 50% ischemic heart disease?
of patients with IHD who have a normal ECG at rest will
develop ECG changes with exercise. Pharmacologic stres-
sors are used for patients who are unable to exercise.
Dobutamine is commonly used with stress echocardiogra-
TREATMENT
phy, whereas adenosine or dipyridamole are used for
nuclear imaging studies. Coronary angiography (also
Desired Outcomes
referred to as a cardiac catheterization or cardiac cath) is
considered the gold standard for the diagnosis of IHD and Once the diagnosis of IHD is established in a patient, the cli-
is indicated when stress testing results are abnormal or nician should provide counseling on lifestyle modications,
symptoms of angina are poorly controlled. Angiography institute appropriate pharmacologic therapy, and evaluate the
involves catheter insertion, usually into the femoral artery, need for surgical revascularization. The major goals for the
and advancement into the aorta and into the coronary treatment of IHD are to:
arteries. Contrast medium is injected through the catheter
into the coronary arteries allowing visualization of the Prevent acute coronary syndromes and death;
coronary anatomy by uoroscopy. Alleviate acute symptoms of myocardial ischemia;
Angina supply. Since angina usually results from increased myocardial

symptoms oxygen demand in the face of a relatively xed reduction in oxy-
gen supply, drug treatment is primarily aimed at reducing oxygen
demand. Short-acting nitrates are indicated to acutely relieve
Anti-anginal Diagnostic
therapy workup angina. -Blockers, calcium channel blockers (CCBs), and long-
-blocker History & physical acting nitrates are traditionally used to reduce the frequency of
Calcium channel blocker stress testing angina and improve exercise tolerance. In most patients with
Nitrates Coronary angiogram
IHD, the most effective treatments to improve myocardial oxygen
supply are invasive mechanical interventions: percutaneous
coronary intervention (PCI) and coronary artery bypass graft
(CABG) surgery. Percutaneous coronary intervention involves
the threading of a catheter to the site of an atherosclerotic lesion
Primary & secondary Control risk
prevention factors in a coronary artery. Then, either a balloon on the tip of the
Lifestyle modifications Hypertension catheter is inated to compress the plaque against the arterial wall
Antiplatelet therapy Dyslipidemia (balloon angioplasty) or a device is used to cut away the plaque.
ACE-I or ARB Obesity
Often, a stent (a wire mesh tube resembling a spring) is placed at
-blocker Metabolic syndrome
Statin Cigarette smoking the site of balloon angioplasty to hold the vessel open. Coronary
artery bypass graft surgery involves using a leg vein or mammary
FIGURE 44. General treatment strategies for angina follow in
artery to form a conduit around an atherosclerotic plaque.
clockwise fashion from the top center. ACE-I, angiotensin-
converting enzyme inhibitor; ARB, angiotensin receptor blocker. Adverse treatment effects can largely be averted by avoiding
drug interactions and the use of drugs that may have unfavor-
able effects on comorbid diseases. For example, -blockers may
Prevent recurrent symptoms of myocardial ischemia; and exacerbate preexisting bronchospasm. -Blockers are not
Avoid or minimize adverse treatment effects. absolutely contraindicated in bronchospastic disease, but should
be avoided in patients with poorly controlled symptoms. While
The treatment approach to address these goals is illustrated in patients often require combination anti-anginal therapy, there is
Fig. 44. a potential pharmacodynamic drug interaction with the concur-
rent use of -blockers and nondihydropyridine calcium channel
blockers. Since both drug classes slow electrical conduction
through the atrioventricular (AV) node, serious bradycardia or
The primary strategies for preventing ACS and death are to: heart block may result with their concomitant use. Appropriate
drug dosing and monitoring also reduces the risk for adverse
Modify cardiovascular risk factors; treatment effects. Drugs should be initiated in low doses, with
Slow the progression of coronary atherosclerosis; and careful up-titration as necessary to control symptoms of angina
Stabilize existing atherosclerotic plaques. and cardiovascular risk factors.
The treatment algorithm in Fig. 45 summarizes the appro-

Lifestyle Modications
priate management of IHD. Risk factor modication is accom-
plished through lifestyle changes and pharmacologic therapy. Lifestyle modications include smoking cessation, dietary mod-
Both 3-hydroxy-3-methylglutaryl coenzyme A reductase ications, increased physical activity, and weight loss. Lifestyle
inhibitors (HMG-CoA reductase inhibitors or statins) and modications reduce cardiovascular risk factors, slow the pro-
angiotensin-converting enzyme (ACE) inhibitors are believed to gression of IHD, and decrease the risk for IHD-related compli-
provide vasculoprotective effects (properties that are generally pro- cations. Cigarette smoking is the single most preventable cause
tective of the vasculature, which may include anti-inammatory of IHD. Smoking cessation substantially reduces the risk of
effects, antiplatelet effects, improvement in endothelial function, death from IHD.11 The clinician should ascertain smoking status
and improvement in arterial compliance and tone), and in addi- on the patients initial clinic visit and provide counseling on the
tion to aspirin, have been shown to reduce the risk of acute coro- importance of smoking cessation at each subsequent visit for
nary events as well as mortality in patients with IHD. Angiotensin patients who continue to smoke. There are several pharmaco-
receptor blockers (ARBs) may be used in patients who cannot tol- logic aids for smoking cessation. Transdermal nicotine replace-
erate ACE inhibitors because of side effects (e.g., chronic cough). ment therapy has been shown to be safe in patients with IHD.12
b-Blockers have been shown to decrease morbidity and improve Weight loss, through caloric restriction and increased physi-
survival in patients who have suffered an MI. cal activity, should be encouraged in patients who have a body
Therapies to alleviate and prevent angina are aimed at mass index greater than 25 kg/m2. Dietary modication is
improving the balance between myocardial oxygen demand and important for risk factor management, and dietary counseling
FIGURE 45. The treatment algo-

rithm for ischemic heart disease.
It begins at the top (black section),
which suggests risk factor modi-
cations as the rst treatment
modality. Moving down to the dark
gray section, appropriate
antiplatelet therapy is selected. The
light gray section identies patients
at high-risk for major adverse car-
diac events and suggests appropri-
ate drug therapy to decrease car-
diovascular risk. The white section
at the bottom recommends appro-
priate anti-anginal therapy. ACE-I,
angiotensin-converting enzyme
inhibitor; ARB, angiotensin receptor
blocker; BMS, bare metal stent; BP,
blood pressure; CABG, coronary
artery bypass graft; CCB, calcium
channel blocker; DES, drug-eluting
stent; IR, immediate-release; LA,
long-acting; LDL, low-density
lipoprotein; LV, left ventricular;
NTG, nitroglycerin; PCI, percuta-
neous coronary intervention; SL,
sublingual.
should be provided to all patients with newly diagnosed Limit consumption of saturated fat found in fatty meats,
angina regardless of weight. The American Heart Association full-fat dairy products, and hydrogenated vegetable oils to
recommends a diet that includes a variety of fruits, vegetables, less than 7% of total calories.
grains, low-fat or non-fat dairy products, sh, legumes, poultry, Consume at least two servings of sh per week.
and lean meats.13 Fatty sh, such as salmon and herring, are Consume at least six servings of grains, ve servings of fruits
high in omega-3 fatty acids, which have been shown to reduce and vegetables, and two servings of non-fat or low-fat dairy
triglyceride concentrations and slow atherosclerotic plaque products per day.
progression.13 A Mediterranean diet rich in sh in addition to Limit daily sodium intake to 2.4 grams (6 grams of salt) for
fruit, cooked and raw vegetables, and olive oil has been shown blood pressure control.
to reduce mortality after MI.14 Specic dietary recommenda-
tions for patients with IHD should include the following:13 Exercise facilitates both weight loss and blood pressure
reduction. In addition, regular exercise improves functional
Limit fat intake to less than 30% of total caloric consumption. capacity and symptoms in chronic stable angina.1 Once drug
Limit cholesterol intake to less than 200 mg per day. therapy for IHD is instituted, patients should be encouraged
to begin a low level of exercise for 20 to 30 minutes at a time, Coronary Artery Bypass Graft Surgery
with increases in exercise duration and intensity as symptoms As an alternative to PCI, CABG surgery, or open-heart sur-
allow.15 gery, may be performed if the patient is found to have
extensive coronary atherosclerosis (generally greater than
70% occlusion of three or more coronary arteries) or is
Interventional Approaches
refractory to medical treatment. In the former case, CABG
surgery has been shown to reduce mortality from IHD.
Percutaneous Coronary Intervention
During CABG surgery, veins from the leg or arteries on the
When drug therapy fails or if extensive coronary atherosclerosis
inside of the chest wall (i.e., internal mammary arteries) are
is present, PCI is often performed to restore coronary blood
surgically removed. In the case of venous conduits, one end
ow, relieve symptoms, and prevent major adverse cardiac
of the removed blood vessel is attached to the aorta, and the
events. Patients with one or more critical coronary stenoses
other end is attached to the coronary artery distal to the
(i.e., greater than 70% occlusion of the coronary lumen)
atherosclerotic plaque. However, when internal mammary
detected during coronary angiography may be candidates for
arteries are used, the distal end of the artery is detached
PCI. Several catheter-based interventions may be used during
from the chest wall and anastomosed to the coronary artery
PCI, including:
distal to the plaque. A median sternotomy, in which an inci-
sion the length of the sternum is made, is commonly required
Percutaneous transluminal coronary angioplasty (PTCA);
to gain access to the thoracic cavity and expose the heart. As
Intracoronary bare metal stent placement;
the new blood vessels are being engrafted, the patient is
Intracoronary drug-eluting stent placement; and
typically placed on cardiopulmonary bypass (i.e., heart-lung
Rotational atherectomy.
machine) to maintain appropriate myocardial and systemic
perfusion. Because of the extremely invasive nature of this
During PCI, a catheter is advanced into the blocked coro-
surgery, CABG surgery is often a treatment of last resort in
nary artery, as described for cardiac catheterization. If PTCA
patients with IHD.
(i.e., balloon angioplasty) is performed, a balloon at the end
of the catheter is inated inside the artery at the site of the
critical stenosis. When inated, this balloon catheter dis- Pharmacologic Therapy
places the atherosclerotic plaque out of the lumen of the
artery, restoring normal myocardial blood ow. In addition Pharmacotherapy to Prevent Acute Coronary
to angioplasty, most PCI procedures involve the insertion of Syndromes and Death
an intracoronary stent. In this case, a special balloon catheter
containing a small wire stent (similar in size and shape to the Antiplatelet Agents
spring at the tip of a ball point pen) is used. When the bal- Platelets play a major role in the pathophysiology of ACS.
loon is inated, the wire stent (bare metal stent) is deployed Specically, platelets adhere to the site of atherosclerotic
in the wall of the coronary artery, forming a sort of bridge to plaque rupture where they become activated, aggregate, and
maintain normal coronary blood ow. While bare metal stimulate thrombus formation and ACS. Thromboxane is a
stents are very effective in restoring coronary blood ow, potent platelet activator. Aspirin inhibits cyclooxygenase, an
restenosis (re-narrowing of the coronary artery after a PCI enzyme responsible for the production of thromboxane.
to improve coronary blood ow) at the site of stent deploy- Through its effects on thromboxane, aspirin inhibits platelet
ment is common, requiring additional PCI. Drug-eluting activation and aggregation. In patients with stable or
stents have thus been developed to reduce the incidence of unstable angina, aspirin has been consistently shown to reduce
restenosis and are commonly used in patients undergoing PCI. the risk of major adverse cardiac events, particularly MI.1618
These stents are impregnated with low concentrations of Antiplatelet therapy with aspirin should be considered for all
antiproliferative medications, such as paclitaxel or sirolimus, patients without contraindications, particularly in patients with
which are slowly released locally within the coronary artery a history of myocardial infarction. Aspirin doses of 75 to 325 mg
over several weeks. The antiproliferative effects of these drugs daily have been shown to be cardioprotective. If aspirin is
signicantly inhibit restenosis, decreasing the need for contraindicated (e.g., aspirin allergy, active peptic ulcer dis-
repeated PCI procedures. Despite the effectiveness of both bare ease, or active internal bleeding) or is not tolerated by the
metal and drug-eluting stents, acute thrombotic occlusion is patient, other antiplatelet agents such as clopidogrel should
still possible. Therefore, following PCI with either type of be considered.
stent, combination antiplatelet therapy (discussed later) is Recent studies have suggested that combination
required for at least 1 month and perhaps indenitely to antiplatelet therapy may be synergistic in reducing the risk of
reduce this risk. Lastly, rotational atherectomy may be per- IHD-related events. In patients with ACS, the combination of
formed wherein a special catheter is used to essentially cut aspirin and clopidogrel 75 mg daily for up to 9 months was
away the atherosclerotic plaque, restoring coronary blood ow. more effective than aspirin alone in decreasing the risk of
death, MI, and stroke.19 This combination also prevents com- ACE Inhibitors and Angiotensin Receptor Blockers
plications following PCI.20 The American College of Chest Angiotensin II is a neurohormone produced primarily in the
Physicians recommends the combination of aspirin and kidney. It is a potent vasoconstrictor and stimulates the produc-
clopidogrel for 9 to 12 months in patients with IHD who have tion of aldosterone. Together, angiotensin II and aldosterone
undergone PCI.21 For isolated PCI procedures, the recom- increase blood pressure and sodium and water retention
mended duration of combination aspirin and clopidogrel (increasing ventricular wall tension), cause endothelial dysfunc-
therapy is as follows: tion, promote blood clot formation, and cause myocardial
brosis.
At least 2 weeks for bare metal stent placement. Angiotensin-converting enzyme (ACE) inhibitors antagonize
At least 2 to 3 months for sirolimus-eluting stent placement. the effects of angiotensin II and have consistently been shown to
At least 6 months following paclitaxel-eluting stent placement. decrease morbidity and mortality in patients with heart failure
or a history of MI.25,26 A recent meta-analysis of 22 clinical trials
Statins
with ACE inhibitors in post-MI patients found that ACE
Over the last decade, several studies in tens of thousands of inhibitors reduced 1-year mortality by 16% to 32% percent, and
patients have revealed that lowering cholesterol, specically the mortality-reducing effects were sustained for up to 4 years.25
lowering LDL cholesterol with statins, is effective for both pri- In addition, there is evidence that ACE inhibitors reduce the risk
mary and secondary prevention of IHD-related events. Statins of vascular events in patients with chronic stable angina or risk
shown to decrease morbidity and mortality associated with factors for IHD.27,28 Specically, in nearly 10,000 patients with
IHD include lovastatin, simvastatin, pravastatin, and atorvas- vascular disease (including IHD) or risk factors for vascular dis-
tatin.22,23 A recent meta-analysis showed that the risk of major ease, such as diabetes, ramipril reduced the risk of death, acute
adverse cardiac events is reduced by 21% with the use of MI, and stroke by 22% compared to placebo after an average of
statins in patients at high risk for IHD-related events.23 5 years of treatment.27 Similar results have been demonstrated
Several studies have investigated whether statins possess with perindopril in patients with IHD.28
pharmacologic properties in addition to their LDL cholesterol In the absence of contraindications, ACE inhibitors should be
lowering effect that may confer additional benets in IHD.24 considered in ischemic heart disease patients who also have dia-
These studies were prompted by evidence that patients with betes mellitus, left ventricular dysfunction, history of myocardial
normal LDL cholesterol derived benet from statins. Statins infarction, or any combination of these.1 In addition, they should
have been shown to modulate the following characteristics also be considered in all patients with IHD and in patients at high-
thought to stabilize atherosclerotic plaques and contribute to the risk for developing IHD based on ndings from the studies sum-
cardiovascular risk reduction seen with these drugs: marized above. Angiotensin receptor blockers may be used in
patients who cannot tolerate ACE inhibitors due to side effects
Shift LDL cholesterol particle size from predominantly small, (e.g., chronic cough). Angiotensin receptor blockers also antago-
dense, highly atherogenic particles to larger, less atherogenic nize the effects of angiotensin II. In one large trial, valsartan was
particles. as effective as captopril at reducing morbidity and mortality in
Improve endothelial function leading to more effective post-MI patients.26 However, there are far more data supporting
vasoactive response of the coronary arteries. the use of ACE inhibitors in IHD. Therefore, ACE inhibitors
Prevent or inhibit inammation by lowering C-reactive pro- should remain rst-line in patients with a history of MI, dia-
tein and other inammatory mediators thought to be betes, or left ventricular dysfunction. The ACE inhibitors and
involved in atherosclerosis. ARBs with indications for patients with or at risk for IHD or
Possibly improving atherosclerotic plaque stability. IHD-related complications are listed in Table 45.
In summary, to control risk factors and prevent major Control of Risk Factors
adverse cardiac events, statin therapy should be considered in all A major component of any IHD treatment plan is control of
patients with ischemic heart disease, particularly in those with modiable risk factors, including dyslipidemia, hypertension,
elevated low-density lipoprotein cholesterol. Statins are potent and diabetes. Treatment strategies for dyslipidemia and
lipid-lowering agents, possess nonlipid-lowering effects that hypertension in the patient with IHD are summarized in the
may provide additional benet to patients with IHD, and have following paragraphs. Visit chapters in this textbook on the
been shown to reduce morbidity and mortality in patients with management of hypertension and dyslipidemia for further
IHD. Based on these benets, statins are generally considered the information.
drugs of choice in patients with dyslipidemias. Moreover, based Because lipoprotein metabolism and the pathophysiology
on evidence that statins improve outcomes in patients with IHD of atherosclerosis are closely linked, treatment of dyslipi-
and normal LDL cholesterol concentration, statins should be demias is critical for both primary and secondary prevention
considered in all patients with IHD at high risk of major adverse of IHD-related cardiac events. In 2001, the Adult Treatment
cardiac events, regardless of baseline LDL cholesterol. Panel III of the National Cholesterol Education Program
TABLE 45. Doses of ACE inhibitors and Angiotensin Receptor Like dyslipidemia, hypertension is a major, modiable risk
Blockers Indicated in Ischemic Heart Disease (IHD). factor for the development of IHD and related complications.
Unfortunately, awareness, treatment, and control of blood
Drug Indications Usual Dosage in IHD
pressure are not nearly enough.30 Aggressive identication
Angiotensin-Converting Enzyme Inhibitors and control of hypertension is warranted in patients with IHD
Captopril HTN, HF, post-MI, 6.2550 mg
to minimize the risk of major adverse cardiac events. Goal
diabetic nephropathy 3 times daily
Enalapril HTN, HF 2.540 mg daily in blood pressure in patients with IHD is less than 140/90 mm Hg
12 divided doses or less than 130/80 mm Hg in patients with diabetes. Because
Fosinopril HTN, HF 1080 mg daily in of their cardioprotective benets, -blockers and ACE
12 divided doses inhibitors (or ARBs in ACE-inhibitor-intolerant patients),
Lisinopril HTN, HF, post-MI 2.540 mg daily
either alone or in combination, are appropriate for most
Perindopril HTN, IHD 48 mg daily
Quinapril HTN, HF, post-MI 520 mg twice daily patients with both hypertension and IHD.
Ramipril HTN, high-risk for 2.510 mg daily in
IHD, HF, post-MI 12 divided doses
Trandolapril HTN, HF, post-MI 14 mg daily
Nitroglycerin to Relieve Acute Symptoms
Short-acting nitrates are rst-line treatment to terminate
Angiotensin Receptor Blockers
Candesartan HTN, HF 432 mg daily acute episodes of angina. All patients with a history of
Valsartan HTN, HF, post-MI 80320 mg daily angina should have sublingual nitroglycerin tablets or spray to
in 12 divided doses relieve acute ischemic symptoms. Nitrates undergo biotransfor-
HF, heart failure; HTN, hypertension; MI, myocardial infarction.
mation to nitric oxide. Nitric oxide activates soluble guanylate
cyclase and leads to increased intracellular concentrations of
cyclic guanosine monophosphate, and ultimately, to smooth
muscle relaxation. Nitrates primarily cause venodilation, lead-
issued guidelines for the management of dyslipidemia and ing to reductions in preload. The resultant decrease in ven-
recommended an LDL cholesterol goal of less than 100 tricular volume and wall tension leads to a reduction in
mg/dL (2.59 mmol/L) for patients with documented IHD or myocardial oxygen demand. In higher doses, nitrates may also
IHD risk equivalents such as diabetes or other vascular dis- cause arterial dilation and reduce afterload. In addition to
ease.8 Statins are the preferred drugs to achieve this goal reducing oxygen demand, nitrates increase myocardial oxygen
based on their potency in lowering LDL cholesterol and supply by dilating the epicardial coronary arteries and collat-
efcacy in preventing cardiac events. Since the publication eral vessels, as well as relieving vasospasm.
of these guidelines, new evidence from several primary Short-acting nitrates are available in tablet and spray for-
and secondary prevention trials suggests that there are mulations for sublingual administration. Sublingual nitroglyc-
additional clinical benets from further reduction in LDL erin tablets are most commonly used to alleviate angina and
cholesterol.29 In response to this evidence, more aggressive are less expensive than the spray. However, the spray is pre-
cholesterol-lowering goals were established for patients at ferred for patients who have difculty opening the tablet con-
very high risk for developing IHD-related events.29 Patients tainer or produce insufcient saliva for rapid dissolution of
with both known IHD and at least one of the following are sublingual tablets. At the onset of an angina attack, a 0.3 to
considered very high risk: 0.4 mg dose of nitroglycerin (tablet or spray) should be adminis-
tered sublingually, and repeated every 5 minutes until symptoms
Multiple major risk factors for IHD, especially diabetes. resolve. Sitting or standing enhances venous pooling and the effec-
Severe and poorly controlled risk factors, particularly smoking. tiveness of nitroglycerin. Sublingual nitroglycerin can also be used
Multiple risk factors of the metabolic syndrome. to prevent effort-induced angina (i.e., angina that occurs with
Patients with ACS. exertion). In this case, the patient should use sublingual nitro-
glycerin 2 to 5 minutes prior to an activity known to cause
The following modications were made to the National angina, with the effects persisting for approximately 30 minutes.
Cholesterol Education Program treatment guidelines in Isosorbide dinitrate, also available in a sublingual form, has a
patients at high or very high risk for IHD-related events: longer half-life with anti-anginal effects lasting up to 2 hours.
The use of short-acting nitrates alone, without concomitant
If LDL cholesterol is 100 mg/dL (2.59 mmol/L) or greater, long-acting anti-anginal therapy, may be acceptable for
statin or other LDL-lowering therapy is indicated along with patients who experience angina symptoms once every few
lifestyle modications. days. However, for patients with more frequent attacks, long-
Intensity of LDL-lowering therapy should be sufcient to acting anti-anginal therapy with -blockers, calcium channel
decrease LDL cholesterol by 30% to 40%. blockers, or long-acting nitrates is recommended.
Goal LDL cholesterol in patients at very high risk may be Phosphodiesterase type 5 inhibitors are commonly pre-
decreased to less than 70 mg/dL (1.81 mmol/L). scribed for erectile dysfunction and include sildenal, vardenal,
and tadalal. Phosphodiesterase degrades cyclic guanosine the onset of angina during exercise. However, there is no evi-
monophosphate (GMP), which is responsible for the vasodila- dence that any of these agents prevent ACS or improve sur-
tory effects of nitrates. Concomitant use of nitrates and phos- vival in patients with chronic stable angina. Recently, the Food
phodiesterase type 5 inhibitors enhances cyclic GMP-mediated and Drug Administration (FDA) approved ranolazine, a new
vasodilation and can result in serious hypotension and even molecular entity, for the treatment of chronic stable angina in
death. Therefore, the use of nitrates within 24 hours of sildenal patients unresponsive to traditional anti-anginal medications.
or vardenal and within 48 hours of tadalal is contraindicated. Combination therapy with two or three anti-anginal drugs is
All patients with IHD should receive a prescription for often needed.
short-acting nitrates and education regarding their use. Points
to emphasize when counseling a patient on nitroglycerin use Beta-Blockers
include: Stimulation of the 1- and 2-adrenergic receptors in the heart
increases heart rate and cardiac contractility. -Blockers
The seated position is generally preferred when using nitro- antagonize these effects and decrease myocardial oxygen
glycerin since the drug may cause dizziness. demand. -Blockers may also reduce oxygen demand by low-
Call 911 if symptoms are unimproved or worsen 5 minutes ering blood pressure and ventricular wall tension. However,
after the rst dose. with marked reductions in heart rate, -blockers may actually
Keep nitroglycerin tablets in the original glass container and increase ventricular wall tension. This is because slower heart
close the cap tightly after use. rates allow the ventricle more time to ll during diastole, lead-
Nitroglycerin should not be stored in the same container as ing to increased left ventricular volume, end diastolic pres-
other medications since this may reduce nitroglycerins sure, and wall tension. However, the net effect of -blockade is
effectiveness. usually a reduction in myocardial oxygen demand. -Blockers
Repeated use of nitroglycerin is not harmful or addictive and do not improve myocardial oxygen supply.
does not result in any long-term side effects. Patients should The properties and recommended doses of various -blockers
not hesitate to use nitroglycerin whenever needed. are summarized in Table 47. -Blockers with intrinsic sympa-
Nitroglycerin should not be used within 24 hours of taking thomimetic activity have partial -agonist effects and cause
sildenal or vardenal or within 48 hours of taking tadalal lesser reductions in heart rate at rest. As a result, -blockers with
because of the potential for life-threatening hypotension. intrinsic sympathomimetic activity may produce lesser reduc-
tions in myocardial oxygen demand and should be avoided in
Pharmacotherapy to Prevent Recurrent Ischemic patients with IHD. Other -blockers appear equally effective at
Symptoms controlling symptoms of angina. The frequency of dosing and
The overall goal of anti-anginal therapy is to allow patients drug cost should be taken into consideration when choosing a
with IHD to resume normal activities without symptoms of particular drug. Agents that can be dosed once or twice daily are
angina and to experience minimal to no adverse drug effects. preferred. Most -blockers are available in inexpensive generic
The drugs traditionally used to prevent ischemic symptoms versions. -Blockers should be initiated in doses at the lower end
are -blockers, calcium channel blockers, and nitrates. These of the usual dosing range, with titration according to symptom
drugs exert their anti-anginal effects by improving the balance and hemodynamic response. The -blocker dose is commonly
between myocardial oxygen supply and demand, with specic titrated to achieve the following:
effects listed in Table 46. -Blockers, calcium channel block-
ers, and nitrates decrease the frequency of angina and delay Resting heart rate between 50 and 60 beats per minute.
Maximum heart rate with exercise of 100 beats per minute
or less or 20 beats per minute above the resting heart rate.
TABLE 46. Effects of Anti-anginal Medications on Myocardial
Oxygen Demand and Supply b-Blockers are rst-line therapy for preventing ischemic
symptoms, particularly in patients with a history of myocardial
Oxygen Demand
infarction. In the absence of contraindications, b-blockers are pre-
Heart Wall Cardiac Oxygen ferred for several reasons. First, b-blockers may prevent cardiac
Anti-anginal Agent Rate Tension Contractility Supply arrhythmias by decreasing the rate of spontaneous depolarization
-Blockers or of ectopic pacemakers. Second, in several large randomized trials,
Calcium channel b-blockers were shown to prevent target organ damage, particu-
blockers larly stroke and heart failure, in patients with hypertension.31
Verapamil, diltiazem Finally, while the long-term effects of b-blockers on morbidity and
Dihydropyridines or
mortality in patients with chronic stable angina are largely
Nitrates
unknown, certain b-blockers have been shown to decrease the risk for
, decreases; , no change; , increases. reinfarction and improve survival in patients who have suffered
TABLE 47. Properties and Dosing of -Blockers in Ischemic disease. However, selectivity is dose dependent, and 1-selec-
Heart Disease tive agents may induce bronchospasm in higher doses.
Calcium channel blockers are preferred in patients with severe
Intrinsic Usual
Receptor Sympathomimetic Dose
peripheral vascular disease who experience symptoms at rest.
Drug Afnity Activity Range There are several precautions to consider with the use of -
blockers in patients with diabetes or heart failure. All -blockers
Acebutolol 1-Selective Yes 100400 mg
twice daily may mask the tachycardia and tremor (but not sweating) that
Atenolol 1-Selective No 25100 mg commonly accompany episodes of hypoglycemia in diabetes.
once daily In addition, non-selective -blockers may alter glucose metab-
Betaxolol 1-Selective No 520 mg olism and slow recovery from hypoglycemia in insulin-
once daily
dependent diabetes. 1-Selective agents are preferred because
Bisoprolol 1-Selective No 2.510 mg
once daily they are less likely to prolong recovery from hypoglycemia.
Carvedilol 1, 1, and 2 No 6.2525 mg Importantly, -blockers should not be avoided in patients
twice daily with IHD and diabetes, particularly in patients with a history
Labetalol 1, 1, and 2 Yes, at 100400 mg of MI who are at a high risk for recurrent cardiovascular
2-receptors twice daily
events. -Blockers are negative inotropes (i.e., they decrease car-
Metoprolol 1-Selective No 50100 mg
twice daily diac contractility). Cardiac contractility is impaired in patients
(once with left ventricular dysfunction. Therefore, -blockers may
daily for worsen symptoms of heart failure in patients with left ventri-
extended- cular dysfunction (i.e., ejection fraction less than 35%). When
release)
used for management of IHD in a patient with heart failure,
Nadolol 1 and 2 No 40120 mg
once daily -blockers should be initiated in very low doses with slow
Penbutolol 1 and 2 Yes 1040 mg up-titration to avoid worsening heart failure symptoms.
once daily Other potential adverse effects from -blockers include
Pindolol 1 and 2 Yes 1040 mg fatigue, sleep disturbances, malaise, depression, and sexual
twice daily
dysfunction. Abrupt -blocker withdrawal may increase the
Propranolol 1 and 2 No 2080 mg
twice daily frequency and severity of angina, possibly because of
(60180 mg increased receptor sensitivity to catecholamines after long-
once daily term -blockade. If the decision is made to stop -blocker
for long- therapy, the dose should be tapered over several days to weeks
acting
to avoid exacerbating angina.
formulation)
Timolol 1 and 2 No 1020 mg
twice daily Calcium Channel Blockers
Calcium channel blockers (CCBs) inhibit calcium entry into
vascular smooth muscle and cardiac cells, resulting in the inhi-
bition of the calcium-dependent process leading to muscle con-
an MI.32 Specic b-blockers associated with mortality reduc- traction. Inhibition of calcium entry into the vascular smooth
tions in clinical trials include metoprolol, propranolol, and muscle cells leads to systemic vasodilation and reductions in
carvedilol.32,33 In a meta-analysis of 82 clinical trials investi- afterload. Inhibition of calcium entry into the cardiac cells
gating the use of -blockers in patients following MI, the rela- leads to reductions in cardiac contractility. Thus, CCBs reduce
tive risk of death was reduced by 23% in patients treated with myocardial oxygen demand by lowering both wall tension
-blockers compared to control subjects.32 Long-term therapy (through reductions in afterload) and cardiac contractility. In
(for at least 6 months) was associated with greater mortality addition, the nondihydropyridine CCBs verapamil and dilti-
benet compared to short-term -blockade (6 weeks or less). azem further decrease myocardial oxygen demand by slowing
-Blockers are contraindicated in patients with severe cardiac conduction through the AV nodes and lowering heart
bradycardia (heart rate less than 50 beats per minute) or AV rate. In contrast, dihydropyridine calcium channel blockers,
conduction defects in the absence of a pacemaker. -Blockers nifedipine in particular, are potent vasodilators that can cause
should be used with particular caution in combination with baroreex-mediated increases in sympathetic tone and heart
other agents that depress AV conduction (e.g., digoxin, vera- rate. Because of their negative chronotropic effects, verapamil
pamil, and diltiazem) because of increased risk for bradycar- and diltiazem are generally more effective anti-anginal agents
dia and heart block. Relative contraindications include than the dihydropyridine CCBs. In addition to decreasing
asthma, bronchospastic disease, severe depression, and myocardial oxygen demand, all CCBs increase myocardial
peripheral vascular disease. 1-Selective blockers are preferred oxygen supply by dilating coronary arteries, thus increasing
in patients with asthma or chronic obstructive pulmonary coronary blood ow and relieving vasospasm.
In randomized, controlled, clinical trials, calcium channel TABLE 48. Nitrate Formulations and Dosing for Chronic Use
blockers were as effective as -blockers at preventing ischemic
symptoms. Calcium channel blockers are recommended as Formulation Dose
initial treatment in IHD when b-blockers are contraindicated or Oral
not tolerated. In addition, CCBs may be used in combination Nitroglycerin extended- 2.5 mg 3 times daily initially, with
release capsules up-titration according to symptoms
with b-blockers when initial treatment is unsuccessful. and tolerance; allow a 1012 hour
However, the combination of a -blocker with either vera- nitrate-free interval
pamil or diltiazem should be used with extreme caution since Isosorbide dinitrate 520 mg 23 times daily, with a daily
all of these drugs decrease AV nodal conduction, increasing the tablets nitrate-free interval of at least
risk for severe bradycardia or AV block when used together. If 14 hours
Isosorbide dinitrate 40 mg 12 times daily, with a daily
combination therapy is warranted, a long-acting dihydropyri- slow-release nitrate-free interval of at least
dine CCB is preferred. -Blockers will prevent reex increases capsules 18 hours
in sympathetic tone and heart rate with the use of calcium Isosorbide mononitrate 20 mg 2 times daily, with doses
channel blockers with potent vasodilatory effects. tablets 7 hours apart
There are several precautions to consider with the use of Isosorbide mononitrate 30120 mg once daily
extended-release
CCBs. Since verapamil and diltiazem slow conduction tablets
through the AV node, these agents are contraindicated in
Transdermal
patients with bradycardia and preexisting conduction disease. Nitroglycerin extended- 0.20.8 mg/hour, on for 1214 hours,
Verapamil and diltiazem should also be used with particular release lm off for 1012 hours
caution in combination with -blockers as well as with
digoxin, which also depresses AV nodal conduction, since the
combination may cause bradycardia or heart block. Calcium
channel blockers have negative inotropic effects that may be
deleterious in patients with preexisting left ventricular systolic interval should occur when the patient is least likely to expe-
dysfunction. However, the degree of negative inotropy varies rience angina. Generally, angina is less common during the
among agents. Amlodipine and felodipine possess less nega- nighttime hours when the patient is sleeping and myocardial
tive inotropic effects and appear to be safe in patients with left oxygen demand is reduced. Thus, it is common to dose long-
ventricular systolic dysfunction.34,35 However, other calcium acting nitrates so that the nitrate-free interval begins in the
channel blockers may cause or exacerbate heart failure in evening. For example, isosorbide dinitrate is typically dosed
patients with systolic dysfunction and should be avoided in on awakening and again 7 hours later.
this population. Finally, there is some evidence that short- Monotherapy with nitrates for the prevention of ischemia
acting calcium channel blockers (particularly short-acting should generally be avoided for a couple of reasons. First,
nifedipine and nicardipine) may increase the risk of cardio- reex increases in sympathetic activity and heart rate, with
vascular events.31 Therefore, short-acting agents should be resultant increases in myocardial oxygen demand, may occur
avoided in the management of IHD. secondary to nitrate-induced venodilation. Second, patients
are unprotected from ischemia during the nitrate-free inter-
Long-Acting Nitrates val. -Blockers and calcium channel blockers are dosed to
Nitrate products are available in both oral and transdermal provide 24-hour protection from ischemia. Treatment with
formulations for chronic use. Commonly used products are long-acting nitrates should be added to baseline therapy with
listed in Table 48. All nitrate products are equally effective at either a b-blocker or calcium channel blocker or a combination
preventing the recurrence of angina when used appropriately. of the two. -Blockers attenuate the increase in sympathetic
The major limitation of nitrate therapy is the development tone and heart rate that occurs during nitrate therapy. In turn,
of tolerance with continuous use. The loss of anti-anginal nitrates attenuate the increase in wall tension during -blocker
effects may occur within the rst 24 hours of continuous therapy. As a result, the combination of -blockers and
nitrate therapy. While the cause of tolerance is unclear, several nitrates is particularly effective at preventing angina and pro-
mechanisms have been proposed. These include depletion of vides greater protection from ischemia than therapy with
the sulfhydryl groups necessary for the conversion of nitrates either agent alone. Monotherapy with nitrates may be appro-
to nitric oxide, activation of neurohormonal systems, priate in patients who have low blood pressure at baseline or
increased intravascular volume, and generation of free radi- who experience symptomatic hypotension with low doses of
cals that degrade nitric oxide. The most effective method to -blockers or calcium channel blockers.
avoid tolerance and maintain the anti-anginal efcacy of Common adverse effects of nitrates include postural
nitrates is to allow a daily nitrate-free interval of at least 8 to hypotension, ushing, and headache secondary to venodila-
12 hours. Nitrates do not provide protection from ischemia tion. Headache often resolves with continued therapy and
during the nitrate-free period. Therefore, the nitrate-free may be treated with acetaminophen. Hypotension is generally
of no serious consequence. However, in patients with hyper- Antioxidants

trophic obstructive cardiomyopathy or severe aortic valve Oxidization of LDL-cholesterol is believed to play a signi-
stenosis, nitroglycerin may cause serious hypotension and cant role in the atherosclerotic process. The antioxidant vita-
syncope. Therefore, long-acting nitrates are relatively con- mins, vitamin E and vitamin C, protect LDL cholesterol
traindicated in these conditions. Because life-threatening from oxidation. Evidence from observational and animal
hypotension may occur with concomitant use of nitrates and studies suggested that increased intake of antioxidant vita-
phosphodiesterase type 5 inhibitors, nitrates should not be used mins might inhibit the formation of atherosclerotic lesions
within 24 hours of taking sildenal or vardenal or within 48 and decrease the risk for cardiovascular events.40 However,
hours of taking tadalal. Skin erythema and inammation several large, randomized, prospective studies found no
may occur with transdermal nitroglycerin administration and benecial effect of vitamin E or other antioxidants on car-
may be minimized by rotating the application site. diovascular outcomes in patients with IHD or IHD risk fac-
tors.41,42 Based on this evidence, current guidelines do not
Ranolazine recommend supplementation with vitamin E or other
Although the exact mechanism of action for ranolazine is antioxidants for the sole purpose of preventing cardiovascu-
unknown, it may be related to partial inhibition of fatty acid lar events.
oxidation and enhanced generation of adenosine triphos-
phate. Ultimately, ranolazine may improve energy efciency, Folic Acid
thus reducing the amount of oxygen supply necessary to meet Elevated homocysteine concentrations have been associated
an increase in oxygen demand. In clinical trials, ranolazine at with an increased risk for cardiovascular disease in both epi-
a dose of 750 to 1000 mg twice daily improved angina and demiologic and clinical studies.43 Several studies have evalu-
increased exercise capacity when added to standard therapy ated the benet of lowering homocysteine levels with folic
with a -blocker or calcium channel blocker.36 Ranolazine has acid supplementation. One study reported a reduction in
the potential to prolong the QT interval and increase the risk major cardiac events with the combination of folic acid, vita-
for the life-threatening arrhythmia, torsades de pointes. min B12, and vitamin B6 following PCI.44 However, a more
Therefore, ranolazine should be reserved for patients who do recent study found an increased risk of instent restenosis and
not respond to traditional anti-anginal medications. Common the need for target-vessel revascularization with folate supple-
adverse effects with ranolazine include dizziness, headache, mentation following coronary stent placement.45 The role of
constipation, and nausea. folate in the management of IHD is currently unclear.
Pharmacotherapy with No Benet or Potentially Herbal Supplements

Harmful Effects Herbal products are widely used for their purported cardiovas-
cular benets; examples of such products include danshen, dong
Hormone Replacement Therapy quai, feverfew, garlic, hawthorn, and hellebore.46 However,
Hormone replacement therapy (HRT) has favorable effects on strong evidence supporting their benets in cardiovascular dis-
lipoprotein cholesterol concentrations. Data from several ease is generally lacking. While there are data from small ran-
observational studies suggested that HRT might reduce the risk domized controlled trials supporting the benets of some herbal
of cardiovascular events in women with IHD. However, subse- supplements, the potential for drug interactions and the lack of
quent randomized controlled studies failed to demonstrate a product standardization limits the products usefulness in clini-
benet with HRT in postmenopausal women.3739 In fact, HRT cal practice. Safety with herbal supplements in patients with IHD
appeared to be harmful in this patient population. In one ran- is a major concern. Unlike prescription and over-the-counter
domized controlled trial with HRT, more women receiving (OTC) medicines, the FDA does not require manufacturers of
HRT had thromboembolic events and developed gallbladder herbal products to submit proof of safety prior to product mar-
disease than those on placebo.37 Similarly, the Womens Health keting. Numerous case reports of adverse cardiovascular events,
Initiative study found no reduction in the risk for IHD in including stroke, MI, and lethal cardiac arrhythmias with
healthy postmenopausal women receiving either estrogen plus ephedra-based products (e.g., Ma huang) led the FDA to ban
progesterone or estrogen alone.38,39 In addition, compared to ephedra-containing products in 2004. However, other herbal
placebo, the risks of thromboembolic events and breast cancer supplements with potentially serious adverse cardiovascular
were higher with estrogen plus progesterone. The risk for stroke effects remain easily accessible to the consumer. Some herbal
was higher with estrogen alone. Based on these ndings, cur- supplements may interact with antiplatelet and antithrombotic
rent guidelines recommend against the use of hormone replace- therapy and increase bleeding risk. Others may reduce the effec-
ment therapy to reduce cardiovascular risk.1 Furthermore, the tiveness of anti-anginal medications. Thus, it is important to
clinician should consider discontinuing hormone replacement assess the use of herbal products in patients with IHD and to
therapy in women who suffer an acute coronary event while counsel patients about the potential for drug interactions and
receiving such therapy. adverse events with herbal therapies.
prophylaxis for anginal attacks due to vasospasm is limited.

Patient Encounter, Part 3: Creating a However, immediate-release nitroglycerin is effective at termi-
Care Plan nating acute anginal attacks due to vasospasm. Therefore, all
patients diagnosed with variant angina should be prescribed
immediate-release nitroglycerin. Calcium channel blockers are
Based on the information presented, create a specic plan
effective for monotherapy of variant angina. Since short-acting
for the management of RJs ischemic heart disease. Your
plan should include: (1) the goals of therapy; calcium channel blockers have been associated with increased
(2) specic nonpharmacologic and pharmacologic risk of adverse cardiac events, they should be avoided.31 Long-
interventions to address these goals; and (3) a plan for acting nitrates may be added to CCB therapy if needed.
follow-up to assess drug tolerance and whether the
therapeutic goals have been achieved.
Elderly Patients with IHD
Elderly patients are more likely than younger patients to have
other comorbidities that may inuence drug selection for the
Cyclooxygenase-2 (COX-2) Inhibitors and Non-steroidal treatment of angina. As a result, polypharmacy is more com-
Anti-Inammatory Drugs (NSAIDs) mon in elderly patients, increasing the risk of drug-drug inter-
Recent data suggest that COX-2 inhibitors, including rofe- actions, and perhaps decreasing medication adherence.
coxib, valdecoxib, and celecoxib, may increase the risk for Additionally, elderly patients are often more susceptible to
MI and stroke.47 There is also some evidence that the non- adverse effects of anti-anginal therapies, particularly the neg-
selective NSAIDs may increase the risk for cardiovascular ative chronotropic and inotropic effects of -blockers and
events.47,48 Rofecoxib was withdrawn from the market in late CCBs. Therefore, drugs should be initiated in low doses with
2004 because of safety concerns. The FDA requested the close monitoring of elderly patients with IHD.
withdrawal of valdecoxib from the market in 2005. The FDA
also asked the manufacturers of celecoxib and non-selective Acute Coronary Syndrome
NSAIDs (prescription and over-the-counter) to include infor-
mation about the potential adverse cardiovascular effects of The management of ACS is discussed in further detail in the
these drugs in their product labeling. The cardiovascular chapter on acute coronary syndromes. It is important to edu-
risk with COX-2 inhibitors and NSAIDs may be greatest in cate patients with IHD on the signs of ACS and what to do if
patients with a history of, or with risk factors for, cardiovas- they appear. Importantly, patients should be instructed to seek
cular disease. The American Heart Association recommends emergent care if symptoms of angina last longer than 20 to
that the use of COX-2 inhibitors be limited to low-dose, 30 minutes, do not improve after 5 minutes of using sublingual
short-term therapy in patients for whom there is no appro- nitroglycerin, or worsen after 5 minutes of using sublingual
priate alternative.48 Patients with cardiovascular disease nitroglycerin. In patients with a history of ACS, it is crucial to
should consult a clinician before using over-the-counter select appropriate pharmacotherapy to prevent recurrent ACS
NSAIDs. and death. Appropriate pharmacotherapy for patients with
a history of ACS includes aspirin, ACE inhibitors or ARBs,
-blockers, and statins. In addition, determining appropriate
goals and instituting appropriate therapy to meet the goals for
SPECIAL POPULATIONS cardiovascular risk factors (e.g., dyslipidemia, hypertension,
and diabetes) is critical.
Variant Angina
Vasospasm as the sole etiology of angina (Prinzmetals or vari-
ant angina) is relatively uncommon. As a result, treatment
OUTCOME EVALUATION
options are not well studied. Nevertheless, based on the phar-
macology of available drugs, several recommendations can be
Assessing for Drug Effectiveness and Safety
made. First, -blockers should be avoided in patients with vari-
ant angina because of their potential to worsen vasospasm due Monitor symptoms of angina at baseline and at each clinic
to unopposed -adrenergic receptor stimulation. In contrast, visit for patients with IHD to assess the effectiveness of anti-
both calcium channel blockers and nitrates are effective in anginal therapy. In particular, assess the frequency and intensity
relieving vasospasm and are preferred in the management of of anginal symptoms. Determining the frequency of sublin-
variant angina. Nitrates have several limitations outlined above, gual nitroglycerin use is helpful in making this assessment. If
most notably the need for an 8- to 12-hour nitrate-free interval. angina is occurring with increasing frequency or intensity,
Therefore, the role of monotherapy with long-acting nitrates as adjust anti-anginal therapy and refer the patient for additional
diagnostic testing (e.g., coronary angiography) and possibly

for coronary interventions (e.g., PCI or CABG surgery). Patient Care and Monitoring
Assess the patient for IHD-related complications, such as
heart failure. The presence of new comorbidities may indicate
worsening IHD requiring additional workup or pharmaco-
1. Assess the patients symptoms to determine whether the
logic therapy. patient should be evaluated by a physician.
Hemodynamic parameters should be routinely monitored to Determine the quality, location, and duration of pain.
assess drug tolerance. Assess blood pressure at baseline, after Determine factors that provoke and relieve pain.
drug initiation and dose titration, then periodically thereafter in Are symptoms characteristic of angina?
patients treated with b-blockers, CCBs, nitrates, ACE inhibitors, 2. Identify risk factors for IHD.
and/or ARBs. Are there any modiable risk factors?
Blood pressure reduction may be particularly pronounced 3. Obtain a thorough history of prescription drug, non-
after initiation and dose titration of -blockers that also pos- prescription drug, and herbal product use.
sess -blocking effects (e.g., labetalol and carvedilol). Is the patient taking any medications/supplements that
Because of the potential for postural hypotension, warn may exacerbate angina or interact with anti-anginal
patients that dizziness, presyncope, and even syncope may drug therapy?
result from abrupt changes in body position during initia- 4. Educate the patient on lifestyle modications to control
tion or up-titration of drugs with -blocking effects. risk factors for IHD.
Closely monitor heart rate in patients treated with drugs 5. Is the patient taking appropriate drug therapy to prevent
that have negative chronotropic effects (e.g., b-blockers, ver- ACS and death? If not, why?
apamil, or diltiazem) or drugs that may cause reex tachy- 6. Is the patient taking appropriate anti-anginal therapy? If
cardia (e.g., nitrates or dihydropyridine CCBs). not, why?
Treatment with -blockers, verapamil, or diltiazem can usu-
7. Develop a plan to assess effectiveness of anti-ischemic
ally be continued in patients with asymptomatic bradycar- therapy after 1 to 2 weeks.
dia. However, reduce or discontinue treatment with these
8. Evaluate the patient to assess for adverse drug reactions,
agents in patients who develop symptomatic bradycardia or
drug intolerance, and drug interactions.
serious conduction abnormalities.
Control of existing risk factors and the presence of new risk 9. Stress the importance of adherence with the therapeutic
regimen, including lifestyle modications.
factors for IHD should also be assessed regularly. Routine
screening for the presence of metabolic syndrome will help 10. Provide patient education regarding disease state,
in assessing the control of known major risk factors and lifestyle modications, and drug therapy:
What are the consequences of untreated IHD?
identifying new risk factors. If new risk factors are identied
What lifestyle modications should the patient follow?
and/or the presence of metabolic syndrome is detected, When should the patient take his or her medications?
modify the pharmacotherapy regimen, as discussed previ- What potential adverse drug effects may occur?
ously, to control these risk factors and lower the risk of IHD Teach the patient how to monitor heart rate and blood
and IHD-related adverse events. pressure to assess tolerance to anti-anginal therapy.
Which drugs may interact with therapy or worsen IHD?
What should the patient do when chest pain or its
Duration of Therapy equivalent occurs?
When should the patient seek emergent care?
Drugs that modify platelet activity, lipoprotein concentra-
tions, and neurohormonal systems reduce the risk for coro-
nary events and death. However, these therapies do not cure
IHD. ABBREVIATIONS
Treatment with antiplatelet (aspirin or clopidogrel), lipid-
lowering, and neurohormonal-modifying therapy for IHD is ACE: angiotensin-converting enzyme
generally lifelong. Similarly, anti-anginal therapy with a - ACE-I: angiotensin-converting enzyme inhibitor
blocker, CCB, and/or nitrate is usually long-term. ACS: acute coronary syndrome
A patient with severe symptoms managed with combination ARB: angiotensin receptor blocker
anti-anginal drugs who undergoes successful coronary AV: atrioventricular
revascularization may be able to reduce anti-anginal therapy. BMS: bare metal stent
However, treatment with at least one agent that improves the BP: blood pressure
balance between myocardial oxygen demand and supply is CABG: coronary artery bypass graft
usually warranted. CCB: calcium channel blocker
CHD: coronary heart disease KEY REFERENCES AND READINGS

CK: creatinine kinase
CK-MB: creatinine kinase, MB fraction Executive Summary of The Third Report of The National Cholesterol
COX-2: cyclooxygenase-2 Education Program (NCEP) Expert Panel on Detection,
DES: drug-eluting stent Evaluation, and Treatment of High Blood Cholesterol in Adults
ECG: electrocardiogram (Adult Treatment Panel III). JAMA 2001;285:24862497.
FDA: Food and Drug Administration Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guide-
line update for the management of patients with chronic sta-
GMP: guanosine monophosphate
ble anginasummary article: a report of the American
HDL: high-density lipoprotein
College of Cardiology/American Heart Association Task
HF: heart failure Force on practice guidelines (Committee on the Management
HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme of Patients with Chronic Stable Angina). J Am Coll Cardiol
A reductase inhibitor 2003;41:159168.
HRT: hormone replacement therapy Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline
HTN: hypertension update for the management of patients with chronic stable angina:
IHD: ischemic heart disease a report of the American College of Cardiology/American Heart
IR: immediate-release Association Task Force on practice guidelines (Committee to
LA: long-acting Update the 1999 Guidelines for the Management of Chronic
LV: left ventricular Stable Angina). 2002. Abrams J. Clinical practice. Chronic stable
angina. N Engl J Med 2005;352:25242533. Also available at
LDL: low-density lipoprotein
www.acc.org/clinical/guidelines/stable/stable.pdf.
MI: myocardial infarction
Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management
MVO2: myocardial oxygen consumption of the metabolic syndrome: an American Heart Association/
NSAID: non-steroidal anti-inammatory drug National Heart, Lung, and Blood Institute Scientic Statement.
NTG: nitroglycerin Circulation 2005; 112(17):27352752.
OTC: over-the-counter Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent
PCI: percutaneous coronary intervention clinical trials for the National Cholesterol Education Program
PTCA: percutaneous transluminal coronary Adult Treatment Panel III guidelines. Circulation 2004;110:
angioplasty 227239.
SL: sublingual
Reference lists and self-assessment questions and answers are

available at www.ChisholmPharmacotherapy.com.

this chapter.
5 ACUTE CORONARY SYNDROMES
Sarah A. Spinler and Simon de Denus
LEARNING OBJECTIVES
1. Dene the role of an atherosclerotic plaque, platelets, and coagulation system in an acute
coronary syndrome.
2. Describe the onset, peak, and duration of elevation of troponin and creatine kinase
myocardial band in acute myocardial infarction.
3. List key electrocardiographic and clinical features identifying a patient with nonST-segment
elevation acute coronary syndrome who is at high risk of myocardial infarction or death.
4. Devise a pharmacotherapy treatment plan for a patient undergoing primary percutaneous
coronary intervention in ST-segment elevation myocardial infarction given patient-specic data.
5. Devise a pharmacotherapy treatment plan for a patient with ST-segment elevation
myocardial infarction given patient-specic data.
6. List the quality indicators of care for myocardial infarction and explain the rationale behind
each indicator.
7. Formulate a monitoring plan for a patient with ST-segment elevation acute coronary
syndrome receiving brinolytics, aspirin, unfractionated heparin, intravenous nitroglycerin,
intravenous -blockers followed by oral -blockers, an angiotensin-converting enzyme
inhibitor, and a statin.
8. Devise a pharmacotherapy treatment and monitoring plan for a patient with nonST-segment
elevation acute coronary syndrome given patient-specic data.
9. Devise a pharmacotherapy and risk-factor modication treatment plan for secondary
prevention of coronary heart disease events in a patient following myocardial infarction.
KEY CONCEPTS of myocardial infarction is conrmed based on the results of the

creatine kinase myocardial band and troponin tests.
The cause of an acute coronary syndrome is the rupture of an Early reperfusion therapy with either primary percutaneous
atherosclerotic plaque with subsequent platelet adherence, acti- coronary intervention or administration of a brinolytic
vation, and aggregation, and the activation of the clotting cas- agent within 3 hours of symptom onset is the recommended
cade. Ultimately, a clot forms composed of brin and platelets. therapy for patients presenting with ST-segment elevation
The American Heart Association and the American College of acute coronary syndrome.
Cardiology recommend strategies, or guidelines, for acute The most recent nonST-segment elevation American College
coronary syndrome patient care for ST-segment and nonST- of Cardiology/American Heart Association clinical practice
segment elevation acute coronary syndrome. guidelines recommend coronary angiography with either per-
Patients with ischemic chest discomfort and suspected acute cutaneous coronary intervention or coronary artery bypass
coronary syndrome are risk-stratied based upon a 12-lead graft surgery revascularization as an early treatment (early
electrocardiogram, past medical history, and results of the crea- invasive strategy) for high-risk and moderate-risk nonST-
tine kinase myocardial band and troponin tests. The diagnosis segment elevation acute coronary syndrome patients.
83
According to the American College of Cardiology/American discomfort is the most frequent reason for patient presen-
Heart Association ST-segment elevation acute coronary syn- tation to emergency departments, with up to 7 million, or
drome practice guidelines, in addition to reperfusion therapy, approximately 3%, of all emergency department visits linked
early pharmacotherapy of ST-segment elevation should to chest discomfort and possible ACS. Coronary heart disease
include intranasal oxygen (if oxygen saturation is less than is the leading cause of premature, chronic disability in the
90%), sublingual nitroglycerin followed by intravenous nitro- United States. The risks of CHD events, such as death, recur-
glycerin, aspirin, an intravenous -blocker, unfractionated rent MI, and stroke, are higher for patients with established
heparin, and brinolysis in eligible candidates. CHD and a history of MI than for patients with no known
According to the American College of Cardiology/American CHD. The cost of CHD is high, with more than $10 billion
Heart Association nonST-segment elevation acute coronary being paid to Medicare beneciaries in 1999, or more than
syndrome practice guidelines, in the absence of contraindica- $10,000 per MI hospital stay, with the average length of hos-
tions, early pharmacotherapy of nonST-segment elevation pital stay for MI in 1999 being 5.6 days.1
should include intranasal oxygen (if oxygen saturation is low), In patients with ST-segment elevation (STE) ACS, in-
sublingual nitroglycerin followed by intravenous nitroglycerin, hospital death rates are approximately 7% for patients who
aspirin, an intravenous -blocker, and unfractionated heparin or are treated with brinolytics and 16% for patients who do
low-molecular-weight heparin. Most patients should receive not receive reperfusion therapy. In patients with nonST-
additional therapy with clopidogrel. High-risk patients should segment elevation (NSTE) MI, in-hospital mortality is less
also receive a glycoprotein IIb/IIIa receptor blocker. than 5%. In-hospital and 1-year mortality rates are higher
Guidelines from the American College of Cardiology/American for women and elderly patients. In the rst year following
Heart Association suggest that, in the absence of contraindica- MI, 38% of women and 25% of men will die, most from
tions, following myocardial infarction from either ST-segment recurrent infarction.1 At 1 year, rates of mortality and rein-
elevation acute coronary syndrome or nonST-segment ele- farction are similar between STE and NSTE MI.
vation coronary syndrome, patients should receive indenite Because reinfarction and death are major outcomes fol-
treatment with aspirin, a beta-blocker, and an angiotensin- lowing ACS, therapeutic strategies to reduce morbidity and
converting enzyme inhibitor.2,3 For nonST-segment eleva- mortality, particularly utilization of coronary angiography,
tion acute coronary syndrome, most patients should receive revascularization, and pharmacotherapy, will have a signi-
clopidogrel, in addition to aspirin, for up to 9 months. Most cant impact on the social and economic burden of CHD in
patients will receive a statin to reduce low-density lipoprotein the United States.
cholesterol to less than 100 mg/dL.
Secondary prevention of death, reinfarction, and stroke is
more cost effective than primary prevention of coronary heart ETIOLOGY
disease events.
Endothelial dysfunction, inammation, and the formation of
Cardiovascular disease (CVD) is the leading cause of death in the fatty streaks contribute to the formation of atherosclerotic
United States and one of the major causes of death worldwide. coronary artery plaques, the underlying cause of coronary
Acute coronary syndromes (ACS), including unstable angina artery disease (CAD). The predominant cause of ACS, in
(UA) and myocardial infarction (MI), are a form of coronary more than 90% of patients, is atheromatous plaque rupture, s-
heart disease (CHD) that comprises the most common cause of suring, or erosion of an unstable atherosclerotic plaque that
CVD death.1 The cause of an acute coronary syndrome is the occludes less than 50% of the coronary lumen prior to the event,
rupture of an atherosclerotic plaque with subsequent platelet adher- rather than a more stable 70% to 90% stenosis of the coronary
ence, activation, and aggregation and the activation of the clotting artery.3 Stable stenoses are characteristic of stable angina.
cascade. Ultimately, a clot forms composed of brin and platelets.
The American Heart Association (AHA) and the American
College of Cardiology (ACC) recommend strategies, or guidelines, PATHOPHYSIOLOGY
for ACS patient care for ST-segment and nonST-segment eleva-
tion ACS. These joint practice guidelines are based upon a review Spectrum of Acute Coronary Syndromes
of available clinical evidence, have graded recommendations Acute coronary syndromes is a term that includes all clinical
based upon evidence, and are updated periodically. These guide- syndromes compatible with acute myocardial ischemia resulting
lines form the cornerstone for quality care of the ACS patient.2,3 from an imbalance between myocardial oxygen demand and
supply.3 In contrast to stable angina, an ACS results primarily
EPIDEMIOLOGY from diminished myocardial blood ow secondary to an occlu-
sive or partially occlusive coronary artery thrombus. Acute coro-
Each year, more than one million Americans will experience an nary syndromes are classied according to electrocardiogram
ACS and 239,000 will die of an MI.1 In the United States, more (ECG) changes into STE ACS (STE MI) or NSTE ACS (NSTE
than 7.6 million living persons have survived an MI.1 Chest MI and unstable angina) (Fig. 51). An STE MI, formerly
CHAPTER 5 / ACUTE CORONARY SYNDROMES 85
known as Q-wave or transmural MI, typically results in an Angiotensin-converting enzyme (ACE) inhibitors, -
injury that transects the thickness of the myocardial wall. blockers, and aldosterone antagonists are all agents that slow
Following an STE MI, pathologic Q waves are frequently seen on down or reverse ventricular remodeling through neurohor-
the ECG, indicating transmural myocardial infarction, while monal blockage and/or through improvement in hemody-
such an ECG manifestation is seen less commonly in patients namics (decreasing preload or afterload).6 These agents also
with NSTE MI.4 NonST-segment elevation MI, formerly improve survival and will be discussed in more detail in sub-
known as nonQ-wave or non-transmural MI, is limited to the sequent sections of this chapter.
sub-endocardial myocardium. Patients in this case do not usu-
ally develop a pathologic Q wave on the ECG. Moreover, an
NSTE MI is smaller and not as extensive as an STE MI. NonST- Complications
elevation MI differs from unstable angina in that ischemia is This chapter will focus on management of the uncomplicated
severe enough to produce myocardial necrosis resulting in the ACS patient. However, it is important for clinicians to recog-
release of a detectable amount of biochemical markers (intracel- nize complications of MI, since MI is associated with increased
lular macromolecules released into the peripheral circulation mortality. The most serious complication of MI is cardiogenic
from necrotic myocytes as a result of myocardial cell death or shock, occurring in approximately 10% of hospitalized MI
infarction), mainly troponins T or I or creatine kinase (CK) patients. Mortality in cardiogenic shock patients with MI is
myocardial band (MB) from the necrotic myocytes in the high, approaching 60%.7 Other complications which may
bloodstream.3 The clinical signicance of serum markers will be result from MI are heart failure, valvular dysfunction, ventric-
discussed in greater detail in later sections of this chapter. ular and atrial tachyarrhythmias, bradycardia, heart block,
pericarditis, stroke secondary to left ventricular thrombus
embolization, venous thromboembolism, and left ventricular
Plaque Rupture and Clot Formation free wall rupture.8 In fact, more than one-quarter of MI
Following plaque rupture, a clot (a partially occlusive or com- patients die, presumably from ventricular brillation, prior to
pletely occlusive thrombus), forms on top of the ruptured reaching the hospital.1
plaque. The thrombogenic contents of the plaque are exposed
to blood elements. Exposure of collagen and tissue factor
Symptoms and Physical Examination Findings
induce platelet adhesion and activation, which promote the
release of platelet-derived vasoactive substances including The classic symptom of an ACS is midline anterior anginal
adenosine diphosphate (ADP) and thromboxane A2 (TXA2).5 chest discomfort, most often occurring when an individual is at
These produce vasoconstriction and potentiate platelet activa- rest, as a severe new onset, or as an increasing angina that is at
tion. Furthermore, during platelet activation, a change in the least 20 minutes in duration. The chest discomfort may radiate
conformation in the glycoprotein IIb/IIIa surface receptors of to the shoulder, down the left arm, and to the back or to the
platelets occurs which cross-links platelets to each other jaw. Associated symptoms which may accompany the chest
through brinogen bridges. This is considered the nal discomfort include nausea, vomiting, diaphoresis, or short-
common pathway of platelet aggregation. Inclusion of ness of breath. While similar to stable angina, the duration may
platelets gives the clot a white appearance. Simultaneously, the be longer and the intensity greater. On physical examination,
extrinsic coagulation cascade pathway is activated as a result no specic features are indicative of ACS.
of exposure of blood components to the thrombogenic lipid
core and endothelium, which are rich in tissue factor. This
leads to the production of thrombin (factor IIa), which con- 12-Lead Electrocardiogram
verts brinogen to brin through enzymatic activity.5 Fibrin There are key features of a 12-lead ECG that identify and
stabilizes the clot and traps red blood cells, which give the clot risk-stratify a patient with an ACS. Within 10 minutes of pres-
a red appearance. Therefore, the clot is composed of cross- entation to an emergency department with symptoms of
linked platelets and brin strands.8 ischemic chest discomfort, a 12-lead ECG should be obtained
and interpreted. If available, a prior 12-lead ECG should be
reviewed to identify whether or not the ndings on the current
Ventricular Remodeling Following an Acute
ECG are new or old, with new ndings being more indicative of
Myocardial Infarction
an ACS. Key ndings on review of a 12-lead ECG that indicate
Ventricular remodeling is a process that occurs in several car- myocardial ischemia or infarction are STE, ST-segment depres-
diovascular conditions including heart failure and following an sion, and T-wave inversion (Fig. 51). ST-segment and/or
MI. It is characterized by left ventricular dilation and reduced T-wave changes in certain groupings of leads help to identify
pumping function of the left ventricle leading to cardiac failure.6 the location of the coronary artery that is the cause of the
Because heart failure represents one of the principal causes of ischemia or infarction. In addition, the appearance of a new
mortality and morbidity following an MI, preventing ventricu- left bundle-branch block accompanied by chest discomfort
lar remodeling is an important therapeutic goal.6 is highly specic for acute MI. About one-half of patients
Ischemic chest discomfort symptoms,

lasting at least 20 minutes;
Suspect acute coronary syndrome
Obtain and interpret a 12-lead ECG within 10 minutes

ST-segment elevation No ST-segment elevation
ST-segment depression T-wave inversion No ECG changes
Initiate reperfusion therapy

in appropriate candidates
(fibrinolysis or primary PCI)
Risk stratification; multilead

continuous ST-segment monitoring;
obtain serial troponin and CK MB
Obtain serial troponin and CK
MB as confirmatory; results
not needed before reperfusion
therapy is initiated; multilead
continuous ST-segment
monitoring
Initiate pharmacotherapy for non-ST-segment

elevation ACS
Initiate adjunctive ST-segment

elevation ACS pharmacotherapy
Negative troponin Positive troponin
and/or CK MB and/or CK MB
Diagnosis of NSTE MI
Stress test to evaluate likelihood of CAD Diagnosis of unstable angina
Negative stress test

Positive stress test
Diagnosis of non-cardiac chest
pain syndrome Evaluate moderate and high-risk
patients for early angiography and
revascularization
FIGURE 51. Evaluation of the acute coronary syndrome patient. (Reprinted from Spinler SA, de Denus S. Acute Coronary Syndromes.
In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill;
2005: 293, with permission.) ACS, acute coronary syndromes; CAD, coronary artery disease; CKMB, creatine kinase myocardial
band; ECG, electrocardiogram; NSTE, non-ST elevation; PCI, percutaneous coronary intervention. Refer to Chapter 6, Figure 62
(page 109) for further details regarding ECG interpretation.
diagnosed with MI present with ST-segment elevation on their ECG. Therefore, it is important to review ndings from the
ECG, with the remainder having ST-segment depression, T- ECG in conjunction with biochemical markers of myocardial
wave inversion, or in some instances, no ECG changes. Some necrosis, such as troponin I or T, and other risk factors for
parts of the heart are more electrically silent than others, CHD to determine the patients risk for experiencing a new
and myocardial ischemia may not be detected on a surface MI or having other complications.
Biochemical Markers/Cardiac Enzymes

Clinical Presentation and Diagnosis
Biochemical markers of myocardial cell death are important
for conrming the diagnosis of MI. The diagnosis of
myocardial infarction is conrmed based upon the results of the
General creatine kinase myocardial band and troponin tests. Evolving MI
The patient is typically in acute distress and may develop is dened by the ACC as typical rise and gradual fall (troponin)
or present with cardiogenic shock. or more rapid rise and fall (CK-MB) of biochemical markers of
Symptoms myocardial necrosis.9 Troponin and CK-MB rise in the blood
The classic symptom of ACS is midline anterior chest following the onset of complete coronary artery occlusion subse-
discomfort. Accompanying symptoms may include arm, quent to myocardial cell death. Their time course is depicted in
back, or jaw pain, nausea, vomiting, or shortness of Fig. 52. Typically, blood is obtained from the patient three
breath. times, once in the emergency department and two additional
Patients less likely to present with classic symptoms times over the next 12 to 24 hours in order to measure tro-
include elderly patients, diabetic patients, and ponin and CK-MB. A single measurement of a biochemical
women.
marker is not adequate to exclude a diagnosis of MI, as up to
Signs 15% of values which were initially below the level of detection
No signs are classic for ACS. (a negative test) rise to the level of detection (a positive
However, patients with ACS may present with signs of test) in subsequent hours. An MI is identied if at least one
acute heart failure including jugular venous distention troponin value is greater than the MI decision limit (set by the
and an S3 sound on auscultation. hospital laboratory) or two CK-MB results are greater than
Patients may also present with arrhythmias and there-
the MI decision limit (set by the hospital laboratory). While
fore may have tachycardia, bradycardia, or heart
troponins and CK-MB appear in the blood within 6 hours of
block.
infarction, troponins stay elevated for up to 10 days while CK-
Laboratory Tests MB returns to normal values within 48 hours. Therefore, if a
Troponin I or T and CK-MB are measured. patient is admitted with elevated troponins and CK-MB and
Blood chemistry tests are performed with particular atten- several days later experiences recurrent chest discomfort, the
tion given to potassium and magnesium, which may
troponin will be less sensitive to detect new myocardial dam-
affect heart rhythm.
age because it will still be elevated. If early reinfarction is sus-
The serum creatinine is measured to identify patients
who may need dosing adjustments for some medica- pected, CK-MB is the preferred diagnostic test.9
tions, as well as those who are at high risk of morbidity
and mortality. Risk Stratication
Baseline complete blood count (CBC) and coagulation
tests (activated partial thromboplastin time and Patient symptoms, past medical history, ECG, and troponin
International Normalized Ratio) should be obtained, as and/or CK-MB are utilized to stratify patients into low,
most patients will receive antithrombotic therapy, which medium, or high risk of death, MI, or likelihood of failing
increases the risk for bleeding. pharmacotherapy and needing urgent coronary angiography
Fasting lipid panel. and percutaneous coronary intervention (PCI). Initial
Other Diagnostic Tests treatment according to risk stratication is depicted in Fig. 51.
The 12-lead ECG is the rst step in management. Patients with ST-segment elevation are at the highest risk of death.
Patients are risk-stratied into two groups: ST-segment Initial treatment of ST-segment elevation ACS should proceed
elevation ACS and suspected nonST-segment elevation without evaluation of the troponin or CK-MB, as these patients
ACS. have a greater than 97% chance of having an MI subsequently
During hospitalization, a measurement of left ventri- diagnosed with biochemical markers. The ACC/AHA denes a
cular function, such as an echocardiogram, is per- target time to initiate reperfusion treatment as within 30 minutes
formed to identify patients with low ejection fractions of hospital presentation for brinolytics (e.g., streptokinase,
(less than 40%) who are at high risk of death following
alteplase, reteplase, and tenecteplase) and within 90 minutes or
hospital discharge.
less from presentation for primary PCI.3 The sooner the infarct-
Selected low-risk patients may undergo early stress
testing. related coronary artery is opened for these patients, the lower
their mortality and the greater the amount of myocardium that
(Adapted from Spinler SA, de Denus S. Acute Coronary is preserved.10,11 While all patients should be evaluated for reper-
Syndromes. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.)
fusion therapy, not all patients may be eligible. Indications and
Pharmacotherapy: A Pathophysiologic Approach. 6th ed.
contraindications for brinolytic therapy are described in the
New York: McGraw-Hill; 2005: 294, with permission.)
treatment section of this chapter. Less than 20% of hospitals in
the United States. are equipped to perform primary PCI. If
SD is a 55-year-old, 85 kg (187 lb) male who developed chest tightness while in a store in Sun Valley, Idaho, after 4 hours of
skiing. SD developed substernal chest tightness at 2030 hours that radiated into his left arm following an altercation with another
patron in the mens room. He became short of breath and diaphoretic. Local paramedics were summoned and he was given
three 0.4 mg sublingual nitroglycerin tablets by mouth, 325 mg aspirin by mouth, and 5 mg metoprolol IV push without relief
of chest discomfort. SD presented to St. Matthews Hospital in Sun Valley at 2115 hours. St. Matthews does not have a cardiac
catheterization laboratory and transport time to St. Matthews in Boise is 1.5 hours door to door via air transport.
PMH
Hypertension (HTN) 10 years
Dyslipidemia 6 months
Two-vessel coronary artery disease (60% right coronary artery [RCA] and 80% left anterior descending artery [LAD] occlusion)
after intracoronary CYPHERTM stent placement to the mid-LAD artery lesion 10 months ago.
FH
Father with myocardial infarction at age 65; mother alive and well; one sibling with hypertension
SH
Smoked 1 pack per day 30 years, quit 10 weeks ago
Allergies
No known drug allergies
Meds
Metoprolol 25 mg by mouth twice daily
ASA 325 mg by mouth once daily
Lovastatin 20 mg by mouth once daily at bedtime
Enalapril 5 mg by mouth once daily
ROS
7/10 chest pain/squeezing, diaphoretic
PE
Head, ears, eyes, nose and throat: normocephalic atraumatic
Cardiovascular: regular rate and rhythm S1, S2, S3, +S3, +S4, no murmurs or rubs
VS: Blood pressure 110/70; heart rate 98 beats per minute; temperature 37C (98.6F)
Lungs: rales bilaterally 1/4 way up
Abd: non-tender, non-distended
Gastrointestinal: normal bowel sounds
Genitourinary: stool guaiac negative
Exts: no bruits, pulses 2+, femoral pulse present, good range of motion
Neurologic: alert and oriented 3, cranial nerves intact
Labs
Sodium 138 mEq/L (138 mmol/L), potassium 4.2 mEq/L (4.2 mmol/L), chloride 105 mEq/L (105 mmol/L), bicarbonate 24 mEq/L
(24 mmol/L), serum creatinine 1.0 mg/dL (88.4 mol/L), glucose 95 mg/dL (5.27 mmol/L), white blood cell count 9.9 103/mm3
(9.9 109/L), hemoglobin 15.7 g/dL (157 g/L or 9.7 mmol/L), hematocrit 47%, platelets 220 103/mm3 (220 109/L), brain
natriuretic peptide 3238 pg/mL (3238 ng/L), troponin I 16 ng/mL (16 mcg/L), oxygen saturation 99% on room air
ECG: normal sinus rhythm, PR 0.16 s, QRS 0.08 s, QTc 0.38 s, occasional polymorphic premature ventricular contractions, 3 mm
ST-segment elevation anterior leads
CXR: congestive heart failure, borderline upper normal heart size
Echocardiogram: hypocontractile left ventricle, akinesis of anterior apical wall, ejection fraction 20%
What information is suggestive of acute MI?

What complications of MI are present?
FIGURE 52. Biochemical

60
markers in suspected acute
coronary syndromes.
(Reprinted from Spinler SA,
50 Diagnosis of MI confirmed (troponin)
de Denus S. Acute Coronary
Multiples of the MI cutoff limit Syndromes. In: DiPiro JT,
Talbert RL, Yee GC, et al,
20 (eds.) Pharmacotherapy:
A Pathophysiologic
Diagnosis of MI confirmed (CK MB) Approach. 6th ed.
10 New York: McGraw-Hill;
2005: 295, with
Indicates time that blood was permission.) AMI, acute
5 obtained for serial measurements myocardial infarction;
of biochemical marker
CKMB, creatine kinase
myocardial band; MI,
2 myocardial infarction.
Diagnosis of MI excluded (troponin or CK MB)
AMI decision limit 1
Upper reference limit
0
0 1 2 3 4 5 6 7 8
Days after onset of AMI
patients are not eligible for reperfusion therapy, additional phar- TREATMENT
macotherapy for STE patients should be initiated in the emer-
gency department and the patient transferred to a coronary Desired Outcomes
intensive care unit. The typical length of stay for a patient with
uncomplicated STE MI is 3 to 5 days. Short-term desired outcomes in a patient with ACS are:
Risk-stratication of the patient with NSTE ACS is more (1) early restoration of blood ow to the infarct-related artery
complex, as in-hospital outcomes for this group of patients to prevent infarct expansion (in the case of MI) or prevent com-
varies with reported rates of death of 0% to 12%, reinfarction plete occlusion and MI (in unstable angina); (2) prevention of
rates of 0% to 3%, and recurrent severe ischemia rates of 5% death and other complications; (3) prevention of coronary
to 20%.12 Not all patients presenting with suspected NSTE artery reocclusion; and (4) relief of ischemic chest discomfort.
ACS will even have CAD. Some will eventually be diagnosed Long-term desired outcomes are control of risk factors,
with non-ischemic chest discomfort. In general, among prevention of additional cardiovascular events, and improve-
NSTE patients, those with ST-segment depression (Fig. 51) ment in quality of life.
and/or elevated troponin and/or CK-MB are at higher risk of
death or recurrent infarction. General Approach to Treatment
General treatment measures for all STE ACS and high- and
intermediate-risk NSTE patients include admission to hospital,
oxygen administration (if oxygen saturation is low, less than
Patient Encounter, Part 2: Treatment 90%), continuous multi-lead ST-segment monitoring for
arrhythmias and ischemia, frequent measurement of vital signs,
bed rest for 12 hours in hemodynamically stable patients, avoid-
ance of Valsalva maneuver (prescribe stool softeners routinely),
Identify your acute treatment goals for SD.
Is reperfusion therapy with brinolysis indicated at this time?
and pain relief (Fig. 53).
What adjunctive pharmacotherapy should be administered Because risk varies and resources are limited, it is impor-
to SD in the emergency department? tant to triage and treat patients according to their risk cate-
What additional pharmacotherapy should be initiated on gory. Initial approaches to treatment of STE and NSTE ACS
the rst day of SDs hospitalization? patients are outlined in Fig. 51. Patients with STE are at high
risk of death, and efforts to re-establish coronary perfusion,
ST-segment elevation ACS Non-ST-segment elevation ACS
Oxygen (if O2 saturation less than 90%)

SL NTG, aspirin
IV UFH IV -blocker IV UFH or SC enoxaparin
IV nitroglycerin
Clopidogrel
(Diltiazem, verapamil, or amlodipine for
patients with ongoing ischemia and
contraindication to -blocker)
Moderate- or high-risk
Low-risk patients
Symptoms less than Symptoms greater than patients
or equal to 12 hours 12 hours
Early PCI (less than or Delayed PCI (greater than

Stress testing, PCI or equal to 12 hours) planned 12 hours) planned
CABG, or fibrinolysis for
selected patients; for PCI Patients
Reperfusion therapy during hospitalization, with negative
administer abciximab or stress test
eptifibatide at time of
PCI and clopidogrel Abciximab or eptifibatide
started at time of PCI
Fibrinolysis
contraindicated No revascularization
Primary PCI Fibrinolysis Initiate early eptifibatide or tirofiban
before PCI in high-risk patients
or 1224 hours with ongoing Patient with positive
symptoms of ischemia or initiate stress test
abciximab or eptifibatide at time
of PCI
Abciximab
Clopidogrel
FIGURE 53. Initial pharmacotherapy for acute coronary syndromes. (Adapted from Spinler SA, de Denus S. Acute Coronary
Syndromes. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York:
McGraw-Hill; 2005: 298, with permission.) Or 12 to 24 hours with ongoing symptoms of ischemia. ACS, acute coronary
syndromes; CABG, coronary artery bypass graft; IV, intravenous; NTG, nitroglycerin; PCI, percutaneous coronary intervention; SC,
subcutaneous; SL, sublingual; UFH, unfractionated heparin.
as well as adjunctive pharmacotherapy, should be initiated intracoronary stent. Results from a recent meta-analysis of trials
immediately. comparing brinolysis to primary PCI indicate a lower mor-
tality rate with primary PCI.14 One reason for the superiority of
Features identifying low-, moderate-, and high-risk NSTE primary PCI compared to brinolysis is that more than 90% of
ACS patients are described using the thrombolysis in myocardial
occluded infarct-related coronary arteries are opened with pri-
infarction (TIMI) risk score in Table 51.13
mary PCI compared to fewer than 60% of coronary arteries
opened with currently available brinolytics.15 In addition,
Nonpharmacologic Therapy intracranial hemorrhage and major bleeding risks from pri-
mary PCI are lower than the risks of severe bleeding events fol-
Primary Percutaneous Coronary Intervention for lowing brinolysis. An invasive strategy of primary PCI is gen-
ST-Segment Elevation Acute Coronary Syndromes erally preferred in patients presenting to institutions with
Early reperfusion therapy with either primary percutaneous skilled interventional cardiologists and a catheterization labo-
coronary intervention or administration of a brinolytic agent ratory immediately available, in patients in cardiogenic shock,
within 3 hours of symptom onset is the recommended therapy for those with contraindications to brinolytics, and those presenting
patients presenting with STE ACS.3 For primary PCI, the patient is with symptom onset greater than 3 hours ago.3 A quality indi-
taken from the emergency department to the cardiac catheteriza- cator (quality indicators are measures of health care perform-
tion laboratory and undergoes coronary angiography with either ance developed from practice guidelines intended to permit the
balloon angioplasty or placement of a bare metal or drug-eluting quality of patient care to be assessed and ultimately improved)
TABLE 51. TIMI Risk Score for NonST-Segment Elevation Percutaneous Coronary Intervention in NonST-
Acute Coronary Syndromes2,17 Segment Elevation Acute Coronary Syndromes
The most recent nonST-segment elevation ACC/AHA clin-
Past Medical History Clinical Presentation
ical practice guidelines recommend coronary angiography with
Age 65 years or older ST-segment depression either PCI or coronary artery bypass graft (CABG) surgery
Three or more risk factors for CAD: (0.5 mm or greater)
revascularization as an early treatment (early invasive strategy)
Hypercholesterolemia Two or more episodes
HTN of chest discomfort for high-risk and moderate-risk NSTE ACS patients.2 Several
DM within the past recent clinical trials support an early invasive strategy with
Smoking 24 hours PCI or CABG versus a medical stabilization management
Family history of premature CHD Positive biochemical strategy, whereby coronary angiography with revasculariza-
Known CAD (50% or greater marker for infarctiona
tion is reserved for patients with symptoms refractory to
stenosis of a coronary artery)
Use of aspirin within the past 7 days pharmacotherapy and patients with signs of ischemia on
Using the TIMI Risk Score
stress testing.17 An early invasive approach results in fewer
One point is assigned for each of the seven medical history and MIs, less need for additional revascularization procedures
clinical presentation ndings. The point total is calculated and over the next year following hospitalization, and less cost than
the patient is assigned a risk for experiencing the composite the conservative medical stabilization approach.17 All
endpoint of death, myocardial infarction, or urgent need for patients undergoing PCI should receive aspirin therapy indef-
revascularization as follows:
initely. Clopidogrel is administered (concomitantly with
High-Risk Medium-Risk Low-Risk
aspirin) for at least 30 days and up to 12 months following
TIMI risk score TIMI risk score TIMI risk score
57 points 34 points 02 points PCI18 (Table 52).
Other Ways to Identify High-Risk Patients
Other ndings that alone or in combination may identify a
high-risk patient: Additional Testing and Risk Stratication
ST-segment depression At some point during hospitalization but prior to discharge,
Positive biochemical marker for infarction
Deep symmetric T-wave inversions (2 mm or greater) patients with MI should have their left ventricular function
Acute heart failure (LVF) evaluated for risk stratication.2,3 The most common way
DM LVF is measured is using an echocardiogram to calculate the
Chronic kidney disease patients left ventricular ejection fraction (LVEF). Left ventri-
Refractory chest discomfort despite maximal pharmacotherapy cular function is the single best predictor of mortality following
for ACS
Recent MI within the past 2 weeks MI. Patients with LVEFs less than 40% are at highest risk of
death. Patients with ventricular brillation or sustained ventri-
a
A positive biochemical marker for infarction is a value of troponin I, tro- cular tachycardia occurring more than 2 days following MI and
ponin T, or creatine kinase MB of greater than the MI detection limit.
ACS, acute coronary syndromes; CAD, coronary artery disease; CHD, those with LVEF less than 30% (measured at least 1 month after
coronary heart disease; DM, diabetes mellitus; HTN, hypertension; MI, STE MI and 3 months after coronary artery revascularization
myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction. with either PCI or CABG) benet from placement of an
(Reprinted from Spinler SA, de Denus S. Acute Coronary Syndromes.
In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Patho- implantable cardioverter debrillator (ICD).3
physiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 296, with Pre-discharge from the hospital stress testing (Fig. 53)
permission.) may be indicated in: (1) moderate- or low-risk patients in order
to determine who would benet from coronary angiography
to establish the diagnosis of CAD and (2) patients following
MI to predict intermediate- and long-term risk of recurrent
in the care of MI patients with ST-segment elevation is the time MI and death.19 In most cases, patients with a positive stress
from hospital presentation to the time that the occluded artery test indicating coronary ischemia will then undergo coronary
is opened with PCI. This door-to-primary PCI time should be angiography and subsequent revascularization of signicantly
equal to or less than 90 minutes.3,16 Unfortunately, most hos- occluded coronary arteries. If a patient has a negative exercise
pitals do not have interventional cardiology services capable of stress test for ischemia, the patient is at lower risk for subse-
performing primary PCI 24 hours a day. Therefore, only 7% of quent CHD events.
MI patients are currently treated with primary PCI.
Percutaneous coronary intervention during hospitalization
Early Pharmacologic Therapy for ST-Segment
for STE MI may also be appropriate in other patients fol-
Elevation Acute Coronary Syndromes
lowing STE MI, such as those in whom brinolysis is not suc-
cessful, those presenting later in cardiogenic shock, those with Pharmacotherapy for early treatment of ACS is outlined in
life-threatening ventricular arrhythmias, and those with per- Fig. 53. According to the ACC/AHA ST-segment elevation
sistent rest ischemia or signs of ischemia on stress testing fol- ACS practice guidelines, in addition to reperfusion therapy,
lowing MI.3,15 early pharmacotherapy of STE should include intranasal oxygen
92
TABLE 52. Pharmacotherapy for Acute Coronary Syndromes (ST-Segment Elevation and NonST-Segment Elevation)2,3,20,21,22
Clinical Condition and ACC/AHA

Drug Guideline Recommendation Contraindicationsa Dose
Aspirin STE ACS, class I recommendation b
Hypersensitivity 160325 mg on hospital day 1
for all patients. Active bleeding 75162 mg daily starting hospital day 2 and continued indenitely
NSTE ACS, class I recommendation Severe bleeding risk
for all patients.
Clopidogrel STE ACS, class I recommendation in Hypersensitivity 300600 mg loading dose on hospital day 1 followed by a maintenance dose
patients allergic to aspirin. Active bleeding of 75 mg orally once daily starting on hospital day 2; no data on loading
NSTE ACS, class I recommendation for Severe bleeding risk dose in patients greater than 75 years old
all hospitalized patients in whom a Administer indenitely in patients with an aspirin allergy (class I
non-interventional approach is planned. recommendation)
In PCI in STE and NSTE ACS, class I Administer for at least 9 months in medically managed patients
recommendation. with NSTE ACS (class I recommendation)
In STE ACS with brinolytics, large Administer for at least 30 days to 1 year in patients with STE or NSTE ACS
randomized trial data published (class I recommendation) undergoing PCI
after 2004 guidelines. Administer for a minimum of 6 months in patients receiving a paclitaxel-
eluting stent during PCI
Administer for a minimum of 3 months in patients receiving a tacrolimus-
eluting stent during PCI
If possible, withhold for at least 5 days in patients in whom CABG
is planned to decrease bleeding risk (class I recommendation)
Unfractionated STE ACS, class I recommendation in Active bleeding For STSE ACS administer 60 units/kg IV bolus (maximum 4000 units) followed
heparin (UFH) patients undergoing PCI, and for History of heparin- by a constant IV infusion at 12 units/kg/hour (maximum 1000 units/hour)
those patients treated with alteplase, induced For NSTE ACS administer 6070 units/kg IV bolus (maximum 5000 units) followed
reteplase, or tenecteplase; class IIa thrombocytopenia by a constant IV infusion of 1215 units/kg/hour (maximum 1000 units/hour)
recommendation for patients not Severe bleeding risk Titrated to maintain aPTT between 1.5 and 2.5 times control for NSTE ACS
treated with brinolytic therapy. Recent stroke and 1.52 times control (approximately 5070 seconds) in STE ACS
NSTE ACS, class I recommendation in The rst aPTT should be measured at 46 hours for NSTE ACS and
combination with aspirin. STE ACS in patients not treated with thrombolytics
PCI, class I recommendation. The rst aPTT should be measured at 3 hours in patients with STE ACS
who are treated with thrombolytics
Low-molecular- STE ACS, class IIb recommendation Active bleeding Enoxaparin 1 mg/kg SC every 12 hours (CrCl greater than or equal to 30 mL/minute)
weight heparin for patients less than 75 years old History of heparin- Enoxaparin 1 mg/kg SC every 24 hours (CrCl 1029 mL/minute)
treated with brinolytics, class III for induced Dalteparin 120 IU/kg SC every 12 hours (maximum single bolus dose
patients greater than 75 years old treated thrombocytopenia of 10,000 units)
with thrombolytics, and class IIa Severe bleeding risk Administer 30 mg IV bolus for STE ACS patients age less than 75 years
for patients not undergoing Recent stroke For STE ACS, rst 2 subcutaneous doses should be 100 mg for patients
reperfusion therapy. CrCl less than weighing equal to or greater than 100 kg (220 lb)
NSTE ACS, class I recommendation in 10 mL/minute
combination with aspirin, class IIa (enoxaparin)
recommendation over UFH in patients CrCl less than
without renal failure who are not 30 mL/minute
anticipated to undergo CABG surgery (dalteparin)
within 24 hours.
Fibrinolytics STE ACS, class I recommendation in patients Absolute and relative Streptokinase: 1.5 million units IV over 60 minutes
presenting within 12 hours following the contraindications per Alteplase: 15 mg IV bolus followed by 0.75 mg/kg IV over 30 minutes (max 50 mg)
onset of symptoms, class IIa in patients Table 53 followed by 0.5 mg/kg (max 35 mg) over 60 minutes (max dose = 100 mg)
presenting between 1224 hours Reteplase: 10 units IV 2, 30 minutes apart
following the onset of symptoms with Tenecteplase:
continuing signs of ischemia. less than 60 kg = 30 mg IV bolus
NSTE ACS: class III recommendation. 6069.9 kg = 35 mg IV bolus
7079.9 kg = 40 mg IV bolus
8089.9 kg = 45 mg IV bolus
greater than or equal to 90 kg = 50 mg IV bolus
Glycoprotein IIb/ NSTE ACS, class IIa recommendation for Active bleeding Adjustment for
IIIa receptor either tiroban or eptibatide for patients Prior stroke Drug with/ renal
blockers with either continuing ischemia, elevated Thrombocytopenia without Dose for insufciency
troponin or other high-risk features, PCI Dose for PCI NSTE ACS or obesity
class I recommendation for patients Abciximab 0.25 mg/kg IV Not None
undergoing PCI, class IIb recommendation bolus followed recom-
for patients without high-risk features who by 0.125 mcg/kg/ mended
are not undergoing PCI. minute (maximum
STE ACS, class IIa for abciximab for primary 10 mcg/minute)
PCI and class IIb for either tiroban or for 12 hours
eptibatide for primary PCI, class III in Eptibatide 180 mcg/kg IV 180 mcg/kg IV Reduce maintenance
combination with a brinolytic agent bolus 2, bolus infusion to
10 minutes apart followed 1 mcg/kg/minute for
with an infusion by an patients with
of 2 mcg/kg/minute infusion of CrCl less than
started after the 2 mcg/kg/minute 50 mL/minute;
rst bolus for for 1896 hours not recommended
1896 hours for patients with
serum creatinine
greater than 4 mg/dL
(354 mol/L); patients
weighing greater than
or equal to 121 kg
(266 lbs) should
receive a maximum
infusion rate of 22.6
mg per bolus and a
maximum infusion
rate of 15 mg/hour
Tiroban Not recommended 0.4 mcg/kg IV Reduce bolus dose
infusion for to 0.2 mcg/kg/minute
30 minutes and the
followed by maintenance
an infusion infusion to
of 0.1 mcg/kg/ 0.05 mcg/kg/minute
minute for for patients with
1896 hours CrCl less than
30 mL/minute
93
94
TABLE 52. Pharmacotherapy for Acute Coronary Syndromes (ST-Segment Elevation and Non-ST-Segment Elevation)2,3,20,21,22 (Continued)
Clinical Condition and ACC/AHA

Drug Guideline Recommendation Contraindicationsa Dose
Nitroglycerin STE and NSTE ACS, class I indication in Hypotension 0.4 mg SL, repeated every 5 minutes 3 doses
patients with ongoing ischemic Sildenal or vardenal 5 to 10 mcg/minute by continuous infusion
discomfort, control of hypertension within 24 hours or Titrated up to 75100 mcg/minute until relief of symptoms or
or management of pulmonary tadalal within limiting side-effects (headache or hypotension with a systolic
congestion. 48 hours blood pressure less than 90 mm Hg or more than 30% below starting
mean arterial pressure levels if signicant hypertension is present)
Topical patches or oral nitrates are acceptable alternatives for
patients without ongoing or refractory symptoms
-Blockersc STE and NSTE ACS, class I recommendation in PR ECG segment greater Target resting heart rate 5060 beats per minute
all patients without contraindications for than 0.24 seconds Metoprolol
oral -blockers, class I (NSTE ACS) and Second- or third-degree 5 mg increments by slow (over 12 minutes) intravenous administration
IIa (STE ACS) for IV -blockers, class IIb AV block Repeated every 5 minutes for a total initial dose of 15 mg
recommendation for patients with Heart rate less than 60 Followed in 12 hours by 2550 mg by mouth every 6 hours
moderate left ventricular failure with signs beats per minute If a very conservative regimen is desired, initial doses can be reduced
of heart failure provided they can be Systolic blood pressure to 12 mg
closely monitored. less than 90 mm Hg Alternatively, initial intravenous therapy can be omitted
Shock Propranolol
Left ventricular failure 0.51 mg intravenous dose
with congestive Followed in 12 hours by 4080 mg by mouth every 68 hours
heart failure Alternatively, initial intravenous therapy can be omitted
Severe reactive airway Atenolol
disease 5 mg IV dose
Followed 5 minutes later by a second 5 mg IV dose then 50100 mg
orally every day initiated 12 hours after the intravenous dose
Alternatively, initial intravenous therapy can be omitted
Esmolol
Starting maintenance dose of 0.1 mg/kg/minute IV
Titration in increments of 0.05 mg/kg/minute every 1015 minutes as tolerated
by blood pressure until the desired therapeutic response has been obtained,
limiting symptoms develop, or a dose of 0.20 mg/kg/minute is reached
Optional loading dose of 0.5 mg/kg may be given by slow IV
administration (25 minutes) for more rapid onset of action
Calcium STE ACS class IIa recommendation and NSTE Pulmonary edema Diltiazem 120360 mg controlled-release once daily
channel ACS class I recommendation for patients Evidence of left ventricular Verapamil 180480 mg sustained-release per day
blockers with ongoing ischemia who are already dysfunction Nifedipine 3090 mg sustained-release once daily
taking adequate doses of nitrates and Systolic blood pressure less Amlodipine 510 mg once daily
-blockers or in patients with than 100 mm Hg
contraindications to or intolerance to PR ECG segment greater than
-blockers (diltiazem or verapamil for STE 0.24 seconds for diltiazem
ACS and diltiazem, verapamil, or or verapamil
amlodipine for NSTE ACS). Second- or third-degree
NSTE ACS, class IIb recommendation for AV block for diltiazem
diltiazem for patients with AMI. or verapamil
Heart rate less than 60 beats per
minute for diltiazem or
verapamil
ACE inhibitors STE ACS, class I recommendation within the Systolic blood pressure less Drug Initial Dose (mg) Target Dose (mg)
rst 24 hours after hospital presentation than 100 mm Hg Captopril 6.2512.5 50 twice daily to 50 three
for patients with anterior wall infarction, History of intolerance to times daily
clinical signs of heart failure and those an ACE inhibitor Enalapril 2.55 10 twice daily
with EF less than 40% in the absence of Bilateral renal artery Lisinopril 2.55 1020 daily
contraindications, class IIa recommendation stenosis Ramipril 1.252 5 twice daily or 10 mg
for all other patients in the absence of Serum potassium greater than once daily
contraindications. 5.5 mEq/L (5.5 mmol/L) Trandolapril 1 4 mg once daily
NSTE ACS, class I recommendation for
patients with heart failure, left ventricular
dysfunction, and EF less than 40%, hypertension,
or type 2 diabetes mellitus.
Consider in all patients with CAD.
Indicated indenitely for all post-AMI patients.
Angiotensin STE ACS, class I recommendation in patients with Systolic blood pressure less Drug Initial Dose (mg) Target Dose (mg)
receptor clinical signs of heart failure or EF less than 40% than 100 mm Hg Candesartan 48 mg 32 mg once daily
blocker and intolerant of an ACE inhibitor, class IIa in Bilateral renal artery Valsartan 40 mg 160 mg twice daily
patients with clinical signs of heart failure or stenosis
EF less than 40% and no documentation of Serum potassium greater than
ACE inhibitor intolerance. 5.5 mEq/L (5.5 mmol/L)
Aldosterone STE ACS, class I recommendation for patients Hypotension Drug Initial Dose (mg) Maximum Dose (mg)
antagonists with MI and EF less than 40% and either Hyperkalemia; serum Eplerenone 25 mg 50 mg once daily
diabetes mellitus or heart failure symptoms potassium greater than Spironolactone 12.5 mg 2550 mg once daily
who are already receiving an ACE inhibitor. 5.5 mEq/L (5.5 mmol/L)
Serum creatinine greater than
2.5 mg/dL (221 mmol/L)
Morphine sulfate STE and NSTE ACS, class I recommendation, Hypotension 25 mg IV dose
for patients whose symptoms are not Respiratory depression May be repeated every
relieved after three serial sublingual Confusion 530 minutes as needed to
nitroglycerin tablets or whose symptoms Obtundation relieve symptoms and
recur with adequate anti-ischemic therapy. maintain patient comfort
a
Allergy or prior intolerance contraindication for all categories of drugs listed in this chart.
b
Class I recommendations are conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective.
Class II recommendations are those conditions for which there is conicting evidence and/or a divergence of opinion about the usefulness/efcacy of a procedure or treatment. For Class IIa
recommendations, the weight of the evidence/opinion is in favor of usefulness/efcacy. Class IIb recommendations are those for which usefulness/efcacy is less well established by
evidence/opinion.
c
Choice of the specic agent is not as important as ensuring that appropriate candidates receive this therapy. If there are concerns about patient intolerance due to existing pulmonary disease, espe-
cially asthma, selection should favor a short-acting agent, such as propranolol or metoprolol or the ultra-short-acting agent esmolol. Mild wheezing or a history of chronic obstructive pulmonary
disease should prompt a trial of a short-acting agent at a reduced dose (e.g., 2.5 mg IV metoprolol, 12.5 mg oral metoprolol, or 25 mcg/kg/minute esmolol as initial doses) rather than complete
avoidance of -blocker therapy.
ACC, American College of Cardiology; ACE, angiotensin-converting enzyme; ACS, acute coronary syndrome; AHA, American Heart Association; AMI, acute myocardial infarction; aPTT, acti-
vated partial thromboplastin time; AV, atrioventricular; CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; CrCl, creatinine clearance; ECG, electrocardiogram; EF,
ejection fraction; MI, myocardial infarction; NSTE, nonST-segment elevation; PCI, percutaneous coronary intervention; STE, ST-segment elevation.
(Reprinted from Spinler SA, de Denus S. Acute Coronary Syndromes. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York:
McGraw-Hill; 2005: 299302, with permission.)
95
(if oxygen saturation is less than 90%), sublingual (SL) nitro- TABLE 53. Indications and Contraindications to Fibrinolytic
glycerin (NTG) followed by intravenous (IV) NTG, aspirin, an Therapy per ACC/AHA Guidelines for Management
IV b-blocker, unfractionated heparin (UFH), and brinolysis in of Patients with ST-Segment Elevation Myocardial
eligible candidates. Recent results from two clinical trials in Infarction3
patients with STE ACS indicate that clopidogrel should be Indications
administered along with aspirin to patients receiving brinolyt- 1. Ischemic chest discomfort at least 20 minutes in duration but
ics to reduce mortality and reinfarction as well as to improve the 12 hours or less since symptom onset
patency of the infarcted artery.20,21 Morphine is administered to and
patients with refractory angina as an analgesic and a venodilator ST-segment elevation of at least 1 mm in height in two or more
contiguous leads, or new or presumed new left bundle-branch
that lowers preload. These agents should be administered early, block
while the patient is still in the emergency department. Dosing 2. Ongoing ischemic chest discomfort at least 20 minutes in dura-
and contraindications for SL and IV NTG, aspirin, IV - tion 1224 hours since symptom onset
blockers, UFH, clopidogrel, and brinolytics are listed in and
Table 52.2,3,22 ST-segment elevation of at least 1 mm in height in two or more
contiguous leads
Absolute Contraindications
Fibrinolytic Therapy Active internal bleeding (not including menses)
Administration of a brinolytic agent is indicated in patients Previous intracranial hemorrhage at any time; ischemic stroke within
with STE ACS who present to the hospital within 24 hours of 3 months
the onset of chest discomfort and have at least a 1 mm STE in Known intracranial neoplasm
Known structural vascular lesion (e.g., arteriovenous malformation)
two or more contiguous ECG leads.3 The mortality benet of Suspected aortic dissection
brinolysis is highest with early administration and diminishes Signicant closed head or facial trauma within 3 months
after 12 hours. The use of brinolytics between 12 and 24 hours
Relative Contraindications
after symptom onset should be limited to patients with ongo- Severe, uncontrolled hypertension on presentation (blood pressure
ing ischemia. Fibrinolytic therapy is preferred over primary PCI greater than 180/110 mm Hg)
in patients presenting within 3 hours of symptom onset where History of prior ischemic stroke greater than 3 months ago, dementia,
there is a delay in door-to-primary PCI less than 90 minutes. or known intracranial pathology not covered above under absolute
contraindications
Other indications and contraindications for brinolysis are
Current use of anticoagulants
listed in Table 53.3 It is not necessary to obtain the results of Known bleeding diathesis
biochemical markers before initiating brinolytic therapy. Traumatic or prolonged (greater than 10 minutes) CPR or major surgery
Because administration of brinolytics result in clot lysis, (less than 3 weeks ago)
patients who are at high-risk of major bleeding (including Non-compressible vascular puncture (such as a recent liver biopsy or
carotid artery puncture)
intracranial hemorrhage) have either a relative or absolute con-
Recent (within 24 weeks) internal bleeding
traindication to brinolytic therapy. Patients presenting with an For streptokinase administration, previous streptokinase use
absolute contraindication will likely not receive brinolytic (greater than 5 days) or prior allergic reactions
therapy, as primary PCI is preferred. Patients with a relative Pregnancy
contraindication may receive brinolytic therapy if the per- Active peptic ulcer
History of severe, chronic, poorly controlled hypertension
ceived risk of death from the MI is higher than the risk of major
hemorrhage. ACC, American College of Cardiology; AHA, American Heart
Comparative pharmacology of commonly prescribed bri- Association; CPR, cardiopulmonary resuscitation.
(Reprinted from Spinler SA, de Denus S. Acute Coronary Syndromes. In:
nolytics is described in Table 54.26 According to the DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A
ACC/AHA STE ACS practice guidelines, a more brin-specic Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 303,
agent such as alteplase, reteplase, or tenecteplase, is preferred with permission.)
over a nonbrin-specic agent, such as streptokinase.3
Fibrin-specic brinolytics open a greater percentage of
infarcted arteries. In a large clinical trial, administration of with streptokinase. However, the risk of systemic bleeding
alteplase reduced mortality by 1% (absolute reduction) and other than intracranial hemorrhage is higher with streptoki-
costs about $30,000 per year of life saved compared to strep- nase than with other, more brin-specic agents.23
tokinase.23 Two other trials compared alteplase to reteplase Twenty to 40 percent of patients presenting with STE ACS
and alteplase to tenecteplase and found similar mortality receive brinolysis compared with 7% receiving primary
between agents.24,25 Therefore, either alteplase, reteplase, or PCI.26,27 Therefore, many patients do not receive early reperfu-
tenecteplase are acceptable as rst-line agents. Intracranial sion therapy. The primary reason for lack of reperfusion therapy
hemorrhage and major bleeding are the most serious side is that most patients present more than 12 hours after the time
effects of brinolytic agents (Table 54). The risk of intracra- of symptom onset.27 The percentage of eligible patients who
nial hemorrhage is higher with brin-specic agents than receive reperfusion therapy is a quality indicator of care in
TABLE 54. Comparison Between Fibrinolytic Agents
TIMI-3 Blood Flow Average

Fibrin Complete Perfusion Systemic Bleeding Wholesale Other Approved
Agent Specicity at 90 Minutes Risk/ICH Risk Administration Price3 Uses
Streptokinase + 35% +++/+ Infusion over $613 Pulmonary embolism, deep
60 minutes vein thrombosis, arterial
thromboembolism,
clearance of an occluded
arteriovenous catheter
Alteplase +++ 5060% ++/++ Bolus followed by $2,750 Pulmonary embolism, stroke,
(rt-PA) infusions over clearance of an occluded
90 minutes; weight- arteriovenous catheter
based dosing
Reteplase ++ 5060% ++/++ Two bolus doses, $2,974
(rPA) 30 minutes apart
Tenecteplase ++++ 5060% +/++ Single bolus $2,833
(TNK-tPA) dose; weight-
based dosing
ICH, intracranial hemorrhage; TIMI, Thrombolysis in Myocardial Blood Flow (TIMI-3 blood ow indicates complete perfusion of the infracted artery).
(Reprinted from Spinler SA, de Denus S. Acute Coronary Syndromes. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic
Approach. 6th ed. New York: McGraw-Hill; 2005: 303, with permission.)
patients with MI.23 The door-to-needle time, the time from Thienopyridines
presentation to start of brinolytic therapy, is another quality Administration of clopidogrel is recommended for all patients
indicator.23 While the ACC/AHA guidelines recommend a with STE ACS (Table 52).3 Clopidogrel blocks adenosine
door-to-needle time of less than 30 minutes, the average diphosphate receptors on platelets, preventing the expression
time in the United States is approximately 37 minutes.27 of glycoprotein IIb/IIIa receptors and thus platelet activation
Therefore, strategies to shorten administration times should and aggregation.
be implemented. Clopidogrel reduces death, MI, or stroke in patients with
NSTE ACS when combined with aspirin.31 It also reduces
death, MI, or stroke in secondary prevention of vascular
Aspirin
events in patients with a recent MI, stroke, or symptomatic
Aspirin has become the preferred antiplatelet agent in the
peripheral vascular disease.32 Most recently, early therapy with
treatment of all ACS.2,3 Aspirin administration to all patients
clopidogrel 75 mg once daily in patients with STE ACS reduced
who dont have contraindications to aspirin therapy within the
mortality and reinfarction in patients treated with brinolyt-
rst 24 hours of hospital admission is a quality care indicator.23
ics without increasing the risk of major bleeding.21 Therefore,
The antiplatelet effects of aspirin are mediated by inhibiting
the combination of clopidogrel and aspirin is indicated for all
the synthesis of TXA2 through an irreversible inhibition of
patients with ACS. For PCI, clopidogrel is administered as a
platelet cyclooxygenase-1. In patients undergoing PCI, aspirin
300 to 600 mg loading dose followed by a 75 mg per day main-
prevents acute thrombotic occlusion during the procedure. In
tenance dose, in combination with aspirin, to prevent suba-
patients receiving brinolytics, aspirin reduces mortality, and
cute stent thrombosis and long-term events, such as the com-
its effects are additive to brinolysis alone.28
posite endpoint of death, myocardial infarction, or need to
Although an initial dose of 160 to 325 mg is required to
undergo repeat PCI.2,18 The most frequent side effect of clopi-
achieve rapid platelet inhibition, long-term therapy with
dogrel is rash or gastrointestinal events (nausea, vomiting, or
doses of 75 to 150 mg daily are as effective as higher doses. In
diarrhea). Rarely, thrombotic thrombocytopenic purpura has
addition, doses of less than 325 mg daily are associated with a
been reported with clopidogrel. The most serious side effect of
lower rate of bleeding.29,30 The major bleeding rate associated
clopidogrel is bleeding, which will be discussed in more detail
with chronic aspirin administration in doses less than 100 mg
in the section on pharmacotherapy for NSTE ACS.
per day is 1.6%, whereas the rate with doses more than 100 mg
per day is 2.3%.30 Therefore, a daily maintenance dose of 75 to
160 mg is recommended.2 Glycoprotein IIb/IIIa Receptor Inhibitors
Other gastrointestinal disturbances, including dyspepsia Abciximab is a rst-line glycoprotein IIb/IIIa receptor
and nausea, are infrequent when low-dose aspirin is used. inhibitor for patients undergoing primary PCI3,15,18 who have
Aspirin therapy should be continued indenitely. not received brinolytics. It should not be administered for
medical management of the STE ACS patient who will not be for binding and inhibition. Limited data, primarily with enoxa-
undergoing PCI. Abciximab, in combination with aspirin, a parin, suggests that LMWHs may be an alternative to UFH in
thienopyridine, and UFH (administered as an infusion for the STE ACS.36 A larger trial evaluating enoxaparin versus UFH in
duration of the procedure), is preferred over eptibatide and combination with brinolytics for STE ACS is ongoing.
tiroban in this setting because abciximab is the most common
glycoprotein IIb/IIIa receptor inhibitor studied in primary PCI
Nitrates
trials, and a meta-analysis of trials demonstrated a reduction in
One sublingual nitroglycerin tablet should be administered
short- and long-term mortality.3,18,33
every 5 minutes for up to three doses in order to relieve myocar-
Dosing and contraindications for abciximab are described in
dial ischemia. If patients have been previously prescribed sub-
Table 52. Glycoprotein IIb/IIIa receptor inhibitors block the
lingual NTG and ischemic chest discomfort persists for more
nal common pathway of platelet aggregation; namely, cross-
than 5 minutes after the rst dose, the patient should be
linking of platelets by brinogen bridges between the glycopro-
instructed to contact emergency medical services before self-
tein IIb and IIIa receptors on the platelet surface. Administration
administering subsequent doses in order to activate emergency
of a glycoprotein IIb/IIIa receptor inhibitor increases the risk of
care sooner. Intravenous nitroglycerin should then be initiated
bleeding, especially if it is given in the setting of recent (less than
in all patients with an ACS who do not have a contraindication
4 hours) administration of brinolytic therapy.31,33 An immune-
and who have persistent ischemia, heart failure, or uncontrolled
mediated thrombocytopenia occurs in approximately 5% of
blood pressure. Intravenous nitroglycerin should be continued
patients receiving abciximab.34
for approximately 24 hours after ischemia is relieved (Table 52).
Nitrates promote the release of nitric oxide from the endothe-
Anticoagulants lium, which results in venous and arterial vasodilation.
Unfractionated heparin, administered as a continuous infu- Venodilation lowers preload and myocardial oxygen demand.
sion, is a rst-line anticoagulant for treatment of patients with Arterial vasodilation may lower blood pressure, thus reducing
STE ACS, both for medical therapy and for patients under- myocardial oxygen demand. Arterial vasodilation also relieves
going PCI.3,15,18 Unfractionated heparin binds to antithrombin coronary artery vasospasm, dilating coronary arteries to
and then to clotting factors Xa and IIa (thrombin). Anti- improve myocardial blood ow and oxygenation. Although
coagulant therapy should be initiated in the emergency used to treat ACS, nitrates have been suggested to play a limited
department and continued for 48 hours or longer in patients role in the treatment of an ACS patient, as two large, randomized
who will be bridged over to receive chronic warfarin anticoag- clinical trials failed to show a mortality benet for IV nitrate
ulation following acute MI.3 In the United States, UFH is typ- therapy followed by oral nitrate therapy in acute MI.37,38 The
ically continued until the patient has undergone PCI during most signicant adverse effects of nitrates are tachycardia,
hospitalization for STE ACS. Unfractionated heparin dosing is ushing, headache, and hypotension. Nitrate administration is
described in Table 52. The dose of the UFH infusion is adjusted contraindicated in patients who have received oral phospho-
frequently to a target activated partial thromboplastin time diesterase 5 inhibitors, such as sildenal and vardenal, within
(aPTT) (Table 52). When co-administered with a brinolytic, the past 24 hours, and tadalal within the past 48 hours.3
aPTTs above the target range are associated with an increased
rate of bleeding, while aPTTs below the target range are associ- Beta-Blockers
ated with increased mortality and reinfarction.35 Unfractionated Intravenous or oral doses of a -blocker should be administered
heparin is discontinued immediately after the PCI procedure. early in the care of a patient with STE ACS, and then oral agents
A meta-analysis of small randomized studies from the 1970s should be continued indenitely. Early administration of a
and 1980s suggests that UFH reduces mortality by approximately -blocker to patients lacking a contraindication within the rst
17%.3 Other benecial effects of anticoagulation are prevention 24 hours of hospitalization is a quality care indicator.2,3 In ACS
of cardioembolic stroke, as well as venous thromboembolism the benet of -blockers mainly results from the competitive
in MI patients.3 Besides bleeding, the most frequent adverse blockade of 1-adrenergic receptors located on the myocardium.
effect of UFH is an immune-mediated clotting disorder, 1-Blockade produces a reduction in heart rate, myocardial con-
heparin-induced thrombocytopenia, which occurs in up to tractility, and blood pressure, decreasing myocardial oxygen
5% of patients treated with UFH. Heparin-induced thrombo- demand. As a result of these effects, -blockers reduce the risk
cytopenia is less common in patients receiving low-molecular- for recurrent ischemia, increase in infarct size and risk of rein-
weight heparins (LMWHs), such as enoxaparin or dalteparin. farction, and occurrence of ventricular arrhythmias in the hours
Low-molecular-weight heparins have not been studied in and days following MI.39
the setting of primary PCI. Low-molecular-weight heparins, Landmark clinical trials have established the role of early
like UFH, bind to antithrombin and inhibit both factor Xa -blocker therapy in reducing MI mortality, reinfarction, and
and IIa. However, because their composition contains mostly arrhythmias. Most of these trials were performed in the 1970s
short saccharide chain lengths, they preferentially inhibit and 1980s before routine use of early reperfusion therapy.40,41
factor Xa over factor IIa, which requires larger chain lengths However, data regarding the acute benet of -blockers in MI
in the reperfusion era is derived mainly from a recently ventricular dysfunction because they can worsen heart failure
reported large clinical trial, which suggests that there may be and potentially increase mortality secondary to their negative
an early risk of cardiogenic shock when initiating intravenous inotropic effects. In patients with heart failure requiring
-blockers followed by oral -blockers early in the course of treatment with a calcium channel blocker, amlodipine, a second-
STE MI, especially in patients presenting with pulmonary generation dihydropyridine that does not cause reex tachy-
congestion.42 Therefore, a low dose of an oral -blocker cardia, is the preferred agent.44
should be initiated, followed by careful assessment for signs
of hypotension and heart failure prior to any dose titration Early Pharmacotherapy for NonST-Segment
in patients with STE MI. Early administration of -blockers Elevation Acute Coronary Syndromes
(to patients without contraindications) within the rst 24 hours
of hospital admission is a standard of quality patient care.3 In general, early pharmacotherapy of NSTE ACS (Fig. 53) is
However, the AHA is currently undertaking a re-evaluation of similar to that of STE ACS with three exceptions: (1) bri-
this practice guideline recommendation given the results of the nolytic therapy is not administered; (2) glycoprotein IIb/IIIa
aforementioned trial reporting adverse effects associated with receptor blockers are administered to high-risk patients for
-blocker use in certain MI populations. medical therapy as well as to PCI patients; and (3) at this time,
The most serious side effects of -blocker administration there are no standard quality indicators for patients with
early in ACS are hypotension, bradycardia, and heart block. NSTE ACS who are not diagnosed with MI.
While initial, acute administration of -blockers is not appro- According to the ACC/AHA nonST-segment elevation
priate for patients who present with decompensated heart ACS practice guidelines, in the absence of contraindications,
failure, initiation of -blockers may be attempted before hos- early pharmacotherapy of NSTE ACS should include intranasal
pital discharge in the majority of patients following treatment oxygen (if oxygen saturation is low), SL NTG followed by IV
of acute heart failure. -Blockers are continued indenitely. NTG, aspirin, an IV b-blocker, and UFH or LMWH. Most
patients should receive additional therapy with clopidogrel.
Calcium Channel Blockers High-risk patients should also receive a glycoprotein IIb/IIIa
Calcium channel blockers in the setting of STE ACS are used for receptor blocker. Morphine is also administered to patients with
relief of ischemic symptoms in patients who have contraindi- refractory angina as described previously. These agents should
cations to -blockers. Patients prescribed calcium channel be administered early, while the patient is still in the emergency
blockers for treatment of hypertension who were not receiving department. Dosing and contraindications for SL and IV NTG
and do not have any contraindications to -blockers should (for selected patients), aspirin, IV -blockers, UFH, and
have the calcium channel blocker discontinued and a -blocker LMWHs are listed in Table 52.2,22
initiated. Although all calcium channel blockers produce coro-
nary vasodilatation and decrease blood pressure, other effects Fibrinolytic Therapy
are more heterogeneous between these agents. Dihydropyridine Fibrinolytic therapy is not indicated in any patient with NSTE
calcium channel blockers (e.g., amlodipine, felodipine, and ACS, as increased mortality has been reported with brinolytics
nifedipine) primarily produce their anti-ischemic effects through compared to controls in clinical trials in which brinolytics have
peripheral vasodilatation with no clinical effects on AV node been administered to patients with NSTE ACS (patients with
conduction and heart rate. The nondihydropyridine calcium normal or ST-segment depression ECGs).10
channel blockers (e.g., diltiazem and verapamil), on the other
hand, have additional anti-ischemic effects by reducing con- Aspirin
tractility, AV nodal conduction, and slowing heart rate. Aspirin reduces the risk of death or developing MI by about
Current data suggest little benet on clinical outcomes 50% (compared to no antiplatelet therapy) in patients with
beyond symptom relief for calcium channel blockers in the NSTE ACS.29 Therefore, aspirin remains the cornerstone of
setting of ACS.43 Moreover, the use of rst-generation short- early treatment for all ACS. Dosing of aspirin for NSTE ACS is
acting dihydropyridines, such as nifedipine, should be avoided the same as that for STE ACS (Table 52). Aspirin is continued
because they appear to worsen outcomes through their negative indenitely.
inotropic effects, induction of reex sympathetic activation,
tachycardia, and increased myocardial ischemia.43 Therefore, Thienopyridines
calcium channel blockers should be avoided in the acute man- For patients with NSTE ACS, clopidogrel started on the rst
agement of MI unless there is a clear symptomatic need or a day of hospitalization as a 300 to 600 mg loading dose and fol-
contraindication to -blockers. lowed the next day by 75 mg orally per day is recommended
Adverse effects and contraindications of calcium channel for most patients.2 Although the use of aspirin in ACS is the
blockers are described in Table 52. Verapamil, diltiazem, mainstay of antiplatelet therapy, morbidity and mortality fol-
and rst-generation dihydropyridines should also be avoided lowing an ACS remain high. Clopidogrel, administered as a
in patients with acute decompensated heart failure or left 300 mg loading dose followed by 75 mg once daily for 9 to
12 months, reduces the combined risk of death from cardiovas- primarily treated with a medical management strategy.2
cular causes, non-fatal MI, or stroke by 20%.45 Administration However, in patients with NSTE ACS undergoing early PCI,
of clopidogrel for at least 30 days in patients undergoing intra- similar rates of death or MI and a slightly higher bleeding rate
coronary stenting is the standard of care. Recently, the combina- with enoxaparin was found in a large trial comparing enoxa-
tion of clopidogrel with aspirin has been extended to 3 months parin and UFH. This trial, however, was confounded by a large
for sirolimus-eluting stents and at least 6 months for patients number of patients who received both UFH and enoxaparin.
with paclitaxel-eluting stents.18 Because of the potential for Therefore, either enoxaparin or UFH may be administered, but
increased risk of bleeding, clopidogrel should be discontinued switching between UFH and enoxaparin should be avoided as it
for at least 5 days before elective CABG surgery.2 appears to increase bleeding rates.48 In some clinical trials, the
risk of heparin-induced thrombocytopenia has been shown to
be lower with LMWHs compared to UFH. Dosing information
Glycoprotein IIb/IIIa Receptor Inhibitors and contraindications are described in Table 52.
Administration of tiroban or eptibatide is recommended for
high-risk NSTE ACS patients as medical therapy without
planned revascularization and for patients with continued or Nitrates
recurrent ischemia despite treatment with aspirin and an anti- Sublingual NTG followed by intravenous NTG should be
coagulant. In these patients, the benet of glycoprotein IIb/IIIa administered to patients with NSTE ACS and ongoing
inhibitors appears to be limited to those undergoing PCI.18,46 ischemia (Table 52). The mechanism of action, dosing, con-
Patients undergoing PCI in these trials received several hours to traindications, and adverse effects are the same as those
days of pre-treatment with the glycoprotein IIb/IIIa receptor described in the section on early pharmacologic therapy for
blocker before proceeding to PCI. Abciximab should not be STE ACS. Intravenous NTG is typically continued for approx-
used in this setting, because its use in such a setting has not imately 24 hours following ischemia relief.
been shown to be benecial.
In patients with NSTE ACS scheduled for early PCI, Beta-Blockers
administration of either abciximab or eptibatide (double Intravenous -blockers followed by oral -blockers should be
bolus) is recommended. The use of tiroban in these patients administered to all patients with NSTE ACS in the absence of
is not recommended, because it has been shown to be inferior contraindications. Benets of -blockers in this patient group
to abciximab.2 Medical therapy with glycoprotein IIb/IIIa are assumed to be similar to those seen in patients with STE
receptor inhibitors in patients not undergoing PCI is reserved ACS. -Blockers are continued indenitely.
for higher-risk patients, such as those with positive troponin
or ST-segment depression, and patients who have continued Calcium Channel Blockers
or recurrent ischemia despite other antithrombotic therapy.2 As described in the previous section, calcium channel blockers
Doses and contraindications to glycoprotein IIb/IIIa receptor should not be administered to most patients with ACS. Their
blockers are described in Table 52. Major bleeding and rates of role is a second-line treatment for patients with certain con-
transfusion are increased with administration of a glycoprotein traindications to -blockers and those with continued ischemia
IIb/IIIa receptor inhibitor in combination with aspirin and an despite -blocker and nitrate therapy. Administration of either
anticoagulant,30 but there is no increased risk of intracranial amlodipine, diltiazem, or verapamil is preferred.2 Agent selec-
hemorrhage in the absence of concomitant brinolytic tion is based on heart rate and left ventricular dysfunction
treatment. The risk of thrombocytopenia with tiroban and (diltiazem and verapamil are contraindicated in patients with
eptibatide appears lower than that with abciximab. Bleeding bradycardia, heart block, or systolic heart failure). Dosing and
risks appear similar between agents. contraindications are described in Table 52.
Anticoagulants
Either UFH or LMWH should be administered to patients with
NSTE ACS. Therapy should be continued for up to 48 hours or Patient Encounter, Part 3: Secondary
until the end of the angiography or PCI procedure. In patients Prevention of MI
initiating warfarin therapy, UFH or LMWHs should be con-
tinued until the International Normalized Ratio (INR) with Identify the long-term treatment goals for SD.
warfarin is in the therapeutic range for 2 consecutive days. The What additional pharmacotherapy should be initiated
addition of UFH to aspirin reduces the rate of death or MI in prior to hospital discharge?
patients with NSTE ACS.47 Enoxaparin was mentioned as Create a care plan for SD for hospital discharge which
preferred over UFH in the 2002 ACC/AHA clinical practice includes pharmacotherapy, desired treatment outcomes,
guidelines, as two large clinical trials found a reduction in the and monitoring for efcacy and adverse effects.
combined endpoint of death, MI, or need for PCI in patients
Secondary Prevention Following Myocardial Clopidogrel

Infarction For patients with either STE or NSTE ACS, clopidogrel
decreases the risk of death, MI, or stroke.21,45 The ACC/AHA
The long-term goals following MI are to: (1) control modiable
guidelines suggest a minimum therapy duration of 9 months in
CHD risk-factors, (2) prevent the development of systolic heart
patients following NSTE ACS.2 In patients receiving clopidogrel
failure, (3) prevent recurrent MI and stroke, and (4) prevent
for STE MI who do not undergo PCI, clopidogrel should be
death, including sudden cardiac death. Pharmacotherapy,
administered for at least 14 to 28 days.21 Patients who have
which has been proven to decrease mortality, heart failure, rein-
undergone a PCI with stent implantation may receive clopidogrel
farction, or stroke, should be initiated prior to hospital dis-
for up to 12 months.18 Because of the risk of bleeding with
charge for secondary prevention. Guidelines from the
concomitant therapy of clopidogrel and aspirin at doses
ACC/AHA suggest that in the absence of contraindications, follow-
greater than 100 mg, low-dose aspirin should be administered
ing MI from either STE ACS or NSTE ACS, patients should receive
with clopidogrel.59 Although not specically studied, longer
indenite treatment with aspirin, a b-blocker, and an ACE
duration of therapy with clopidogrel plus aspirin may be con-
inhibitor.2,3 For NSTE ACS, most patients should receive clopido-
sidered for patients with many recurrent vascular events such
grel, in addition to aspirin, for up to 9 months.2 Most patients will
as stroke, MI, or recurrent ACS.
receive a statin to reduce low-density lipoprotein cholesterol to less
than 100 mg/dL. Selected patients will also be treated with long-
term warfarin anticoagulation. Newer therapies include Anticoagulation
eplerenone, an aldosterone antagonist. For all ACS patients, Warfarin should be considered in selected patients following
treatment and control of modiable risk factors such as hyper- an ACS, including patients with a left ventricular thrombus,
tension, dyslipidemia, and diabetes mellitus is essential. Benets patients demonstrating extensive ventricular wall motion
and adverse effects of long-term treatment with these medica- abnormalities on cardiac echocardiogram, a history of throm-
tions are discussed in more detail below. boembolic disease, or chronic atrial brillation.3 A meta-
analysis of 10 clinical trials of secondary prevention with
Because the costs for chronic preventative pharmacother- aspirin, warfarin, and the combination of the two suggested
apy are the same for primary and secondary prevention, while that warfarin plus low-dose aspirin reduced the rate of MI and
the risk of events is higher with secondary prevention, secondary stroke, but did not reduce mortality. The risk of major bleeding
prevention is more cost effective than primary prevention of was increased more than two-fold.60 Many consider these ben-
CHD. Pharmacotherapy demonstrating cost effectiveness to ets to be small in comparison with the large management
prevent death in the ACS and post-MI patient includes bri- issues related to warfarin therapy, such as INR monitoring
nolytics ($2,000 to $33,000 cost per year of life saved), aspirin, and drug interactions. Furthermore, because a large propor-
glycoprotein IIb/IIIa receptor blockers ($13,700 to $16,500 tion of ACS patients in North America undergo coronary
per year of life added), -blockers (less than $5,000 to $15,000 revascularization with subsequent stent implantation,
cost per year of life saved), ACE inhibitors ($3,000 to $5,000 patients require a combination of aspirin and clopidogrel to
cost per year of life saved), eplerenone ($15,300 to $32,400 per prevent stent thrombosis, a platelet-dependent phenomenon
year of life gained), statins ($4,500 to $9,500 per year of life that warfarin does not effectively prevent.61 Therefore,
saved) and gembrozil ($17,000 per year of life saved).4958 because of the complexity of managing current anticoagu-
Because cost-effectiveness ratios of less than $50,000 per lants, the use of warfarin is unlikely to gain wide acceptance.
added life-year are considered economically attractive from a Despite the superiority of warfarin plus aspirin over aspirin
societal perspective,49 pharmacotherapy described above for alone, it is not currently the preferred antithrombotic agent
ACS and secondary prevention are standards of care because recommended by any professional association practice guide-
of their efcacy and cost attractiveness to payors. lines in the absence of the conditions for select patients out-
lined previously.
Aspirin
Aspirin decreases the risk of death, recurrent infarction, and Beta-Blockers, Nitrates, and Calcium Channel Blockers
stroke following myocardial infarction. Aspirin prescription Current treatment guidelines recommend that following an
at hospital discharge is a quality care indicator in MI ACS, patients should receive a -blocker indenitely2,3 whether
patients.3 All patients should receive aspirin indenitely; they have residual symptoms of angina or not.62 -Blocker pre-
those patients with a contraindication to aspirin should receive scription at hospital discharge in the absence of contraindica-
clopidogrel.2,3 tions is a quality care indicator.3 Overwhelming data support
The risk of major bleeding from chronic aspirin therapy is the use of -blockers in patients with a previous MI.
approximately 2% and is dose-related. Aspirin doses higher Currently, there are no data to support the superiority of one
than 75 to 81 mg are no less effective than doses of 160 to 325 -blocker over another, although the only -blocker with
mg, but do have lower rates of bleeding. Therefore, chronic intrinsic sympathomimetic activity that has been shown to be
doses of aspirin should not exceed 81 mg. benecial following MI is acebutolol.63
Although -blockers should be avoided in patients with class effect while the benets of ARBs are still under study.
decompensated heart failure from left ventricular systolic dys- Angiotensin-converting enzyme inhibitor prescription (or
function complicating an MI, clinical trial data suggest that it alternatively an ARB) at hospital discharge following MI, in the
is safe to initiate -blockers prior to hospital discharge in absence of contraindications, to patients with depressed LVF
these patients once heart failure symptoms have resolved.64 (EF less than 40%) is currently a quality care indicator, and
These patients may actually benet more than those without there are plans to make administration of an ACE inhibitor in
left ventricular dysfunction.65 In patients who cannot tolerate all patients without contraindications a quality care indicator.3
or have a contraindication to a -blocker, a calcium channel Besides hypotension, the most frequent adverse reaction to
blocker can be used to prevent anginal symptoms, but should an ACE inhibitor is cough, which may occur in up to 30% of
not be used routinely in the absence of such symptoms.2,3,62 patients. Patients with an ACE inhibitor cough and either clin-
Finally, all patients should be prescribed short-acting, sub- ical signs of heart failure or LVEF less than 40% may be pre-
lingual NTG or lingual NTG spray to relieve any anginal scribed an ARB.3 Other, less common but more serious adverse
symptoms when necessary and instructed on its use.2,3 effects to ACE inhibitors and ARBs include acute renal failure,
Chronic long-acting nitrate therapy has not been shown to hyperkalemia, and angioedema.
reduce CHD events following MI. Therefore, intravenous
NTG is not routinely followed by chronic, long-acting oral Aldosterone Antagonists
nitrate therapy in ACS patients who have undergone revascu- To reduce mortality, administration of an aldosterone antago-
larization, unless the patient has chronic stable angina or sig- nist, either eplerenone or spironolactone, should be considered
nicant coronary stenoses that were not revascularized.62 within the rst 2 weeks following MI in all patients who are
already receiving an ACE inhibitor (or ARB) and have an EF of
Angiotensin-Converting Enzyme Inhibitors and equal to or less than 40% and either heart failure symptoms or
Angiotensin Receptor Blockers diagnosis of diabetes mellitus.3 Aldosterone plays an important
Angiotensin-converting enzyme inhibitors should be initiated in role in heart failure and in MI because it promotes vascular and
all patients following MI to reduce mortality, decrease reinfarc- myocardial brosis, endothelial dysfunction, hypertension, left
tion, and prevent the development of heart failure.2,3 Dosing and ventricular hypertrophy, sodium retention, potassium and mag-
contraindications are described in Table 52. The benet of ACE nesium loss, and arrhythmias. Aldosterone antagonists have
inhibitors in patients with MI most likely comes from their been shown in experimental and human studies to attenuate
ability to prevent cardiac remodeling. The largest reduction in these adverse effects.70 Spironolactone decreases all-cause mor-
mortality is observed in patients with left ventricular dysfunc- tality in patients with stable, severe heart failure.71
tion (low LVEF) or heart failure symptoms. Early initiation Eplerenone, like spironolactone, is an aldosterone antagonist
(within 24 hours) of an oral ACE inhibitor appears to be crucial that blocks the mineralocorticoid receptor. In contrast to
during an acute MI, as 40% of the 30-day survival benet is spironolactone, eplerenone has no effect on the progesterone or
observed during the rst day, 45% from days 2 to 7, and approx- androgen receptor, thereby minimizing the risk of gynecomas-
imately 15% from days 8 to 30.66 However, current data do not tia, sexual dysfunction, and menstrual irregularities.70 In a recent
support the early administration of intravenous ACE inhibitors clinical trial,72 eplerenone signicantly reduced mortality, as well
in patients experiencing an MI, as mortality may be increased.67 as hospitalization for heart failure in post-MI patients with an
Administration of ACE inhibitors should be continued inde- EF less than 40% and symptoms of heart failure at any time
nitely. Hypotension should be avoided, as coronary artery lling during hospitalization. The risk of hyperkalemia, however, was
may be compromised. Additional trials suggest that most increased. Therefore, patients with a serum creatinine (SCr)
patients with CAD, not just ACS or heart failure patients, ben- greater than 2.5 mg/dL (221 mol/L) or creatinine clearance less
et from ACE inhibitors. Therefore, ACE inhibitors should be than 50 mL/minute or serum potassium concentration of greater
considered in all patients following an ACS in the absence of a than 5.0 mmol/L (5.0 mEq/L) should not receive eplerenone (in
contraindication. addition to either an ACE inhibitor or ARB). Currently, there are
Many patients cannot tolerate chronic ACE inhibitor no data to support that the more selective, more expensive
therapy secondary to adverse effects outlined below. eplerenone is superior to, or should be preferred to, the less
Alternatively, the angiotensin receptor blockers (ARBs), can- expensive generic spironolactone unless a patient has experi-
desartan and valsartan, have been documented in trials to enced gynecomastia, breast pain, or impotence while receiving
improve clinical outcomes in patients with heart failure.68,69 spironolactone. Finally, it should be noted that hyperkalemia is
Therefore, either an ACE inhibitor or candesartan or valsartan just as likely to appear with both of these agents.
are acceptable choices for chronic therapy for patients who
have a low ejection fraction (EF) and heart failure following Lipid-Lowering Agents
MI. Since more than ve different ACE inhibitors have There are now overwhelming data supporting the benets of
proven benets in MI while only two ARBs have been studied, statins in patients with CAD in prevention of total mortality,
the benets of ACE inhibitors are generally considered a cardiovascular mortality, and stroke. According to the National
TABLE 55. Therapeutic Drug Monitoring for Adverse Effects of Pharmacotherapy for Acute Coronary Syndromes
Drug Adverse Effects Monitoring

Aspirin Dyspepsia, bleeding, gastritis Clinical signs of bleeding,a gastrointestinal upset; baseline CBC
and platelet count; CBC platelet count every 6 months
Clopidogrel Bleeding, TTP (rare) Clinical signs of bleedinga; baseline CBC and platelet count;
CBC and platelet count every 6 months following hospital
discharge
Unfractionated heparin Bleeding, heparin-induced thrombocytopenia Clinical signs of bleedinga; baseline CBC and platelet count;
aPTT every 6 hours until target then every 24 hours; daily
CBC; platelet count every 2 days (minimum, preferably
every day)
Low-molecular- Bleeding, heparin-induced thrombocytopenia Clinical signs of bleedinga; baseline CBC and platelet count;
weight heparins daily CBC, platelet count every 2 days (minimum,
preferably every day); SCr daily
Fibrinolytics Bleeding, especially intracranial hemorrhage Clinical signs of bleedinga; baseline CBC and platelet count;
mental status every 2 hours for signs of intracranial
hemorrhage; daily CBC
Glycoprotein IIb/IIIa Bleeding, acute profound thrombocytopenia Clinical signs of bleedinga; baseline CBC and platelet count;
receptor blockers daily CBC; platelet count at 4 hours after initiation then
daily
Intravenous nitrates Hypotension, ushing, headache, tachycardia BP and HR every 2 hours
-Blockers Hypotension, bradycardia, heart block, BP, RR, HR, 12-lead ECG and clinical signs of heart failure
bronchospasm, heart failure, fatigue, every 5 minutes during bolus intravenous dosing; BP, RR, HR,
depression, sexual dysfunction, and clinical signs of heart failure every shift during oral
nightmares, masking hypoglycemia administration during hospitalization, then BP and HR
symptoms in diabetics every 6 months following hospital discharge
Diltiazem and Hypotension, bradycardia, heart block, BP and HR every shift during oral administration during
verapamil heart failure, gingival hyperplasia hospitalization then every 6 months following hospital
discharge; dental exam and teeth cleaning every 6 months
Amlodipine Hypotension, dependent peripheral edema, BP every shift during oral administration during hospitalization,
gingival hyperplasia then every 6 months following hospital discharge; dental
exam and teeth cleaning every 6 months
Angiotensin-converting Hypotension, cough (with ACE inhibitors), BP every 2 hours 3 for rst dose, then every shift during oral
enzyme inhibitors hyperkalemia, prerenal azotemia, administration during hospitalization, then once every
and angiotensin angioedema (ACE inhibitors more so 6 months following hospital discharge; baseline SCr and
receptor blockers than ARBs) potassium; daily SCr and potassium while hospitalized then
every 6 months (or 12 weeks after each outpatient dose
titration); closer monitoring required in selected patients
using spironolactone or eplerenone or if renal insufciency;
counsel patient on throat, tongue, and facial swelling
Aldosterone antagonists Hypotension, hyperkalemia, increased BP and HR every shift during oral administration during
serum creatinine hospitalization, then once every 6 months; baseline SCr
and serum potassium concentration; SCr and potassium at
48 hours, at 7 days, then monthly for 3 months, then every
3 months thereafter following hospital discharge
Warfarin Bleeding, skin necrosis Clinical signs of bleedinga; baseline CBC and platelet count;
CBC and platelet count every 6 months following hospital
discharge; baseline aPTT and INR; daily INR until two
consecutive INRs are within the target range then once
weekly 2 weeks, then every month
Morphine Hypotension, respiratory depression BP and RR 5 minutes after each bolus dose
a
Clinical signs of bleeding include bloody stools, melena, hematuria, hematemesis, bruising, and oozing from arterial or venous puncture sites.
ACE, angiotensin-converting enzyme; aPTT, activated partial thromboplastin time; ARB, angiotensin receptor blocker; BP, blood pressure; CBC,
complete blood count; ECG, electrocardiogram; HR, heart rate; INR, International Normalized Ratio; RR, respiratory rate; SCr, serum creatinine,
TTP, thrombotic thrombocytopenic purpura.
(Reprinted from Spinler SA, de Denus S. Acute Coronary Syndromes. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic
Approach. 6th ed. New York: McGraw-Hill; 2005: 314, with permission.)
Cholesterol Education Program (NCEP) Adult Treatment

Panel recommendations, all patients with CAD should receive Patient Care and Monitoring
dietary counseling and pharmacologic therapy in order to reach
a low-density lipoprotein (LDL) cholesterol of less than 100
mg/dL (2.59 mmol/L), with statins being the preferred agents to
For patients in acute distress and ACS is suspected:
lower LDL cholesterol.73 Results from landmark clinical trials
Follow recommendations in Fig. 51, Table 52, and
have unequivocally demonstrated the value of statins in sec- Fig. 53. Also incorporate into your plan the recommen-
ondary prevention following MI in patients with moderate to dations detailed below under For patients diagnosed
high cholesterol.73,74 Although the primary effect of statins is with ACS.
to decrease LDL cholesterol, statins are believed to produce
many nonlipid-lowering or pleiotropic effects such as anti- For patients diagnosed with ACS:
inammatory and antithrombotic properties. Newer recom- 1. Review patients medical record to determine indications
mendations from the NCEP give an optional LDL cholesterol for each medication.
goal of less than 70 mg/dL (1.81 mmol/L).75,76 In patients with an 2. Review patients medical record to determine contraindi-
ACS, statin therapy initiation should not be delayed and statins cations for each medication. For aspirin, -blockers, ACE
should be prescribed at or prior to discharge in most patients.77 inhibitors, and ARBs, document contraindications in
A brate derivative or niacin should be considered in select patients medical record.
patients with a low high-density lipoprotein (HDL) cholesterol 3. Review doses of medications for appropriateness. Aspirin
less than 40 mg/dL (1.04 mmol/L) and/or a high triglyceride dose should be less than 160 mg/day. Titration toward target
level greater than 200 mg/dL (2.26 mmol/L). In a large ran- doses of ACE inhibitors and -blockers should be in progress.
domized trial in men with established CAD and low levels of 4. Interview the patient to assess complementary or alterna-
HDL cholesterol, the use of gembrozil (600 mg twice daily) tive medication use. Counsel appropriately based on
signicantly decreased the risk of non-fatal myocardial infarc- indications and drug interactions.
tion or death from coronary causes.78 5. Evaluate the patients medical record and medication his-
tory, and conduct a patient interview to assess for the
Other Modiable Risk Factors presence of drug allergies, adverse drug reactions, and
Smoking cessation, managing hypertension, weight loss, and drug interactions.
tight glucose control for patients with diabetes mellitus, in addi- 6. Educate the patient on lifestyle modications, including
tion to treatment of dyslipidemia, are important treatments smoking cessation, diet, weight loss, and exercise. For
for secondary prevention of CHD events.3 Smoking cessation patients with diabetes mellitus, tight glucose control
should be emphasized.
counseling at the time of discharge following MI is a quality
care indicator.3 The use of nicotine patches or gum, or of 7. Provide patient education with regard to CAD, MI, indi-
bupropion alone or in combination with nicotine patches, cations for medications, and potential adverse effects and
drug interactions.
should be considered in appropriate patients.3 Hypertension
What is CAD?
should be strictly controlled according to published guidelines.79
How can the progression of CAD and MI be prevented?
Patients who are overweight should be educated on the impor- How does each medication benet the patient?
tance of regular exercise, healthy eating habits, and reaching Why is adherence important?
and maintaining an ideal weight.80 Finally, because diabetics What potential adverse effects may occur?
have up to a four-fold increased risk of mortality compared to What potential drug interactions may occur?
non-diabetics, the importance of tight glucose control, as well Warning signs to report to the physician or emergency
as other CHD risk factor modications, cannot be overstated.81 medical services include chest squeezing, burning, or
pain; jaw pain; pain radiation down the arm; bleeding;
and loss of consciousness.
OUTCOME EVALUATION Dial 911 if there is no chest discomfort relief after one
sublingual NTG tablet.
To determine the efcacy of nonpharmacologic and pharma- Important to train caregiver or relative to administer
cotherapy for both STE and NSTE ACS, monitor patients for: cardiopulmonary resuscitation (CPR).
(1) relief of ischemic discomfort; (2) return of ECG changes to 8. Document smoking cessation counseling and patient receipt
baseline; and (3) absence or resolution of heart failure signs. of discharge instructions in the patients medical record.
Monitoring parameters for recognition and prevention of
adverse effects from ACS pharmacotherapy are described in
Table 55. In general, the most common adverse reactions ABBREVIATIONS
from ACS therapies are hypotension and bleeding. To treat for
bleeding and hypotension, discontinue the offending agent(s) ACC: American College of Cardiology
until symptoms resolve. Severe bleeding resulting in hypoten- ACE: angiotensin-converting enzyme
sion secondary to hypovolemia may require blood transfusion. ACS: acute coronary syndromes
ADP: adenosine diphosphate TTP: thrombotic thrombocytopenic purpura

AHA: American Heart Association TXA2: thromboxane A2
AMI: acute myocardial infarction UA: unstable angina
aPTT: activated partial thromboplastin time UFH: unfractionated heparin
ARB: angiotensin receptor blocker
AV: atrioventricular Reference lists and self-assessment questions and answers are
bpm: beats per minute available at www.ChisholmPharmacotherapy.com.
CABG: coronary artery bypass graft (surgery)
CAD: coronary artery disease Log into the website: www.pharmacotherapyprinciples.com
CBC: complete blood count
CHD: coronary heart disease
CK: creatine kinase
this chapter.
CK-MB: creatine kinase myocardial band
CPR: cardiopulmonary resuscitation
CrCl: creatinine clearance KEY REFERENCES AND READINGS
CVD: cardiovascular disease
DM: diabetes mellitus American Heart Association. Heart disease and stroke statistics
ECG: electrocardiogram 2004 update. Dallas, TX: American Heart Association; 2005.
EF: ejection fraction Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines
HDL: high-density lipoprotein for the management of patients with ST-elevation myocardial
HR: heart rate infarctionexecutive summary: a report of the American
HTN: hypertension College of Cardiology/American Heart Association Task Force on
ICD: implantable cardioverter debrillator Practice Guidelines (Committee to revise the 1999 Guidelines for
ICH: intracranial hemorrhage the Management of Patients with Acute Myocardial Infarction).
INR: International Normalized Ratio Circulation 2004;110:588636.
IV: intravenous Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for
LAD: left anterior descending (artery) unstable angina/nonST-segment elevation MI: a method for
LDL: low-density lipoprotein prognostication and therapeutic decision-making. JAMA
LMWH: low-molecular-weight heparin 2000;284:835842.
LVEF: left ventricular ejection fraction Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guide-
LVF: left ventricular function line update for the management of patients with unstable
MB: myocardial band angina and nonST-segment elevation myocardial infarction
MI: myocardial infarction summary article: a report of the American College of Cardiology/
NCEP: National Cholesterol Education Program American Heart Association task force on practice guidelines
NSTE: nonST-segment elevation (Committee on the Management of Patients with Unstable
NTG: nitroglycerin Angina). J Am Coll Cardiol 2002;40:13661374.
PCI: percutaneous coronary intervention Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guide-
RCA: right coronary artery line update for the management of patients with chronic stable
rPA: reteplase anginasummary article: a report of the American College
RR: respiratory rate of Cardiology/American Heart Association Task Force on prac-
rt-PA: alteplase tice guidelines (Committee on the Management of Patients
SC: subcutaneous with Chronic Stable Angina). J Am Coll Cardiol 2003;41:
SCr: serum creatinine 159168.
SL: sublingual Popma JJ, Berger P, Ohman EM, et al. Antithrombotic therapy dur-
STE: ST-segment elevation ing percutaneous coronary intervention. The Seventh ACCP
TIMI: Thrombolysis in myocardial infarction Conference on Antithrombotic and Thrombolytic Therapy.
TNK-tPA: tenecteplase Chest 2004; 126(Suppl):576S599S.
6 ARRHYTHMIAS
James E. Tisdale
LEARNING OBJECTIVES
1. Describe the phases of the cardiac action potential, compare and contrast the cellular
ionic changes corresponding to each phase, and explain the relationship between the
cardiac action potential and the electrocardiogram (ECG).
2. Describe the modied Vaughan-Williams classication of antiarrhythmic drugs, and
compare and contrast the effects of available antiarrhythmic drugs on ventricular
conduction velocity, refractory period, automaticity, and inhibition of specic myocardial
ion channels.
3. Compare and contrast the risk factors for and the features, mechanisms, etiologies,
symptoms, and goals of therapy of: (1) sinus bradycardia; (2) atrioventricular (AV) nodal
blockade; (3) atrial brillation (AF); (4) paroxysmal supraventricular tachycardia (PSVT);
(5) ventricular premature depolarizations (VPDs); (6) ventricular tachycardia (VT, including
torsades de pointes); and (7) ventricular brillation (VF).
4. Compare and contrast appropriate nonpharmacologic and pharmacologic treatment
options for sinus bradycardia and AV nodal blockade.
5. Compare and contrast the mechanisms of action of drugs used for ventricular rate control,
conversion to sinus rhythm and maintenance of sinus rhythm in patients with AF, and
explain the importance of anticoagulation for patients with AF.
6. Compare and contrast the mechanisms of action of drugs used for acute termination of PSVT.
7. Compare and contrast the role of drug therapy versus nonpharmacologic therapy for long-
term prevention of recurrence of PSVT.
8. Describe the role of drug therapy for management of asymptomatic and symptomatic VPDs.
9. Compare and contrast the mechanisms of action of drugs used for the treatment of acute
episodes of VT (including torsades de pointes), and describe options and indications for
nonpharmacologic treatment of VT and VF.
10. Design individualized drug therapy treatment plans for patients with: (1) sinus bradycardia;
(2) AV nodal blockade; (3) AF; (4) PSVT; (5) VPDs; (6) VT (including torsades de pointes);
and (7) VF.
KEY CONCEPTS Numerous drugs (-blockers, diltiazem, verapamil, digoxin,

and amiodarone) can cause bradyarrhythmias (sinus brady-
Cardiac arrhythmias may be caused by abnormal impulse for- cardia and AV nodal blockade).
mation (automaticity), abnormal impulse conduction (reentry), The goals of treatment of AF are: (1) ventricular rate control
or both. with drugs that inhibit AV nodal conduction; (2) restoration
107
of sinus rhythm with direct current cardioversion or antiar- Bachmanns bundle

rhythmic drugs (commonly referred to as cardioversion or
conversion to sinus rhythm); (3) maintenance of sinus Sinus node
rhythm/reduction in the frequency of episodes using anti-
Internodal
arrhythmic drugs; and (4) prevention of stroke. pathways Left bundle
Antiarrhythmic drug therapy for maintenance of sinus branch
AV node
rhythm/reduction in frequency of episodes of AF should be Posterior
initiated only in patients in whom symptoms persist despite Bundle division
maximal doses of drugs for ventricular rate control. of His Anterior
The majority of patients with AF should receive warfarin ther- division
Purkinje
apy (titrated to an International Normalized Ratio of 2 to 3) fibers
for stroke prevention, particularly if they have other risk fac- Right bundle
branch
tors for stroke.
Adenosine is the drug of choice for termination of paroxysmal
supraventricular tachycardia.
Asymptomatic ventricular premature depolarizations should FIGURE 61. The cardiac conduction system. AV, atrioventri-
not be treated with antiarrhythmic drug therapy. cular. (Reprinted with permission from Cummins RO, (ed.)
Implantable cardioverter-debrillators are more effective than ACLS Provider Manual. Dallas: American Heart Association;
2003:253.)
antiarrhythmic drugs for reduction in the risk of sudden car-
diac death due to VT or VF.
The purpose of drug therapy for VF is facilitation of electrical followed by ventricular contraction. Malfunction of the
debrillation; in the absence of electrical debrillation, drug hearts electrical conduction system may result in dysfunc-
therapy alone will not terminate VF. tional atrial and/or ventricular contraction.
Drugs with the potential to cause QT interval prolongation
and torsades de pointes should be avoided or used with The Cardiac Conduction System
extreme caution in patients with other risk factors for torsades
Under normal circumstances, the sinoatrial (SA) node (also
de pointes.
known as the sinus node), located in the upper portion of the
right atrium, serves as the pacemaker of the heart and generates
the electrical impulses that subsequently result in atrial and
NORMAL AND ABNORMAL CARDIAC ventricular depolarization (Fig. 61).1 The SA node serves as
CONDUCTION AND ELECTROPHYSIOLOGY the hearts pacemaker because it has the greatest degree of auto-
maticity, which is dened as the ability of a cardiac ber or tis-
The heart functions via both mechanical and electrical activity. sue to initiate depolarizations spontaneously. In adults at rest,
The mechanical activity of the heart refers to atrial and ventric- the normal intrinsic depolarization rate of the SA node is 60 to
ular contraction, the mechanism by which blood is delivered to 100 per minute. Other cardiac bers also possess the property of
tissues. When deoxygenated blood returns to the heart via the automaticity, but normally the intrinsic depolarization rates are
venous circulation, the blood enters the right atrium. Right slower than that of the SA node. For example, the normal intrin-
atrial contraction and changes in right ventricular pressure sic depolarization rate of the atrioventricular (AV) node is 40 to
result in delivery of blood to the right ventricle through the tri- 60 per minute, while that of the ventricular tissue is 30 to 40 per
cuspid valve. Right ventricular contraction pumps blood minute. Therefore, because of greater automaticity, the SA node
through the pulmonic valve through the pulmonary arteries to normally serves as the pacemaker of the heart. However, if the
the lungs, where the blood becomes oxygenated. The blood then SA node fails to generate depolarizations at a rate faster than that
ows through the pulmonary veins into the left atrium. Left of the AV node, the AV node may take over as the pacemaker.
atrial contraction and changes in left ventricular (LV) pressure Similarly, if the SA node and AV node fail to generate depo-
result in delivery of blood through the mitral valve into the left larizations at a rate greater than 30 to 40 per minute, ventri-
ventricle. Contraction of the left ventricle results in pumping of cular tissue may take over as the pacemaker.
blood through the aortic valve and to the tissues of the body. Following initiation of the electrical impulse from the SA
The mechanical activity of the heart (contraction of the node, the impulse travels through the internodal pathways of the
atria and ventricles) occurs as a result of the electrical activity specialized atrial conduction system and Bachmanns bundle
of the heart. The heart possesses an intrinsic electrical conduc- (Fig. 61).1 The atrial conducting bers do not traverse the
tion system (Fig. 61).1 Normal myocardial contraction cannot entire breadth of the left and right atria, as impulse conduction
occur without proper and normal function of the hearts elec- occurs across the internodal pathways, and when the impulse
trical conduction system. Electrical depolarization of the atria reaches the end of Bachmanns bundle, atrial depolarization
results in atrial contraction, and ventricular depolarization is spreads as a wave similar to that which occurs upon throwing a
CHAPTER 6 / ARRHYTHMIAS 109
pebble into water. As the impulse is conducted across the atria, creates a vertical upstroke of the action potential, such that the
each depolarized cell excites and depolarizes the surrounding potential reaches 20 to 30 mV. This is phase 0, which represents
connected cells, until both atria have been completely depolar- ventricular depolarization. At this point, the fast sodium chan-
ized. Atrial contraction follows normal atrial depolarization. nels become inactivated, and ventricular repolarization begins.
Following atrial depolarization, impulses are conducted The remaining phases of the action potential, 1 through 4, rep-
through the AV node, located in the lower right atrium resent ventricular repolarization. Phase 1 repolarization occurs
(Fig. 61).1 The impulse then enters the bundle of His, and is primarily as a result of an efux of potassium ions (Fig. 62).2
conducted through the ventricular conduction system, con- During phase 2 repolarization, potassium ions continue to exit
sisting of the left and right bundle branches. The left ventricle the cell, but the membrane potential is balanced by an inux of
requires a larger conduction system than the right ventricle calcium and sodium ions, transported through slow calcium
due to its larger mass; therefore, the left bundle branch bifur- and slow sodium channels, resulting in a plateau. During phase
cates into the left anterior and posterior divisions (also com- 3, the efux of potassium ions greatly exceeds calcium and
monly known as fascicles). The bundle branches further sodium inux, resulting in the major component of ventricular
divide into the Purkinje bers, through which impulse con- repolarization. During phase 4, sodium ions are actively
duction results in ventricular depolarization, after which ven- pumped out of the myocyte via the sodium-potassium ATPase
tricular contraction occurs. pump, resulting in restoration of membrane potential to its rest-
ing value. An understanding of the ionic uxes that are respon-
sible for each phase of the action potential facilitates under-
The Ventricular Action Potential
standing of the effects of specic drugs on the action potential.
The ventricular action potential is depicted in Fig. 62.2 For example, drugs that primarily inhibit ion ux through
Myocyte resting membrane potential is usually 70 to 90 mV, sodium channels inuence phase 0 (ventricular depolarization),
due to the action of the sodium-potassium adenosine triphos- while drugs that primarily inhibit ion ux through potassium
phatase (ATPase) pump, which maintains relatively high extra- channels inuence the repolarization phases, particularly
cellular sodium concentrations and relatively low extracellular phase 3.
potassium concentrations. During each action potential cycle,
the potential of the membrane increases to a threshold potential,
The Electrocardiogram
usually 60 to 80 mV. When the membrane potential reaches
this threshold, the fast sodium channels open, allowing sodium The electrocardiogram (ECG) is a non-invasive means of
ions to rapidly enter the cell. This rapid inux of positive ions measuring the electrical activity of the heart. The relationship
FIGURE 62. The ventricular

action potential depicting the
R
ow of specic ions responsi-
1mV T ble for each phase. The
P specic phases of the action
Q ECG potential that correspond to
Overshoot S the absolute and relative
+30 refractory periods are por-
Phase 1: Transient efflux of K+
trayed, and the relationship
Myocardial between phases of the action
cell Phase 2: Influx of Ca2+ and Na+
+ 0 potential and the ECG are
Na 140 10 mM
K
+
4 Phase 3: Efflux of K+ greater than shown. Ca, calcium; ECG,
2+ 135" Phase 0: Fast Na+ - influx of Ca2+ and Na+ electrocardiogram; K, potas-
Ca 2 10 mM influx sium; Na, sodium. (Reprinted
with permission from
Tension
Pauler P-E. Textbook in
Extracellular fluid mV
Medical Physiology and
70 Threshold Pathophysiology, Essentials
and Clinical Problems.
(Internal - external Phase 4: Na+ - K+ - pump
potential) = 90 Contraction Copenhagen: Copenhagen
Medical Publishers; 2000.2)
0 Relative 300 ms Accessed at http://www.m.
Absolute refractory period refractory
Fast Na+-channels are closed period ku.dk/ppauler/chapter11/
chapter%2011.htm.
Steep phase 0 means rapid depolarization KMc
between the ventricular action potential and the ECG is (premature) electrical stimulus is initiated during the relative
depicted in Fig. 62.2 The P wave on the ECG represents atrial refractory period, it can be conducted abnormally, potentially
depolarization (atrial depolarization is not depicted in the in an arrhythmia.
action potential shown in Fig. 62, which shows only the ventri-
cular action potential, but not the atrial action potential).
Phase 0 of the action potential corresponds to the QRS complex; Mechanisms of Cardiac Arrhythmias
therefore, the QRS complex on the ECG is a non-invasive rep- In general, cardiac arrhythmias are caused by (1) abnormal
resentation of ventricular depolarization. The T wave on the impulse formation; (2) abnormal impulse conduction; or (3) both.
ECG corresponds to phase 3 repolarization of the ventricles.
The interval from the beginning of the Q wave to the end of Abnormal Impulse Initiation
the T wave, known as the QT interval, is used as a non-invasive Abnormal initiation of electrical impulses occurs as a result of
marker of ventricular repolarization time. Atrial repolarization abnormal automaticity. If the automaticity of the SA node
is not displayed on the ECG, because it occurs during ventri- increases, this results in an increased rate of generation of
cular depolarization and is obscured by the QRS complex. impulses and a rapid heart rate (sinus tachycardia). If other
Several intervals and durations are routinely measured on cardiac bers become abnormally automatic, such that the
the ECG. The PR interval represents the time of conduction of rate of initiation of spontaneous impulses exceeds that of the
impulses from the atria to the ventricles through the AV node; SA node, other types of tachyarrhythmias may occur. Many
the normal PR interval in adults is 0.12 to 0.2 seconds. The cardiac bers possess the capability for automaticity, includ-
QRS duration represents the time required for ventricular ing the atrial tissue, the AV node, the Purkinje bers, and the
depolarization, which is normally 0.08 to 0.12 seconds in ventricular tissue. In addition, bers with the capability of
adults. The QT interval represents the time required for ven- initiating and conducting electrical impulses are present in
tricular repolarization. The QT interval varies with heart the pulmonary veins. Abnormal atrial automaticity may result
ratethe faster the heart rate, the shorter the QT interval, and in premature atrial contractions or may precipitate atrial
vice versa. Therefore, the QT interval is corrected for heart tachycardia or atrial brillation (AF); abnormal AV nodal
rate using Bazetts equation3, which is: automaticity may result in junctional tachycardia (the AV
node is also sometimes referred to as the AV junction).
QT Abnormal automaticity in the ventricles may result in ventric-
QTC =
RR ular premature depolarizations (VPDs) or may precipitate
ventricular tachycardia (VT) or ventricular brillation (VF).
where QTc is the QT interval corrected for rate, and RR is the In addition, abnormal automaticity originating from the pul-
interval from the onset of one QRS complex to the onset of monary veins is a precipitant of AF.
the next QRS complex, measured in seconds. The normal QTc Automaticity of cardiac bers is controlled in part by activ-
interval in adults is 0.36 to 0.44 seconds. ity of the sympathetic and parasympathetic nervous systems.
Enhanced activity of the sympathetic nervous system may
result in increased automaticity of the SA node or other auto-
Refractory Periods matic cardiac bers. Enhanced activity of the parasympathetic
After an electrical impulse is initiated and conducted, there is nervous system tends to suppress automaticity; conversely,
a period of time during which cells and bers cannot be depo- inhibition of activity of the parasympathetic nervous system
larized again. This period of time is referred to as the absolute increases automaticity. Other factors may lead to abnormal
refractory period (Fig. 62),2 and corresponds to phases 1, 2, increases in automaticity of extra-SA nodal tissues, including
and approximately half of phase 3 repolarization on the action hypoxia, atrial or ventricular stretch [as might occur following
potential. The absolute refractory period also corresponds long-standing hypertension or after the development of heart
to the period from the Q wave to approximately the rst failure (HF)], and electrolyte abnormalities such as hypokalemia
half of the T wave on the ECG (Fig. 62). During this period, or hypomagnesemia.
if there is a premature stimulus for an electrical impulse, this
impulse cannot be conducted, because the tissue is absolutely Abnormal Impulse Conduction
refractory. The mechanism of abnormal impulse conduction is tradi-
However, there is a period of time following the absolute tionally referred to as reentry. Reentry is often initiated as
refractory period during which a premature electrical stimu- a result of an abnormal premature electrical impulse (abnormal
lus can be conducted, and is often conducted abnormally. automaticity); therefore, in these situations, the mechanism of
This period of time is called the relative refractory period the arrhythmia is both abnormal impulse formation (auto-
(Fig. 62).2 The relative refractory period corresponds roughly maticity) and abnormal impulse conduction (reentry). In order for
to the latter half of phase 3 repolarization on the action poten- reentry to occur, three conditions must be present. There must be
tial and to the latter half of the T wave on the ECG. If a new (1) at least two pathways down which an electrical impulse may
travel (which is the case in the majority of cardiac bers); (2) a the electrical impulse reenters a previously stimulated path-
unidirectional block in one of the conduction pathways (this way in the wrong direction. This results in circular movement
unidirectional block is sometimes a result of prolonged refrac- of electrical impulses; as the impulse travels in this circular
toriness in this pathway); and (3) slowing of the velocity of fashion, it excites each cell around it, and if the impulse is
impulse conduction down the other conduction pathway. traveling at a rate faster than the intrinsic rate of the SA node,
The process of reentry is depicted in Fig. 63.4 Under nor- a tachycardia occurs in the tissue in question. Reentry may
mal circumstances, when a premature impulse is initiated, it occur in numerous tissues, including the atria, the AV node,
cannot be conducted in either direction down either pathway and the ventricles.
because the tissue is in its absolute refractory period from the Prolonged refractoriness and/or slowed impulse conduc-
previous beat. A premature impulse may be conducted down tion velocity may be present in cardiac tissues for a variety of
both pathways if it is only slightly premature and arrives after reasons. Myocardial ischemia may alter ventricular refractory
the tissue is no longer refractory. However, when refractori- periods or impulse conduction velocity, facilitating ventricu-
ness is prolonged down one of the pathways, a precisely timed lar reentry. In patients with past myocardial infarction, the
premature beat may be conducted down one pathway, but infarcted myocardium is dead and cannot conduct impulses.
cannot be conducted in either direction in the pathway with However, there is typically a border zone of tissue which is
prolonged refractoriness because the tissue is still in its damaged, and in which refractory periods and conduction
absolute refractory period (Fig. 63, panel 1a).4 When the velocity are often deranged, facilitating ventricular reentry. In
third condition for reentry is present, that is, when the veloc- patients with left atrial or LV hypertrophy as a result of long-
ity of impulse conduction in the other pathway is slowed, the standing hypertension, refractory periods and conduction
impulse traveling forward down the other pathway still can- velocity are often perturbed. In patients with HF due to LV
not be conducted. However, because the impulse in the other dysfunction, ventricular refractoriness and conduction veloc-
pathway is traveling so slowly, by the time it circles around ity are often altered due to LV hypertrophy, collagen deposi-
and travels upward down the other pathway, that pathway is tion, and other anatomic and structural changes.
no longer in its absolute refractory period, and now the
impulse may travel upward in that pathway. In other words,
Vaughan-Williams Classication
of Anti-arrhythmic Drugs
1a 1b
The Vaughan-Williams classication of antiarrhythmic drugs,
rst described in 19705 and subsequently further expanded,6,7
is presented in Table 61. This classication is based on the
effects of specic drugs on ventricular conduction velocity,
repolarization/refractoriness and automaticity. Class I drugs,
which are the sodium channel blocking agents, primarily
2a 2b
inhibit ventricular automaticity and slow conduction velocity.
However, due to differences in the potency of the drugs to slow
conduction velocity, the class I drugs are subdivided into class
IA, IB, and IC. The class IC drugs have the greatest potency for
slowing ventricular conduction, the class IA drugs have inter-
FIGURE 63. The process of initiation of reentry. (1a) Two path-
ways for impulse conduction, with bidirectional block in one
mediate potency, and the class IB drugs have the lowest
pathway (shaded area), resulting in a non-viable reentrant loop. potency, with minimal effects on conduction velocity. Class II
(1b) Two pathways for impulse conduction; slowing of conduc- drugs are the adrenergic -receptor inhibitors (-blockers),
tion down one pathway, with no change in refractory period class III drugs are those that inhibit ventricular repolarization
down the other pathway, resulting in unidirectional block. The or prolong refractoriness, and class IV drugs are the calcium
retrograde impulse may reenter the area of unidirectional block, channel blockers (CCBs), diltiazem and verapamil.
potentially resulting in a tachyarrhythmia. (2a) Two pathways for The Vaughan-Williams classication of antiarrhythmic
impulse conduction; lack of unidirectional block, therefore the
potential reentrant pathway is non-viable. (2b) Two pathways for
drugs has been criticized for a number of reasons. The classica-
impulse conduction; refractory period is prolonged down one tion is based on the effects of drugs on normal, rather than dis-
pathway, with no change in conduction down the other pathway, eased, myocardium. In addition, many of the drugs may be
resulting in unidirectional block. The retrograde impulse may placed into more than one class. For example, the class IA drugs
reenter the area of unidirectional block, potentially resulting in a prolong repolarization/refractoriness, either via the parent
tachyarrhythmia. (Reprinted with permission from Bauman JL, drug8,9 or an active metabolite,10 and therefore also may be placed
Dekker Schoen M. Arrhythmias. In: DiPiro JT, Talbert RL, Yee GC, in class III. Sotalol is also a -blocker, and therefore ts into
et al. (eds.) Pharmacotherapy. A Physiologic Approach, 6th ed.
New York: McGraw-Hill; 2005:324.4)
class II. Amiodarone inhibits sodium and potassium channels, is
a non-competitive inhibitor of -receptors, and inhibits calcium
TABLE 61. Vaughan-Williams Classication of Anti-arrhythmic specic arrhythmias are generally composed of two words; the
Agents rst word indicates the location of the electrophysiologic abnor-
mality resulting in the arrhythmia (sinus, AV node, atrial, or
Conduction Repolarization/
Class Drug Velocity Refractoriness Automaticity
ventricular), and the second word describes the arrhythmia in
terms of whether it is abnormally slow (bradycardia) or fast
IA Quinidine
(tachycardia), or the type of arrhythmia (block, brillation, or
Procainamide
Disopyramide utter).
IB Lidocaine 0/ /0
Mexiletine
Tocainide SUPRAVENTRICULAR ARRHYTHMIAS
IC Flecainide 0
Moricizine Sinus Bradycardia
Propafenone
II -blockers:a 0 0 0
Sinus bradycardia is an arrhythmia that originates in the SA
Acebutolol node, dened by a sinus rate less than 60 beats per minute
Atenolol (bpm).12
Betaxolol
Bisoprolol Epidemiology and Etiology
Carteolol
Carvedilolb
Many individuals, particularly those who partake in regular
Esmolol vigorous exercise, have heart rates less than 60 bpm. For those
Labetalolb individuals, sinus bradycardia is normal and healthy, and does
Metoprolol not require evaluation or treatment. However, some indi-
Nadolol viduals develop symptomatic sinus node dysfunction. In the
Penbutolol
Pindolol
absence of correctable underlying causes, idiopathic sinus
Propranolol node dysfunction is referred to as sick sinus syndrome,12 and
Timolol occurs with greater frequency with advancing age. The prev-
III Amiodaronec 0 0 alence of sick sinus syndrome is approximately 1 in 600 indi-
Dofetilide viduals over the age of 65 years.12
Ibutilide Sick sinus syndrome leading to sinus bradycardia may be
Sotalol
caused by degenerative changes in the sinus node that occur
IV Calcium 0 0 0 with advancing age. However, there are other possible etiolo-
channel
blockers:a
gies of sinus bradycardia, including drugs (Table 62).13
Diltiazem
Verapamil
, increase/prolong; , decrease; 0, no effect; 0/, does not change or TABLE 62. Etiologies of Sinus Bradycardia12,13
may decrease: /0, decreases or does not change.
Idiopathic (sick sinus syndrome)
Adenosine and digoxin are agents used for the management of arrhythmias
that do not t into the Vaughan Williams classication. Myocardial ischemia
a
Slows conduction, prolongs refractory period, and reduces automaticity Carotid-sinus hypersensitivity
in SA node and AV node tissue, but not in the ventricles. Neurocardiac syncope
b
Combined and -blocker. Electrolyte abnormalities: hypokalemia or hyperkalemia
c
Amiodarone slows conduction velocity and inhibits automaticity.
Hypothyroidism
Hypothermia
channels, and therefore may be placed into any of the four classes. Amyloidosis
For this reason, drugs within each class cannot be considered Sarcoidosis
interchangeable. Nonetheless, despite attempts to develop Systemic lupus erythematosus
mechanism-based classications that better distinguish the Scleroderma
Sleep apnea
actions of antiarrhythmic drugs,11 the Vaughan-Williams classi- Drugs:
cation continues to be widely used because of its simplicity and Amiodarone Flecainide
the fact that it is relatively easy to remember and understand. -Blockers Fluoxetine
Cisplatin Isradipine
Citalopram Nitroglycerin
CARDIAC ARRHYTHMIAS Clonidine Propafenone
Cocaine Sotalol
In general, cardiac arrhythmias are classied into two broad cat- Digoxin Thalidomide
egories: supraventricular (those occurring above the ventricles) Diltiazem Verapamil
Donepezil
and ventricular (those occurring in the ventricles). The names of
-blockers outweigh the risks associated with sinus bradycar-

Clinical Presentation and Diagnosis: dia. In these patients, a permanent pacemaker may be
Sinus Bradycardia implanted in order to allow the patient to maintain therapy
with -blockers.
Acute treatment of the symptomatic patient consists pri-
Symptoms
Many patients are asymptomatic, particularly those with marily of administration of the anticholinergic drug atropine,
normal resting heart rates less than 60 bpm as a result of which may be given in doses of 0.5 mg intravenously (IV)
physical tness due to regular vigorous exercise. every 3 to 5 minutes. The maximum recommended total dose
Susceptible patients may develop symptoms, depending of atropine is 3 mg;14 however, this total dose should not be
on the degree of heart rate lowering. administered to patients with sinus bradycardia, but rather
Symptoms of bradyarrhythmias include dizziness, fatigue, should be reserved for patients with cardiac arrest due to asys-
lightheadedness, syncope, chest pain (in patients with tole, as complete vagal inhibition at this dose can increase
underlying myocardial ischemia), and shortness of breath myocardial oxygen demand and precipitate ischemia or tachy-
and other symptoms of heart failure (in patients with arrhythmias in patients with underlying coronary artery disease
underlying left ventricular dysfunction).
(CAD). Therefore, for management of sinus bradycardia, the
Diagnosis maximum atropine dose should be approximately 2 mg. In
Cannot be made on the basis of symptoms alone, as the patients with hemodynamically unstable or severely sympto-
symptoms of all bradyarrhythmias are similar. matic sinus bradycardia that is unresponsive to atropine and in
History of present illness, presenting symptoms, and whom temporary or transvenous pacing is not available or is
12-lead ECG that reveals sinus bradycardia.
ineffective, epinephrine (2 to 10 mcg/minute, titrate to response)
Assess possible correctable etiologies, including myocar-
and/or dopamine (2 to 10 mcg/kg/minute) may be adminis-
dial ischemia, serum potassium concentration (for hyper-
kalemia), and thyroid function tests (for hypothyroidism). tered.14 Both drugs stimulate adrenergic - and -receptors.
Determine whether the patient is taking any drugs known In patients with sinus bradycardia due to underlying cor-
to cause sinus bradycardia. If the patient is currently tak- rectable disorders (such as electrolyte abnormalities or
ing digoxin, determine the serum digoxin concentration hypothyroidism), management consists of correcting those
and ascertain whether it is supratherapeutic (greater than disorders.
2 ng/mL [2.56 nmol/L]).
Nonpharmacologic Therapy
Pathophysiology Long-term management of patients with sick sinus syndrome
Sick sinus syndrome leading to sinus bradycardia occurs as a requires implantation of a permanent pacemaker.12
result of brotic tissue in the SA node, which replaces normal
SA node tissue.12
Outcome Evaluation
Monitor the patient for heart rate and alleviation of symptoms.
Treatment
Monitor for adverse effects of medications, such as atropine
(dry mouth, mydriasis, urinary retention, and tachycardia).
Desired Outcomes
The desired outcomes for treatment are to restore normal
heart rate and alleviate patient symptoms.
AV Nodal Blockade
Pharmacologic Therapy AV nodal blockade occurs when conduction of electrical
Treatment of sinus bradycardia is only necessary in patients impulses through the AV node is impaired to varying degrees.
who become symptomatic. If the patient is taking any med- AV nodal blockade is classied into three categories. First-
ication(s) that may cause sinus bradycardia, the drug(s) should degree AV block is dened simply as prolongation of the PR
be discontinued whenever possible. If the patient remains in interval to greater than 0.2 seconds. During rst-degree AV
sinus bradycardia after discontinuation of the drug(s) and block, all impulses initiated by the SA node that have resulted
after ve half-lives of the drug(s) have elapsed, then the in atrial depolarization are conducted through the AV node; the
drugs(s) can usually be excluded as the etiology of the abnormality is simply that the impulses are conducted more
arrhythmia. In certain circumstances, however, discontinua- slowly than normal through the AV node, resulting in prolon-
tion of the medication(s) may be undesirable, even if it may gation of the PR interval.15 Second-degree AV block is further
be the cause of symptomatic sinus bradycardia. For example, distinguished into two types: Mobitz type I (also known as
if the patient has a history of myocardial infarction or HF, dis- Wenckebach) and Mobitz type II. In both types of second-
continuation of a -blocker is undesirable, because -blockers degree AV block, some of the impulses initiated by the SA node
have been shown to reduce mortality and prolong life in are not conducted through the AV node. This often occurs in
patients with those diseases, and the benets of therapy with a regular pattern; for example, every third or fourth impulse
generated by the SA node may not be conducted. During

third-degree AV block, which is also referred to as complete Clinical Presentation and Diagnosis:
heart block, none of the impulses generated by the SA node AV Nodal Blockade
are conducted through the AV node. This results in AV disso-
ciation, during which the atria continue to depolarize nor-
Symptoms
mally as a result of normal impulses initiated by the SA node; First-degree AV nodal blockade is rarely symptomatic,
however, the ventricles initiate their own depolarizations, because it rarely results in bradycardia.
because no SA nodegenerated impulses are conducted to the Second-degree AV nodal blockade may cause bradycar-
ventricles. Therefore, on the ECG, there is no relationship dia, as not all impulses generated by the SA node are
between the P waves and the QRS complexes. conducted through the AV node to the ventricles.
In third-degree AV nodal blockade, or complete heart
Epidemiology and Etiology block, the heart rate is usually 30 to 40 bpm, resulting in
The incidence of AV nodal blockade is unknown. AV nodal symptoms.
blockade may be caused by degenerative changes in the AV Symptoms of bradyarrhythmias such as second- or
third-degree AV block consist of dizziness, fatigue,
node. In addition, there are many other possible etiologies of
lightheadedness, syncope, chest pain (in patients with
AV nodal blockade, including drugs (Table 63).13
underlying myocardial ischemia), and shortness of
breath and other symptoms of heart failure (in patients
Pathophysiology with underlying left ventricular dysfunction).
First-degree AV nodal blockade occurs due to inhibition of con-
Diagnosis
duction within the upper portion of the node.15 Mobitz type I
Made on the basis of patient presentation, including his-
second-degree AV nodal blockade occurs as a result of inhibition
tory of present illness and presenting symptoms, as well
of conduction further down within the node.12,15 Mobitz type II as a 12-lead ECG that reveals AV nodal blockade.
second-degree AV nodal blockade is caused by inhibition of Assess potentially correctable etiologies, including
conduction within or below the level of the bundle of His.12,15 myocardial ischemia, serum potassium concentration (for
Third-degree AV nodal blockade may be a result of inhibition of hyperkalemia), and thyroid function tests (for hypothy-
conduction either within the AV node or within the bundle of roidism)
His or the His-Purkinje system.12,15 AV block may occur as a Determine whether the patient is taking any drugs known
result of age-related AV node degeneration. to cause AV block.
If the patient is currently taking digoxin, determine the
serum digoxin concentration and ascertain whether it is
supratherapeutic (greater than 2 ng/mL [2.56 nmol/L]).
TABLE 63. Etiologies of Atrioventricular Nodal

Blockade12,13,15 Treatment
Idiopathic degeneration of the atrioventricular node Desired Outcomes

Myocardial ischemia or infarction The desired outcomes for treatment are to restore normal
Neurocardiac syncope sinus rhythm and alleviate patient symptoms.
Carotid-sinus hypersensitivity
Electrolyte abnormalities: hypokalemia or hyperkalemia
Hypothyroidism Pharmacologic Therapy
Hypothermia Treatment of rst-degree AV nodal blockade is rarely neces-
Infectious diseases: Chagas disease or endocarditis sary, because symptoms rarely occur. However, the ECGs of
Amyloidosis patients with rst-degree AV nodal blockade should be mon-
Sarcoidosis
Systemic lupus erythematosus itored to assess the possibility of progression of rst-degree
Scleroderma AV nodal blockade to second- or third-degree block. Second-
Sleep apnea or third-degree AV nodal blockade requires treatment,
Drugs: because bradycardia usually results in symptoms. If the
Adenosine Hydroxychloroquine patient is taking any medication(s) that may cause AV nodal
-Blockers Phenylpropanolamine
Amiodarone Propafenone blockade, the drug(s) should be discontinued whenever possi-
Carbamazepine Propofol ble. If the patients rhythm still exhibits AV nodal blockade
Chloroquine Sotalol after discontinuing the medication(s) and after ve half-lives
Digoxin Thioridazine of the drug(s) have elapsed, then the drug(s) can usually be
Diltiazem Tricyclic antidepressants excluded as the etiology of the arrhythmia. However, in cer-
Gatioxacin Verapamil
tain circumstances, discontinuation of a medication that is
inducing AV nodal blockade may be undesirable. For example, TABLE 64. Etiologies of Atrial Fibrillation
if the patient has a history of myocardial infarction or HF, dis-
Hypertension
continuation of a -blocker is undesirable because -blockers
Coronary artery disease
have been shown to reduce mortality and prolong life in Heart failure
patients with those diseases, and the benets of therapy with Diabetes
-blockers outweighs the risks associated with AV nodal Hyperthyroidism
blockade. In these patients, a permanent pacemaker may be Rheumatic heart disease
Diseases of the heart valves:
implanted in order to allow the patient to maintain therapy
Mitral stenosis or regurgitation
with -blockers. Mitral valve prolapse
Acute treatment of patients with second- or third-degree Chronic obstructive pulmonary disease
AV nodal blockade consists primarily of administration of Pulmonary embolism
atropine, which may be administered in the same doses as rec- Idiopathic (lone atrial brillation)
Thoracic surgery:
ommended for management of sinus bradycardia. In patients
Coronary artery bypass graft surgery
with hemodynamically unstable or severely symptomatic AV Pulmonary resection
nodal blockade that is unresponsive to atropine and in whom Thoracoabdominal esophagectomy
temporary or transvenous pacing is not available or is ineffective, Drugs:13
epinephrine (2 to 10 mcg/minute, titrate to response) and/or Adenosine Milrinone
Albuterol Theophylline
dopamine (2 to 10 mcg/kg/minute) may be administered.14
Alcohol
In patients with second- or third-degree AV block due to Ipratropium bromide
underlying correctable disorders (such as electrolyte abnor-
malities or hypothyroidism), management consists of correcting
those disorders.
risk factor for development of AF. However, AF occurs com-
Nonpharmacologic Therapy monly in patients with CAD. In addition, HF is increasingly
Long-term management of patients with AV nodal blockade recognized as a cause of AF; approximately 25% to 30% of
due to idiopathic degeneration of the AV node requires patients with New York Heart Association (NYHA) class III
implantation of a permanent pacemaker.12 heart failure have AF,17 and the arrhythmia is present in as many
as 50% of patients with NYHA class IV heart failure.18
Outcome Evaluation Drug-induced AF is relatively uncommon, and the list of
Monitor the patient for termination of AV nodal blockade drugs that may induce AF is relatively small.13 However, acute
and restoration of normal sinus rhythm, heart rate, and alle- ingestion of large amounts of alcohol may cause AF; this
viation of symptoms. phenomenon has been referred to as the holiday heart
If atropine is administered, monitor the patient for adverse syndrome.19
effects including dry mouth, mydriasis, urinary retention,
and tachycardia. Pathophysiology
Atrial brillation may be caused by both abnormal
Atrial Fibrillation impulse formation and abnormal impulse conduction.
Traditionally, AF was believed to be initiated by premature
Atrial brillation (AF) is the most common arrhythmia impulses initiated in the atria. However, it is now understood
encountered in clinical practice. It is important for clinicians that in many patients AF is triggered by electrical impulses
to understand AF, because it is associated with substantial generated within the pulmonary veins.20 These impulses initi-
morbidity and mortality and because many strategies for drug ate the process of reentry within the atria, and AF is believed
therapy are available. Drugs used to treat AF often have a nar- to be sustained by multiple reentrant wavelets operating
row therapeutic index and a broad adverse effect prole. simultaneously within the atria.21 Some believe that, at least in
some patients, the increased automaticity in the pulmonary
Epidemiology and Etiology veins may be the sole mechanism of AF and that the multiple
Approximately 2.3 million Americans have AF. The prevalence reentrant wavelet hypothesis may be incorrect.21 However, the
of AF increases with advancing age; roughly 9% of patients concept of multiple simultaneous reentrant wavelets remains
between the ages of 80 and 89 years have AF.16 Similarly, the the predominant hypothesis regarding the mechanism of AF.
incidence of AF increases with age, and it occurs more com- Atrial brillation leads to electrical remodeling of the atria.
monly in men than women.16 Episodes of AF that are of longer duration and episodes that
Etiologies of AF are presented in Table 64. The common occur with increasing frequency result in progressive shorten-
feature of the majority of etiologies of AF is the development of ing of atrial refractory periods, further potentiating the reen-
left atrial hypertrophy. Hypertension may be the most important trant circuits in the atria.22 Therefore, it is often said that atrial
to hours, or rarely as long as 7 days, and terminate suddenly

Clinical Presentation and Diagnosis: and spontaneously. Some patients with paroxysmal AF have
Atrial Fibrillation episodes that do not terminate spontaneously but require
intervention, and this is known as persistent AF. Approximately
one-third of patients with AF progress to the point of perma-
Symptoms
Approximately 20% to 30% of patients with AF remain nent AF; these patients are subsequently never in normal sinus
asymptomatic. rhythm, but rather are always in AF.
Symptoms typical of tachyarrhythmias include palpita- Atrial brillation is associated with substantial morbidity and
tions, dizziness, lightheadedness, shortness of breath, mortality. Atrial brillation is associated with a risk of ischemic
chest pain (if underlying CAD is present), near-syncope, stroke of approximately 5% per year.23 The risk of stroke is
and syncope. Patients commonly complain of palpitations; increased two- to seven-fold in patients with AF compared to
often the complaint is I can feel my heart beating fast or patients without this arrhythmia.23 Atrial brillation is the cause
It feels like my heart is going to beat out of my chest. of roughly one of every six strokes.21 During AF, atrial contrac-
Other symptoms are dependent on the degree to which tion is absent. Therefore, due to the fact that atrial contraction is
cardiac output is diminished, which is in turn dependent
responsible for approximately 30% of left ventricular lling, this
on the heart rate and the degree to which stroke volume
blood that is not ejected from the left atrium to the left ventricle
is reduced by the rapidly beating heart.
In some patients, the rst symptom of AF is stroke. pools in the atrium, particularly in the left atrial appendage.
Blood pooling facilitates the formation of a thrombus, which
Diagnosis subsequently may travel through the mitral valve into the left
Because the symptoms of all tachyarrhythmias are
ventricle and may be ejected during ventricular contraction. The
dependent on heart rate and are therefore essentially the
thrombus then may travel through a carotid artery into the brain,
same, the diagnosis depends on the presence of AF on
the ECG. resulting in an ischemic stroke.
Atrial brillation is characterized on ECG by an absence
of P waves, an undulating baseline that represents
roughly 350 to 600 attempted atrial depolarizations per Patient Encounter, Part 2: Medical
minute, and an irregularly irregular rhythm, meaning that History, Physical Exam and Diagnostic
the intervals between the R waves are irregular and that Tests
there is no pattern to the irregularity.
PMH
Hypertension 15 years
Coronary artery disease 10 years
brillation begets atrial brillation, that is, AF causes atrial Myocardial infarction 1998
electrophysiologic alterations that promote further AF.21,22 Heart failure 3 years
The AV node is incapable of conducting 350 to 600
impulses per minute; however, it may conduct 100 to 200 Meds
Aspirin 81 mg once daily
impulses per minute, resulting in ventricular rates ranging
Metoprolol 50 mg twice daily
from 100 to 200 bpm. Enalapril 5 mg twice daily
Atrial brillation is classied as paroxysmal, persistent, or Furosemide 40 mg daily
permanent (Fig. 64).23 Patients with paroxysmal AF have
episodes that start suddenly and spontaneously, last minutes PE
Height 510 (178 cm), wt. 80 kg (176 lb), BP 110/70 mm Hg,
pulse 135 bpm, RR 20/minute; remainder of physical exam
non-contributory
Labs
All within normal limits
Chest x-ray: Mild pulmonary edema
DA is a 58-year-old male who presents to the emergency
Echo: Moderately reduced left ventricular function, left ven-
department (ED) complaining that his heart is beating fast,
tricular ejection fraction 35%
which started when he was taking out the garbage. He also
complains of feeling lightheaded and short of breath. His ECG: Atrial brillation
pulse is irregularly irregular, with a rate of 135 bpm.
What is your assessment of DAs condition?
What information is suggestive of atrial brillation? What are your treatment goals?
What additional information do you need in order to What pharmacologic or nonpharmacologic alternatives
develop a treatment plan? are available for each treatment goal?
FIGURE 64. Classication of atrial brilla-

tion. 1Episodes that generally last less than
or equal to 7 days (most less than 24 hours).
2
Episodes that usually last greater than 7 days.
3
Cardioversion failed or not attempted. 4Either
paroxysmal or persistent atrial brillation may
be recurrent. (Reprinted with permission from
Fuster V, Rydn LE, Asinger RW, et al.
ACC/AHA /ESC guidelines for the manage-
ment of patients with atrial brillation: a
report of the American College of Cardiology,
American Heart Association Task Force on
Practice Guidelines and the European Society
of Cardiology Committee for Practice
Guidelines and Policy Conferences
(Committee to Develop Guidelines for the
Management of Patients with Atrial Fibrillation).
J Am Coll Cardiol 2001; 38:1266ilxx.23)
Atrial brillation leads to the development of HF, as a result the latter portion of the T wave (i.e., the relative refractory
of tachycardia-induced cardiomyopathy.25 Atrial brillation period), to avoid delivering an electrical impulse that may be
increases the risk of mortality approximately two-fold compared conducted abnormally, which may result in a life-threatening
to that in patients without AF;23 the causes of death are likely ventricular arrhythmia.
stroke or HF. The remainder of this section will be devoted to manage-
ment of hemodynamically stable AF.
Treatment
Pharmacologic Therapy
Desired Outcomes Ventricular Rate Control is achieved by inhibiting the pro-
The goals of therapy of AF are: (1) ventricular rate control; portion of electrical impulses conducted from the atria to
(2) termination of AF and restoration of sinus rhythm (commonly the ventricles through the AV node. Therefore, drugs that
referred to as cardioversion or conversion to sinus rhythm); are effective for ventricular rate control are those that
(3) maintenance of sinus rhythm, or reduction in the frequency of inhibit AV nodal impulse conduction: -blockers, diltiazem,
episodes of paroxysmal AF; and (4) prevention of stroke. verapamil, and digoxin (Tables 65 and 66). Amiodarone
also inhibits AV nodal conduction, but is not a preferred
Hemodynamically Unstable AF drug for ventricular rate control in AF due to its unfavor-
For patients who present with an episode of AF that is hemo- able adverse-effect prole (Table 66).
dynamically unstable, emergent conversion to sinus rhythm is In patients who present with their rst detected episode of
necessary using direct current cardioversion (DCC). AF, or for those who present with an episode of persistent AF,
Hemodynamic instability may be dened as the presence of any ventricular rate control is usually initially achieved using intra-
one of the following:14 (1) patient has altered mental status, venous drugs. A decision algorithm for selecting a specic drug
(2) hypotension (systolic blood pressure less than 90 mm Hg) for acute ventricular rate control is presented in Fig. 65. In gen-
or other signs of shock, (3) ventricular rate greater than 150 bpm, eral, IV diltiazem is a preferred drug for ventricular rate control
and/or (4) patient is experiencing squeezing, crushing chest pain in patients with normal LV function, as ventricular rate control
suggestive of myocardial ischemia. can often be achieved within several minutes. In patients with
Direct current cardioversion is the process of administer- HF due to LV dysfunction, digoxin may be preferred because dil-
ing a synchronized electrical shock to the chest. The purpose tiazem is associated with negative inotropic effects and may
of DCC is to simultaneously depolarize all of the myocardial exacerbate HF.26 However, in patients with HF who are substan-
cells, resulting in interruption and termination of the multi- tially symptomatic and in whom it is undesirable to wait 4 to
ple reentrant circuits and restoration of normal sinus rhythm. 6 hours for the effects of digoxin to occur, IV diltiazem may be
The initial energy level of the shock is 100 joules (J); if the used for up to 24 hours without inducing HF exacerbation in
DCC attempt is unsuccessful, successive cardioversion most patients.
attempts may be made at 200, 300, and 360 J.14 Delivery of the A decision strategy for long-term rate control in patients
shock is synchronized to the ECG by the cardioverter with paroxysmal or permanent AF is presented in Fig. 66. In
machine, such that the electrical charge is not delivered during general, while digoxin is effective for ventricular rate control in
TABLE 65. Drugs for Ventricular Rate Control in Atrial Fibrillation
Drug Mechanism of Action Loading Dose Daily Dose Drug Interactions

-Blockersa Inhibit AV nodal conduction Esmolol: 500 mcg/kg IV Esmolol: 50200 mcg/kg/minute
by slowing AV nodal over 1 minute continuous infusion
conduction and Propranolol: 0.15 mg/kg IV Propranolol: 80240 mg/day
prolonging AV nodal Metoprolol: 2.55 mg Metoprolol: 50200 mg/day
refractoriness IV 23 doses
Diltiazem Inhibits AV nodal conduction 1. 0.25 mg/kg IV load Continuous infusion Inhibits elimination
by slowing AV nodal over 2 minutes of 515 mg/hour of cyclosporine
conduction and prolonging 2. If necessary, Oral: 120360 mg/day
AV nodal refractoriness 0.35 mg/kg IV over
2 minutes after rst dose
Verapamil Inhibits AV nodal conduction 1. 510 mg IV 120360 mg/day Inhibits digoxin
by slowing AV nodal over 23 minutes elimination
conduction and prolonging 2. If necessary, an
AV nodal refractoriness additional dose of
510 mg may be
administered 30 minutes
later
Digoxin Inhibits AV nodal 0.25 mg every 2 hours 0.1250.25 mg PO Amiodarone,
conduction by: up to 1.5 mg once daily verapamil,
1. Vagal stimulation quinidine
2. Directly slowing inhibit digoxin
AV nodal conduction elimination
and prolonging
AV nodal refractoriness
AV, atrioventricular; IV, intravenous; PO, orally.

a
While oral -blockers are important agents for mortality reduction in patients with heart failure, intravenous -blockers should be avoided, due to the
potential for heart failure exacerbation.
patients at rest, digoxin is less effective than CCBs or -blockers slow atrial conduction velocity and/or prolong refractoriness,
for ventricular rate control in patients undergoing physical facilitating interruption of reentrant circuits and restoration of
activity, including activities of daily living. This is likely because sinus rhythm. DCC is generally more effective than drug therapy
activation of the sympathetic nervous system during exercise for conversion of AF to sinus rhythm. However, patients who
and activity overwhelms the stimulating effect of digoxin on the undergo elective DCC must be sedated and/or anesthetized to
parasympathetic nervous system. Therefore, in patients with avoid the discomfort associated with delivery of 100 to 360 J of
normal LV function, CCBs or -blockers are preferred for long- electricity to the chest. Therefore, it is important that patients
term ventricular rate control. Diltiazem may be preferable to scheduled to undergo elective DCC do not eat within approxi-
verapamil in older patients due to a lower incidence of consti- mately 8 to 12 hours of the procedure to avoid aspiration of
pation. However, in patients with HF, oral diltiazem and vera- stomach contents during the period of sedation/anesthesia.
pamil are contraindicated as a result of their negative inotropic This often factors into the decision as to whether to employ
activity and propensity to exacerbate HF. Therefore, the options elective DCC or drug therapy for conversion of AF to sinus
in this population are -blockers or digoxin. The majority of rhythm. If a patient presents with AF requiring conversion to
patients with HF receive therapy with oral -blockers for the sinus rhythm, and the patient has eaten a meal that day, then
goal of achieving mortality reduction. In patients with HF that pharmacologic methods must be used for cardioversion on that
develop rapid AF while receiving therapy with -blockers, day, or DCC must be postponed to the following day to allow
digoxin should be administered for purposes of ventricular rate for a period of fasting prior to the procedure.
control. Fortunately, studies have found the combination of A decision strategy for conversion of AF to sinus rhythm is
digoxin and -blockers to be effective for ventricular rate con- presented in Fig. 67. The cardioversion decision strategy
trol, likely as a result of suppression of the inhibitory effects of depends greatly on the duration of AF. If the AF episode began
the sympathetic nervous system on the efcacy of digoxin. within 48 hours, conversion to sinus rhythm is safe and may
be attempted with elective DCC or specic drug therapy
Conversion to Sinus Rhythm Termination of AF in hemodynami- (Fig. 67). However, if the duration of the AF episode is longer
cally stable patients may be performed using antiarrhythmic than 48 hours or if there is uncertainty regarding the duration of
drug therapy or elective DCC. Drugs that may be used for con- the episode, two strategies for conversion may be considered.
version to sinus rhythm are presented in Table 67; these agents Because data indicate that a thrombus may form in the left
TABLE 66. Adverse Effects of Drugs Used to Treat atrium during AF episodes of 48 hours or longer, conversion
Arrhythmias should be deferred unless it is known that an atrial thrombus is
not present. In the past, common practice in patients with AF of
Drug Adverse Effects
greater than 48 hours duration was to anticoagulate patients
Adenosine Chest pain, ushing, shortness of breath, sinus with warfarin, maintaining a therapeutic International
bradycardia/AV block
Normalized Ratio (INR) for 3 weeks, after which cardioversion
Amiodarone IV: Hypotension, sinus bradycardia
Oral: Blue-grey skin discoloration, may be performed. Patients were subsequently anticoagulated
photosensitivity, corneal microdeposits, for 4 weeks following the restoration of sinus rhythm. Today,
pulmonary brosis, hepatotoxicity, sinus rather than send patients with ongoing AF home for 3 weeks of
bradycardia, hypo- or hyperthyroidism, AV block anticoagulation, it is becoming standard practice at many insti-
Atropine Tachycardia, urinary retention, blurred vision,
tutions to perform a transesophageal echocardiogram (TEE) to
dry mouth, mydriasis
Digoxin Nausea, vomiting, anorexia, green-yellow determine whether an atrial thrombus is present; if such a
halos around objects, ventricular arrhythmias thrombus is not present, DCC or pharmacologic cardiover-
Diltiazem Hypotension, sinus bradycardia, heart failure sion may be performed within 24 hours. If this strategy is
exacerbation, AV block selected, patients should undergo anticoagulation with intra-
Dofetilide Torsades de pointes
venous unfractionated heparin, with the dose targeted to a
Esmolol Hypotension, sinus bradycardia, AV block,
heart failure exacerbation partial thromboplastin time (PTT) of 60 seconds (range 50 to
Flecainide Dizziness, blurred vision, heart failure 70 seconds), or warfarin therapy (target INR 2.5; range 2 to 3)
exacerbation for several days prior to the TEE and cardioversion procedure.
Ibutilide Torsades de pointes If no thrombus is present during TEE and cardioversion is
Lidocaine Dizziness, confusion, seizures (if dose too high)
successful, patients should undergo anticoagulation with war-
Metoprolol Hypotension, sinus bradycardia, AV block,
fatigue, heart failure exacerbationa farin (target INR 2.5; range 2 to 3) for at least 4 weeks. If a
Procainamide Hypotension, torsades de pointes thrombus is observed during TEE, then cardioversion should be
Propafenone Dizziness, blurred vision postponed and anticoagulation should be continued inde-
Propranolol Hypotension, bradycardia, AV block, heart nitely. Another TEE should be performed prior to a subsequent
failure exacerbationa
cardioversion attempt.27
Sotalol Sinus bradycardia, AV block, fatigue, torsades
de pointes Conversion of AF to sinus rhythm is usually performed in
Verapamil Hypotension, heart failure exacerbation, patients with the rst detected episode of AF or in patients
bradycardia, AV block, constipation (oral) with an episode of persistent AF. In patients with permanent
AV, atrioventricular; IV, intravenous.
AF, conversion to sinus rhythm is usually not attempted
a
Associated with intravenous administration, inappropriately high oral because cardioversion is unlikely to be successful, and in those
doses at initiation of therapy, or overly aggressive and rapid dose titration.
FIGURE 65. Decision algorithm for ven-

First detected episode or persistent atrial fibrillation tricular rate control using intravenous drug
therapy for patients presenting with the
rst detected episode or an episode of per-
Assess LV function
sistent atrial brillation that is hemody-
namically stable.

Diltiazem is generally preferred over vera-
LVEF greater than or equal to 40% LVEF less than 40%
and/or no history of HF and/or history of HF
pamil because of a lower risk of severe
hypotension.

Intravenous diltiazem can be used cau-
CCB Asymptomatic Symptomatic tiously for up to 24 hours in patients with
-blocker or mildly (rapid rate non-decompensated heart failure.
Digoxin symptomatic control needed) bpm, beats per minute; CCB, calcium
Amiodarone channel blocker (diltiazem or verapamil);
Diltiazem HF, heart failure; LV, left ventricular; LVEF,
Digoxin left ventricular ejection fraction.
Amiodarone
Diltiazem
(Algorithm adapted with permission from
Tisdale JE, Moser LR. Tachyarrhythmias. In:
Mueller BA, Bertch KE, Dunsworth TS,
Assess heart rate control. Goal less than 100 bpm or reduction of heart rate by greater than 20% et al. (eds.) Pharmacotherapy Self-
with symptom relief. Assessment Program, 4th ed. Kansas City:
American College of Clinical Pharmacy;
Goal not metincrease dose of initial 2001: 217267.)50
Goal metchange to oral therapy
drug or add a second drug
FIGURE 66. Decision algorithm for long-term

Paroxysmal or permanent atrial fibrillation ventricular rate control with oral drug therapy
for patients with paroxysmal or permanent atrial
Assess LV function brillation. bpm, beats per minute; CCB, calcium
channel blocker (diltiazem or verapamil); HF,
LVEF less than 40%
heart failure; LV, left ventricular function; LVEF,
LVEF greater than or equal to 40%
and/or no history of HF and/or history of HF left ventricular ejection fraction. (Algorithm
adapted with permission from Tisdale JE, Moser
-blocker LR. Tachyarrhythmias. In: Mueller BA, Bertch KE,
-blocker
or CCB Digoxin Dunsworth TS, et al. (eds.) Pharmacotherapy
Digoxin Amiodarone Self-Assessment Program, 4th ed. Kansas City:
Amiodarone
American College of Clinical Pharmacy; 2001:
217267.)50
Assess heart rate control. Goal less than 100 bpm or reduction of heart rate by greater
than 20% with symptom relief.
Goal not metincrease dose of initial

drug or add a second drug
patients in whom sinus rhythm is restored successfully, AF patients is not permanent maintenance of sinus rhythm, but
usually recurs shortly thereafter. rather reduction in the frequency of episodes of paroxysmal AF.
In recent years, numerous studies have been performed to
Maintenance of Sinus Rhythm/Reduction in the Frequency of determine whether drug therapy for maintenance of sinus
Episodes of Paroxysmal AF In many patients, permanent main- rhythm is preferred to drug therapy for ventricular rate con-
tenance of sinus rhythm following cardioversion is an unreal- trol.2831 In these studies, patients have been assigned randomly
istic goal. Many, if not most, patients experience recurrence of to receive therapy either with drugs for rate control or with
AF after cardioversion. Therefore, a more realistic goal for many drugs for rhythm control (Table 68). These studies have found
TABLE 67. Drugs for Conversion of Atrial Fibrillation to Normal Sinus Rhythm
Continuous
Treatment Loading Dose Infusion Rate Drug Interactions
Amiodarone 57 mg/kg IV over 7001200 mg over Inhibits elimination of
3060 minutes 24 hours digoxin and warfarin
Dofetilide See belowa; patients Cimetidine,
must be hospitalized hydrochlorothiazide,
for 3 days during ketoconazole,
initiation of therapy medroxyprogesterone,
promethazine,
trimethoprim,
verapamil (all inhibit
dofetilide
elimination)
Ibutilide 1 mg IV over 10 minutes,
followed by a second
1 mg IV dose if necessary
Propafenone 600 mg single oral dose
Flecainide 200300 mg single oral dose
Procainamide 1217 mg/kg, no faster 14 mg/minute Cimetidine, ranitidine,
than 20 mg/minute and trimethoprim
inhibit procainamide
elimination
IV, intravenously.
a
Dofetilide dosing:
Calculated Creatinine Clearance Dofetilide Dose
Greater than 60 mL/minute 500 mcg twice daily
4060 mL/minute 250 mcg twice daily
2040 mL/minute 125 mcg twice daily
Less than 20mL/minute Contraindicated
FIGURE 67. Decision algorithm for conversion

Atrial Fibrillation
of atrial brillation to normal sinus rhythm.
DCC, direct current cardioversion; IV, intra-
venously; LVEF, left ventricular ejection fraction;
Duration less than Duration greater than TEE, transesophageal echocardiogram.
48 hours 48 hours or unknown
Target International Normalized Ratio = 2.5
(range 2 to 3).
(Algorithm adapted with permission from Tisdale
LVEF greater LVEF less LVEF greater than LVEF less JE, Moser LR. Tachyarrhythmias. In: Mueller BA,
than or equal than 40% or equal to 40% than 40%
to 40%
Bertch KE, Dunsworth TS, et al. (eds.) Pharmaco-
therapy Self-Assessment Program, 4th ed. Kansas
City: American College of Clinical Pharmacy;
Consider DCC Consider DCC 2001: 217267.)50
or amiodarone
Ibutilide may be used
cautiously
If DCC unfeasible or undersirable or Delayed DCC

unsuccessful, use 1 of the following: Warfarin for 3 weeks then DCC
Amiodarone Then warfarin for 4 more weeks
Dofetilide
Ibutilide OR
Propafenone
Flecainide
Procainamide Early DCC
Start heparin IV
TEE to rule out atrial thrombus
If no thrombus: If thrombus present:

DCC within 24 hours No DCC
Then warfarin for 4 weeks Warfarin indefinitely
no signicant differences in mortality in patients who received should be initiated only in those patients with episodes of parox-
rhythm control therapy versus those who received rate control ysmal AF who continue to experience symptoms despite maximum
therapy.2831 However, patients assigned to the rhythm control tolerated doses of drugs for ventricular rate control. A decision
strategy were more likely to be hospitalized28,30,31 and were strategy for maintenance therapy of sinus rhythm is presented
more likely to experience adverse effects associated with drug in Fig. 68. Drug therapy for maintenance of sinus rhythm
therapy.28,29 Therefore, drug therapy for the purpose of main- and/or reduction in the frequency of episodes of paroxysmal AF
taining sinus rhythm or reducing the frequency of episodes of AF should not be initiated in patients with underlying correctable
causes of AF, such as hyperthyroidism; rather, the underlying
cause of the arrhythmia should be corrected.
TABLE 68. Drugs for Maintenance of Sinus Rhythm/
Reduction in the Frequency of Episodes
Stroke Prevention All patients with paroxysmal, persistent, or
of Atrial Fibrillation
permanent AF should receive therapy for stroke prevention,
Drug Dose unless compelling contraindications exist. A decision strategy
for stroke prevention in AF is presented in Fig. 69.27 In
Amiodarone 100400 mg PO once daily
Dofetilide As described in Table 67 general, most patients require therapy with warfarin; in some
Sotalol 80160 mg PO twice daily patients with no additional risk factors for stroke, aspirin may be
Propafenone 150300 mg PO three times daily acceptable. For some patients, serious consideration of the
Flecainide 100150 mg PO twice daily benets of warfarin versus the risks of bleeding associated
Procainamide 50 mg/kg/day, divided 46 daily
with warfarin therapy is warranted. The potential bleeding
PO, orally. risks associated with warfarin may outweigh the benets in
FIGURE 68. Decision algorithm for mainte-

Symptomatic paroxysmal or persistent atrial fibrillation despite rate control therapy nance of sinus rhythm/reduction in the fre-
quency of episodes of atrial brillation.
CAD, coronary artery disease; LVEF, left ventri-
cular ejection fraction; LVH, left ventricular
No CAD and LVEF hypertrophy. (Algorithm adapted with permis-
LVEF less than or sion from Tisdale JE, Moser LR.
greater than 40% CAD
equal to 40% Tachyarrhythmias. In: Mueller BA, Bertch KE,
Hypertension with LVH
Dunsworth TS, et al. (eds.) Pharmacotherapy
Self-Assessment Program, 4th ed. Kansas City:
Flecainide or propafenone American College of Clinical Pharmacy; 2001:
Dofetilide or sotalol Amiodarone or dofetilide
or sotalol 217267.)50
Amiodarone or dofetilide Amiodarone
patients with a pretreatment INR of greater than 2.0, alcoholism,

anticipated poor compliance, a history of falls, or current Patient Encounter, Part 3: Creating a
bleeding diathesis. In these situations, patients are at risk of Care Plan
severe bleeding associated with warfarin, including intracere-
bral bleeding, which may be associated with consequences as
Based on the information presented, create a care plan for DAs
serious as those associated with a thrombotic stroke.
acute AF episode, and for long-term management of his AF.
Outcome Evaluation Your plan should include: (1) a statement of the drug-
Monitor the patient to determine whether the goal of ven- related needs and/or problems, (2) the goals of therapy,
tricular rate control is met: heart rate less than 100 bpm (3) a patient-specic detailed therapeutic plan, and (4) a
or decrease in heart rate of 20% from the pretreatment plan for follow-up to determine whether the goals have
value. been achieved and adverse effects avoided.
Monitor ECG to assess continued presence of AF and to
determine whether conversion to sinus rhythm has
occurred.
Paroxysmal Supraventricular Tachycardia
Monitor INR approximately monthly to make sure it is ther-
apeutic (target 2.5; range 2 to 3). Paroxysmal supraventricular tachycardia (PSVT) is a term that
Monitor patients for adverse effects of specic drug therapy refers to a number of arrhythmias that occur above the ventri-
(Table 66). Monitor patients receiving warfarin for signs cles and that require atrial or AV nodal tissue for initiation and
and symptoms of bruising or bleeding. maintenance.32 The most common of these arrhythmias is
FIGURE 69. Decision algorithm for stroke preven-

Paroxysmal, persistent or permanent atrial fibrillation tion in atrial brillation.27

Risk factors for stroke: prior transient ischemic
attack or stroke; hypertension; heart failure; rheu-
matic heart valve disease; prosthetic heart valve.
Age less than Age greater than
65 years
Age 6575 years
75 years Target International Normalized Ratio = 2.5
(range 2 to 3).
(Algorithm adapted with permission from Tisdale
JE, Moser LR. Tachyarrhythmias. In: Mueller BA,
No risk Risk No risk Risk
Bertch KE, Dunsworth TS, et al. (eds.) Pharmaco-
factors factors factors factors
therapy Self-Assessment Program, 4th ed. Kansas
City: American College of Clinical Pharmacy; 2001:
217267.)50
Aspirin
Aspirin Warfarin or Warfarin Warfarin
Warfarin
known as atrioventricular reciprocating tachycardia, in which pathway and retrograde through the faster pathway; in approxi-
the arrhythmia is caused by a reentrant circuit that involves the mately 10% of patients, the reentrant circuit is reversed.32
AV node or tissue adjacent to the AV node. Other types of PSVT
include the relatively uncommon Wolff-Parkinson-White syn-
Treatment
drome, which is caused by reentry through an accessory extra-
AV nodal pathway. For the purposes of this section, the term
Desired Outcomes
PSVT will refer to AV nodal reentrant tachycardia.
The desired outcomes for treatment are to terminate the
arrhythmia, restore sinus rhythm, and prevent recurrence.
Epidemiology and Etiology
Drug therapy is employed to terminate the arrhythmia and
While PSVT can be associated with myocardial ischemia or
restore sinus rhythm; nonpharmacologic measures are
infarction, it often occurs in relatively young individuals with
employed to prevent recurrence.
no history of cardiac disease. The overall incidence of PSVT is
unknown.
Termination of PSVT
Hemodynamically unstable PSVT should be treated with
Pathophysiology
immediate synchronized DCC, using an initial energy level of
Paroxysmal supraventricular tachycardia is caused by reentry 50 J; if the DCC attempt is unsuccessful, successive cardiover-
that includes the AV node as a part of the reentrant circuit. Typically,
sion attempts may be made at 100, 200, 300, and 360 J.14
electrical impulses travel forward (antegrade) down the AV node
The primary method of termination of hemodynamically
and then travel back up the AV node (retrograde) in a repetitive cir-
stable PSVT is inhibition of impulse conduction and prolon-
cuit. In some patients, the retrograde conduction pathway of the
gation of the refractory period within the AV node. Since
reentrant circuit may exist in extra-AV nodal tissue adjacent to the
PSVT is propagated via a reentrant circuit involving the AV
AV node. One of these pathways usually conducts impulses rapidly,
node, inhibition of conduction within the AV node interrupts
while the other usually conducts impulses slowly. Most commonly,
and terminates the reentrant circuit.
during PSVT the impulse conducts antegrade through the slow
Prior to initiation of drug therapy for termination of hemo-
dynamically stable PSVT, some simple nonpharmacologic
methods known as vagal maneuvers may be attempted.33 Vagal
Clinical Presentation and Diagnosis: maneuvers stimulate the activity of the parasympathetic
PSVT nervous system, which inhibits AV nodal conduction, facili-
tating termination of the arrhythmia. Perhaps the simplest
May occur at any age, but most commonly during the
vagal maneuver is cough, which stimulates the vagus nerve.
fourth and fth decades of life.32 Instructing the patient to cough two or three times may suc-
Occurs more commonly in females than in males; cessfully terminate the PSVT. Another vagal maneuver that
approximately two-thirds of patients that experience may be attempted is carotid sinus massage; one of the carotid
PSVT are women.32 sinuses, located in the neck in the vicinity of the carotid arter-
Symptoms
ies, may be gently massaged, stimulating vagal activity.33
Symptoms typical of tachyarrhythmias include palpita- Carotid sinus massage should not be performed in patients
tions, dizziness, lightheadedness, shortness of breath, with a history of stroke or transient ischemic attack, or in
chest pain (if underlying CAD is present), near-syncope, those in whom carotid bruits may be heard on auscultation.
and syncope. Patients commonly complain of palpitations; The Valsalva maneuver, during which patients bear down
often the complaint is I can feel my heart beating fast or against a closed glottis, may also be attempted.33
It feels like my heart is going to beat out of my chest. If vagal maneuvers are unsuccessful, intravenous drug therapy
Other symptoms are dependent on the degree to which should be initiated.32 Drugs that may be used for termination of
cardiac output is diminished, which is in turn dependent hemodynamically stable PSVT are presented in Table 69. A
on the heart rate and the degree to which stroke volume decision strategy for pharmacologic termination of hemody-
is reduced by the rapidly beating heart.
namically stable PSVT is presented in Fig. 610.33 Adenosine is
Diagnosis the drug of choice for pharmacologic termination of PSVT and is
Because the symptoms of all tachyarrhythmias are successful in 90% to 95% of patients. The drug is associated with
dependent on heart rate and are therefore essentially the adverse effects (Table 66) including ushing, sinus bradycardia
same, diagnosis depends on the presence of PSVT on the or AV nodal blockade, and bronchospasm in susceptible patients.
ECG, characterized by narrow QRS complexes (usually
In addition, adenosine may cause chest pain that mimics the dis-
less than 0.12 seconds). P waves may or may not be visible,
depending on the heart rate.
comfort of myocardial ischemia, but which is not actually asso-
PSVT is a regular rhythm and occurs at rates ranging from ciated with ischemia. The half-life of adenosine is approximately
100 to 250 bpm. 10 seconds, due to deamination in the blood; therefore, in the
vast majority of patients, adverse effects are of short duration.
TABLE 69. Drugs for Termination of Paroxysmal Supraventricular Tachycardia
Drug Mechanism Dose Drug Interactions

Adenosine Direct AV nodal 6 mg IV rapid bolus Theophylline inhibits
inhibition If no response in 12 minutes, response to adenosine
12 mg IV rapid bolus Dipyridamole
If no response in 12 minutes, accentuates response
12 mg IV rapid bolus to adenosine
Verapamil Direct AV nodal 1. 510 mg IV over 23 minutes Inhibits digoxin
inhibition 2. If necessary, an additional elimination
dose of 5-10 mg may be
administered 30 minutes later
Diltiazem Direct AV nodal 1. 0.25 mg/kg IV load over 2 minutes Inhibits elimination of
inhibition 2. If necessary, 0.35 mg/kg IV over cyclosporine
2 minutes after rst dose
Digoxin 1. Vagal stimulation 0.25 mg IV every 2 hours, Amiodarone and
2. Direct AV nodal up to 1.5 mg verapamil (inhibit
inhibition digoxin elimination)
-Blockers Direct AV nodal Esmolol: 500 mcg/kg IV, over
inhibition 1 minute then 50200 mcg/
kg/minute continuous infusion
Propranolol: 0.15 mg/kg IV
Metoprolol: 2.55 mg IV 23 doses
Amiodarone Direct AV nodal 57 mg/kg IV over 3060 minutes Inhibits elimination of
inhibition then 7001200 mg IV digoxin and warfarin
infusion over 24 hours
AV, atrioventricular; IV, intravenous
If adenosine therapy is unsuccessful for termination of Nonpharmacologic Therapy: Prevention of Recurrence

PSVT, subsequent choices of therapy depend on whether the In the past, prevention of recurrence of PSVT was attempted
patient has HF and/or a depressed left ventricular ejection using long-term oral therapy with drugs such as verapamil or
fraction (LVEF). digoxin. Unfortunately, oral therapy with these drugs was asso-
ciated with relatively limited success. Currently, the treatment of
choice for long-term prevention of recurrence of PSVT is
PSVT radiofrequency catheter ablation. During this procedure, a
catheter is introduced transvenously and directed to the right
Vagal maneuvers
atrium under uoroscopic guidance. The catheter is directed to
the AV node, and radiofrequency energy is delivered to ablate, or
Adenosine
destroy, one of the pathways of the reentrant circuit. This proce-
dure usually achieves a complete cure of PSVT and is associated
LVEF greater than or LVEF less than with a relatively low risk of complications, and therefore obvi-
equal to 40% or 40% or
no history of HF history of HF ates the need for long-term antiarrhythmic drug therapy in this
population.
Diltiazem or verapamil Digoxin
Outcome Evaluation
-blocker Amiodarone
Monitor patients for termination of PSVT and restoration of
Digoxin Diltiazem normal sinus rhythm.
Monitor patients for adverse effects of adenosine or any
FIGURE 610. Decision algorithm for termination of paroxysmal other anti-arrhythmic agents administered (Table 66).
supraventricular tachycardia. HF, heart failure; LVEF, left ven-
tricular ejection fraction; PSVT, paroxysmal supraventricular
tachycardia. (Algorithm adapted with permission from Tisdale JE,
VENTRICULAR ARRHYTHMIAS
Moser LR. Tachyarrhythmias. In: Mueller BA, Bertch KE,
Dunsworth TS, et al. (eds.) Pharmacotherapy Self-Assessment Ventricular Premature Depolarizations
Program, 4th ed. Kansas City: American College of Clinical
Ventricular premature depolarizations (VPDs) are ectopic
Pharmacy; 2001: 217267.)50
electrical impulses originating in ventricular tissue, resulting
in wide, misshapen, abnormal QRS complexes. Ventricular Pharmacologic Therapy

premature depolarizations are also commonly known by Asymptomatic VPDs should not be treated with anti-
other terms, including premature ventricular contractions arrhythmic drug therapy. Based on the knowledge that complex
(PVCs), ventricular premature beats (VPBs), and ventricular or frequent VPDs increase the risk of sudden cardiac death in
premature contractions (VPCs). patients with a history of myocardial infarction, the Cardiac
Arrhythmia Suppression Trials (CAST I and II)37,38 tested the
Epidemiology, Etiology, and Pathophysiology hypothesis that suppression of asymptomatic VPDs with the
Ventricular premature depolarizations occur with variable fre- drugs ecainide, encainide, or moricizine in patients with a rel-
quency, depending on underlying comorbid conditions. The atively recent history of myocardial infarction would lead to a
prevalence of complex or frequent VPDs is approximately 33% reduction in the incidence of sudden cardiac death. However, the
and 12% in men with and without CAD, respectively;34 in results of the trial showed that not only did these antiarrhythmic
women, the prevalence of complex or frequent VPDs is 26% agents not reduce the risk of sudden cardiac death, patients who
and 12% in those with and without CAD, respectively.35 received therapy with encainide or ecainide experienced a sig-
Ventricular premature depolarizations occur more commonly nicant increase in the risk of death compared to those that
in patients with ischemic heart disease, a history of myocardial received placebo.37 During the continuation of the study with
infarction, and HF due to LV dysfunction. They may also occur moricizine, a trend was found toward an increase in the inci-
as a result of hypoxia, anemia, and following cardiac surgery. dence of death in the patients who received this antiarrhythmic
drug as well.38 A subsequent meta-analysis of studies of other
Ventricular premature depolarizations occur as a result of
Vaughan-Williams class I drugs, including quinidine, pro-
abnormal ventricular automaticity, as a result of enhanced
cainamide, and disopyramide, found that the patients with
activity of the sympathetic nervous system and altered electro-
complex VPDs who received these drugs following myocardial
physiologic characteristics of the heart during myocardial
infarction were also at increased risk of death.39 Therefore, all
ischemia and following myocardial infarction.
available evidence shows that patients with complex VPDs fol-
In patients with underlying CAD or a history of myocardial
lowing myocardial infarction do not benet from therapy with
infarction, the presence of complex or frequent VPDs is associated
antiarrhythmic agents and that many of these drugs increase
with an increased risk of mortality due to sudden cardiac death.36
the risk of death. Therefore, asymptomatic VPDs should not
be treated.
Treatment
Patients with symptomatic VPDs should be treated with -
blockers, as the majority of patients with symptomatic VPDs
Desired Outcomes
have underlying CAD. -Blockers have been shown to reduce
The desired outcomes for treatment are to alleviate patient
mortality in this population and have been shown to be effec-
symptoms.
tive for VPD suppression.40
Outcome Evaluation
Clinical Presentation and Diagnosis: Monitor patients for relief of symptoms.
Ventricular Premature Monitor for adverse effects of -blockersheart rate, blood
Depolarizations pressure, fatigue, masking of symptoms of hypoglycemia
and/or glucose intolerance (in patients with diabetes),
VPDs are usually categorized as simple or complex: sim- wheezing or shortness of breath (in patients with asthma or
ple VPDs are those that occur as infrequent, isolated sin-
chronic obstructive pulmonary disease), etc.
gle abnormal beats; complex VPDs are those that occur
more frequently and/or in specic patterns.
Two consecutive VPDs are referred to as a couplet.35 The Ventricular Tachycardia
term bigeminy refers to VPDs occurring with every other
beat; trigeminy means VPDs occurring with every third Ventricular tachycardia is a series of three or more consecutive
beat; quadrigeminy means VPDs occurring every fourth VPDs at a rate of greater than 100 bpm. Ventricular tachy-
beat.35 VPDs occurring at a rate of more than 10 per hour cardia is dened as non-sustained if it lasts less than 30 seconds
or 6 or more per minute are dened as frequent.35 and terminates spontaneously; sustained VT lasts greater than
30 seconds and does not terminate spontaneously, but rather
Symptoms
requires therapeutic intervention for termination.
The majority of patients who experience simple or com-
plex VPDs are asymptomatic. Occasionally, patients with
complex or frequent VPDs may experience symptoms of Epidemiology, Etiology, and Pathophysiology
palpitations, lightheadedness, fatigue, near-syncope or Etiologies of VT are presented in Table 610. The incidence of
syncope. VT is variable, depending on underlying comorbidities. Up to
20% of patients who experience acute myocardial infarction
TABLE 610. Etiologies of Ventricular Tachycardia and

Ventricular Fibrillation Clinical Presentation and Diagnosis:
Ventricular Tachycardia
Coronary artery disease
Myocardial infarction
Heart failure Symptoms
Electrolyte abnormalities: hypokalemia and hypomagnesemia As with other tachyarrhythmias, symptoms associated
Drugs: with VT are dependent primarily on heart rate and
Adenosine include palpitations, dizziness, lightheadedness, shortness
Amiodarone
of breath, chest pain (if underlying CAD is present), near-
Chlorpromazine
syncope, and syncope.
Digoxin
Disopyramide Patients with non-sustained VT may be asymptomatic, if
Flecainide the duration of the arrhythmia is sufciently short.
Ibutilide However, if the rate is sufciently rapid, patients with
Moricizine non-sustained VT may experience symptoms.
Procainamide Patients with sustained VT are usually symptomatic, pro-
Propafenone vided that the rate is fast enough to provoke symptoms.
Sotalol Patients with rapid sustained VT may be hemodynami-
Terbutaline cally unstable.
Theophylline
In some patients, sustained VT results in the absence of a
Thioridazine
pulse, resulting in the syndrome of sudden cardiac death.
Trazodone
Tricyclic antidepressants Diagnosis
Diagnosis of VT requires ECG conrmation of the
arrhythmia.
Ventricular tachycardia is characterized by wide, mis-
experience ventricular arrhythmias.41 Approximately 2% to shapen QRS complexes, with the rate varying from 100
4% of patients with myocardial infarction develop VT during to 250 bpm.
the period of hospitalization.41 Non-sustained VT occurs in In the majority of patients with VT, the shape and appear-
34% to 79% of patients with HF.42 Other etiologies of VT ance of the QRS complexes are consistent and similar,
include electrolyte abnormalities such as hypokalemia, and is referred to as monomorphic VT. However, some
hypoxia, and some drugs (Table 610). patients experience polymorphic VT, in which the shape
and appearance of the QRS complexes vary.
Ventricular tachycardia is usually initiated by a precisely
timed VPD, occurring during the relative refractory period,
which provokes reentry within ventricular tissue.
Sustained VT requires immediate intervention, because is required. A decision algorithm for management of hemody-
if untreated, the rhythm may cause sudden cardiac death namically stable VT is presented in Fig. 611. Amiodarone is
via hemodynamic instability and the absence of a pulse considered the preferred rst-line antiarrhythmic agent for
(pulseless VT) or via degeneration of VT into VF. management of VT, regardless of the patients underlying LV
function.14 In patients with normal LV function who do not
Treatment respond to amiodarone, IV procainamide may be adminis-
tered;14 data suggest superior efcacy of procainamide com-
Desired Outcomes pared with that of lidocaine.43 However, in patients with HF
The desired outcomes for treatment are to terminate the due to LV dysfunction, procainamide should be avoided, due to
arrhythmia and restore sinus rhythm, and to prevent sudden
cardiac death.
TABLE 611. Drugs for Termination of Ventricular Tachycardia
Pharmacologic Therapy Drug Loading Dose Maintenance Dose

Procainamide 1217 mg/kg IV, no faster 14 mg/minute
Termination of VT Hemodynamically unstable VT should be than 20 mg/minute continuous infusion
terminated immediately using synchronized DCC beginning Lidocaine 0.50.75 mg/kg IV bolus 14 mg/minute
with 100 J and increasing subsequent shocks to 200, 300, and Repeat every 510 minutes continuous infusion
360 J.14 In the event that VT is present but the patient has no to a total of 3 mg/kg
pulse (and therefore no blood pressure), asynchronous deb- Amiodarone 150 mg IV over 1 mg/minute contin-
rillation should be performed, starting with 200 J and increas- 10 minutes uous infusion for
ing to 300 and 360 J.14 6 hours, 0.5 mg/
minute for 18 hours
Drugs used for the termination of hemodynamically stable
VT are presented in Table 611. Intravenous drug administration IV, intravenously.
Outcome Evaluation
VT
Monitor patients for termination of VT and restoration of
normal sinus rhythm.
Monitor patients for adverse effects of antiarrhythmic drugs
Amiodarone administered (Table 66).
If ineffective: Ventricular Fibrillation

Ventricular brillation is irregular, disorganized, chaotic elec-
LVEF greater than or equal LVEF less than 40% trical activity in the ventricles resulting in absence of ventric-
to 40% or no history of HF or history of HF ular depolarizations, and, consequently, lack of pulse, cardiac
output, and blood pressure.

Approximately 400,000 people die of sudden cardiac death
Procainamide DCC
annually in the United States. While some of these deaths
occur as a result of asystole, the majority occur as a result of
primary VF or VT that degenerates into VF. Etiologies of VF
are presented in Table 610 and are similar to those of VT.
Lidocaine
Treatment
FIGURE 611. Decision algorithm for termination of hemody-
namically stable ventricular tachycardia.
DCC, direct current cardioversion; HF, heart failure; LVEF, left Desired Outcomes
ventricular ejection fraction; VT, ventricular tachycardia. The desired outcomes for treatment are to: (1) terminate VF,
(Algorithm adapted with permission from Tisdale JE, Moser LR. (2) achieve return of spontaneous circulation, and (3) achieve
Tachyarrhythmias. In: Mueller BA, Bertch KE, Dunsworth TS, et al. patient survival to hospital admission (in those with out-of-
(eds.) Pharmacotherapy Self-Assessment Program, 4th ed. Kansas hospital cardiac arrest) and to hospital discharge.
City: American College of Clinical Pharmacy; 2001:217267.)50
Pharmacologic and Nonpharmacologic Therapy
an increased risk of hypotension and drug-induced torsades de Ventricular brillation is by denition hemodynamically
pointes and due to negative inotropic activity.14 unstable, due to the absence of pulse and blood pressure.
Initial management includes provision of basic life support,
Nonpharmacologic Therapy: Prevention of Sudden including calling for help and initiation of cardiopulmonary
Cardiac Death resuscitation (CPR).48 Oxygen should be administered as soon
In patients who have experienced VT and are at risk for sud-
den cardiac death, implantation of an implantable cardioverter-
debrillator (ICD) is the treatment of choice.44 An ICD is a device Clinical Presentation and Diagnosis:
that provides internal electrical cardioversion of VT or debril- Ventricular Fibrillation
lation of VF; the ICD does not prevent the patient from devel-
oping the arrhythmia, but it reduces the risk that the patient
will die of sudden cardiac death as a result of the arrhythmia. Symptoms
Whereas in the past ICD implantation required a thoracotomy, VF results in immediate loss of pulse and blood pressure.
these devices now may be implanted transvenously, similarly to Patients who are in the standing position at the onset of
VF suddenly immediately collapse to the ground.
pacemakers, markedly reducing the complication rate.
ICDs have been found to be signicantly more effective Diagnosis
than antiarrhythmic agents such as amiodarone or sotalol for The absence of a pulse does not guarantee VF, as the
reducing the risk of sudden cardiac death;45,46 therefore, ICDs pulse may also be absent in patients with asystole, VT, or
are preferred therapy.44 However, many patients with ICDs pulseless electrical activity.
Conrmation of the diagnosis with an ECG is necessary
receive concurrent antiarrhythmic drug therapy to reduce the
in order to determine appropriate treatment. ECG reveals
frequency with which patients experience the discomfort of no organized, recognizable QRS complexes. If treatment
shocks and to prolong battery life of the devices. Combined is not initiated within a few minutes, death will occur, or
pharmacotherapy with amiodarone and a -blocker is more at best, resuscitation of the patient with permanent
effective than monotherapy with sotalol or -blockers for anoxic brain injury.
reduction in the frequency of ICD shocks.47
as it is available. Most importantly, debrillation should be

performed as soon as possible. It is critically important to Ventricular fibrillation/pulseless ventricular tachycardia
understand that the only means of successfully terminating
VF and restoring sinus rhythm is electrical debrillation.
Debrillation should be attempted using 200 J, after which Call for help, initiate CPR
CPR should be resumed immediately while the debrillator
charges; if the rst shock was unsuccessful, subsequent deb-
rillation shocks should be 360 J.48 Defibrillation attempts 12 times
If VF persists following one or two debrillation shocks,
drug therapy may be administered. The purpose of drug
administration for treatment of VF is to facilitate successful deb-
rillation. Drug therapy alone will not result in termination of VF. Ventricular fibrillation/pulseless ventricular
tachycardia still present
Drugs that are used for facilitation of debrillation in patients
with VF are listed in Table 612. Drug administration should
occur during CPR, before or after delivery of a debrillation
shock. The vasopressor agents epinephrine or vasopressin are Epinephrine or Vasopressin
administered initially, because it has been shown that a critical
factor in successful debrillation is maintenance of coronary
perfusion pressure, which is achieved via the vasoconstricting Amiodarone
effects of these drugs. A decision algorithm for the treatment of
VF is presented in Fig. 612. Epinephrine and vasopressin are
equally effective for facilitation of debrillation leading to survival
to hospital admission in patients with out-of-hospital cardiac Lidocaine
arrest due to VF. Amiodarone is more effective than lidocaine
FIGURE 612. Decision algorithm for resuscitation of ventricular
for facilitation of debrillation leading to survival to hospital
brillation or pulseless ventricular tachycardia.
admission in patients with VF,49 which is the reason that amio- CPR, cardiopulmonary resuscitation.
darone administration is recommended earlier than lidocaine
A debrillation attempt should be made after every dose of
administration in the decision algorithm.48 Note that the drug.

amiodarone doses recommended for administration during a If epinephrine is selected, the drug should continue to be
resuscitation attempt for VF (Table 612) are different than administered every 3 to 5 minutes throughout the remainder
those recommended for administration for termination of VT of the resuscitation attempt.
(Table 611).
Outcome Evaluation
Monitor the patient for return of pulse and blood pressure,
and for termination of VF and restoration of normal sinus
rhythm. Torsades de Pointes
After successful resuscitation, monitor the patient for
Torsades de pointes is a specic polymorphic VT that is asso-
adverse effects of drugs administered (Table 66). ciated with prolongation of the QT interval in the sinus beats
that precede the arrhythmia.13
TABLE 612. Drugs for Facilitation of Debrillation Epidemiology and Etiology

in Patients with Ventricular Fibrillation The incidence of torsades de pointes in the population at large
is unknown. The incidence of torsades de pointes associated
Drug Dose with specic drugs ranges from less than 1% to as high as 8%
Epinephrine 1 mg IV every 35 minutes to 10%, depending on dose and plasma concentration of the
Vasopressin 40 units IV single dose drug and the presence of other risk factors for the arrhythmia.
Amiodarone 300 mg IV diluted in 2030 mL D5W Torsades de pointes may be inherited or acquired. Patients
One subsequent dose of 150 mg IV may be with specic genetic mutations may have the inherited long
administered QT syndrome, in which the QT interval is prolonged, and these
Lidocaine 11.5 mg/kg IV bolus patients are at risk for torsades de pointes. Acquired torsades
Follow with additional IV boluses of 0.50.75 mg/kg de pointes may be caused by numerous drugs (Table 613); the
up to total of 3 mg/kg list of drugs that are known to cause torsades de pointes
IV, intravenous. continues to expand.
TABLE 613. Drugs That Have Been Reported to Cause

Torsades de Pointes13 Clinical Presentation and Diagnosis:
Torsades de pointes
Amiodarone Ibutilide
Amitriptyline Indapamide
Arsenic Levooxacin Symptoms
Bepridil Levomethadyl As with other tachyarrhythmias, symptoms associated
Chloroquine Loratadine
with torsades de pointes are dependent primarily on heart
Chlorpromazine Methadone
rate and include palpitations, dizziness, lightheadedness,
Ciprooxacin Metoclopramide
Clarithromycin Pentamidine shortness of breath, chest pain (if underlying CAD is pres-
Disopyramide Pimozide ent), near-syncope, and syncope.
Dofetilide Procainamide Torsades de pointes may be hemodynamically unstable if
Doxepin Propafenone the rate is sufciently rapid.
Droperidol Quinidine Like sustained monomorphic VT, torsades de pointes may
Erythromycin Sertraline result in the absence of a pulse, or may rapidly degener-
Famotidine Sotalol ate into VF, resulting in the syndrome of sudden cardiac
Flecainide Tacrolimus death.
Fluconazole Thioridazine
Fluoxetine Trazodone Diagnosis
Gatioxacin Trimethoprim-sulfamethoxazole Diagnosis of torsades de pointes requires examination of
Haloperidol the arrhythmia on ECG.
Torsades de pointes, or twisting of the points, appears
on ECG as apparent twisting of the wide QRS complexes
Pathophysiology around the isoelectric baseline.
Torsades de pointes is caused by circumstances, often drugs, The arrhythmia is associated with heart rates from 150 to
that lead to prolongation in the repolarization phase of the 300 bpm.
ventricular action potential (Fig. 62) manifested on the ECG Characteristic feature: a long-short initiating sequence,
which occurs as a result of a ventricular premature beat
by prolongation of the QT interval. Prolongation of ventricu-
followed by a compensatory pause, which is followed by
lar repolarization occurs via inhibition of efux of potassium
the rst beat of the torsades de pointes.
through potassium channels; therefore, drugs that inhibit con- Episodes of torsades de pointes may self-terminate, with
ductance through potassium channels may cause QT interval frequent recurrence.
prolongation and torsades de pointes. Prolongation of ven-
tricular repolarization likely promotes the development of early
ventricular afterdepolarizations during the relative refractory
period, which may provoke reentry leading to torsades de pointes. likelihood of the arrhythmia increases markedly in patients
with concomitant risk factors.
Drug-induced torsades de pointes rarely occurs in patients The onset of torsades de pointes associated with oral drug
without specic risk factors for the arrhythmia (Table 614). In therapy is somewhat variable and in some cases may be
most cases, administration of a drug known to cause torsades delayed; often, a patient can be taking a drug known to cause
de pointes is unlikely to cause the arrhythmia; however, the torsades de pointes for months or longer without problem,
until another risk factor for the arrhythmia becomes present,
which then may trigger the arrhythmia.
TABLE 614. Risk Factors for Drug-Induced Torsades de Pointes13
In some patients, torsades de pointes may be of short dura-
QTc interval greater than 500 milliseconds tion and may terminate spontaneously. However, torsades de
Increase in QTc interval by more than 60 milliseconds compared pointes may not terminate on its own, and if left untreated,
with the pretreatment value may degenerate into VF and result in sudden cardiac death.13
Female gender
Several drugs, including terfenadine, astemizole, and cisapride
Heart failure
Electrolyte abnormalities: hypokalemia and hypomagnesemia have been withdrawn from the United States market as a
Bradycardia result of causing deaths due to torsades de pointes.
Elevated plasma concentrations of QT interval-prolonging drugs
due to drug interactions or absence of dose adjustment for Prevention and Treatment
organ dysfunction
Rapid intravenous infusion of torsades-inducing drugs
Concomitant administration of more than one agent known to Desired Outcomes
cause QT interval prolongation/torsades de pointes The desired outcomes for treatment include the: (1) preven-
Possible genetic predisposition tion of torsades de pointes, (2) termination of torsades de
Previous history of drug-induced torsades de pointes pointes, (3) prevention of recurrence, and (4) prevention of
QTc, corrected QT interval sudden cardiac death.
Pharmacologic and Nonpharmacologic Therapy Alternatively, a continuous magnesium infusion may be ini-
In patients with risk factors for torsades de pointes, drugs tiated after the rst bolus, at a rate of 0.5 to 1 g/hour. Alternative
with the potential to cause QT interval prolongation and tor- treatments include: transvenous insertion of a temporary pace-
sades de pointes should be avoided or used with extreme caution, maker for overdrive pacing, which shortens the QT interval and
and diligent QT interval monitoring should be performed. may terminate torsades de pointes; intravenous isoproterenol 2
Management of drug-induced torsades de pointes includes to 10 mcg/minute, to increase the heart rate and shorten the QT
discontinuation of the potentially causative agent. Patients interval; intravenous lidocaine, which may shorten the duration
with hemodynamically unstable torsades de pointes should of ventricular repolarization; or intravenous phenytoin, which
undergo immediate synchronized DCC. In patients with may also shorten the duration of ventricular repolarization,
hemodynamically stable torsades de pointes, electrolyte administered at a dose of 10 to 15 mg/kg infused at a rate of 25
abnormalities such as hypokalemia and hypomagnesemia to 50 mg/minute.
should be corrected. Hemodynamically stable torsades de
pointes is often treated with intravenous magnesium, irre- Outcome Evaluation
spective of whether the patient is hypomagnesemic; magne- Monitor vital signs (heart rate and blood pressure).
sium has been shown to terminate torsades de pointes in nor- Monitor the ECG to determine the QTc interval (maintain
momagnesemic patients. Intravenous magnesium may be less than 450 milliseconds) and for the presence of torsades
administered in doses of 1 to 2 g, diluted in 50 to 100 mL D5W, de pointes.
administered over 5 to 10 minutes; doses may be repeated to a Monitor serum potassium and magnesium concentrations.
total of 12 g. Monitor for symptoms of tachycardia.
1. Perform a thorough medication history to determine whether the patient is receiving

any prescription or non-prescription drugs that may cause or contribute to the devel-
opment of an arrhythmia.
2. Evaluate the patient for the presence of drug-induced diseases, drug allergies, and
drug interactions.
3. Determine and monitor the patients serum electrolyte concentrations to determine
the presence or absence of hypokalemia, hyperkalemia, hypomagnesemia, or hyper-
magnesemia.
4. Consider the patients heart rate, blood pressure, and symptoms to determine
whether he or she is hemodynamically stable or unstable.
5. Monitor the patients 12-lead ECG or single rhythm strips to determine if an arrhyth-
mia is present and to identify the specic arrhythmia, and evaluate and monitor the
patients symptoms.
6. Develop drug therapy treatment plans for management of the specic arrhythmia that
the patient is experiencing: sinus bradycardia, AV nodal blockade, AF, PSVT, VPDs, VT
(including torsades de pointes), or VF.
7. Develop specic drug therapy monitoring plans for the treatment plan implemented.
Monitoring includes assessment of symptoms, ECG, adverse effects of drugs, and
potential drug interactions.
8. In those receiving warfarin for AF, determine whether the patients INR is therapeutic.
9. Provide information regarding safe and effective warfarin therapy:
Notify appropriate clinicians in the event of severe bruising, blood in urine or
stool, or frequent nosebleeds;
Avoid radical changes in diet;
Avoid alcohol;
Do not take non-prescription medications or herbal/alternative/complementary medi-
cines without notifying your physician, pharmacist, and/or health care team members.
10. Stress the importance of adherence to the therapeutic regimen.
11. Provide patient education regarding disease state and drug therapy.
ABBREVIATIONS KEY REFERENCES AND READINGS
AF: Atrial brillation 2005 American Heart Association guidelines for cardiopulmonary
ATPase: adenosine triphosphatase resuscitation and emergency cardiac care, part 7.2. Management
AV: atrioventricular of cardiac arrest. Circulation 2005;112:IV-57 to IV-66.
BP: blood pressure 2005 American Heart Association guidelines for cardiopulmonary
bpm: beats per minute resuscitation and emergency cardiac care, part 7.3. Management
Ca: calcium of symptomatic bradycardia and tachycardia. Circulation 2005;
CAD: coronary artery disease 112:IV-67 to IV-177.
CAST: Cardiac Arrhythmia Suppression Trial Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, et al. ACC/
CCB: calcium channel blocker AHA/ESC guidelines for the management of patients with
CPR: cardiopulmonary resuscitation supraventricular arrhythmiasexecutive summary: a report of
DCC: direct current cardioversion the American College of Cardiology/American Heart Association
ECG: electrocardiogram Task Force on Practice Guidelines and the European Society of
ED: emergency department Cardiology Committee for Practice Guidelines (writing com-
HF: heart failure mittee to develop guidelines for the management of patients
ICD: implantable cardioverter-debrillator with supraventricular arrhythmias). J Am Coll Cardiol 2003;42:
INR: International Normalized Ratio 14931531.
IV: intravenous Fuster V, Rydn LE, Cannon DS, et al. ACC/AHA/ESC 2006 guide-
J: Joules lines for the management of patients with atrial brillation
K: potassium executive summary; a report of the American College of
LV: left ventricular Cardiology/American Heart Association Task Force on Practice
LVEF: left ventricular ejection fraction Guidelines and the European Society of Cardiology Committee
Na: sodium for Practice Guidelines (Writing Committee to Revise the 2001
NYHA: New York Heart Association Guidelines for the Management of Patients with Atrial
PO: oral Fibrillation). Circulation 2006;114:700752.
PSVT: paroxysmal supraventricular tachycardia Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guide-
PTT: partial thromboplastin time lines for clinicians who treat patients with amiodarone.
PVC: premature ventricular contraction Practice Guidelines Subcommittee, North American Society
QTc: corrected QT interval of Pacing and Electrophysiology. Arch Intern Med 2000;160:
RR: respiratory rate 17411748.
SA: sinoatrial Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in
TEE: transesophageal echocardiogram atrial brillation. Chest 2004;126(Suppl):429S456S.
VPB: ventricular premature beat Snow V, Weiss KB, LeFevre M, et al. Management of newly detected
VPC: ventricular premature contraction atrial brillation: a clinical practice guideline from the American
VPD: ventricular premature depolarization Academy of Family Physicians and the American College of
VF: ventricular brillation Physicians. Ann Intern Med 2003;139:10091017.
VT: ventricular tachycardia Tisdale JE. Arrhythmias. In: Tisdale JE, Miller DA, eds. Drug-Induced
Diseases. Prevention, Detection and Management. Bethesda,
Reference lists and self-assessment questions and answers are MD: American Society of Health-Systems Pharmacists; 2005:
available at www.ChisholmPharmacotherapy.com. 289327.

this chapter.
7 VENOUS THROMBOEMBOLISM
Stuart T. Haines and Edith A. Nutescu
LEARNING OBJECTIVES
1. Identify risk factors and signs and symptoms of deep vein thrombosis and pulmonary
embolism.
2. Describe the processes of hemostasis and thrombosis, including the role of the vascular
endothelium, platelets, coagulation cascade, and thrombolytic proteins.
3. Determine a patients relative risk (low, moderate, high, or very high) of developing venous
thrombosis.
4. State at least two potential advantages of the low-molecular-weight heparins and
fondaparinux over unfractionated heparin.
5. Formulate an appropriate prevention strategy for a patient at risk for deep vein thrombosis.
6. Identify factors that place a patient at high risk of bleeding while receiving antithrombotic
drugs.
7. Select and interpret laboratory test(s) to monitor antithrombotic drugs.
8. Identify and analyze warfarin drug-drug and drug-food interactions.
9. Manage a patient with an elevated International Normalized Ratio (INR) with or without
bleeding.
10. Formulate an appropriate treatment plan for a patient who develops a deep vein
thrombosis or pulmonary embolism, and develop a comprehensive education plan for a
patient who is receiving an antithrombotic drug.
KEY CONCEPTS appropriate for each patients level of risk should be routinely
employed. Prophylaxis should be continued throughout the
Antithrombotic therapies require meticulous and systematic period of risk.
monitoring, as well as ongoing patient education. Well-organized In the absence of contraindications, the treatment of VTE
anticoagulation management services improve the quality of should initially include a rapid-acting anticoagulant (e.g.,
patient care and reduce the overall cost. unfractionated heparin, low-molecular-weight heparin, or
The risk of venous thromboembolism (VTE) is related to fondaparinux) overlapped with warfarin for at least 5 days
several easily identiable factors including age, prior history and until the patients INR is greater than 2. Anticoagulation
of VTE, major surgery (particularly orthopedic procedures therapy should be continued for a minimum of 3 months.
of the lower extremities), trauma, malignancy, pregnancy, However, the duration of anticoagulation therapy should be
estrogen use, and hypercoagulable states. These risks are based on the patients risk of VTE recurrence and major bleeding.
additive. Bleeding is the most common adverse effect associated with
The diagnosis of VTE must be conrmed by an objective antithrombotic drugs. A patients risk of major hemorrhage is
test. related to the intensity and stability of therapy, age, concur-
At the time of hospital admission, all patients should be eval- rent drug use, history of gastrointestinal bleeding, risk of falls
uated for their risk of VTE, and strategies to prevent VTE or trauma, and recent surgery.
133
Most patients with an uncomplicated deep vein thrombosis clot) and recurrent thromboembolic events cause long-term
(DVT) can be managed safely at home. pain and suffering.
Warfarin is prone to numerous clinically important drug- The treatment of VTE is fraught with substantial risks.3
drug and drug-food interactions. Antithrombotic drugs require precise dosing and meticulous
monitoring, as well as ongoing patient education.4,5 Well organ-
Venous thromboembolism (VTE) is one of the most common ized anticoagulation management services improve the quality
cardiovascular disorders in the United States. VTE is mani- of patient care and reduce the overall cost. A systematic approach
fested as deep vein thrombosis (DVT) and pulmonary to drug therapy management substantially reduces these risks,
embolism (PE) resulting from thrombus formation in the but bleeding remains a common and serious complication.6
venous circulation (Fig. 71).1 It is often provoked by pro- Therefore, preventing VTE is paramount to improving out-
longed immobility and vascular injury and is most frequently comes. When VTE is suspected, a rapid and accurate diagnosis
seen in patients who have been hospitalized for a serious med- is critical to making appropriate treatment decisions. The
ical illness, trauma, or major surgery. VTE can also occur with optimal use of antithrombotic drugs requires not only an
little or no provocation in patients who have an underlying in-depth knowledge of their pharmacology and pharmacoki-
hypercoagulable disorder. netic properties, but also a comprehensive approach to patient
While VTE may initially cause few or no symptoms, the management.7
rst overt manifestation of the disease may be sudden death.2
Death from PE can occur within minutes, before effective EPIDEMIOLOGY AND ETIOLOGY
treatment can be given. In addition to the symptoms pro-
duced by the acute event, the long-term sequelae of VTE such The true incidence of VTE in the general population is
as the post-thrombotic syndrome (PTS; a complication of unknown because many patients, perhaps more than 50%,
VTE occurring due to damage to the vein caused by a blood have no overt symptoms or go undiagnosed.8 An estimated
FIGURE 71. Venous circulation. (Reproduced

from Haines ST, Zeolla M, Witt DM. Venous
thromboembolism. In: DiPiro JT, Talbert RL,
Yee GC, et al, (eds.) Pharmacotherapy: A
Pathophysiologic Approach. 6th ed. New York:
Jugular vein McGraw-Hill; 2005: 374, with permission.)
Subclavian vein
Superior vena cava Cephalic vein
Basilic vein
Inferior vena cava
Iliac vein
Femoral vein
Great saphenous vein
Popliteal vein
Small saphenous vein
Anterior tibial vein
Dorsal venous arch

CHAPTER 7 / VENOUS THROMBOEMBOLISM 135
2 million people in the United States develop VTE each year; thrombosis is perhaps the strongest risk factor for recurrent
600,000 are hospitalized and 60,000 die. The estimated annual VTE, presumably because of the destruction of venous valves and
direct medical costs of managing the disease are well over $1 obstruction of blood ow caused by the initial event. Rapid blood
billion. The best available data indicate the age-adjusted inci- flow has an inhibitory effect on thrombus formation, but a
dence of symptomatic VTE in Caucasians is 117 per 100,000 slow rate of ow reduces the clearance of activated clotting
per year.9 The incidence of VTE nearly doubles in each decade factors in the zone of injury and slows the inux of regulatory
of life over the age of 50 and is slightly higher in men. The age- substances. Stasis tips the delicate balance of procoagulation
adjusted incidence of PE has declined slightly in recent years, and anticoagulation in favor of thrombogenesis. The rate of
presumably because of heightened awareness of VTE, effective blood ow in the venous circulation, particularly in the deep
prevention strategies, early diagnosis, and prompt treatment. veins of the lower extremities, is relatively slow. Valves in the
However, as the population ages, the total number of cases of deep veins of the legs, as well as contraction of the calf and
DVT and PE continues to rise. thigh muscles, facilitate the ow of blood back to the heart
and lungs. Damage to the venous valves and periods of pro-
The risk of VTE is related to several easily identiable
longed immobility result in venous stasis. Vessel obstruction,
factors including age, prior history of VTE, major surgery
either from a thrombus or external compression, promotes
(particularly orthopedic procedures of the lower extremities),
clot propagation. Numerous medical conditions and surgical
trauma, malignancy, pregnancy, estrogen use, and hypercoagu-
procedures are associated with reduced venous blood ow
lable state (Table 71).2 These risk factors are additive and can
and increase the risk of VTE (Table 71). Greater than normal
be easily identied in clinical practice. A prior history of venous
blood viscosity, seen in myeloproliferative disorders like poly-
cythemia vera, for example, may also contribute to slowed
blood ow and thrombus formation.
TABLE 71. Risk Factors for Venous Thromboembolism A growing list of hereditary deciencies, gene mutations,
and acquired diseases have been linked to hypercoagulability
Risk Factor Example
(Table 71).10 Activated protein C resistance is the most
Age Risk doubles with each decade after age 50 common genetic disorder of hypercoagulability, found in
Prior history of VTE Strongest known risk factor for DVT and PE nearly 5% of individuals of northern European descent and in as
Venous stasis Major medical illness (e.g., congestive many as 40% of those who suffer an idiopathic DVT. Although
heart failure) these patients have normal plasma concentrations of protein C,
Major surgery (e.g., general anesthesia for they have a mutation on factor V that renders it resistant to
greater than 30 minutes)
Paralysis (e.g., due to stroke or spinal cord degradation by activated protein C. This mutation is known as
injury) factor V Leiden, named after the city of Leiden, Holland, where
Polycythemia vera the defect was initially reported. The prothrombin 20210A
Obesity mutation is also a relatively common defect, occurring in as
Varicose veins many as 3% of healthy individuals of southern European
Vascular inujury Major orthopedic surgery (e.g., knee and descent and 16% of those with an idiopathic DVT. Although
hip replacement)
less common, inherited deciencies of the natural anticoagu-
Trauma (esp. fractures of the pelvis, hip, or leg)
Indwelling venous catheters lants protein C, protein S, and antithrombin place patients at a
Hypercoagulable Malignancy, diagnosed or occult high lifetime risk for VTE. Conversely, high concentrations of
states Activated protein C resistance/factor V Leiden factors VIII, IX, and XI also increase the risk of VTE. Some
Prothrombin (20210A) gene mutation patients have multiple genetic defects.
Protein C deciency Acquired disorders of hypercoagulability include malig-
Protein S deciency nancy, antiphospholipid antibodies, estrogen use, and preg-
Antithrombin deciency
Factor VIII excess (greater than 90th percentile) nancy.2 The strong link between cancer and thrombosis has been
Factor XI excess (greater than 90th percentile) recognized since the late 1800s.11 Tumor cells secrete a number
Antiphospholipid antibodies of procoagulant substances that activate the clotting cascade.
Dysbrinogenemia Furthermore, patients with cancer often have suppressed levels
PAI-l excess of protein C, protein S, and antithrombin. Antiphospholipid
Pregnancy/postpartum
antibodies, commonly found in patients with autoimmune dis-
Drug therapy Estrogen-containing oral contraceptive pills
orders such as systemic lupus erythematosus and inammatory
Estrogen replacement therapy
SERMs bowel disease, can cause venous and arterial thrombosis.12 The
HIT antiphospholipid antibody syndrome is associated with repeated
pregnancy loss. The precise mechanism by which these antibod-
DVT, deep vein thrombosis; HIT, heparin-induced thrombocytopenia;
PAI-l, plasminogen activator inhibitor; PE, pulmonary embolism; SERM, ies provoke thrombosis is unclear, but they activate the coagula-
selective estrogen receptor modulator; VTE, venous thromboembolism. tion cascade and platelets, as well as inhibit the anticoagulant
activity of proteins C and S. Estrogen-containing contraceptives, adherence, prevent the activation of the coagulation cas-
estrogen replacement therapy, and many of the selective estro- cade, and facilitate brinolysis.15,16 Vascular injury exposes
gen receptor modulators (SERMs) increase the risk of venous the subendothelium (Fig. 73). Platelets readily adhere to
thrombosis.2,13 While the mechanisms are not clearly under- the subendothelium, using glycoprotein Ib receptors found
stood, estrogens increase serum clotting factor concentrations on their surfaces and facilitated by von Willebrand factor.
and induce activated protein C resistance. Increased serum This causes platelets to become activated, releasing a num-
estrogen concentrations may explain, in part, the increased risk ber of procoagulant substances that stimulate circulating
of VTE during pregnancy and the postpartum period.14 platelets to expose glycoprotein IIb-IIIa receptors and allow
platelets to adhere to one another, resulting in platelet
aggregation. The damaged vascular tissue releases tissue fac-
PATHOPHYSIOLOGY tor which activates the extrinsic pathway of the coagulation
cascade (Fig. 74).
The arrest of bleeding following vascular injury, or hemo- The clotting cascade is a stepwise series of enzymatic
stasis, is essential to life.15 Within the vascular system, reactions that result in the formation of a brin mesh.15,16
blood remains in a uid state, transporting oxygen, nutri- Clotting factors circulate in the blood in inactive forms.
ents, plasma proteins, and waste. With vascular injury, a Once a precursor is activated by specic stimuli, it activates
dynamic interplay between thrombogenic (activating) and the next precursor in the sequence. The nal steps in the cas-
antithrombotic (inhibiting) forces result in the local for- cade are the conversion of prothrombin to thrombin and
mation of a hemostatic plug that seals the vessel wall and brinogen to brin. Thrombin plays a key role in the coag-
prevents further blood loss (Figs. 72, 73, and 74). A dis- ulation cascade; it is responsible not only for the production
ruption of this delicate system of checks and balances may of brin, but also for the conversion of factors V and VIII,
lead to inappropriate clot formation within the blood ves- creating a positive feedback loop that greatly accelerates the
sel that can obstruct blood ow or embolize to a distant entire cascade. Thrombin also enhances platelet aggregation.
vascular bed. Traditionally, the coagulation cascade has been divided into
Under normal circumstances, the endothelial cells that three distinct parts: the intrinsic, the extrinsic, and the com-
line the inside of blood vessels maintain blood flow by mon pathways (Fig. 74). This articial division is mislead-
producing a number of substances that inhibit platelet ing because there are numerous interactions between the
three pathways.
A number of tempering mechanisms control coagulation
(Fig. 72).15,16 Without effective self-regulation, the coagula-
Activators Inhibitors tion cascade would proceed unabated until all the clotting
Vessel wall injury factors and platelets are consumed. The intact endothelium
endothelium
von Willebrand factor Heparin adjacent to the damaged tissue actively secretes several
Thrombomodulin
Platelet adhesion antithrombotic substances including heparan sulfate, throm-
and aggregation bomodulin, protein C, and protein S. Activated protein C
inhibits factor Va and VIIIa activity. Antithrombin and
Tissue factor Coagulation Antithrombin
cascade activated Protein C
heparin cofactor II (HCII) are circulating proteins that
Factor VIIa
Factor Xa Protein S inhibit thrombin and factor Xa. Heparan sulfate exponen-
Factor XIIa Tissue factor
Thrombin
pathway inhibitor
tially accelerates antithrombin and HCII activity. Tissue
Thrombin
factor pathway inhibitor (TFPI) inhibits the extrinsic coagu-
Fibrin formation lation pathway. When these self-regulatory mechanisms are
Factor XIIIa intact, the formation of the brin clot is limited to the zone
Stabilized fibrin clot of tissue injury. However, disruptions in the system often
Tissue plasminogen Plasminogen activator
activator inhibitor-1 result in inappropriate clot formation.
Fibrinolysis and
clot degradation The brinolytic protein plasmin degrades the brin mesh
into soluble end products collectively known as brin split
Recanalization products or brin degradation products.15,16 The brinolytic
and healing system is also under the control of a series of stimulatory and
inhibitory substances. Tissue plasminogen activator (t-PA)
FIGURE 72. Hemostasis and thrombosis. (Reproduced from and urokinase plasminogen activator (u-PA) convert plas-
Haines ST, Zeolla M, Witt DM. Venous thromboembolism. In: minogen to plasmin. Plasminogen activator inhibitor-1 (PAI-1)
DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A inhibits the plasminogen activators and 2-antiplasmin
Pathophysiologic Approach. 6th ed. New York: McGraw-Hill;
2005: 376, with permission.)
inhibits plasmin activity. Aberrations in the brinolytic system
have also been linked to hypercoagulability.
FIGURE 73. Vascular injury and

Endothelium Extrinsic coagulation pathway thrombosis. ADP, adenosine diphos-
(see Figure 74) phate; CO, cyclooxygenase; GP Ib,
Subendothelium
glycoprotein Ib; GP IIb/IIa, glycopro-
X
tein IIb/IIa; HK, high-molecular-
weight kininogen; PAF, platelet-
t-PA VIIIa Ca
platelet activating factor-1; PAI-1, plasminogen
IXa
u-PA II activator inhibitor; PF-4 platelet
ADP surface Xa
receptors factor-4; PGG/PGH, prostaglandins;
PAF Va Ca
PGI, prostacyclin; PLA, phospholi-
Collagen
Tissue pase A; TS, thromboxane synthetase;
Factor Thrombin IIa TXA2, thromboxane A2; t-PA, tissue
TXA2/PGH2 phospholipid plasminogen activator; u-PA, uroki-
Epinephrine nase plasminogen activator; vWF,
PLA2 -Granule ADP von Willebrand factor. (Reproduced
Vessel Serotonin
vWF
arachidonic
from Haines ST, Zeolla M, Witt DM.
wall
acid Dense vW Venous thromboembolism. In: DiPiro
GPIb body PF-4 JT, Talbert RL, Yee GC, et al, (eds.)
receptor HK
Fibrinogen Pharmacotherapy: A Pathophysiologic
TS
Approach. 6th ed. New York:
PGG2/PGH2 TXA2 McGraw-Hill; 2005: 376, with
PAI-1 permission.)
Fibrinogen
Platelet
TXA2
Heparan sulfate
GP IIb/IIIa
Thrombomodulin receptor
complex
CLINICAL PRESENTATION AND DIAGNOSIS DVT caused by damage to the venous valves, produces chronic
lower extremity swelling, pain, tenderness, skin discoloration,
Although a thrombus can form in any part of the venous and ulceration. The D-dimer test, a quantitative measure of b-
circulation, the majority begin in the lower extremities. Once rin breakdown in the serum, is a marker of acute thrombotic
formed, a venous thrombus may behave in several ways activity and may help to distinguish between an acute DVT and
including: (1) remain asymptomatic, (2) spontaneously lyse, the post-thrombotic syndrome. Symptomatic PE often produces
(3) obstruct the venous circulation, (4) propagate into more shortness of breath, tachypnea, and tachycardia. Hemoptysis,
proximal veins, (5) embolize, and/or (6) slowly incorporate while distressing, occurs in less than one-third of patients. The
into the endothelial layer of the vessel.15 The majority of physical exam may reveal diminished breath sounds, crackles,
patients with VTE never develop symptoms.2 However, even wheezes, or a pleural friction rub during auscultation of the
those who initially experience no symptoms may suffer long- lungs. Cardiovascular collapse, characterized by cyanosis, shock,
term consequences, such as the postthrombotic syndrome and oliguria, is an ominous sign.18
and recurrent VTE. The symptoms of DVT or PE are non- Given that VTE can be debilitating or fatal, it is important to
specic, and it is extremely difcult to distinguish VTE from treat it quickly and aggressively.8 On the other hand, because
other disorders.17 Therefore, objective tests are required to conrm major bleeding induced by antithrombotic drugs can be equally
or exclude the diagnosis. Patients with deep vein thrombosis harmful, it is important to avoid treatment when the diagnosis is
often present with unilateral leg pain and swelling. Similarly, not reasonably certain. Assessment of the patients status should
the postthrombotic syndrome, a long-term complication of focus on the search for risk factors in the patients medical history
FIGURE 74. Coagulation cascade.

AT, antithrombin; HCII, heparin
cofactor II; TFPI, tissue factor
pathway inhibitor. (Reproduced
from Haines ST, Zeolla M, Witt DM.
Venous thromboembolism. In:
DiPiro JT, Talbert RL, Yee GC, et al,
(eds.) Pharmacotherapy: A
Pathophysiologic Approach. 6th ed.
New York: McGraw-Hill; 2005: 377,
with permission.)
(Table 71).17 Venous thrombosis is uncommon in the absence of these reasons, non-invasive tests, such as ultrasonography, com-
risk factors, and the effects of these risks are additive. Conversely, puted tomography (CT) scans, and the ventilation/perfusion
even in the absence of symptoms, VTE should be strongly sus- (V/Q) scan are frequently used in clinical practice for the initial
pected in those with multiple risk factors. evaluation of patients with suspected VTE.
Because radiographic contrast studies are the most accu-
rate and reliable methods for the diagnosis of VTE, they are
considered the gold standards in clinical trials.17 Contrast PREVENTION OF VENOUS THROMBOEMBOLISM
venography allows visualization of the entire venous system
in the lower extremities and abdomen. Pulmonary angiogra- Given that VTE is often clinically silent and potentially fatal,
phy allows the visualization of the pulmonary arteries. The prevention strategies have the greatest potential to improve
diagnosis of VTE can be made if there is a persistent intralu- patient outcomes.2 To rely on the early diagnosis and treat-
minal lling defect observed on multiple x-ray lms. Contrast ment of VTE is unacceptable because many patients will die
studies are expensive, invasive procedures that are technically before treatment can be initiated. Furthermore, even clinically
difcult to perform and evaluate. Severely ill patients often are silent disease is associated with long-term morbidity from the
unable to tolerate the procedure, and many develop hypoten- postthrombotic syndrome and predisposes the patient to
sion and cardiac arrhythmias. Furthermore, the contrast future thromboembolic events. Despite an immense body of
medium is irritating to vessel walls and toxic to the kidneys. For literature that overwhelmingly supports the widespread use of
Clinical Presentation and Diagnosis of Clinical Presentation and Diagnosis of

Deep Vein Thrombosis Pulmonary Embolism
General General
Venous thromboembolism most commonly develops in Pulmonary embolism most commonly develops in patients
patients with identiable risk factors (Table 71) during or with risk factors for VTE (Table 72) during or following a
following a hospitalization. Many, perhaps the majority of hospitalization. While many patients will have symptoms
patients, have asymptomatic disease. Patients may die sud- of DVT prior to developing a PE, many do not. Patients may
denly of pulmonary embolism. die suddenly before effective treatment can be initiated.
Symptoms Symptoms
The patient may complain of leg swelling, pain, or warmth. The patient may complain of cough, chest pain, chest
Symptoms are non-specic and objective testing must be tightness, shortness of breath, or palpitations.
performed to establish the diagnosis. The patient may spit or cough up blood (hemoptysis).
The patient may complain of dizziness or lightheadedness.
Signs
Symptoms may be confused for a myocardial infarction
The patients supercial veins may be dilated and a
and objective testing must be performed to establish the
palpable cord may be felt in the affected leg.
diagnosis.
The patient may experience pain in back of the knee in
the affected leg when the examiner dorsiexes the foot Signs
while the knee is slightly bent. The patient may have tachypnea (increased respiratory
rate) and tachycardia (increased heart rate).
Laboratory Tests
The patient may appear diaphoretic (sweaty).
Serum concentrations of D-dimer, a by-product of throm-
The patients neck veins may be distended.
bin generation, is usually elevated. The patient may have
The examiner may hear diminished breath sounds, crackles,
an elevated erythrocyte sedimentation rate (ESR) and
wheezes, or pleural friction rub during auscultation of the
white blood cell (WBC) count.
lungs.
Diagnostic Tests In massive PE, the patient may appear cyanotic and may
Duplex ultrasonography is the most commonly used test become hypotensive. In such cases, oxygen saturation by
to diagnosis DVT. It is a non-invasive test that can meas- pulse oximetry or arterial blood gas will likely indicate
ure the rate and direction of blood ow and visualize clot that the patient is hypoxic.
formation in proximal veins of the legs. It cannot reliably In the worst cases, the patient may go into circulatory
detect small blood clots in distal veins. Coupled with a shock and die within minutes.
careful clinical assessment, it can rule in or out (include
Laboratory Tests
or exclude) the diagnosis in the majority of cases.
Serum concentrations of D-dimer, a by-product of thrombin
Venography (also known as phlebography) is the gold
generation, is usually elevated. The patient may have an ele-
standard for the diagnosis of DVT. However, it is an inva-
vated ESR and WBC count.
sive test that involves injection of radiopaque contrast dye
into a foot vein. It is expensive and can cause anaphylaxis Diagnostic tests
and nephrotoxicity. V/Q scan and CT scans are the most commonly used tests to
diagnose PE. A V/Q scan measures the distribution of blood
and air ow in the lungs. When there is a large mismatch
pharmacologic and nonpharmacologic strategies to prevent between blood and air ow in one area of the lung, there is
VTE, prophylaxis is underutilized in most hospitals. Even a high probability that the patient has a PE. Spiral CT scans
can detect emboli in the pulmonary arteries.
when prophylaxis is given, many patients receive prophylaxis
Pulmonary angiography is the gold standard for the diag-
that is less than optimal. Educational programs and comput- nosis of PE. However, it is an invasive test that involves
erized clinical decision support systems have been shown to injection of radiopaque contrast dye into the pulmonary
improve the appropriate use of VTE prevention methods.2 artery. The test is expensive and associated with a signi-
The goal of an effective VTE prophylaxis program is to cant risk of mortality.
identify all patients at risk, determine each patients level of
risk, and select and implement regimens that provide suf-
cient protection for the level of risk. At the time of hospital by the American College of Chest Physicians (ACCP)
admission, all patients should be evaluated for their risk of VTE, Conference on Antithrombotic Therapy are widely used in
and strategies to prevent VTE appropriate for each patients North America (Table 72).2 Several pharmacologic and
level of risk should be routinely employed. Prophylaxis should be nonpharmacologic methods are effective for preventing
continued throughout the period of risk. The risk classication VTE, and these can be used alone or in combination. Non-
criteria and recommended prophylaxis strategies published pharmacologic methods improve venous blood ow by
TABLE 72. Risk Classication and Consensus Guidelines for VTE Prevention2
Calf Vein Symptomatic Fatal PE

Level of Risk Thrombosis (%) PE (%) (%) Prevention Strategies
Low
Minor surgery, age less than 40 years, 2 0.2 0.002 Ambulation
and no clinical risk factors
Moderate
Major or minor surgery, age 4060 years, 1020 12 0.10.4 UFH 5000 units SC every 12 hours
and no clinical risk factors Dalteparin 2500 units SC every 24 hours
Major surgery, age less than 40 years, Enoxaparin 40 mg SC every 24 hours
and no clinical risk factors Tinzaparin 3500 units SC every 24 hours
Minor surgery, with clinical risk factor(s) IPC
Acutely ill (e.g., myocardial Graduated compression stockings
infarction, ischemic stroke, heart
failure exacerbation), and no
clinical risk factors
High
Major surgery, age greater than 60 years, 2040 24 0.41 UFH 5000 units SC every 8 hours
and no clinical risk factors Dalteparin 5000 units SC every 24 hours
Major surgery, age 4060 years, Enoxaparin 40 mg SC every 24 hours
with clinical risk factor(s) Fondaparinux 2.5 mg SC every 24 hours
Acutely ill (e.g., myocardial infarction, Tinzaparin 75 units/kg SC every 24 hours
ischemic stroke, heart failure IPC
exacerbation), with clinical risk factor(s)
Highest
Major lower extremity 4080 410 0.25 Adjusted dose UFH SC every 8 hours
orthopedic surgery (aPTT greater than 36 seconds)
Hip fracture Dalteparin 5000 units SC every 24 hours
Multiple trauma Desirudin 15 mg SC every 12 hours
Major surgery, age greater than 40 years, Enoxaparin 30 mg SC every 12 hours
and prior history of VTE Fondaparinux 2.5 mg SC every 24 hours
Major surgery, age greater than 40 years, Tinzaparin 75 units/kg SC every 24 hours
and malignancy Warfarin (target INR = 23)
Major surgery, age greater than 40 years, IPC with UFH 5000 units SC every 8 hours
and hypercoagulable state
Spinal cord injury or stroke with
limb paralysis
aPTT, activated partial thromboplastin time; INR, International Normalized Ratio; IPC, intermittent pneumatic compression; PE, pulmonary embolism;
SC, subcutaneous; UFH, unfractionated heparin; VTE, venous thromboembolism.
mechanical means, while drug therapy prevents thrombus unable to wear compression stockings because of the size or
formation by inhibiting the coagulation cascade. shape of their legs.
Similar to graduated compression stockings, intermittent
pneumatic compression (IPC) devices increase the velocity of
blood ow in the lower extremities.2 These devices sequen-
Ambulation as soon as possible following surgery lowers the tially inate a series of cuffs wrapped around the patients
incidence of VTE in low-risk patients.2 Walking increases legs from the ankles to the thighs and then deate in 1- to
venous blood ow and promotes the ow of natural 2-minute cycles. IPC has been shown to reduce the risk of VTE
antithrombotic factors into the lower extremities. Graduated by more than 60% following general surgery, neurosurgery,
compression stockings (GCS) reduce the incidence of VTE by and orthopedic surgery. Although IPC is well tolerated and
approximately 60% following general surgery, neurosurgery, safe to use in patients who have contraindications to pharma-
and stroke. Compared with anticoagulant drugs, graduated cologic therapies, it does have a few drawbacks: it is more
compression stockings are relatively inexpensive and safe. They expensive than the use of graduated compression stockings, it
are a good choice in low- to moderate-risk patients when phar- is a relatively cumbersome technique, and some patients may
macologic interventions are contraindicated. When combined have difculty sleeping while using it. Continuous passive
with pharmacologic interventions, graduated compression motion devices, electrical calf muscle stimulation, and plantar
stockings have an additive effect. However, some patients are compression system devices are also used in some institutions,
but they have not been shown to be as effective as other compared to low-dose unfractionated heparin after hip and
mechanical methods. knee replacement surgery and in other very-high-risk popu-
Inferior vena cava (IVC) lters, also known as Greeneld lations. Even so, unfractionated heparin remains a highly
lters, provide short-term protection against pulmonary effective, cost-conscious choice for many patient popula-
embolism in very-high-risk patients by preventing the tions, provided that it is given in the appropriate dose
embolization of a thrombus formed in the lower extremities (Table 72). Low-dose UFH (5000 units every 8 or 12 hours)
into the pulmonary circulation.2 Insertion of a lter into the given subcutaneously (SC) has been shown to reduce the
IVC is a minimally invasive procedure. Despite the wide- risk of VTE by 55% to 70% both in patients undergoing a
spread use of IVC lters, there are very limited data regard- wide range of general surgical procedures and following a
ing their effectiveness and long-term safety. The evidence myocardial infarction or stroke. For the prevention of VTE
suggests that IVC lters, particularly in the absence of effec- following hip and knee replacement surgery, the effectiveness
tive antithrombotic therapy, increase the long-term risk of of low-dose UFH is considerably lower. Adjusted-dose UFH
recurrent DVT. In the only randomized clinical trial exam- therapy provided subcutaneously, which requires dose adjust-
ining the short- and long-term effectiveness of the lters in ments to maintain the activated partial thromboplastin time
patients with a documented proximal DVT, treatment with (aPTT) at the high end of the normal range, may be used in
IVC lters reduced the risk of pulmonary embolism by more the highest-risk patient populations. However, adjusted-dose
than 75% during the rst 12 days following insertion.19 UFH has been studied in only a few, relatively small clinical
However, this benet was not sustained during 2 years of trials and requires frequent laboratory monitoring. The
follow-up and the long-term risk of recurrent deep vein LMWHs and fondaparinux appear to provide a high degree
thrombosis was nearly two-fold higher in those who received of protection against VTE in most high-risk populations.
a lter. Although IVC lters can reduce the short-term risk The appropriate prophylactic dose for each LMWH product is
of PE in patients at highest risk, they should be reserved for indication-specic (Table 72). There is no evidence that one
patients in whom other prophylactic strategies cannot be LMWH is superior to another for the prevention of VTE.
used. To further reduce the long-term risk of VTE in associ- Fondaparinux was signicantly more effective than enoxa-
ation with IVC lters, pharmacologic prophylaxis is neces- parin in several clinical trials that enrolled patients undergoing
sary and warfarin therapy should begin as soon as the high-risk orthopedic procedures, but has not been shown to
patient is able to tolerate it. reduce the incidence of symptomatic pulmonary embolism or
mortality.20 To provide optimal protection, some experts
believe that the LMWHs should be initiated prior to surgery.2
Warfarin is another commonly used option for the preven-
Numerous randomized clinical trials have extensively evaluated tion of VTE following orthopedic surgeries of the lower
pharmacologic strategies for VTE prophylaxis.2 Appropriately extremities.2 Warfarin appears to be as effective as the
selected drug therapies can dramatically reduce the incidence of LMWHs for the prevention of symptomatic VTE events in the
VTE following hip replacement, knee replacement, general sur- highest-risk populations. When used to prevent VTE, the dose
gery, myocardial infarction, and ischemic stroke (Table 72). of warfarin must be adjusted to maintain an International
The choice of medication and dose to use for VTE prevention Normalized Ratio (INR) between 2 and 3. Oral administration
must be based on the patients level of risk for thrombosis and and low drug cost give warfarin some advantages over the
bleeding complications, as well as the cost and availability of an LMWHs and fondaparinux. However, warfarin does not
adequate drug therapy monitoring system. achieve its full antithrombotic effect for several days, requires
The ACCP Conference on Antithrombotic Therapy rec- frequent monitoring and periodic dosage adjustments, and
ommended against the use of aspirin as the primary method carries a substantial risk of major bleeding. Warfarin should
of VTE prophylaxis.2 Antiplatelet drugs clearly reduce the only be used when a systematic patient monitoring system is
risk of coronary artery and cerebrovascular events in patients available.
with arterial disease, but aspirin produces a very modest The optimal duration for VTE prophylaxis following sur-
reduction in VTE following orthopedic surgeries of the lower gery is not well established.2 Prophylaxis should be given
extremities. The relative contribution of venous stasis in the throughout the period of risk. For general surgical procedures
pathogenesis of venous thrombosis compared with that of and medical conditions, once the patient is able to ambulate
platelets in arterial thrombosis likely explains the reason for regularly and other risk factors are no longer present, prophy-
this difference. laxis can be discontinued. The risk of VTE in the rst month
The most extensively studied drugs for the prevention of following hospital discharge among patients who have under-
VTE are unfractionated heparin (UFH), the low-molecular- gone total hip replacement or hip fracture repair is very high.
weight heparins (LMWHs; dalteparin, enoxaparin, and tinza- Therefore, extended prophylaxis for 21 to 35 days following
parin), fondaparinux, and warfarin.2 The LMWHs and hospital discharge with an LMWH, fondaparinux, or warfarin
fondaparinux provide superior protection against VTE when is recommended.
few days to 6 months), the aim of therapy is to prevent prop-

Patient Encounter 1, Part 1 agation or local extension of the clot, embolization, and death.
In the long-term (i.e., more than 6 months after the rst
event), the aim of therapy is to prevent complications, such as
the postthrombotic syndrome, pulmonary hypertension, and
KK is a 69-year-old obese female who fell on her way to
church and fractured her right hip. She is hospitalized and
recurrent VTE.8, 21
will undergo surgery to repair her fractured right hip.
PMH General Treatment Principles
Hypertension 12 years; dyslipidemia 10 years; obesity
Anticoagulant drugs are considered the mainstay of therapy
20 years; degenerative joint disease 5 years; recurrent
urinary tract infections
for patients with VTE, and the therapeutic strategies for DVT
and PE are essentially identical.8, 22 In the absence of con-
FH traindications, the treatment of VTE should initially include a
Non-signicant rapid-acting anticoagulant (e.g., unfractionated heparin, low-
SH molecular-weight heparin, or fondaparinux) overlapped with
Smoke one-half pack per day for 25 years; occasional warfarin for at least 5 days and until the patients International
alcohol use Normalized Ratio (INR) is greater than 2. Anticoagulation ther-
The patient has Medicare, but due to her xed income, has apy should be continued for a minimum of 3 months. However,
difculty paying for medications, leading to occasional the duration of anticoagulation therapy should be based on the
periods of non-compliance.
patients risk of VTE recurrence and major bleeding. The treat-
Current Meds ment of VTE can be divided into acute, subacute, and chronic
Metoprolol 100 mg by mouth twice daily phases (Fig. 75).23,24 The acute treatment phase of VTE is
Hydrochlorothiazide 25 mg by mouth daily typically accomplished by administering a fast-acting par-
Vytorin 10/40 (ezetimibe 10 mg/simvastatin 40 mg) by enteral anticoagulant (Table 73). The subacute and chronic
mouth daily
phase treatments of VTE are usually accomplished using oral
Salsalate 750 mg by mouth twice daily
Trimethoprim-sulfamethoxazole SS tablets by mouth twice
anticoagulant agents, such as warfarin.8,24 In certain popula-
daily for 7 days (last treatment was 1 month ago) tions, such as patients with cancer and women who are preg-
Shark cartilage 3 tablets by mouth daily nant, the LMWHs are the preferred agents during subacute
Enteric-coated aspirin 81 mg by mouth daily and chronic treatment phases.8 In the last decade, several
Ginseng 2 tablets by mouth daily novel anticoagulants, such as direct thrombin inhibitors and
Allergies
factor Xa inhibitors have emerged as potential alternatives for
No known drug allergies the acute, subacute, and chronic phases of treatment. As data
from clinical trials using these new agents in VTE treatment
PE continue to emerge, their role in clinical practice will be better
VS: blood pressure 145/90 mm Hg; heart rate, 72; respira-
understood.8,21
tory rate, 16; temperature , 37.4C (99.3F); weight 280 lb
(127.3 kg); body mass index (BMI) 40 kg/m2
Labs
Acute phase: 514 days Chronic phase: greater than
Within normal limits; estimated glomerular ltration rate = 6 months
IV or SC UFH
74 mL/minute SC LMWH PO Warfarin:
SC Fondaparinux INR 1.52 or
INR 23 (preferred )
Which risk factor(s) predispose KK to VTE?
VTE
What is KKs estimated risk for developing VTE? 12 weeks 36 months 6 months-indefinite
Given KKs presentation and history, create an appropriate
VTE prophylaxis plan including the pharmacologic agent,
dose, route and frequency of administration, duration of Subacute phase: UP to 6 months
PO Warfarin: INR 23
therapy, monitoring parameters, and patient education.
SC LMWH: In cancer patients, or patients
with contraindication(s) to warfarin.
FIGURE 75. Treatment approach for patients with VTE. INR,

International Normalized Ratio; IV, intravenous; LMWH, low-
TREATMENT OF VENOUS THROMBOEMBOLISM molecular-weight heparin; PO, oral; SC, subcutaneous; UFH,
unfractionated heparin; VTE, venous thromboembolism.
Desired Therapeutic Outcomes (Adapted from Nutescu EA. Emerging options in the treatment
of venous thromboembolism. Am J Health Syst Pharm
The goal of VTE treatment is to prevent short- and long-term 2004;61(Suppl 7):S16, with permission.)
complications of the disease. In the short-term (i.e., the rst
TABLE 73. Pharmacologic Options for the Initial Treatment TABLE 74. Thrombolysis for the Treatment of VTE
of Acute VTE21,24,34
Thrombolytic therapy should be reserved for patients who pres-
Unfractionated Heparin ent with shock, hypotension, right ventricular strain, or massive
IV administration:a use weight-based dosing nomogram DVT with limb gangrene
(Table 75) Diagnosis must be objectively conrmed before initiating throm-
or bolytic therapy
SC administration: 17,500 units given every 12 hours (an initial Thrombolytic therapy is most effective when administered as
5000 unit IV bolus dose is recommended to obtain rapid soon as possible after PE diagnosis, but benet may extend up to
anticoagulation) 14 days after symptom onset
Adjust subsequent doses to attain a goal aPTT based on the Approved PE thrombolytic regimens:
institution-specic therapeutic range Streptokinase 250,000 units intravenously over 30 minutes
followed by 100,000 units/hour for 24 hoursa
Low-Molecular-Weight Heparins Urokinase 4400 units/kg intravenously over 10 minutes
Dalteparin:b 200 units/kg SC once daily or 100 units/kg SC twice followed by 4400 units/kg/hour for 1224 hoursa
daily Alteplase 100 mg intravenously over 2 hours
Enoxaparin: 1.5 mg/kg SC once daily or 1 mg/kg SC twice daily; Factors that increase the risk of bleeding must be evaluated
if CrCl is less than 30 mL/minute: 1 mg/kg SC once daily before thrombolytic therapy is initiated (i.e., recent surgery,
Tinzaparin: 175 units/kg SC once daily trauma or internal bleeding, uncontrolled hypertension, recent
Factor Xa Inhibitor stroke, or intracranial hemorrhage)
Fondaparinux: Baseline labs should include CBC and blood typing in case
For body weight less than 50 kg (110 lb) use 5 mg SC once daily transfusion is needed
For body weight 50100 kg (110220 lb) use 7.5 mg SC once Unfractionated heparin should not be used during thrombolytic
daily therapy. Neither the aPTT nor any other anticoagulation parame-
For body weight greater than 100 kg (220 lb) use 10 mg SC once ter should be monitored during the thrombolytic infusion
daily aPTT should be measured following the completion of
thrombolytic therapy:
a
IV administration preferred due to improved dosing precision. If aPTT less than 2.5 times the control value, unfractionated
b
Not FDA approved for treatment of VTE. heparin infusion should be started and adjusted to maintain
aPTT, activated partial thromboplastin time; CrCl, creatinine clearance;
aPTT in therapeutic range
FDA, Food and Drug Administration; IV, intravenous; SC, subcutaneous;
VTE, venous thromboembolism. If aPTT greater than 2.5 times the control value, remeasure
every 24 hours and start unfractionated heparin infusion
when aPTT is less than 2.5
Avoid phlebotomy, arterial puncture, and other invasive procedures
Treatment Options during thrombolytic therapy to minimize the risk of bleeding
a
2-Hour infusions of streptokinase and urokinase are as effective and
Pharmacologic Therapy safe as alteplase. aPTT, activated partial thromboplastin time; CBC,
complete cell blood count; DVT, deep vein thrombosis; PE, pulmonary
embolism; VTE, venous thromboembolism.
Thrombolytics
The role of thrombolysis in the treatment of VTE is contro-
versial. Thrombolytic agents are proteolytic enzymes that
have the ability to dissolve, or lyse, the brin clot. of death or recurrent PE in patients treated with thrombolytics
Thrombolytics are administered systemically or directly into when compared to those treated with heparin alone. However,
the thrombus using a catheter-directed infusion.8 Compared this small benet was offset by a higher risk of major bleed-
to anticoagulants, thrombolytics restore venous patency more ing.27 Tissue plasminogen activator (t-PA), streptokinase, and
quickly; however, the bleeding risk associated with their use is urokinase have all been studied and are Food and Drug
signicantly higher.25 In patients with DVT, thrombolytics Administration (FDA) approved in the treatment of PE. All
decrease short-term pain and swelling and prevent destruc- three agents have comparable thrombolytic capacity but t-PA
tion of the venous valves. It is not clear if thrombolytics has the potential advantage of a shorter infusion time.
decrease the incidence and severity of postthrombotic syn- Reteplase is not currently FDA-approved for the treatment of
drome. Clinical trials have failed to show any long-term ben- PE, but it has also been studied. Reteplase is administered as
ets from the routine use of thrombolytics; therefore, their two 10 unit IV boluses given 30 minutes apart.8,28 Given the
use in the majority of patients is not recommended.8,25 In a relative lack of data to support their routine use, thrombolytics
select group of high-risk patients with massive iliofemoral should be reserved for select high risk circumstances (Table 74).
DVT who are at risk of limb gangrene, thrombolysis may be Candidates for thrombolytic therapy are patients with acute
considered8 (Table 74). massive embolism who are hemodynamically unstable [systolic
In patients with acute PE, the use of thrombolytics provides blood pressure (SBP) less than 90 mm Hg] and at low risk for
short-term benets such as restoring pulmonary artery bleeding.8 The use of thrombolytics in hemodynamically stable
patency and hemodynamic stability.8,26 A recent meta-analysis of patients with right ventricular dysfunction is controversial but
nine small randomized clinical trials showed a slightly lower risk some experts support their use.
Unfractionated Heparin nonspecic binding to cellular proteins, UFH has several lim-
Unfractionated heparin has traditionally been the drug of itations, including poor bioavailability when given subcuta-
choice for indications requiring a rapid anticoagulation, neously and signicant intra- and interpatient variability in
including the acute treatment of VTE. Commercially available anticoagulant response.5,22
UFH preparations are isolated from porcine intestinal mucosa Unfractionated heparin can be administered via the intra-
or bovine lung. Unfractionated heparin is composed of a het- venous (IV) or subcutaneous (SC) route. When rapid antico-
erogeneous mixture of glycosaminoglycans with variable agulation is required, unfractionated heparin should be
length, molecular weight, and pharmacologic properties. administered intravenously and an initial bolus dose should
Unlike thrombolytics, UFH and other anticoagulants will not be given. For the treatment of VTE, UFH is generally given as
dissolve a formed clot but prevent its propagation and a continuous IV infusion. Intermittent IV bolus dosing is
growth.5,29 Heparin exerts its anticoagulant effect by aug- associated with a higher risk of bleeding and is therefore not
menting the natural anticoagulant antithrombin (AT). A spe- recommended. When given SC, the bioavailability of UFH
cic pentasaccharide sequence on the heparin molecule binds ranges from 30% to 70%, depending on the dose given.
to AT and causes a conformational change that greatly accel- Therefore, higher doses of unfractionated heparin must be
erates its activity (Fig. 76). This complex inhibits thrombin given if the SC route of administration is used. Onset of anti-
(factor IIa), as well as factors Xa, IXa, XIa, and XIIa. Thrombin coagulation is delayed by 1 to 2 hours after the SC injection.
and factor Xa are most sensitive to this inhibition and are Due to the risk of hematomas and erratic absorption, intra-
inactivated in an equal 1:1 ratio. In order to inactivate throm- muscular (IM) administration is not recommended. The
bin, the UFH molecule needs to form a ternary complex by half-life of UFH is dose dependent and ranges from 30 to
binding to both AT and thrombin. Only UFH molecules that 90 minutes, but may be signicantly longer, up to 150 minutes,
are at least 18 saccharide units long are able to form this with high doses. Unfractionated heparin is eliminated by two
bridge between AT and thrombin. In contrast, inhibition of mechanisms: (1) enzymatic degradation via a saturable zero-
factor Xa does not require the formation of a ternary complex. order process, and (2) renally via a rst-order process. Lower
Unfractionated heparin molecules as short as ve saccharide UFH doses are primarily cleared via enzymatic processes,
units can catalyze the inactivation of factor Xa. Due to its while higher doses are primarily renally eliminated. Clearance
Unfractionated heparin (Xa:IIa 1:1) FIGURE 76.

Thrombin (IIa) Mechanism of action
Pentasaccharide Thrombin (IIa) Ternary of unfractionated
complex
heparin, low-molecular-
weight heparin

(LMWH), and fonda-
parinux. (Reproduced
Conformational change
Factor Xa Factor Xa
from Haines ST, Zeolla
M, Witt DM. Venous
Antithrombin
thromboembolism. In:
DiPiro JT, Talbert RL,
Low-molecular-weight heparin (Xa:IIa 3-4:1) Yee GC, et al, (eds.)
Most LMWH Pharmacotherapy:
Thrombin (IIa) chains too short
Pentasaccharide to form ternary A Pathophysiologic
Thrombin (IIa) complex Approach. 6th ed.
New York:
McGraw-Hill; 2005:
381, with permission.)
Factor Xa Factor Xa
Antithrombin
Fondaparinux (100% Xa)

Pentasaccharide
Antithrombin
Factor Xa Factor Xa
of UFH can be impaired in patients with renal and hepatic Subsequent doses of SC unfractionated heparin need to be
dysfunction. Patients with active thrombosis may require higher adjusted based on the patients response.5, 8
UFH doses due to a more rapid elimination or variations in
the plasma concentrations of heparin-binding proteins.
Due to signicant variability in interpatient response and
changes in patient response over time, unfractionated heparin
Antithrombin deciency and elevated factor VIII levels that
requires close monitoring and periodic dose adjustment. The
are common in pregnant patients have also been linked to
response to unfractionated heparin can be monitored using a
higher UFH dose requirements. The requirement of these
variety of laboratory tests including the aPTT, the whole blood
higher UFH doses is termed heparin resistance.5,15
clotting time, activated clotting time (ACT), antifactor Xa
The dose of UFH required to achieve a therapeutic antico-
activity, and the plasma heparin concentration.5, 31 Although it
agulant response is correlated to the patients weight.
has several limitations, the aPTT is the most widely used test in
Traditional dosing regimens consist of a 5000 unit bolus dose
clinical practice to monitor UFH. Traditionally, therapeutic
followed by an infusion administered at 1000 to 1200
aPTT range is dened as 1.5 to 2.5 times the control aPTT
units/hour.5 However, weight-based dosing regimens are
value. However, due to variations in the reagents and instru-
more likely to exceed the therapeutic threshold in the rst 24
ments used to measure the aPTT in different laboratories, each
hours after initiating treatment.30 Achieving a therapeutic
institution should establish a therapeutic range for UFH. The
aPTT in the rst 24 hours after initiating unfractionated
institution-specic therapy range should correlate with a
heparin is critical because this has been shown to lower the
plasma heparin concentration of 0.2 to 0.4 units/mL by prota-
risk of recurrent VTE.5,30 For non-obese patients, the actual
mine titration or 0.3 to 0.7 units/mL by an amidolytic
body weight should be used to calculate the initial UFH dose
antifactor Xa assay.5,31 An aPTT should be obtained at base-
(Table 75). For obese patients, using the actual body weight
line, 6 hours after initiating the heparin infusion, and 6 hours
to calculate the initial dose is controversial. Some experts rec-
after each dose change, as this is the time required to reach
ommend using an adjusted body weight instead. The infusion
steady state. The UFH dose is then adjusted based on the aPTT
rate is then adjusted based on laboratory monitoring of the
measurement and the institutional-specic therapeutic range.
patients response. Unfractionated heparin can also be admin-
(Table 75) In patients with heparin resistance, antifactor
istered via the SC route; however, IV infusion is preferred by
Xa concentrations may be a more accurate method of moni-
most clinicians because it can be dosed more precisely. If the
toring the patients response.5,31
SC route is selected, an initial 5000 unit IV bolus should be
Side effects associated with UFH include bleeding, throm-
given followed by 17,500 units given SC every 12 hours.
bocytopenia, hypersensitivity reactions, and with prolonged
use, alopecia, hyperkalemia, and osteoporosis.22,29 Bleeding
TABLE 75. Weight-Baseda Dosing for UFH Administered by
Continuous Intravenous Infusion for Venous
is the most common adverse effect associated with antithrombotic
Thromboembolism drugs, including UFH therapy. A patients risk of major hemor-
rhage is related to the intensity and stability of therapy, age, con-
Initial Loading Dose Initial Infusion Rate current drug use, history of gastrointestinal bleeding, risk of falls or
80100 units/kg (maximum = 1720 units/kg/hour (maximum = trauma, and recent surgery. Several risk factors can increase the
10,000 units) 2300 units/hour) risk of unfractionated heparininduced bleeding (Table 76).
Maintenance Infusion Rate The risk of bleeding is related to the intensity of anticoagulation.
aPTT (seconds) Dose Adjustment
Less than 37 (or less than 80 units/kg bolus then increase
12 seconds below infusion by 4 units/kg/hour TABLE 76. Risk Factors for Major Bleeding While Taking
institution-specic Anticoagulation Therapy
therapeutic range)
3747 (or 112 seconds below 40 units/kg bolus then increase Anticoagulation intensity (e.g., INR greater than 5, aPTT greater
institution-specic therapeutic infusion by 2 units/kg/hour than 120 seconds)
range) Initiation of therapy (rst few days and weeks)
4871 (within institution-specic No change Unstable anticoagulation response
therapeutic range) Age greater than 65 years
7293 (or 122 seconds above Decrease infusion by Concurrent antiplatelet drug use
institution-specic therapeutic 2 units/kg/hour Concurrent non-steroidal anti-inammatory drug or aspirin use
range) History of gastrointestinal bleeding
Greater than 93 (or greater than Hold infusion for 1 hour Recent surgery or trauma
22 seconds above institution- then decrease by High risk for fall/trauma
specic therapeutic range) 3 units/kg/hour Heavy alcohol use
Renal failure
a
Use actual body weight for all calculations. Adjusted body weight (ABW) Cerebrovascular disease
may be used for obese patients (greater than 130% of IBW). ABW = IBW + Malignancy
(actual body weight IBW) 0.7.
aPTT, activated partial thromboplastin time; IBW, ideal body weight; aPTT, activated partial thromboplastin time; INR, International
UFH, unfractionated heparin. Normalized Ratio.
Higher aPTT values are associated with an increased risk of TABLE 77. Contraindications to Anticoagulation Therapy
bleeding. The risk of major bleeding is 1% to 5% during
General
the rst few days of treatment. 3 In addition to the aPTT,
Active bleeding
hemoglobin, hematocrit, and blood pressure should also be Hemophilia or other hemorrhagic tendencies
monitored. Concurrent use of UFH with other antithrom- Severe liver disease with elevated baseline PT
botic agents, such as thrombolytics and antiplatelet agents, Severe thrombocytopenia (platelet count less than 20,000)
also increases the risk of bleeding. Patients receiving UFH Malignant hypertension
Inability to meticulously supervise and monitor treatment
therapy should be closely monitored for signs and symp-
Product-Specic Contraindications
toms of bleeding, including epistaxis, hemoptysis, hema- UFH
turia, bright red blood per rectum, tarry stools, severe Hypersensitivity to unfractionated heparin
headache, and joint pain. If major bleeding occurs, UFH History of HIT
should be stopped immediately and the source of bleeding LMWHs
Hypersensitivity to low-molecular-weight heparin,
treated.3,5 If necessary, use protamine sulfate to reverse the
unfractionated heparin, pork products, methylparaben,
effects of UFH. The usual dose is 1 mg protamine sulfate or propylparaben
per 100 units of UFH, up to a maximum of 50 mg, given as History of HIT or suspected HIT
a slow IV infusion over 10 minutes. The effects of UFH are Fondaparinux
neutralized in 5 minutes, and the effects of protamine per- Hypersensitivity to fondaparinux
Severe renal insufciency (creatinine clearance less than
sist for 2 hours. If the bleeding is not controlled or the anti-
30 mL/minute)
coagulant effect rebounds, repeated doses of protamine Body weight less than 50 kg (110 lb)
may be administered.5 Bacterial endocarditis
Heparin-induced thrombocytopenia (HIT) is a very seri- Thrombocytopenia with a positive in vitro test for antiplatelet
ous adverse effect associated with UFH use. Platelet counts antibodies in the presence of fondaparinux
Lepirudin
should be monitored every 2 to 3 days during the course of
Hypersensitivity to hirudins
UFH therapy.5 HIT should be suspected if the platelet count Argatroban
drops by more than 50% from baseline or to below 120,000. Hypersensitivity to argatroban
In patients with contraindications to anticoagulation therapy, Warfarin
UFH should not be administered (Table 77). Hypersensitivity to warfarin
Pregnancy
Unfractionated heparin is an FDA pregnancy category C
History of warfarin-induced skin necrosis
drug and may be used to treat VTE during pregnancy. Inability to obtain follow-up PT/INR measurements
Unfractionated heparin should be used with caution in the Inappropriate medication use or lifestyle behaviors
peripartum period due to the risk of maternal hemorrhage.
HIT, heparin-induced thrombocytopenia; INR, International Normalized
Unfractionated heparin is not secreted into the breast milk Ratio; LMWHs, low-molecular-weight heparins; PT, prothrombin time;
and is safe for use by women who wish to breastfeed.14 For UFH, unfractionated heparin.
the treatment of VTE in children, the UFH dose is 50 units/kg
bolus followed by an infusion of 20,000 units/m2/24 hours.
Alternatively, a loading dose of 75 units/kg followed by an half-lives, allowing once- or twice-daily administration,
infusion of 28 units/kg/hour if less than 12 months old improved subcutaneous bioavailability, and dose-independent
and 20 units/kg/hour if greater than 1 year old may be renal clearance. In addition, LMWHs have a more favorable
considered.32 side-effect prole than UFH. They are also associated with a
lower incidence of HIT and osteopenia. Three LMWHs are
Low-Molecular-Weight Heparins currently available in the United States: dalteparin, enoxa-
The LMWHs are smaller heparin fragments obtained by parin, and tinzaparin.5,29
chemical or enzymatic depolymerization of UFH. Low- Like UFH, LMWHs prevent the propagation and growth of
molecular-weight heparins are heterogeneous mixtures of formed thrombi. The anticoagulant effect is mediated
glycosaminoglycans and each product has slightly different through a specic pentasaccharide sequence that binds to AT.
molecular weight distributions and pharmacologic properties.5 The primary difference in the pharmacologic activity of UFH
Compared with unfractionated heparin, LMWHs have and LMWH is their relative inhibition of thrombin (factor
improved pharmacodynamic and pharmacokinetic properties. IIa) and factor Xa. Smaller heparin fragments cannot bind AT
They exhibit less binding to plasma and cellular proteins, and thrombin simultaneously (Fig. 76). Due to their smaller
resulting in a more predictable anticoagulant response. chain length, LMWHs have relatively greater activity against
Consequently, routine monitoring of anticoagulation activity factor Xa and inhibit thrombin to a lesser degree. The
and dose adjustments are not required in the majority of antifactor Xa:IIa activity ratio for the LMWHs range from
patients. Low-molecular-weight heparins have longer plasma 2:1 to 4:1. The SC bioavailability of the LMWHs is greater
than 90%. The peak anticoagulant effect of the LMWHs is DVT treatment results in cost savings and improved patient
reached 3 to 5 hours after a SC dose. The elimination half-life satisfaction and quality of life.8
is 3 to 6 hours and is agent-specic. In patients with renal Laboratory methods of measuring a patients response to
impairment, the half-life of LMWHs is prolonged.5,21,29 LMWH may be warranted in certain situations.5 Although
The dose of LMWHs for the treatment of VTE is deter- controversial, measurement of antifactor Xa activity has
mined based on the patients weight and administered been the most widely used method in clinical practice and is
subcutaneously once or twice daily (Table 73). Once-daily recommended by the College of American Pathologists.37
dosing of enoxaparin appears to be as effective as twice-daily Monitoring of antifactor Xa activity may be considered
dosing; however, some data suggest that twice-daily dosing in adult patients who are morbidly obese (weight greater than
may be more effective in patients who are obese or have 150 kg [330 lb] or BMI greater than 50 kg/m2), weigh less than
cancer.8,21 The dose of enoxaparin is expressed in milligrams, 50 kg (110 lb), or have signicant renal impairment (CrCl less
whereas the doses of dalteparin and tinzaparin are expressed than 30 mL/minute). Laboratory monitoring may also be
in units of antifactor Xa activity. Due to their predictable useful in children and pregnant women. When monitoring
anticoagulant effect, routine monitoring is not necessary in antifactor Xa activity, the sample should be obtained
the majority of patients.5 Low-molecular-weight heparins approximately 4 hours after the SC dose is administered,
have been evaluated in a large number of randomized trials when peak concentration is anticipated. The therapeutic
and have been shown to be at least as safe and effective as range for antifactor Xa activity has not been clearly dened,
UFH for the treatment of VTE.8,21 Indeed, the rate of mor- and there is a limited correlation between antifactor Xa
tality was lower in patients treated with a LMWH in clinical activity and safety or efcacy. For the treatment of VTE, an
trials. This mortality benet was primarily seen in patients acceptable antifactor Xa activity range is 0.6 to 1 unit/mL
with cancer.33 with twice-daily dosing. In patients treated with once-daily
Prior to initiating treatment with a LMWH, baseline labo- LMWH regimens, a target level between 1 and 2 units/mL is
ratory tests should include PT (prothrombin time)/INR, recommended by some experts.8,37
aPTT, complete blood cell count (CBC), and serum creatinine. Similar to UFH, bleeding is the major complication asso-
Monitor the CBC every 3 to 4 days during the rst 2 weeks of ciated with LMWHs. The frequency of major bleeding
therapy, and every 2 to 4 weeks with extended use.5 Use appears to be numerically lower with LMWHs than with
LMWHs cautiously in patients with renal impairment. UFH.33 The incidence of major bleeding reported in clinical
Specic dosing recommendations for patients with a creati- trials is less than 3%.8 Minor bleeding, especially bruising at
nine clearance (CrCl) less than 30 mL/minute are currently the injection site, occurs frequently. Protamine sulfate will
available for enoxaparin but lacking for other agents of the partially reverse the anticoagulant effects of the LMWHs and
class (Table 73). Current guidelines recommend the use of should be administered in the event of major bleeding. Due
UFH over LMWH in patients with severe renal dysfunction to its limited binding to LMWH chains, protamine only neu-
(CrCl less than 30 mL/minute).8 tralizes 60% of their antithrombotic activity. If the LMWH
was administered within the previous 8 hours, give 1 mg
Most patients with an uncomplicated DVT can be man-
protamine sulfate per 1 mg of enoxaparin or 100 anti
aged safely at home. LMWHs can be easily administered in
factor Xa units of dalteparin or tinzaparin. If the bleeding
the outpatient setting, thus enabling the treatment of VTE
is not controlled, give 0.5 mg of protamine sulfate for every
at home. Several large clinical trials have demonstrated the
antifactor Xa 100 units of LMWH. Give smaller prota-
efcacy and safety of LMWHs used for outpatient treatment mine doses if more than 8 hours have lapsed since the last
of DVT.8,34,35 Acceptance of this treatment approach has LMWH dose.5
increased tremendously over the last several years among The incidence of HIT is lower with LMWHs than with
clinicians. Patients who can be treated safely at home are UFH. However, LMWHs cross-react with heparin antibodies
stable and have normal vital signs, have low bleeding risk, in vitro and should not be given as an alternative anticoagu-
and have no other comorbid conditions requiring hospital- lant in patients with a diagnosis or history of HIT.5 Monitor
ization.34,35 Although the treatment of patients with PE in platelet counts every few days during the rst 2 weeks and
the outpatient setting is controversial, patients with sub- periodically thereafter.5
massive PE who are hemodynamically stable can be safely Low-molecular-weight heparins are an excellent alterna-
treated in the outpatient setting as well.36 Patients consid- tive to UFH for the treatment of VTE in pregnant women.34
ered for outpatient therapy need to be reliable or have ade- The LMWHs do not cross the placenta, and they are FDA
quate caregiver support and must be able to strictly adhere pregnancy category B. Because the pharmacokinetics of
to the prescribed treatment regimen and recommended LMWHs may change during pregnancy, monitor antifactor
follow-up visits. Close patient follow-up is critical to the Xa activity every 3 to 4 weeks to make dose adjustments.34
success of any outpatient DVT treatment program.35 Home Low-molecular-weight heparins have also been used to treat
VTE in pediatric patients. Children less than 1 year old of therapy. Monitoring antifactor Xa activity to guide fonda-
require higher doses (e.g., enoxaparin 1.5 mg/kg SC every parinux dosing is not recommended.29,38,39
12 hours). Monitor antifactor Xa activity to guide dosing As with other anticoagulants, the major side effect associ-
in children.32 ated with fondaparinux is bleeding. Fondaparinux should be
used with caution in elderly patients because their risk of
Factor Xa Inhibitors bleeding is higher. Patients receiving fondaparinux should be
Fondaparinux, the rst agent in this class, is an indirect inhibitor carefully monitored for signs and symptoms of bleeding. A
of factor Xa, and exerts its anticoagulant activity by accelerating CBC should be obtained at baseline and monitored periodi-
AT. Fondaparinux contains the specic 5-saccharide sequence cally to detect the possibility of occult bleeding. In the event of
found in unfractionated heparin that is responsible for its phar- major bleeding, fresh frozen plasma and factor concentrates
macologic activity. Due to its small size, fondaparinux exerts should be given. In the case of a life-threatening bleed, recom-
inhibitory activity specically against factor Xa and has no effect binant factor VIIa may be considered, but this is a very costly
on thrombin (factor IIa)38 (Fig. 76). Fondaparinux is currently option and it can also increase the risk of thrombosis.
the only agent of the class that is commercially available in the Fondaparinux is not reversed by protamine.29,38,39
United States. Idraparinux and razaxaban are antifactor Xa Fondaparinux is pregnancy category B, but there are very
inhibitors currently undergoing Phase III clinical trials. limited data regarding its use during pregnancy. Use in pedi-
Fondaparinux and idraparinux are administered SC; razaxaban atric patients has not been studied.29,38,39
is administered orally. After SC administration, fondaparinux is
completely absorbed, and peak plasma concentrations are
Direct Thrombin Inhibitors (DTIs)
reached within 2 to 3 hours.38
Given that thrombin is the central mediator of coagulation
As synthetic drugs (unlike UFH and the LMWHs), factor
and amplies its own production, it is a natural target for
Xa inhibitors cannot transmit animal pathogens, are consis-
pharmacologic intervention. Direct thrombin inhibitors
tent from batch-to-batch, and are available in an unlimited
(DTIs) bind thrombin and prevent interactions with its sub-
supply. Other favorable attributes of the antifactor Xa
strates (Fig. 77). Several injectable DTIs are approved for use
inhibitors include a predictable and linear dose-response rela-
in the United States including lepirudin, bivalirudin, arga-
tionship, rapid onset of activity, and long half-life.29 Factor Xa
troban, and desirudin. Several oral DTIs are currently in
inhibitors do not require routine coagulation monitoring
or dose adjustments. Fondaparinux has a half-life of 17 to
21 hours, permitting once-daily administration, but the anti-
coagulant effects of fondaparinux will persist for 2 to 4 days Substrate
after stopping the drug. In patients with renal impairment, the recognition site
anticoagulant effect persists even longer. Idraparinux has a
signicantly longer duration of activity and is being devel-
oped for once-weekly injection. Neither fondaparinux nor Catalytic Thrombin
Thrombin
site (IIa)
idraparinux are metabolized in the liver and therefore have (IIa)
few drug interactions. However, concurrent use with other
antithrombotic agents will increase the risk of bleeding.
Unlike the heparins, factor Xa inhibitors do not affect platelet Fibrin-binding Lepirudin
function and do not react with the heparin platelet factor-4 site
(PF-4) antibodies seen in patients with HIT. Some centers use
fondaparinux in patients with a history of HIT who require
anticoagulation therapy.29,38,39
Fondaparinux has been used for the treatment of DVT Thrombin
Thrombin
and PE in two large Phase III trials and is approved by the (IIa)
(IIa)
FDA for these indications. Fondaparinux is as safe and effec-
tive as IV UFH for the treatment of PE and SC LMWH for
DVT treatment.36,40 The recommended dose for fonda- Argatroban
Bivalirudin
parinux in the treatment of VTE is based on the patients or
Dabigatran
weight (Table 73). Fondaparinux is renally eliminated and
accumulation can occur in patients with renal dysfunction. FIGURE 77. Mechanism of action of direct thrombin inhibitors.
Due to the lack of specic dosing guidelines, fondaparinux is (Reproduced from Haines ST, Zeolla M, Witt DM. Venous
contraindicated in patients with severe renal impairment thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al,
(eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed.
(CrCl less than 30 mL/minute). Baseline renal function
should be measured and monitored closely during the course
development. These agents differ in terms of their chemical thrombosis in patients with HIT and in patients with HIT
structure, molecular weight, and binding to the thrombin undergoing PCI.29,38,41
molecule. Potential advantages of DTIs include a targeted Small-molecule direct thrombin inhibitors have been
specicity for thrombin, the ability to inactivate clot-bound structurally modied for oral administration. Approximately
thrombin, and an absence of platelet interactions that can 10 oral DTIs are in development. There was considerable
lead to HIT. Unlike heparins, DTIs do not require antithrombin excitement about ximelagatran, the rst oral DTI to complete
as a co-factor and do not bind to plasma proteins. Therefore several large Phase III clinical trials.29,38,41 Ximelagatran was
they produce a more predictable anticoagulant effect. DTIs are given in xed doses without laboratory monitoring for VTE
considered the drugs of choice for the treatment of VTE in prophylaxis and acute and long-term VTE treatment. While
patients with a diagnosis or history of HIT.29,38,41 these studies showed that ximelagatran was as effective as
The prototype of this class is hirudin, which was originally standard treatment regimens, the FDA denied its approval due
isolated from the salivary glands of the medicinal leech, to concerns regarding liver toxicity. Dabigatran is another
Hirudo medicinalis. Hirudin itself is not commercially avail- promising oral DTI that is currently undergoing Phase III
able, but recombinant technology has permitted production clinical trials for the treatment of VTE.
of hirudin derivatives, namely lepirudin and desirudin.29,38,41 Contraindications to the use of DTIs and risk factors for
Lepirudin has a short half-life of approximately 40 minutes bleeding are similar to those of other antithrombotic agents
after IV administration and 120 minutes when given SC. (Tables 76 and 77). Bleeding is the most common side effect
Elimination of lepirudin is primarily renal; therefore, doses reported with the use of DTIs. Concurrent use of DTIs with
must be adjusted based on the patients renal function. The thrombolytics signicantly increases bleeding complications.
dose should be monitored and adjusted to achieve an aPTT Currently, there are no known antidotes to reverse the effects
ratio of 1.5 to 2.5 times the baseline measurement. Lepirudin of the DTIs. Fresh frozen plasma, factor concentrates, or
is currently approved for use in patients with HIT and related recombinant factor VIIa should be given in the event of a
thrombosis. Up to 40% of patients treated with lepirudin will major bleed. DTIs can increase the PT/INR and can interfere
develop antibodies to the drug.29,38,41 with the accuracy of monitoring and dosing of warfarin
Bivalirudin, a smaller-molecular-weight DTI, is given by IV therapy. Data on the use of DTIs in pregnancy and pediatric
infusion. Bivalirudin has a shorter elimination half-life (~25 patients are very limited.29,38,41
minutes) than lepirudin and is only partially eliminated
renally. Unlike lepirudin, bivalirudin is a reversible inhibitor Warfarin
of thrombin and provides transient antithrombotic activity. Warfarin has been the primary oral anticoagulant used in the
Patients with moderate or severe renal impairment (CrCl less United States for the past 60 years. Warfarin is the anticoagu-
than 60 mL/minute) may require dose adjustment because lant of choice when long-term or extended anticoagulation is
clearance of bivalirudin is reduced by approximately 20% in required. Warfarin is FDA-approved for the prevention and
these patients. Bivalirudin is approved for use in patients with treatment of VTE, as well as the prevention of thromboem-
unstable angina undergoing percutaneous transluminal coro- bolic complications in patients with myocardial infarction,
nary angioplasty. The activated clotting time is used to monitor atrial brillation, and heart valve replacement. While very
the anticoagulant effect of bivalirudin during percutaneous effective, warfarin has a narrow therapeutic index, requiring
coronary intervention (PCI).29,38,41 frequent dose adjustments and careful patient monitoring.15,29
Desirudin is a SC administered DTI approved for VTE Warfarin exerts its anticoagulant effect by inhibiting the
prevention after hip replacement surgery but is not yet com- production of the vitamin Kdependent coagulation factors
mercially available in the United States. Desirudin has an II (prothrombin), VII, IX, and X, as well as the anticoagu-
elimination half-life of 2 to 3 hours and is typically dosed lant proteins C and S (Fig. 78). Warfarin has no effect on
every 12 hours. It is primarily eliminated through the kidneys, circulating coagulation factors that have been previously
so dose reduction is needed in patients with renal impair- formed, and its full antithrombotic activity is delayed for 7
ment. The aPTT should be used to measure desirudins anti- to 15 days. This delay is related to half-lives of the clotting
coagulant activity.29,38,41 factors: 60 to 100 hours for factor II (prothrombin), 6 to
Argatroban is a small synthetic molecule that binds 8 hours for factor VII, 20 to 30 hours for factor IX, and 24
reversibly to the active site of thrombin (Fig. 77). Argatroban to 40 hours for factor X. Proteins C and S, the natural anti-
is IV administered and has a 40 to 50 minute elimination half- coagulants, are inhibited more rapidly due to their shorter
life. The aPTT must be monitored to assess its anticoagulant half-lives, 8 to 10 hours and 40 to 60 hours, respectively.
activity. Argatroban is hepatically metabolized; therefore, dose Reductions in the concentration of natural anticoagulants
reductions and careful monitoring are recommended in before the clotting factors are depleted can lead to a para-
patients with hepatic dysfunction. Renal impairment has no doxical hypercoagulable state during the rst few days of
inuence on the elimination half-life or dosing of argatroban. warfarin therapy. It is for this reason that patients with
Argatroban is approved for prevention and treatment of acute thrombosis should receive a fast-acting anticoagulant
FIGURE 78. Pharmacologic activity and

metabolism of warfarin. CYP, cytochrome
Warfarin P-450 isoenzyme. (Reproduced from
Liver cell
Haines ST, Zeolla M, Witt DM. Venous
thromboembolism. In: DiPiro JT, Talbert
RL, Yee GC, et al, (eds.) Pharmacotherapy:
CYP1A1 A Pathophysiologic Approach. 6th ed.
CYP2C9 S R CYP1A2 New York: McGraw-Hill; 2005: 389,
CYP3A4 with permission.)
FPO
Vitamin K
reductase
Reduced vitamin K
Oxidized vitamin K
Vitamin Kdependent Dietary

carboxylase vitamin K
Precursors: Functional:
Factors II, VII, IX, X Factors II, VII, IX, X
Protein C & S Protein C & S
(heparin, LMWH, or fondaparinux) while transitioning to patients (greater than 75 years of age); patients with heart failure,
warfarin therapy.4,29,34 liver disease, or poor nutritional status; and patients who are tak-
Warfarin is a racemic mixture of two isomers, the S and the ing interacting medications or are at high risk of bleeding.4,21
R forms. The S-isomer is two to ve times more potent than the Loading doses of warfarin (e.g., 15 to 20 mg) are not recom-
R-isomer. Both isomers are extensively bound to albumin. The mended. These large doses can lead to the false impression
two isomers are metabolized in the liver via several isoenzymes that a therapeutic INR has been achieved in 2 to 3 days and
including cytochrome P-450 (CYP)1A2, 2C9, 2C19, 2C18, and also increases the risk of bleeding.4 Before initiating therapy,
3A4 (Fig. 78). Hepatic metabolism of warfarin varies greatly screen the patient for any contraindications to anticoagula-
among patients, leading to very large interpatient differences in tion therapy and risk factors for major bleeding (Tables 76
dose requirements and genetic variations in these isoenzymes; and 77). In addition, conduct a thorough medication history
specically, polymorphisms in the CYP2C92, CYP2C93, and including the use of prescription and over-the-counter drugs,
the VKORC1 haplotypes result in a signicantly lower warfarin and any herbal supplements to detect interactions that may
dose requirement to achieve a therapeutic response.4,42 affect warfarin dosing requirements. In patients with acute VTE,
Warfarin does not follow linear kinetics. Small dose adjust- a rapid-acting anticoagulant (UFH, LMWH, or fondaparinux)
ments can lead to large changes in anticoagulant response. should be overlapped with warfarin for a minimum of 5 days
The dose of warfarin is determined by each patients individ- and until the INR is greater than 2 and stable. This is important
ual response to therapy and the desired intensity of anticoag- because the full antithrombotic effect will not be reached until 5
ulation. In addition to hepatic metabolism, warfarin dose to 7 days or even longer after initiating warfarin therapy.4,8 The
requirements are inuenced by diet, drug-drug interactions, typical maintenance dose of warfarin for most patients will be
and health status. Therefore, the dose of warfarin must be between 25 and 55 mg per week, although some patients require
determined by frequent clinical and laboratory monitor- higher or lower doses. Adjustments in the maintenance warfarin
ing.4,22,34 While there are conicting data regarding the opti- dose should be determined on the total weekly dose and by
mal warfarin induction regimen, most patients can start with reducing or increasing the weekly dose by 5% to 25%. When
5 mg daily and subsequent doses are determined based on adjusting the maintenance dose, wait at least 7 days to ensure that
INR response (Fig. 79). When initiating therapy, it is difcult a steady state has been attained on the new dose before checking
to predict the precise warfarin maintenance dose that a patient the INR again. Checking the INR too soon can lead to inappro-
will require. Patients who are younger (less than 55 years of priate dose adjustments and unstable anticoagulation status.4
age) and otherwise healthy can safely use higher warfarin
initiation doses (e.g., 7.5 or 10 mg). A more conservative Warfarin requires frequent laboratory monitoring to ensure
initiation dose (e.g., 5 mg or less) should be given to elderly optimal outcomes and minimize complications. The prothrombin
FIGURE 79. Initiation of warfarin

Can a PT/INR be obtained therapy. INR, International
daily? Normalized Ratio; PT, prothrombin
time. (Reproduced from Haines ST,
Zeolla M, Witt DM. Venous throm-
NO YES
boembolism. In: DiPiro JT, Talbert RL,
Yee GC, et al, (eds.) Pharmacotherapy:
Start warfarin with 5 mg daily Start warfarin with 5 mg daily A Pathophysiologic Approach. 6th ed.
Consider 2.5-mg dose if patient Consider 7.510-mg dose if patient New York: McGraw-Hill; 2005: 391,
age greater than 60; concurrent age less than 60; no concurrent use of with permission.)
use of interacting medications; or interacting medications; and
bleeding risk is high bleeding risk is low
Measure PT/INR on day 3 or 4

INR less than 1.5 - Increase weekly dose 525% Measure PT/INR on day 2
INR = 1.5 1.9 No dose change INR less than 1.5 No dose change
INR = 2 2.5 Decrease weekly dose 25 50% INR= 1.5 1.9 Decrease dose 25 50%
INR greater than 2.5 Decrease INR = 2 2.5 Decrease dose 50 75%
weekly dose 50% or hold INR greater than 2.5 hold next dose
Measure PT/INR on day 5 7

Measure PT/INR on day 3
INR less than 1.5- Increase weekly dose 1025%
INR less than 1.5 Increase dose 0 25%
INR = 1.51.9 Increase weekly dose 0 20%
INR = 1.5 1.9 No dose change
INR = 2 3 No dose change
INR = 2 2.5 Decrease dose 25 50%
INR greater than 3 Decrease
INR greater than 2.5 Decrease 50% or hold next dose
weekly dose 10 25% or hold
Measure PT/INR on day 8 10 Measure PT/INR on day 4

INR less than 1.5 -Increase weekly dose 10 25% INR less than 1.5 Increase dose 025%
INR = 1.4 1.9 Increase weekly dose 5 20% INR = 1.51.9 No dose change or
INR = 2 3 No dose change increase 10 25%
INR greater than 3 Decrease INR = 23 Decrease dose 0 25%
weekly dose 1025% or hold INR greater than 3 Decrease 50% or hold next dose
Measure PT/INR on day 1114 Measure PT/INR on day 5

INR less than 1.4 -Increase weekly dose 10 20% INR less than 1.5 Increase dose 25%
INR = 1.4 1.9 No dose change INR = 1.51.9 Increase dose 0 25%
INR = 2 3 Decrease weekly dose 10 20% INR = 2 3 No dose change or
INR greater than 3 Decrease decrease dose 10 25%
weekly dose 5 20% or hold INR greater than 3 Decrease 25 50%
time is the most frequently used test to monitor warfarins anti- the INR should be monitored at least every 2 to 3 days during
coagulant effect. The PT measures the biological activity of fac- the rst week of therapy. Once a stable response to therapy is
tors II, VII, and X. Due to wide variation in reagent sensitivity, achieved, INR monitoring is performed less frequently, weekly
different thromboplastins will result in different PT results, for the rst 1 to 2 weeks, then every 2 weeks, and monthly there-
potentially leading to inappropriate dosing decisions.4,22 In after.4 At each encounter, carefully question the patient regard-
order to standardize result reporting, the World Health ing any factors that may inuence the INR result. These factors
Organization (WHO) developed a reference thromboplastin include adherence to therapy, the use of interacting medications,
and recommended the INR to monitor warfarin therapy. The consumption of vitamin Krich foods, alcohol use, and general
INR corrects for the differences in thromboplastin reagents and health status. Patients should also be questioned about symp-
uses the following formula: INR = (PTPatient/PTControl)ISI. The toms related to bleeding and thromboembolic events. Warfarin
International Sensitivity Index (ISI) is a measure of the throm- dose adjustments should take into account not only the INR
boplastins responsiveness compared to the WHO reference.4 result, but also patient-related factors that inuence the result.
The goal or target INR for each patient is based on the indica- Structured anticoagulation therapy management services
tion for warfarin therapy. For the treatment and prevention of (anticoagulation clinics) have been demonstrated to improve
VTE, the INR target is 2.5 with an acceptable range of 2 to 3. In the efcacy and safety of warfarin therapy when compared to
certain high-risk patients (e.g., mechanical heart valves), a usualmedical care. Some patients engage in self-testing and self-
higher target INR of 3 with a range of 2.5 to 3.5 is recom- management by using a point of care PT/INR device approved
mended.4 Before initiating warfarin therapy, a baseline PT/INR for home use. Highly motivated and well-trained patients are
and CBC should be obtained. After initiating warfarin therapy, good candidates for self-testing or self-management.4,7,22,34
Similar to other anticoagulants, warfarins primary side of warfarin overdose or over-anticoagulation, vitamin K may
effect is bleeding. Warfarin can unmask an existing lesion. be used to reverse warfarins effect (Fig. 710).4 Vitamin K can
The incidence of warfarin-related bleeding appears to be be given by the IV or oral route; the SC route is no longer rec-
highest during the rst few weeks of therapy. The annual inci- ommended. When given SC, vitamin K is erratically absorbed
dence of major bleeding ranges from 1% to 10% depending and frequently ineffective. The IV route is reserved for cases of
on the quality of warfarin therapy management. Bleeding in severe warfarin overdose (e.g., INR greater than 20) or major
the gastrointestinal tract is most common. Intracranial hem- bleeding. Anaphylactoid reactions have been reported with
orrhage (ICH) is one of the most serious complications, as it rapid IV administration, therefore slow infusion is recom-
often causes severe disability and death. The intensity of anti- mended. An oral dose of vitamin K will reduce the INR within
coagulation therapy is related to bleeding risk. Higher INRs 24 hours. If the INR is still elevated after 24 hours, another
result in higher bleeding risk, and the risk of ICH increases dose of oral vitamin K can be given. The dose of vitamin K
when the INR exceeds 4.3,4 Instability and wide uctuations in should be based on the INR elevation. A dose of 1 to 2.5 mg is
the INR are also associated with higher bleeding risk. In cases sufcient when the INR is between 5 and 9, but 5 mg may be
Is patient experiencing signs or symptoms of bleeding?

or
Is rapid reversal of excessive anticoagulation required?
Yes No
Determine the site and severity of

bleeding
Administer vitamin K 10 mg via slow IV
infusion, along with fresh-frozen plasma What is INR
or prothrombin complex as needed. value?
Check INR in 12 hours, and repeat
vitamin K infusion as needed until INR
normalized or within therapeutic range.
Above therapeutic 59 Greater than 9

range but less than 5
Does the patient have risk
factors for bleeding?
Consider omitting Yes
next dose of warfarin. No
Check INR in 37 days.
Omit next 13 doses of Are conditions present
Restart warfarin at
warfarin that increase the
reduced dose.
AND administer vitamin K patient's risk of
2.5 mg orally. Check INR thromboembolic complications? Omit next 13 doses of
every 2448 hours. warfarin
Restart at reduced dose. AND
Yes administer vitamin K
No 5 mg orally or 13 mg by
slow IV infusion. Check
Omit next 13 doses of Omit next 13 doses of INR in 1224 hours.
warfarin. Consider warfarin If INR still greater than 9, repeat
administering vitamin K AND administration of
2.5 mg orally, if INR greater than 8. administer vitamin K vitamin K.
Avoid using higher doses 2.55 mg orally and check Check INR every 24 hours.
(510 mg) of vitamin K. INR every 2448 hours. Restart warfarin at
Check INR every 2448 hours. Restart at reduced dose reduced dose once
Restart at reduced dose once therapeutic. therapeutic.
once therapeutic.
FIGURE 710. Management of an elevated INR in patients taking warfarin. Dose reductions should be
made by determining the weekly warfarin dose and reducing the weekly dose by 10% to 25% based on
the degree of INR elevation. Conditions that increase the risk of thromboembolic complications include
history of hypercoagulability disorders (e.g., protein C or S deciency, presence of antiphospholipid anti-
bodies, antithrombin deciency, or activated protein C resistance), arterial or venous thrombosis within
the previous month, thromboembolism associated with malignancy, mechanical mitral valve in conjunc-
tion with atrial brillation, previous stroke, poor ventricular function, or co-existing mechanical aortic
valve. INR, International Normalized Ratio; IV, intravenous. (Reproduced from Haines ST, Zeolla M,
Witt DM. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy:
A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 394, with permission.)
required for INRs greater than 9. Higher doses (e.g., 10 mg) TABLE 78. Clinically Signicant Warfarin Drug Interactions
can lead to prolonged warfarin resistance. In cases of life-
Increase Decrease Increase
threatening bleeding, fresh frozen plasma or clotting factor con-
Anticoagulation Anticoagulation Bleeding
centrates should be administered, in addition to IV vitamin K. Effect ( INR) Effect ( INR) Risk
In cases in whom the INR is less than 9 and there is no active
Acetaminophen Amobarbital Argatroban
bleeding or imminent risk of bleeding, simply withholding Alcohol binge Butabarbital Aspirin
warfarin until the INR decreases to within therapeutic range Allopurinol Carbamazepine Clopidogrel
and reducing the weekly dose with more frequent monitoring Amiodarone Cholestyramine Danaparoid
is appropriate.4 Cephalosporins Dicloxacillin Dipyridamole
Non-hemorrhagic side effects related to warfarin are rare (with MTP Griseofulvin Low-molecular-
side chain) Nafcillin weight heparins
but can be severe when they occur. Warfarin-induced skin Chloral hydrate Phenobarbital Non-steroidal
necrosis presents as an eggplant-colored skin lesion or a Chloramphenicol Phenytoin anti-inammatory
maculopapular rash that can progress to necrotic gangrene. Cimetidine Primidone drugs
It usually manifests in fatty areas such as the abdomen, but- Ciprooxacin Rifampin Ticlopidine
tocks, and breasts. The incidence is less than 0.1%, and it Clobrate Secobarbital Unfractionated heparin
Danazol Sucralfate
generally appears during the rst week of therapy. Patients Disulram Vitamin K
with protein C or S deciency or those who receive large Doxycycline
loading doses of warfarin are at greatest risk. The mechanism Erythromycin
is thought to be due to imbalances between procoagulant Fenobrate
and anticoagulant proteins early in the course of warfarin Fluconazole
Fluorouracil
therapy. Warfarin-induced purple toe syndrome is another Fluoxetine
rare side effect; patients present with a purplish discol- Fluvoxamine
oration of their toes. If these side effects are suspected, war- Gembrozil
farin therapy should be discontinued immediately and an Inuenza vaccine
alternative anticoagulant given. There is a theoretical risk Isoniazid
Itraconazole
that warfarin may cause accelerated bone loss with long- Lovastatin
term use, but to date there is no evidence to support this Metronidazole
concern. Warfarin is teratogenic and is FDA pregnancy cate- Miconazole
gory X. It should be avoided during pregnancy, and women Moxalactam
of child-bearing potential should be instructed to use an Neomycin
Noroxacin
effective form of contraception. Unfractionated heparin and Ooxacin
LMWH are the agents of choice for the treatment of VTE Omeprazole
during pregnancy.4,22 Phenylbutazone
Piroxicam
Warfarin is prone to numerous clinically signicant drug- Propafenone
drug and drug-food interactions (Tables 78, 79, and 710) Propoyxphene
Patients on warfarin should be questioned at every encounter Quinidine
to assess for any potential interactions with foods, drugs, Sertraline
Sulfamethoxazole
herbal products, and nutritional supplements. When an Sulnpyrazone
interacting drug is initiated or discontinued, more frequent Tamoxifen
monitoring should be instituted. In addition, the dose of Testosterone
warfarin can be modied (increased or decreased) in antici- Vitamin E
pation of the expected impact on the INR.4,43 Warfarin- Zarlukast
related drug interactions can generally be divided into two INR, International Normalized Ratio; UFH, unfractionated heparin.
major categories: pharmacokinetic and pharmacodynamic.
Pharmacokinetic interactions are most commonly due to
changes in hepatic metabolism or binding to plasma pro-
teins. Drugs that affect the CYP2C9, CYP3A4, and CYP1A2 the INR.4,43 There are increasing reports regarding dietary
have the greatest impact on warfarin metabolism. supplements, nutraceuticals, and vitamins that can interact
Interactions that impact the metabolism of the S-isomer with warfarin.44 Patients on warfarin may experience changes
result in greater changes in the INR than interactions affect- in the INR due to uctuating intake of dietary vitamin K.
ing the R-isomer. Pharmacodynamic drug interactions Patients should be instructed to maintain a consistent diet
enhance or diminish the anticoagulant effect of warfarin, and avoid large uctuations in vitamin K intake rather than
increasing the risk of bleeding or clotting, but may not alter strictly avoiding vitamin Krich foods.45
TABLE 79. Potential Warfarin Interactions with Herbal and TABLE 710. Vitamin K Content of Select Foodsa
Nutritional Products
Very High (greater High Medium Low (less
Increased Anticoagulation Effect Decreased Anticoagulation than 200 mcg) (100200 mcg) (50100 mcg) than 50 mcg)
(Increase Bleeding Risk or INR) Effect ( INR)
Brussels sprouts Basil Apple, green Apple, red
Amica ower Coenzyme Q10 Chickpea Broccoli Asparagus Avocado
Angelica root Ginseng Collard greens Canola oil Cabbage Beans
Anise Green tea Coriander Chive Cauliower Breads
Asafoetida St. Johns wort Endive Coleslaw Mayonnaise and grains
Bogbean Kale Cucumber Pistachios Carrot
Borage seed oil Lettuce, red leaf (w/peel) Squash, Celery
Bromelain Parsley Green onion/ summer Cereal
Capsicum Spinach scallion Coffee
Celery Swiss Chard Lettuce, Corn
Chamomile Tea, black butterhead Cucumber
Clove Tea, green Mustard greens (w/o peel)
Danshen Turnip greens Soybean oil Dairy
Devils claw Watercress products
Dong quai Eggs
Fenugreek Fruit (varies)
Feverfew Lettuce,
Garlic iceberg
Ginger Meats, sh,
Ginkgo poultry
Horse chestnut Pasta
Licorice root Peanuts
Lovage root Peas
Meadowsweet Potato
Onion Rice
Papain Tomato
Parsley a
Passionower herb Approximate amount of vitamin K per 100-g (3.5-oz) serving.
Poplar
Quassia
Red clover
Rue Patient Encounter 1, Part 2
Sweet clover
Turmeric
Vitamin E
Willow bark KK has been hospitalized for right hip fracture repair. Two
INR, International Normalized Ratio.
weeks after her discharge from the hospital, she presents to
the emergency department with complaints of swelling,
redness, and pain in her right lower extremity. KK states her
symptoms started 3 days ago and have gotten progressively
Nonpharmacologic worse. During your interview, the patient states that she
was sent home with a prescription for fondaparinux 2.5 mg
Thrombectomy SC daily. A duplex ultrasound shows a proximal DVT in her
Most cases of VTE can be successfully treated with anticoag- right lower extremity. All of her other laboratory values are
ulation. In some cases, removal of the occluding thrombus within normal limits.
by surgical intervention may be warranted. Surgical
thrombectomy can be considered in patients with massive Which of KKs symptoms are consistent with an acute DVT?
iliofemoral DVT when there is a risk of limb gangrene due to Design an appropriate treatment plan for KK. Your plan
should include acute and chronic therapyspecify the
venous occlusion. The procedure can be complicated by
drug(s), dose(s), route, frequency of administration, and
recurrence of thrombus formation. In patients who present
duration of each therapy, as well monitoring parameters,
with massive PE, pulmonary embolectomy can be performed patient education, and follow-up plan.
in emergency cases when conservative measures have failed. Assuming KK continues to take the prescription and over-
Patients who are hemodynamically unstable and have a con- the-counter medications listed in her medication history
traindication to thrombolysis are candidates for pulmonary obtained during her hospitalization, should any of these
embolectomy. Administer heparin by IV infusion to achieve medications be discontinued or changed? If changed,
a therapeutic aPTT during the operation and postopera- what alternative therapy would you recommend?
tively. Thereafter, give warfarin for the usual recommended Is KK a candidate for outpatient treatment of her DVT?
duration.8,21
Vena Cava Interruption and in patients who have recurrent VTE while taking anticoag-
Inferior vena cava (IVC) interruption is indicated in patients ulation therapy.8,46 IVC interruption is accomplished by insert-
with PE who have a contraindication to anticoagulation therapy ing a lter through the internal jugular vein or femoral vein
and advancing it into the IVC using ultrasound or uoroscopic
guidance. IVC lters reduce the short-term risk of PE, but this
Patient Encounter 2, Part 1 benet is not sustained in the long term. The incidence of DVT
at 1 year after IVC lter insertion is higher when compared to
patients without lters. Survival after a PE is no different in
patients with lters versus patients without lters.19 Therefore,
BA is a 38-year-old female who presents to the emergency anticoagulation therapy should be resumed as soon as possible
department complaining of chest pain, shortness of breath,
after lter insertion and continued as long as the lter is in
and lightheadedness. The patient states that her symptoms
started with some mild left calf pain approximately 5 days place due to the high risk of DVT.8,46 Temporary or removable
ago. She started feeling short of breath and experiencing lters are currently under study, and these may replace the per-
chest pain last evening. She could not sleep and her short- manent lters now used in practice.8,46
ness of breath has gotten progressively worse in the last
several hours. BA was hospitalized because she was sus- Compression Stockings
pected to have a pulmonary embolism. Postthrombotic syndrome occurs in 20% to 50% of patients
within 8 years after a DVT. Wearing graduated compression
PMH
Obesity 12 years; asthma stockings (GCS) after a DVT reduces the risk of PTS by as
much as 50%. Current guidelines recommend the use of GCS
FH with an ankle pressure of 30 to 40 mm Hg for 2 years after a
Mother died of a stroke; paternal grandmother had clots in
DVT. To be effective, GCS must t properly. Traditionally,
her legs
strict bed rest has been recommended after a DVT, but this
SH approach has now been refuted and patients should be
The patient is a school teacher encouraged to ambulate as tolerated.8,34
Current meds
Albuterol (salbutamol) metered-dose inhaler as needed
Ortho-Tri-Cyclen Lo by mouth daily APPROACH TO TREATING PATIENTS WITH
Echinacea 1 to 2 tablets by mouth daily as needed VENOUS THROMBOEMBOLISM
Multivitamin 1 tablet by mouth daily
Allergies Once the diagnosis of VTE has been conrmed with an
Shellsh, no known drug allergies objective test, promptly start anticoagulation therapy in full
therapeutic doses. If there is high clinical suspicion of VTE, anti-
PE
VS: blood pressure 104/64 mm Hg; heart rate 102; respiratory coagulation therapy can be initiated while waiting for the results
rate 20; temperature 38C (100.4F); weight 211 lb (96 kg); of diagnostic tests.8 Initiate therapy with a quick-acting antico-
height 65 inches (165 cm) agulant such as UFH (given IV), an LMWH (given SC), or fon-
daparinux (given SC) (Figs. 75 and 711). In patients with
Labs
Within normal limits; estimated glomerular ltration rate adequate renal function, the LMWHs are preferred over UFH.8
(GFR) 101 mL/minute Recent evidence also supports the use of SC fondaparinux as an
alternative option to UFH or LMWH for the initial treatment of
Procedures/Tests
VTE.8,21 For the long-term treatment phase, warfarin is the pre-
Electrocardiograph: normal sinus rhythm
Chest x-ray: slightly enlarged heart
ferred approach except for patients with cancer, in whom an
Ventilation/perfusion (V/Q) scan: high probability of PE LMWH is recommended. Initiate warfarin on the rst day of
therapy after the rst dose of UFH, LMWH, or fondaparinux is
What signs and symptoms are consistent with the diagnosis given. Overlap the injectable agent with warfarin therapy for a
of PE in BAs case? What are the most likely etiologies for minimum of 5 days. Warfarin should be dosed to achieve a goal
pulmonary embolism in this case? INR range of 2 to 3. Once the INR is stable and above 2, the
What are appropriate initial and chronic treatment options injectable anticoagulant should be discontinued. Anticoagulation
for BA? therapy is continued for a minimum of 3 months but should be
If unfractionated heparin is chosen as the initial anticoagu-
given longer depending on the underlying etiology of the VTE and
lation treatment option, what is the goal aPTT?
What is BAs goal INR for warfarin therapy?
the patients risk factors (Table 711).8,21,34 Use a thrombolytic only
How long should BA remain on anticoagulation therapy? if the patient has a massive iliofemoral DVT and is at risk of limb
Given the list of medications BA took prior to hospitalization, gangrene. In patients with PE, use a thrombolytic if the patient is
should any of these medications be discontinued or changed? hemodynamically unstable (i.e., SBP less than 90 mm Hg). If there
If changed, what alternative therapy would you recommend? is a contraindication to anticoagulation therapy or the patient
has failed therapy with an anticoagulant, a vena cava lter should
-If VTE not objectively confirmed order

appropriate diagnostic testing
-Consider giving UFH 5000 units IV
Objectively
confirmed VTE
Consider vena Anticoagulant

Yes
cava filter contraindicated?
SBP less than 90 mm Hg

No or need for vasopressor
therapy
Contraindication to PE with evidence

No thrombolytic Yes
of shock?
therapy?
Consider outpatient treatment
if patient is:
Consider -Hemodynamically stable
No
thrombolytic -Free of severe renal disease
therapy -Low bleeding risk
-Free of co-existing conditions that
Initiate would require hospitalization
anticoagulation
Yes therapy with:
Consider UFH or LMWH or
embolectomy in Fondaparinux
critically ill patients and warfarin
Consider long- Hypercoagulable

term warfarin Yes state or idiopathic
therapy VTE?
No
Warfarin therapy
for 3 to 6 months
FIGURE 711. Treatment of venous thromboembolism. LMWH, low-molecular-weight heparin; PE, pulmonary
embolism; SBP, systolic blood pressure; UFH, unfractionated heparin; VTE, venous thromboembolism. (Reproduced
from Haines ST, Zeolla M, Witt DM. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.)
Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 398, with permission.)
be inserted. Encourage early ambulation as tolerated by the VTE, (3) preventing treatment-related complications, and
patient during the initial treatment phase.8,21 (4) reducing the likelihood of long-term complications
including recurrent events.
Given that VTE is often clinically silent and potentially fatal,
OUTCOME EVALUATION strategies to increase the widespread use of prophylaxis have
the greatest potential to improve patient outcomes.
Achieve optimal outcomes by (1) preventing the occurrence Relying on the early diagnosis and treatment of VTE is unac-
of VTE in patients who are at risk, (2) administering effec- ceptable because many patients will die before treatment can
tive treatments in a timely manner to patients who develop be initiated.
Effective VTE prophylaxis programs screen and identify all

patients at risk, determine each patients level of risk, and Patient Encounter 2, Part 2
select and implement regimens that provide sufcient pro-
tection for the level of risk.
Periodically evaluate patients who receive prophylaxis dur-
BA is a 38-year-old female with acute PE discharged home
ing the course of treatment for signs and symptoms of VTE,
on warfarin therapy. She was referred to a local area
such as swelling, pain, warmth, and redness of lower extrem- antithrombosis center for monitoring of her oral anticoagu-
ities, and for DVT, as well as chest pain, shortness of breath, lation therapy and has been maintained on warfarin 6 mg
palpitations, and hemoptysis. daily for the last 3 months. The patient presents today for a
Providing effective treatment in a timely manner is the primary routine visit for anticoagulation monitoring and her INR is
goal for patients who develop VTE. Treat DVT and PE quickly 8.3. She reports that 6 days ago she was started on metron-
and aggressively with effective doses of anticoagulant drugs. idazole 500 mg by mouth twice daily, which was pre-
The short-term aim of therapy is to prevent propagation or scribed by her primary care physician for a vaginal infec-
local extension of the clot, embolization, and death. tion. In addition, the primary care physician told the
Regularly monitor patients for the development of new patient that her thyroid gland was enlarged and ordered
some lab tests to determine if she has a thyroid problem.
symptoms or worsening of existing symptoms.
The patient has not heard what the results are. She also
Anticoagulant drugs require precise dosing and meticulous
reports that her intake of vitamin Krich foods (spinach,
monitoring. Closely monitor patients receiving anticoagu- broccoli, and cabbage) has increased signicantly over the
lant therapy for signs and symptoms of bleeding, including last month because she is trying to lose weight. BA has no
epistaxis, hemoptysis, hematuria, bright red blood per rec- other complaints today and denies any signs or symptoms
tum, tarry stools, severe headache, and joint pain. If major of bleeding.
bleeding occurs, stop therapy immediately and treat the
source of bleeding. In addition, closely monitor patients for What is the most likely explanation for elevated INR in BAs
potential drug-drug and drug-food interactions and adher- case?
ence with the prescribed regimen. Should BA be given vitamin K? If yes, discuss the dose,
The long-term (i.e., more than 3 months after the rst event) goals route of administration, and an appropriate patient moni-
toring plan.
of therapy are to prevent complications such as the postthrom-
How will you manage BAs warfarin therapy? Outline a
botic syndrome, pulmonary hypertension, and recurrent VTE.
plan including specic dose changes, timing of monitor-
Encourage all patients who have had DVT to wear graduated ing, and patient education.
compression stockings.
Continue warfarin therapy for an appropriate duration
based on the presence of ongoing risk factors.
TABLE 711. Duration of Anticoagulation Therapy for the Treatment of VTE
Duration of
Therapy
Patient Characteristics Drug (Months) Comments
First episode of VTE secondary Warfarin 3 Recommendation applies to both proximal and calf
to a transient (reversible) vein thrombosis
risk factor
First episode of VTE and cancer Low-molecular- 6 Low-molecular-weight heparin is recommended over
weight heparin warfarin
First episode of idiopathic VTE with Warfarin 12 Continue warfarin therapy after 12 months if patient is
or without a documented at low risk for bleeding
hypercoagulable abnormality
First episode of VTE with documented Warfarin 24+ Continue warfarin therapy after 24 months if patient is
antiphospholipid antibodies at low risk for bleeding
or two or more hypercoagulable
abnormalities
Second episode of VTE Warfarin 24+ Continue warfarin therapy after 24 months if patient is
at low risk for bleeding
VTE, venous thromboembolism.

Patient Care and Monitoring If the patient is to be treated with UFH, measure aPTT (or
antifactor Xa activity) 6 hours after initiating the IV infu-
sion. Adjust dose if necessary (Table 75) and measure
aPTT (or antifactor Xa activity) every 6 hours after each
Day 1 dose change until therapeutic. Measure aPTT (or anti
1. It is critical to rst conrm diagnosis of VTE factor Xa activity) daily thereafter.
Clinical assessment: look for risk factors for VTE Arrange for follow-up and long-term anticoagulation ther-
If DVT symptoms are present, obtain a venous ultrasound apy management. Communicate with the patients primary
If PE is suspected, obtain a V/Q or computed tomography scan care physician and/or refer to a local antithrombosis serv-
D-dimer: this test may be a helpful adjunct to either a ice, if available. If the patient is to be treated primarily in
venous ultrasound or V/Q scan the hospital, these arrangements can be made 1 to 2 days
2. Obtain baseline laboratory tests. These tests must be prior to hospital discharge.
obtained prior to initiating anticoagulation therapy: 6. Document all activities in medical record.
Prothrombin time (PT) and calculated International
Day 2
Normalized Ratio (INR)
1. If the patient is being treated with UFH, remeasure aPTT (or
Activated partial thromboplastin time (aPTT)
antifactor Xa activity), and adjust dose if necessary. If
Serum creatinine
patient is being treated with LMWH or fondaparinux, con-
Complete blood cell count (CBC) with platelets
tinue therapy.
3. Medications:
2. Interview the patient to determine if there is worsening or
Screen the patients pharmacy prole for potential drug-
new symptoms related to VTE. Ask the patient about overt
drug interactions with anticoagulation therapy
bruising or bleeding, particularly at the injection site, as
Initiate unfractionated heparin (UFH) or low-molecular-
well as changes in stool or urine color.
weight heparin (LMWH) or fondaparinux by injection (see
Table 73 for dosing guidelines) 3. Advise the patient to limit physical activity if pain persists
Start warfarin sodium orally every evening (see Fig. 79 for and to elevate the extremity; increase activity as tolerated.
dosing guidelines) 4. Document activities in medical record.
Start pain medication if necessary (avoid non-steroidal anti-
Days 3 to 5
inammatory drugs)
1. Measure PT/INR every 1 to 2 days.
4. Patient Education:
2. Interview the patient to determine if there is worsening or
Educate the patient regarding the purpose of therapy and
new symptoms related to VTE. Inquire about and evaluate
importance of proper monitoring of anticoagulant drugs.
patient adherence to therapy. Ask the patient about overt
Assist the patient to determine an appropriate provider for
bruising or bleeding, particularly at the injection site, as
long-term monitoring of anticoagulation therapy.
well as changes in stool or urine color. Advise the patient
If LMWH or fondaparinux is selected, teach the patient
to limit physical activity if pain persists and to elevate the
how to self-administer (if the patient or a family member is
extremity; increase activity as tolerated. Reinforce previous
unwilling or unable to self-administer, visiting nurse serv-
patient education regarding vitamin K intake and potential
ices should be arranged). Initial injection should be admin-
drug-drug interactions with warfarin.
istered in the medical ofce or hospital.
Inform patient about the effects of vitamin Krich foods on 3. Hold or adjust warfarin dose as necessary. If the patient
warfarin therapy. Moderate intake (less than 500 to 1000 is being treated with UFH, measure aPTT daily (or anti
mcg) of vitamin K is acceptable. Provide patient with writ- factor Xa activity), and adjust dose if necessary. If the
ten material regarding vitamin K content of foods. patient is being treated with an LMWH or fondaparinux,
Inform the patient about the potential drug-drug interac- continue therapy.
tions with warfarin, including over-the-counter medications 4. Document activities in medical record.
and dietary supplements (Tables 78, 79, and 710).
Instruct the patient to call the health care practitioner Days 6 to 8
responsible for monitoring warfarin therapy before starting 1. Measure PT/INR every 2 to 3 days. Obtain CBC or platelet
any new medications or dietary supplements. count.
Instruct the patient regarding nonpharmacologic strategies 2. Interview the patient to determine if there is worsening or
including elevation of the affected extremity and anti- new symptoms related to VTE. Inquire about and evaluate
embolic exercises such as exion/extension of the ankle patient adherence to therapy. Ask the patient about overt
(for lower extremity VTE) or hand squeezing/relaxation (for bruising or bleeding, particularly at the injection site, as
upper extremity VTE). well as changes in stool or urine color. Advise the patient
5. Next steps: to limit physical activity if pain persists and to elevate the
If the patient is to be treated at home, dispense to the extremity; increase activity as tolerated. Reinforce previous
patient a 5- to 7-day supply of prelled LMWH or fonda- patient education regarding vitamin K intake and potential
parinux syringes in patient-specic dose. drug-drug interactions with warfarin.
(Continued)
3. Hold or adjust warfarin dose as necessary. Discontinue UFH, Days 15 to 90

LMWH, or fondaparinux if INR is greater than 2 on two con- 1. Measure PT/INR every 1 to 4 weeks based on the stability
secutive occasions. If the patient requires continued treat- of the INR and patients health status.
ment with UFH, measure aPTT, and adjust dose if necessary. 2. Interview the patient to determine if there is worsening or
4. If the patient is treated with UFH or LMWH and platelet new symptoms related to VTE. Inquire about and evaluate
count has dropped by more than 50% from baseline or is patient adherence to therapy. Ask the patient about overt
less than 120 103/L, evaluate the patient for heparin- bruising or bleeding as well as changes in stool or urine
induced thrombocytopenia (HIT). color. Encourage the patient to increase activity as toler-
5. Document activities in medical record. ated. Reinforce previous patient education regarding vita-
min K intake and potential drug-drug interactions with
Days 9 to 14 warfarin.
1. Measure PT/INR every 3 to 5 days. 3. Adjust warfarin dose as necessary. Consider restarting
2. Interview the patient to determine if there is worsening or LMWH or fondaparinux if INR drops below 1.5.
new symptoms related to VTE. Inquire about and evaluate 4. Document activities in medical record.
patient adherence to therapy. Ask the patient about overt
bruising or bleeding, particularly at the injection site, as Three Months and Beyond
well as changes in stool or urine color. Advise the patient 1. Measure PT/INR every 1 to 4 weeks based on the stability
to elevate the extremity and increase activity as tolerated. of the INR and patients health status.
Reinforce previous patient education regarding vitamin K 2. Interview the patient to determine if there is worsening or
intake and potential drug-drug interactions with warfarin. new symptoms related to VTE. Inquire about and evaluate
3. Hold or adjust warfarin dose as necessary. Discontinue UFH, patient adherence to therapy. Ask the patient about overt
LMWH, or fondaparinux if INR is greater than 2 on two con- bruising or bleeding as well as changes in stool or urine
secutive occasions. If the patient requires continued treatment color. Reinforce previous patient education regarding vita-
with UFH, re-measure aPTT, and adjust dose if necessary. min K intake and potential drug-drug interactions with
4. Obtain CBC or platelet count. If the patient is treated with warfarin.
UFH or LMWH and platelet count has dropped by more 3. Re-evaluate the risks and benets of continuing warfarin
than 50% from baseline or is less than 120 103/L, eval- therapy.
uate the patient for HIT. 4. Document activities in medical record.
5. Document activities in medical record.
ABBREVIATIONS IM: intramuscular

INR: International Normalized Ratio
ABW: adjusted body weight IPC: intermittent pneumatic compression (device)
ACCP: American College of Chest Physicians ISI: International Sensitivity Index
ACT: activated clotting time IV: intravenous
ADP: adenosine diphosphate IVC: inferior vena cava
aPTT: activated partial thromboplastin time LMWH: low-molecular-weight heparin
AT: antithrombin PAF: platelet activating factor
BMI: body mass index PAI-1: plasminogen activator inhibitor-1
CBC: complete blood count PCI: percutaneous coronary inhibitor
CO: cyclooxygenase PE: pulmonary embolism
CrCl: creatinine clearance PF-4: platelet factor-4
CT: computed tomography PGG/PGH: prostaglandins
CYP: cytochrome P-450 isoenzyme PGI: prostacyclin
DTI: direct thrombin inhibitor PLA: phospholipase A
DVT: deep vein thrombosis PO: oral
ESR: erythrocyte sedimentation rate PT: prothrombin time
FDA: Food and Drug Administration PTS: postthrombotic syndrome
GCS: graduated compression stockings SBP: systolic blood pressure
GFR: glomerular ltration rate SC: subcutaneous
GP: glycoprotein SERM: selective estrogen receptor modulator
HCII: heparin co-factor II TFPI: tissue factor pathway inhibitor
HIT: heparin-induced thrombocytopenia t-PA: tissue plasminogen activator
HMWK: high-molecular-weight kininogen TS: thromboxane synthetase
IBW: ideal body weight TXA: thromboxane A
ICH: intracranial hemorrhage UFH: unfractionated heparin
u-PA: urokinase plasminogen activator Bates SM, Ginsberg JS. Clinical practice. Treatment of deep-vein
V/Q: ventilation/perfusion (scan) thrombosis. N Engl J Med 2004;351:268277.
VTE: venous thromboembolism Buller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for
vWF: von Willebrand factor venous thromboembolic disease: The Seventh ACCP Conference
WBC: white blood cell (count) on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:
WHO: World Health Organization 401S428S.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous throm-
Reference lists and self-assessment questions and answers are boembolism: The Seventh ACCP Conference on Antithrombotic
available at www.ChisholmPharmacotherapy.com. and Thrombolytic Therapy. Chest 2004;126:338S400S.
Hirsh JC, Raschke R. Heparin and low-molecular-weight heparin:
The Seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest 2004;126:188S203S.
Levine M, Raskob GP, Beyth RJ, et al. Hemorrhagic complications of
this chapter. anticoagulant treatment: The Seventh ACCP Conference on
Antithrombotic and Thrombolytic Therapy. Chest 2004;126:
KEY REFERENCES AND READINGS 287S310S.
Weitz JI, Hirsh J, Samama MM. New anticoagulant drugs: The Seventh
Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of ACCP Conference on Antithrombotic and Thrombolytic Therapy.
the vitamin K antagonists: The Seventh ACCP Conference on Chest 2004;126:265S286S.
Antithrombotic and Thrombolytic Therapy. Chest 2004;126:
204S233S.
8 STROKE
Susan R. Winkler
LEARNING OBJECTIVES
1. Understand the types of cerebrovascular disease including transient ischemic attack,

cerebral infarction, and cerebral hemorrhage.
2. Understand the pathophysiology of cerebral ischemia and cerebral hemorrhage.
3. Identify the modiable and non-modiable risk factors associated with ischemic stroke and
hemorrhagic stroke.
4. Identify risk factors for ischemic stroke in a patient and provide the appropriate patient
education.
5. Discuss the various treatment options for acute ischemic stroke and hemorrhagic stroke.
6. Determine whether thrombolytic therapy is indicated in a patient with acute ischemic
stroke.
7. Develop an appropriate patient-specic therapeutic plan for acute ischemic stroke.
8. Develop an appropriate therapeutic plan for outpatient management of a patient with
ischemic stroke, including an appropriate agent to prevent stroke recurrence.
KEY CONCEPTS will differ accordingly and thrombolytic (brinolytic) therapy

must be avoided until a hemorrhagic stroke is ruled out.
Strokes can either be ischemic (88%) or hemorrhagic (12%). In carefully selected patients, alteplase is effective in limiting
Ischemic stroke is the abrupt development of a focal neuro- the infarct size and protecting brain tissue from ischemia and
logic decit that occurs due to inadequate blood supply to an cell death by restoring blood ow. Treatment must be given
area of the brain. Most often, this is due to a thrombotic or within 3 hours of the onset of symptoms and offers no bene-
embolic arterial occlusion leading to cerebral infarction. t if given beyond this time period.
Hemorrhagic stroke is a result of bleeding into the brain and Early aspirin therapy is recommended in most patients with
other spaces within the central nervous system and includes acute ischemic stroke within the rst 24 to 48 hours after
subarachnoid hemorrhage, intracerebral hemorrhage, and stroke onset and should be continued for at least 2 weeks.
subdural hematomas. Aspirin is typically considered to be the rst-line secondary
There are two main classications of cerebral ischemic events: prevention agent for ischemic stroke and decreases the risk of
transient ischemic attacks and cerebral infarction. subsequent stroke by approximately 25% in both men and
A major goal in the long-term treatment of ischemic stroke women with previous transient ischemic attacks or stroke.
involves the prevention of a recurrent stroke through the There is no proven treatment for intracerebral hemorrhage.
reduction and modication of risk factors. Management is based on neurointensive care treatment and
All patients should have a brain computed tomography scan prevention of complications. Oral nimodipine is recom-
or magnetic resonance imaging scan to differentiate an mended in subarachnoid hemorrhage to prevent delayed
ischemic stroke from a hemorrhagic stroke, as the treatment cerebral ischemia.
161
EPIDEMIOLOGY AND ETIOLOGY and middle layer of the meninges, most often due to trauma
or rupture of a cerebral aneurysm or arteriovenous malfor-
Cerebrovascular disease (CVD), or stroke, is the third leading mation (AVM). Intracerebral hemorrhage (ICH) is bleeding
cause of death in the United States and the second most com- directly into the brain parenchyma, often as a result of
mon cause of death worldwide. Over 700,000 strokes occur in chronic, uncontrolled hypertension. Subdural hematomas
the United States each year. Strokes can either be ischemic result from bleeding under the dura which covers the brain
(88% of all strokes) or hemorrhagic (12% of all strokes). Figure 81 and most often occur as a result of head trauma.
provides a classication of stroke by mechanism. New strokes
account for 500,000 of this total, while recurrent strokes
account for the remaining 200,000 strokes each year. Stroke is PATHOPHYSIOLOGY
the leading cause of long-term disability in adults, with 90% of
survivors having residual decits. Moderate to severe disability Classication of Cerebral Ischemic Events
is seen in 70% of survivors. The American Heart Association
estimates that there are 4.7 million survivors of stroke in the There are two main classications of ischemic events, tran-
United States. The societal impact and economic burden is sient ischemic attack (TIA) and cerebral infarction. A TIA is a
great, with costs exceeding $57 billion per year in the United temporary reduction in perfusion to a focal region of the brain
States. Stroke mortality has declined due to improved recogni- causing a short-lived disturbance of function. TIAs have a rapid
tion and treatment of risk factors; however, risk factor man- onset (5 minutes) and short duration (2 to 15 minutes, up to
agement is still inadequate today. Stroke incidence increases 24 hours). The symptoms vary depending on the area of the
with age, especially after age 55, resulting in an increased stroke brain affected; however, no decit remains after the attack. A TIA
incidence due to aging of the population.1 may be the only warning of an impending stroke, with the great-
est risk occurring in the rst several weeks. Cerebral infarction is
Ischemic stroke is the abrupt development of a focal neurologic similar to a TIA; however, symptoms last longer than 24 hours,
decit that occurs due to inadequate blood supply to an area of the and in 90% of patients residual decits remain after the event.
brain. Most often, this is due to a thrombotic or embolic arterial
occlusion leading to cerebral infarction. A thrombotic occlusion
occurs when a thrombus forms inside an artery in the brain. An Classication of Hemorrhagic Events
embolism refers to a clot originating outside of the brain in which
A sudden severe headache, nausea and vomiting, and photo-
a piece of the clot breaks loose and is carried to the brain.
phobia may be the rst signs and symptoms of hemorrhagic
Hemorrhagic stroke is a result of bleeding into the brain stroke. Neck pain and nuchal rigidity may also be experienced
and other spaces within the central nervous system and includes at the time of the hemorrhage. Patients may complain that
subarachnoid hemorrhage, intracerebral hemorrhage, and sub- the headache is the worst headache of my life, especially if
dural hematomas. Subarachnoid hemorrhage (SAH) results the cause is an SAH. It is important to note that a diagnosis
from sudden bleeding into the space between the inner layer of the type of stroke cannot be made solely on signs and
FIGURE 81.
STROKE Classication of
Primary stroke. (Adapted
15% hemorrhage from Fagan SC,
85% Intraparenchymal Hess DC. Stroke.
Subarachnoid In: DiPiro JT,
Ischemic stroke Talbert RL, Yee
GC, et al, (eds.)
Pharmacotherapy:
20% 25% 20% 30% 5% A Pathophysiologic
Approach. 6th ed.
Atherosclerotic Penetrating Cardiogenic Cryptogenic Other, unusual New York:
cerebrovascular artery disease embolism stroke causes McGraw-Hill;
disease (Lacunes) Atrial fibrillation Prothrombic states
2005: 416, with
Valve disease Dissections permission.)
Ventricular thrombi Arteritis
Many others Migraine/vasospasm
Drug abuse
Many more
Hypoperfusion Arteriogenic
emboli
CHAPTER 8 / STROKE 163
TABLE 81. Signs and Symptoms of Stroke is released, contributing to platelet aggregation and vasocon-
striction. The vessel injury also activates the coagulation cas-
Sudden weakness, numbness, or paralysis of the face, arm, or leg
cade, which leads to thrombin production. Thrombin converts
(especially on one side of the body)
Loss of speech or trouble talking or understanding language brinogen to brin, leading to clot formation as brin mole-
Sudden loss of vision cules, platelets, and blood cells aggregate. Figures 82 and 83
Sudden severe headache depict these processes.
Unexplained dizziness or loss of balance or coordination Once the initial event occurs, secondary events occur at the
cellular level that contribute to cell death. Regardless of the
specic initiating event, the cellular processes that follow may
symptoms, as many of these overlap between the types of be similar. Excitatory amino acids such as glutamate accumu-
stroke. Table 81 identies the signs and symptoms of stroke. late within the cells, causing intracellular calcium accumula-
tion. Inammation occurs and oxygen free radicals are
formed ending in the common pathway of cell death.
Pathophysiology of Ischemic Stroke Often, there is a core of ischemia containing unsalvageable
There are three major pathophysiologic mechanisms underly- brain cells. Surrounding this core is an area often termed the
ing the occurrence of ischemic stroke including large-vessel ischemic penumbra. In this area, cells are still salvageable;
disease, small-vessel disease, and embolism. In ischemic however, this is a time-sensitive endeavor, as without restora-
stroke, there is an interruption of the blood supply to an area tion of adequate perfusion, cell death continues throughout a
of the brain either due to thrombus formation or an larger area of the brain. This process ultimately leads to neu-
embolism. Loss of cerebral blood ow results in a failure of rologic decits. No agents have been shown to be effective at
energy production in the affected brain cells. This lack of providing neuroprotection at this time.
blood ow results in tissue hypoperfusion, tissue hypoxia, and
cell death. Lipid deposits in the vessel wall cause turbulent Pathophysiology of Hemorrhagic Stroke
blood ow and lead to vessel injury, exposing vessel collagen
to blood. This vessel injury initiates the platelet aggregation The pathophysiology of hemorrhagic stroke is not as well stud-
process due to the exposed subendothelium. Platelets release ied as that of ischemic stroke; however, it is a more complex
adenosine diphosphate (ADP), which causes platelet aggrega- process than previously thought. Much of the process is related
tion and consolidation of the platelet plug. Thromboxane A2 to the presence of blood in the brain tissue and/or surrounding
FIGURE 82. Platelet

aggregation. This
gure shows the
process of platelet
VESSEL INJURY HEMOSTASIS aggregation. Vessel
injury occurs resulting
in adhesion of the
platelets to the vessel
wall. This leads to
continued adhesion
Tethering & Stable Thrombus
and aggregation of
translocation aggregation formation platelets resulting in
thrombus formation.
Adhesion
Spreading
Exposed proteins
at injured site
FIGURE 83. The physiologic clotting cascade. Clot

Vessel or tissue injury formation beginning with vessel or tissue injury. Tissue
injury starts the complex process involving clotting
factors and resulting in cross-linked brin. This is a
Factor VII
schematic of the factors and steps involved in the
Tissue factor
Factor Xl process.
Factor XIa
Factor IX Factor VIIa-Tissue factor complex
Factor VIIIa
Factor IXa
Factor VIII Factor V
Factor X
Factor Xa Factor Va
Prothrombin
Thrombin
Fibrinogen
Fibrin
Factor XIII
Factor XIIIa
Fibrin
crosslinked
spaces resulting in compression. It is now known that the one of the major risk factors for both ischemic and hemor-
hematoma that forms may continue to grow and enlarge after rhagic stroke. For ICH specically, uncontrolled hypertension
the initial bleed and that early growth of the hematoma is asso- is thought to be the cause of hemorrhage in 60% to 70% of
ciated with a poor outcome. Brain tissue swelling and injury is patients.5 Other risk factors for hemorrhagic stroke include
a result of inammation caused by thrombin and other blood trauma, cigarette smoking, cocaine use, heavy alcohol use, and
products. This can lead to increased intracranial pressure and cerebral aneurysm and AVM rupture. Tables 82 and 83 pro-
herniation.2,3 vide a listing of risk factors in ischemic stroke.
Risk Factors
DESIRED TREATMENT OUTCOMES
Assessment of risk factors for ischemic stroke as well as for
hemorrhagic stroke is an important component of the diagno- The short-term goals of treatment for acute ischemic stroke
sis and treatment of patients. A major goal in the long-term include reducing secondary brain damage by re-establishing
treatment of ischemic stroke involves the prevention of a recurrent and maintaining adequate perfusion to marginally ischemic
stroke through the reduction and modication of risk factors. The areas of the brain and to protect these areas from the effects
major focus of primary prevention (prevention of the rst of ischemia (i.e., neuroprotection). The long-term goals of
stroke) is also reduction and modication of risk factors. Risk treatment include prevention of a recurrent stroke through
factors for ischemic stroke can be divided into modiable and reduction and modication of risk factors and by use of
non-modiable factors. Every patient should have risk factors appropriate treatments.
assessed and treated, if possible, as management of risk factors
can decrease the occurrence and/or recurrence of stroke.4
Non-modiable risk factors include age, gender, race/
TABLE 82. Non-modiable Risk Factors for Ischemic Stroke
ethnicity, and heredity. Ischemic stroke risk is increased in those
greater than 55 years of age, in men, and in African-Americans, Age (greater than 55 years of age)
Hispanics, and Asian-Pacic Islanders. It is also increased in Gender (males greater than females)
those with a family history of stroke. Modiable risk factors Race (African-American, Hispanic, or Asian-Pacic Islander)
include a number of treatable disease states and lifestyle factors Ethnicity
Heredity
that can greatly inuence overall stroke risk. Hypertension is
Clinical Presentation and Diagnosis Patient Encounter, Part 1
General GR is a 68-year-old African-American male who presents to

The patient may not be able to reliably report the his- the emergency department with dizziness and loss of speech
tory owing to cognitive or language decits. A reliable that began 1 hour ago. His past medical history is signicant
history may have to come from a family member or for hypertension, diabetes mellitus, hypercholesterolemia, and
another witness. benign prostatic hypertrophy (BPH). Social history is signi-
cant for smoking 1 pack per day for the last 38 years. Current
Symptoms
medications include metoprolol 50 mg twice daily, insulin
The patient may complain of weakness on one side of the
NPH 20 units twice daily, and simvastatin 20 mg daily.
body, inability to speak, loss of vision, vertigo, or falling.
Stroke patients may complain of headache; however, with
What signs and symptoms does GR have that are sugges-
hemorrhagic stroke, the headache can be severe.
tive of stroke?
Signs What non-modiable and modiable risk factors does GR
Patients usually have multiple signs of neurologic dys- have for acute ischemic stroke?
function, and the specic decits are determined by the
area of the brain involved.
Hemiparesis or monoparesis occur commonly, as does a The short-term goals for the treatment of hemorrhagic
hemisensory decit. stroke include rapid neurointensive care treatment to maintain
Patients with vertigo and double vision are likely to have adequate oxygenation, breathing, and circulation. Management
posterior circulation involvement.
of increased intracranial pressure and blood pressure (BP) are
Aphasia is seen commonly in patients with anterior circu-
lation strokes.
important in the acute setting. Long-term management includes
Patients may also suffer from dysarthria, visual eld prevention of complications and prevention of a recurrent bleed
defects, and altered levels of consciousness. and delayed cerebral ischemia.
Prevention of long-term disability and death related to the
Laboratory Tests
stroke are important regardless of the type of stroke.
There are no specic laboratory tests for stroke.
Tests for hypercoagulable states, such as protein C de-
ciency and antiphospholipid antibody, should be done TABLE 83. Modiable Risk Factors for Ischemic Stroke
only when the cause of stroke cannot be determined
based on the presence of well-known risk factors for Hypertension (single most important risk factor)
stroke. Cardiac disease
Atrial brillation (most important and treatable cardiac cause of
Other Diagnostic Tests stroke)
A computed tomography (CT) scan of the head will reveal Mitral stenosis
an area of hyperintensity (white) identifying that a hemor- Mitral annular calcication
rhage has occurred. The CT scan will either be normal Left atrial enlargement
or hypointense (dark) in an area where an infarction has Structural abnormalities such as atrial-septal aneurysm
occurred. The CT scan may take 24 hours (rarely longer) Myocardial infarction
Transient ischemic attacks or prior stroke (major independent risk
to reveal the area of infarction.
factor)
Magnetic resonance imaging (MRI) of the head will
Diabetes (independent risk factor)
reveal areas of ischemia earlier and with better resolution Hypercholesterolemia
than a CT scan. Some types of imaging can reveal an Lifestyle factors
evolving infarct within minutes. Cigarette smoking
Carotid Doppler studies will determine whether the Excessive alcohol use
patient has a high degree of stenosis in the carotid arter- Physical inactivity
ies supplying blood to the brain (extracranial disease). Obesity
The electrocardiogram will determine whether the patient Diet
has atrial brillation, which is a major risk factor for Cocaine and intravenous drug use
Low socioeconomic status
stroke.
Increased hematocrit
A transthoracic echocardiogram will identify whether
Sickle cell disease
there are heart valve abnormalities or problems with wall Elevated homocysteine level (still under study, but may be related
motion resulting in emboli to the brain. to stroke risk)
Migraine (risk not clear)
Asymptomatic carotid stenosis
Oral contraceptives (with estrogen content greater than 50 mcg)
GENERAL APPROACH TO TREATMENT TREATMENT OF ACUTE ISCHEMIC STROKE
All patients should have a brain computed tomography Acute stroke is considered to be an acute medical emergency.
(CT) scan or magnetic resonance imaging (MRI) scan to differen- Identication of the time and manner of stroke onset is an
tiate an ischemic stroke from a hemorrhagic stroke, as the treat- important determinant in treatment. The time the patient was
ment will differ accordingly and thrombolytic (brinolytic) therapy last without symptoms is used as the time of stroke onset.
must be avoided until a hemorrhagic stroke is ruled out (in other Since patients typically do not experience pain, determining the
words, until it is determined that it is not a hemorrhagic stroke). onset time can be difcult. It is also important to document
A CT scan is the most important diagnostic test in patients risk factors and previous functional status of the patient to
with acute stroke. For those with an ischemic stroke, an eval- assess current disability due to the stroke.
uation should be done to determine the appropriateness of
reperfusion therapy. In hemorrhagic stroke, a surgical evalua-
Supportive Measures
tion should be completed to assess the need for surgical clip-
ping of an aneurysm or other procedure to control the bleed Acute complications of stroke include cerebral edema, increased
and prevent re-bleeding and other complications. Figure 84 intracranial pressure, seizures, and hemorrhagic conversion. In
provides an algorithm for the initial management of the acute the acute setting, several supportive interventions and treat-
stroke patient. ments to prevent acute complications should be initiated.
Acute stroke
Neurosurgical
SAH
consultation
Blood on CT Yes
(or MRI)
Hydration with NS; BP Consider neurosurgical
No management; consultation, especially
ICH treat elevated glucose, if cerebellar ICH and/or
Hydration with NS; BP
management hyperthermia; consider O2 intraventricular blood
(see Tables 8-4 and 8-5);
treat elevated glucose,
hyperthermia; consider O2
Yes Yes Antithrombotic therapy

Time of onset Meets t-PA criteria IV t-PA per
after 24 hours; stroke
less than 3 hours (see Table 8-6) NINDS protocol
etiology evaluation
No No
Spontaneous Yes Anterior Yes

improvement or circulation
resolution of symptoms signs/symptoms
No No Emergent carotid
duplex
Consider IA thrombolysis,
experimental therapy, or Vascular surgery
empiric anticoagulation High-grade consultation for
(especially if basilar artery Yes
symptomatic ICA possible CEA;
thrombosis, arterial dissection, stenosis antithrombotic
venous sinus thrombosis) therapy
No
Aspirin; DVT Antithrombotic
prophylaxis (if therapy; continue
needed); stroke stroke etiology
etiology evaluation evaluation
FIGURE 84. Acute stroke treatment algorithm. BP, blood pressure; CEA, carotid endarterectomy; CT, computed
tomography; DVT, deep vein thrombosis; IA, intra-arterial; ICA, internal carotid artery; ICH, intracerebral hemor-
rhage; IV, intravenous; MRI, magnetic resonance imaging; NINDS, National Institute of Neurological Disorders and
Stroke; NS, normal saline; SAH, subarachnoid hemorrhage; t-PA, tissue plasminogen activator.
Tissue oxygenation should be maintained acutely. Measure TABLE 85. Recommendations for Ischemic Stroke (Eligible
the oxygen saturation using pulse oximetry and supplement the for Alteplase)
patient with oxygen if necessary. The oxygen saturation should
Before treatment, if systolic BP is Labetalol 1020 mg IV
be maintained at 95% or greater.6 Volume status and elec- greater than 185 mm Hg or over 12 minutes (may
trolytes should be corrected. If required, the blood glucose diastolic BP is greater than repeat or double every
should be corrected, as both hyperglycemia and hypoglycemia 110 mm Hg 10 minutes)
may worsen brain ischemia. When hypoglycemia is present, During and after treatment, Nitroprusside
bolus with 50% dextrose immediately. A blood glucose that is if diastolic BP is greater than 0.250.3 mcg/kg/minute
severely elevated should be lowered cautiously to less than 140 mm Hg titrated to response
300 mg/dL (16.7 mmol/L) using subcutaneous insulin. If the If systolic BP is greater than Labetalol or nicardipine
patient is febrile, treat with acetaminophen, as fever is associated 230 mm Hg or diastolic BP infusion 35 mg/hour
is 121140 mm Hg titrated to response
with brain ischemia and increased morbidity and mortality
If systolic BP is 180230 mm Hg Labetalol 1020 mg IV
after stroke. Alternately, cooling devices can be used.7
or diastolic BP is over 12 minutes (may
Intravenous (IV) and subcutaneous heparin will signicantly 105120 mm Hg repeat or double every
decrease the risk of developing deep vein thrombosis (DVT) 10 minutes)
post-stroke. Heparin 5000 units subcutaneously every 12 hours
BP, blood pressure; IV, intravenous.
should be given for DVT prophylaxis in patients who are not
candidates for intravenous alteplase. In patients receiving IV Nonpharmacologic Therapy
alteplase, the administration of subcutaneous heparin should
be delayed 24 hours to avoid bleeding complications. Carotid Endarterectomy and Middle Cerebral Artery
In the setting of acute ischemic stroke, many patients will Embolectomy
have an elevated BP in the rst 24 to 48 hours.8 Blood pressure It is unknown whether carotid endarterectomy is of value
should be optimized; however, hypertension should generally when performed emergently after stroke, meaning within the
not be treated initially in acute stroke patients, as this may cause rst 24 hours after symptoms begin.9 It appears that patients
decreased blood ow in ischemic areas, potentially increasing with mild to moderate neurologic decits, crescendo TIAs or
the infarction size. The cautious use of antihypertensive med- stroke-in-evolution can be operated on safely within the rst
ications may be necessary in patients who are otherwise candi- few hours after the onset of symptoms. Patients with more
dates for thrombolytic therapy, including those with severely severe neurologic decits should only be considered for
elevated blood pressure (systolic BP greater than 220 mm Hg carotid endarterectomy when the procedure can be per-
or diastolic BP greater than 120 mm Hg), and those with formed within the rst few hours after the onset of symptoms.
other medical disorders requiring immediate lowering of BP. It is not indicated for patients with permanent decits from a
Tables 84 and 85 provide recommendations on blood pres- moderate to severe completed stroke.
sure management in those eligible and those not eligible for Middle cerebral artery embolectomy remains controversial
alteplase. In those not eligible for alteplase, when blood pres- in the acute treatment of stroke. Patients who may benet
sure is lowered, aim for a 10% to 15% reduction. Avoid using from this procedure are those who have good collateral circu-
sublingual calcium channel blockers, as these may lower BP lation and can be operated on within the rst few hours after
too rapidly. Blood pressure should be checked three times with the onset of symptoms.
each reading taken 5 minutes apart. Due to the lack of proven efcacy of any of these procedures
when performed emergently in acute ischemic stroke, they are not
TABLE 84. Blood Pressure Recommendations for Ischemic routinely recommended except within a research environment.
Stroke (Not Eligible for Alteplase)
Thrombolytic Therapy
Systolic BP less than 220 mm Hg or Observe unless other end-
diastolic BP less than 120 mm Hg organ involvement Systemic Thrombolytic Therapy
Systolic BP greater than 220 mm Hg Labetalol 1020 mg IV
or diastolic BP 121140 mm Hg over 12 minutes (may Alteplase
repeat or double every
10 minutes); Alteplase (rt-PA; Activase) is an IV thrombolytic (brinolytic)
nicardipine infusion that was approved for acute stroke treatment in 1996 based on
35 mg/hour titrated to the results of the National Institute of Neurological Disorders
response and Stroke (NINDS) rt-PA Stroke Trial.10 The current
Diastolic BP greater than 140 mm Hg Nitroprusside American Stroke Association guidelines include alteplase as
0.250.3 mcg/kg/minute the only Food and Drug Administration (FDA) approved acute
titrated to response
treatment for ischemic stroke and strongly encourage early
BP, blood pressure; IV, intravenous. diagnosis and treatment of appropriate patients.11
Based on several assessment scales, patients treated with Studies following the NINDS trial protocol have supported
alteplase were 30% more likely to have minimal or no disability alteplase use in acute ischemic stroke and have shown similar
at 3 months compared with patients given placebo. Alteplase rates for both response and intracerebral hemorrhage occur-
treatment resulted in an 11% to 13% absolute increase in rence. Studies that have varied from this protocol and adminis-
patients with excellent outcomes at 3 months and a benet was tered alteplase beyond the 3-hour window have failed to show a
seen regardless of patient age, stroke sub-type, stroke severity, benet to treatment. When the clinical trials are pooled, study
or prior use of aspirin.12 Intracerebral hemorrhage within results show that the sooner alteplase is given after acute stroke,
36 hours after stroke onset occurred in 6.4% of those given the greater the benet seen in neurologic outcome.13 Current
alteplase versus 0.6% in those given placebo (p less than 0.001). guidelines recommend against using alteplase beyond 3 hours
There was no signicant difference in mortality between the after stroke onset, as beyond this time the risk outweighs the
two groups at 3 months. In carefully selected patients, benet.12
alteplase is effective in limiting the infarct size and protecting Antiplatelet agents, anticoagulants, and invasive procedures
brain tissue from ischemia and cell death by restoring blood ow. such as the insertion of a central line or the placement of a naso-
Treatment must be given within 3 hours of the onset of symptoms gastric tube should be avoided for 24 hours after the infusion of
and offers no benet if given beyond this time period. A dose of alteplase to prevent bleeding complications. Bladder catheteriza-
0.9 mg/kg (maximum 90 mg) is recommended; the rst 10% is tion should also be avoided for 30 minutes post-infusion.
given as an IV bolus and the remainder is infused over 1 hour. Efcacy is measured by the elimination of existing neurologic
Table 86 details the inclusion and exclusion criteria for the decits and the long-term improvement in neurologic status
administration of alteplase in acute ischemic stroke. and functioning based on neurologic examinations and other
outcome measures. Neurologic examinations should be com-
TABLE 86. Inclusion and Exclusion Criteria for Alteplase Use pleted every 15 minutes during the infusion of alteplase, every
in Acute Ischemic Stroke 30 minutes for the rst 6 hours after the infusion, and then every
4 hours up to 24 hours after alteplase administration. In the
Inclusion Criteria
18 years of age or older NINDS trial, neurologic function was assessed 24 hours after the
Clinical diagnosis of ischemic stroke causing a measurable administration of alteplase using the National Institutes of
neurologic decit Health Stroke Scale (NIHSS). This scale quanties neurologic
Time of symptom onset well established to be less than decits in patients who have had a stroke and is easy to perform.
180 minutes before treatment would begin At 3 months, four outcome measures were used including the
Exclusion Criteria Barthel Index, modied Rankin scale, Glasgow outcome scale,
Evidence of intracranial hemorrhage on CT scan of the brain
prior to treatment
and the NIHSS. The Barthel Index is a measure of the ability to
Only minor or rapidly improving stroke symptoms perform activities of daily living, the modied Rankin scale is a
Clinical presentation suggestive of subarachnoid hemorrhage simplied overall assessment of functioning, and the Glasgow
even with a normal head CT outcome scale is a global assessment of functioning.
Active internal bleeding The major adverse effects of thrombolytic therapy are
Known bleeding diathesis, including but not limited to (1) platelet
count less than 100 103/mm3 (100 109/L); (2) heparin within
bleeding, including intracerebral hemorrhage and serious
48 hours with an elevated aPTT; or (3) current oral anticoagulant systemic bleeding. Mental status changes and a severe
use (e.g., warfarin) or recent use with an elevated PT (greater than headache may indicate an intracerebral hemorrhage. Signs of
15 seconds) or INR (greater than 1.7) bleeding include easy bruising; hematemesis; guaiac-positive
Intracranial surgery, serious head trauma, or previous stroke stools; black, tarry stools; hematoma formation; hematuria;
within 3 months
Suspected aortic dissection associated with stroke
bleeding gums; and nosebleeds.
Suspected subacute bacterial endocarditis or vasculitis
History of gastrointestinal or urinary tract hemorrhage within Streptokinase
21 days Streptokinase is not indicated for use in acute ischemic stroke
Major surgery or serious trauma within 14 days treatment. Three large randomized controlled trials evaluat-
Recent arterial puncture at a non-compressible site
Lumbar puncture within 7 days
ing streptokinase were stopped early due to a high incidence
History of intracranial hemorrhage of hemorrhage in the streptokinase-treated patients.1416 At
Known arteriovenous malformation or aneurysm the present time, there is no indication for the use of strep-
Witnessed seizure at the same time as the onset of stroke tokinase or thrombolytics other than alteplase in the acute
symptoms occurred treatment of ischemic stroke.
Recent acute myocardial infarction
SBP greater than 185 mm Hg or DBP greater than 110 mm Hg at
the time of treatment, or patient requires aggressive treatment to Intra-arterial Thrombolytics
reduce blood pressure to within these limits Intra-arterial thrombolytics may improve outcomes in selected
patients with acute ischemic stroke due to large-vessel occlusion.
aPTT, activated partial thromboplastin time; CT, computed tomography;
DBP, diastolic blood pressure; INR, International Normalized Ratio; PT, Patients in the Prolyse in Acute Cerebral Thromboembolism II
prothrombin time; SBP, systolic blood pressure. (PROACT II) trial were given 9 mg prourokinase (r-pro UK)
plus heparin or heparin alone within 6 hours of symptom 48 hours of the onset of acute stroke symptoms were less likely
onset.17 In those patients receiving prourokinase plus heparin, to suffer early recurrent stroke, death, and disability. Early
40% had slight or no disability at 90 days. In the heparin-only aspirin therapy is recommended in most patients with acute
group, 25% had slight or no disability at 90 days. No difference ischemic stroke within the rst 24 to 48 hours after stroke onset and
in mortality was found between the groups, although the inci- should be continued for at least 2 weeks. The administration of
dence of intracranial hemorrhage was greater in the r-pro UK anticoagulants and antiplatelet agents should be delayed for
plus heparin group versus heparin alone. Note in particular, the 24 hours in those patients receiving alteplase.
drug used in this trial is not FDA-approved and is not currently
available for clinical use. Intra-arterial thrombolytics are typi-
Ancrod
cally avoided except at major stroke centers where there is more
experience with this route of administration. Alteplase is the Ancrod is an investigational agent that acts to decrease plasma
only product currently available; therefore, when intra-arterial brinogen levels. It may be benecial in patients with acute
thombolytics are given, alteplase must be used. Due to the limi- ischemic stroke when administered within 3 hours of symptom
tations of intra-arterial thrombolysis, current guidelines recom- onset. In a randomized, parallel-group, double-blind, placebo-
mend that treatment with IV alteplase in eligible patients not be controlled trial, an improved functional status was observed in
delayed by waiting for intra-arterial thrombolytics. more patients receiving ancrod (42.2%) than in patients receiv-
ing placebo (34.4%; p = 0.04).22 No difference in mortality was
seen between the groups; however, there was a non-signicant
Heparin
increase in symptomatic intracranial hemorrhages in the ancrod
Intravenous heparin has been commonly used in acute stroke group (5.2% versus 2.0%; p = 0.06). Patients received ancrod or
therapy; however, no adequately designed trials have been placebo as a 72-hour continuous infusion, followed by 1-hour
done to establish its efcacy and safety. Current acute infusions at 96 and 120 hours. Prior to the completion of this
ischemic stroke treatment guidelines do not recommend rou- trial, previous trials showed a trend toward an improved out-
tine, urgent anticoagulation with heparin or low-molecular- come, although the number of patients studied was small and a
weight heparins (LMWHs) due to the lack of a proven benet 6-hour treatment window was used. Based upon available clini-
in improving neurologic function and the risk of intracranial cal trials, ancrod appears to have a potential benet. However, it
bleeding.11,18 Heparin may prevent early recurrent stroke in is not recommended for clinical use because its efcacy and
patients with large-vessel atherothrombosis or those thought safety have not been denitively established.11
to be at high risk of recurrent stroke (i.e., cardioembolic
stroke); however, more study is required.
The major complications of heparin include evolution of PREVENTION OF ACUTE ISCHEMIC STROKE
the ischemic stroke into a hemorrhagic stroke, bleeding, and
thrombocytopenia. The occurrence of severe headache and Primary Prevention
mental status changes may indicate an intracerebral hemor-
rhage. Signs of bleeding include easy bruising; hematemesis; Aspirin
guaiac-positive stools; black, tarry stools; hematoma formation; Randomized trials have been completed assessing the role of
hematuria; bleeding gums; and nosebleeds. The hemoglobin, antiplatelet therapy with aspirin for primary stroke preven-
hematocrit, and platelet count should be obtained at least every tion. The use of aspirin in patients with no history of stroke or
3 days to detect bleeding and thrombocytopenia. ischemic heart disease reduced the incidence of non-fatal
myocardial infarction (MI) but not of stroke. A meta-analysis
Low-Molecular-Weight Heparins and Heparinoids of eight trials found that the risk of stroke was slightly
Low-molecular-weight heparins and heparinoids are not rec- increased with aspirin use, especially hemorrhagic stroke.
ommended in the treatment of acute ischemic stroke.11 A Major bleeding risk was also increased with aspirin use.4
meta-analysis was performed using data from 10 randomized Aspirin is benecial in the primary prevention of MI, but not
controlled trials.19 A non-signicant decrease in combined for primary stroke prevention.
death and disability and a non-signicant increase in case
fatality and hemorrhage were seen. A reduction in venous Statin Therapy
thromboembolic events was observed in acute stroke patients; Hyperlipidemia has not clearly been established as a risk factor
however, there was also an increase in extracranial bleeding. for stroke, although it is a modiable risk factor for coronary
heart disease. Recent studies show that statin use may reduce
the incidence of a rst stroke in high-risk patients (e.g., hyper-
Aspirin
tension, coronary heart disease, or diabetes) including patients
Aspirin in acute ischemic stroke has been studied in two large, with normal lipid levels. A recent meta-analysis showed a 25%
randomized trials, the International Stroke Trial and the Chinese risk reduction for fatal and non-fatal strokes with statin use.4
Acute Stroke Trial.20,21 Patients who received aspirin within 24 to Patients with a history of MI, elevated lipid levels, diabetes, and
of 60% to 99% who are between 40 and 75 years of age if there

Patient Encounter, Part 2 is a 5-year life expectancy and the operative risks are low.28
Carotid Angioplasty
Carotid angioplasty with or without stenting is typically
In the emergency department an IV line is placed, a physical
restricted to patients who are refractory to medical therapy
and neurologic exam is completed, and GR is moved to the
stroke unit. The CT scan is negative for hemorrhagic stroke. and are not surgical candidates. Clinical trials are currently
ongoing to further dene the role of carotid angioplasty in
Identify your treatment goals for GR. both symptomatic and asymptomatic patients.
What acute management would be appropriate for GR at
this point?
other risk factors may benet from treatment with a lipid- Aspirin
lowering agent; however, even patients with normal lipid levels In a recent meta-analysis including 144,051 patients with pre-
may benet from treatment. vious MI, acute MI, previous TIA or stroke, and acute stroke, as
well as others at high risk, aspirin was found to decrease the risk
Blood Pressure Management of recurrent stroke by approximately 25%.29 Aspirin is typi-
Lowering blood pressure in patients who are hypertensive has cally considered to be the rst-line secondary prevention agent for
been shown to reduce the relative risk of stroke, both ischemic ischemic stroke and decreases the risk of subsequent stroke by
and hemorrhagic, by 35% to 45%.23 Also, the more blood pres- approximately 25% in both men and women with previous tran-
sure is lowered, the greater the reduction in stroke risk.24 All sient ischemic attacks or stroke. A wide range of doses have been
patients should have their blood pressure monitored and con- used (30 to 1500 mg per day); however, enteric-coated aspirin
trolled appropriately based on current guidelines for blood pres- 325 mg orally once daily is the most widely used and recom-
sure management. However, no one agent has been clearly shown mended regimen. The FDA has approved doses of 50 to 325 mg
to be more benecial than any other for preventing stroke. for secondary ischemic stroke prevention. In those who fail
aspirin therapy, increasing the daily dose of aspirin or switching
Secondary Prevention to either clopidogrel or the combination of extended-release
dipyridamole plus aspirin are options. Clopidogrel is a rea-
Nonpharmacologic Therapy sonable alternative if aspirin is not tolerated, and it may be con-
sidered as rst-line therapy in patients with peripheral arterial
Carotid Endarterectomy disease. Adverse effects of aspirin include gastrointestinal intol-
The benet of carotid endarterectomy for prevention of recur- erance, gastrointestinal bleeding, and hypersensitivity reactions.
rent stroke has been studied previously in major trials.25,26 A
recent meta-analysis has been completed that has combined these Warfarin
clinical trials to evaluate 6,092 patients.27 Carotid endarterectomy Warfarin has not been adequately studied in non-cardioembolic
has been shown to be benecial for preventing ipsilateral stroke stroke, but it is often recommended in patients after antiplatelet
in patients with symptomatic carotid artery stenosis of 70% or agents fail. One small retrospective study suggests that warfarin
greater and is recommended in these patients. In patients with is better than aspirin.30 More recent clinical trials have not
symptomatic stenosis of 50% to 69%, a moderate reduction in found oral anticoagulation in those patients without atrial b-
risk is seen in clinical trials. In all patients with stenosis of 50% to rillation or carotid stenosis to be better than antiplatelet ther-
69% and a recent stroke, carotid endarterectomy is appropriate. apy. In the majority of patients without atrial brillation,
In other patients, surgical risk factors and surgeon skill should antiplatelet therapy is recommended over warfarin. In patients
be considered prior to surgery. The patient should have, at a with atrial brillation, long-term anticoagulation with warfarin
minimum, a life expectancy of 5 years, and the surgical risk of is recommended and is effective in both primary and secondary
stroke and/or death should be less than 6%. Carotid endarterec- prevention of stroke.12 The goal International Normalized
tomy is not benecial for symptomatic carotid stenosis less than Ratio (INR) for this indication is 2 to 3.
50% and should not be considered in these patients.
There are data to suggest that patients with asymptomatic Ticlopidine
carotid artery stenosis of 60% or more benet from carotid Ticlopidine is slightly more benecial in stroke prevention than
endarterectomy if it is performed by a qualied surgeon with aspirin in both men and women.31,32 The usual recommended
low complication rates (less than 3%). At this time, there is con- dosage is 250 mg orally twice daily. Ticlopidine is costly, and
siderable controversy over how this information can be applied side effects include bone marrow suppression, rash, diarrhea,
to clinical practice. A current review recommends considering and an increased cholesterol level. Neutropenia is seen in
carotid endarterectomy in patients with carotid artery stenosis approximately 2% of patients. Thrombotic thrombocytopenic
purpura (TTP) occurs in 1 of every 2000 to 4000 patients treated

with ticlopidine. For these reasons, monitoring of the complete Patient Encounter, Part 3
blood cell count (CBC) is required every 2 weeks for the rst
3 months of therapy. Ticlopidine is an alternative in patients who
cannot tolerate or who have failed aspirin therapy; however,
GR is ready for discharge after spending 5 days in the hospital.
because of the costly laboratory monitoring required and the
adverse effect prole, many clinicians choose an alternative agent What would be an appropriate discharge plan for GR at
such as clopidogrel or aspirin/extended-release dipyridamole. this time?
What specic medications would you recommend upon
Clopidogrel discharge?
Clopidogrel is slightly more effective than aspirin with a relative-
risk reduction of 7.3% more than that provided by aspirin.33 The guidelines also make the recommendation that due to a slight
usual dose is 75 mg orally taken on a daily basis. Clopidogrel has benet in the absolute risk reduction in ischemic stroke with
a signicantly lower incidence of diarrhea and neutropenia than clopidogrel and the combination of aspirin/ER dipyridamole,
ticlopidine, and laboratory monitoring is typically not required. these agents may be preferred if cost is factored out.
There are 11 case reports of TTP occurring secondary to clopi-
dogrel, with the majority occurring within the rst 2 weeks of Blood Pressure Management
therapy. Currently, clopidogrel is favored over ticlopidine; Hypertension is an important risk factor for stroke; however, it
however, clinicians need to be aware that there is a potential had been unclear if lowering BP reduced the incidence of sec-
for the development of TTP. Clopidogrel may be preferred as ondary ischemic stroke. In the PROGRESS trial, it was shown
monotherapy; in the MATCH trial, low-dose aspirin plus clopi- that blood pressure reduction using the angiotensin-converting
dogrel combination therapy compared to clopidogrel alone did enzyme inhibitor (ACE-I) perindopril alone resulted in a 28%
not show a signicant benet.34 This trial found that the addi- reduction in recurrent stroke compared to placebo. With the
tion of aspirin increased the risk of major bleeding. However, addition of the diuretic indapamide to perindopril, a 43% reduc-
there is no difference in the bleeding risk between aspirin and tion in stroke recurrence was seen.36 This reduction in stroke
clopidogrel as monotherapy, and the cost of clopidogrel is sig- incidence occurred even in patients who were not hypertensive.
nicantly higher than the cost of aspirin. In patients with a previous history of stroke or TIA, the Joint
National Committee on the Prevention, Detection, Evaluation,
Extended-Release (ER) Dipyridamole plus and Treatment of High Blood Pressure (JNC 7) recommends
Immediate-Release (IR) Aspirin a diuretic and an ACE-I.37 Table 87 provides drug and dosing
Combination therapy with extended-release dipyridamole plus recommendations for the treatment of ischemic stroke.
immediate-release aspirin was more effective than either treat-
ment alone in the European Stroke Prevention Study 2 TABLE 87. Recommendations for Pharmacotherapy of
(ESPS2).35 In this study, patients received either placebo, aspirin Ischemic Stroke
25 mg twice daily, ER dipyridamole 200 mg twice daily, or a Primary Agents Alternatives
combination of both agents. The individual agents produced
Acute t-PA 0.9 mg/kg IV (maximum t-PA (various doses)
risk reductions of 18.1% with aspirin and 16.3% with ER dipyri-
Treatment 90 mg) over 1 hour in intra-arterially
damole, whereas the combination produced a 37% risk reduc- selected patients within up to 6 hours
tion. Headache and diarrhea were common adverse effects of 3 hours of onset after onset in
dipyridamole, while bleeding was more common in the treat- Aspirin 160325 mg daily selected patients
ment groups receiving aspirin. This is the rst study showing started within 48 hours
of onset
that combination antiplatelet therapy has additive effects over
each agent alone. The currently available formulation is a com- Secondary Aspirin 50325 mg daily Ticlopidine
Prevention Clopidogrel 75 mg daily 250 mg twice
bination product containing 25 mg aspirin and 200 mg ER Aspirin 25 mg + extended- daily
dipyridamole. This agent is not an option for patients who are release dipyridamole
intolerant to aspirin; however, it may be useful in patients who 200 mg twice daily
have failed clopidogrel or aspirin monotherapy. Further trials Cardioembolic Warfarin (INR 23)
are underway to compare this combination to each individual All ACE-I + diuretic or ARB;
component at full doses. Trials comparing this combination to blood pressure lowering:
other antiplatelet agents are also necessary. Peridopril 28 mg daily
Indapamide 1.255 mg daily;
Statin therapy
Recommendations
The most recent CHEST guidelines continue to recommend ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin
aspirin therapy for the secondary prevention of stroke.12 The receptor blocker; INR, International Normalized Ratio; IV, intravenous;
t-PA, tissue plasminogen activator.
TREATMENT OF ACUTE HEMORRHAGIC STROKE Intracerebral Hemorrhage Trial compared three different doses
and placebo. Doses were 40, 80, or 160 mcg/kg or placebo given
Supportive Measures as an IV infusion over 1 to 2 minutes within 4 hours after the
onset of symptoms. Hematoma growth was decreased at
Acute hemorrhagic stroke is considered to be an acute medical 24 hours, mortality was decreased at 90 days, and overall func-
emergency. Initially, patients experiencing a hemorrhagic tioning was increased at 90 days. Further studies are ongoing to
stroke should be transported to a neurointensive care unit. evaluate the role of recombinant factor VIIa in ICH treatment.41
There is no proven treatment for intracerebral hemorrhage.
Management is based on neurointensive care treatment and
prevention of complications. Treatment should be provided to OUTCOME EVALUATION
manage the needs of the critically ill patient including man-
agement of increased intracranial pressure, seizures, infections, Stroke outcomes are measured based on the neurologic sta-
and prevention of re-bleeding and delayed cerebral ischemia. In tus and functioning of the patient after the acute event. The
those with severely depressed consciousness, rapid endotracheal National Institutes of Health Stroke Scale (NIHSS) is a
intubation and mechanical ventilation may be necessary. Blood measure of daily functioning and is used to assess patient
pressure is often elevated after hemorrhagic stroke and appro- status following a stroke.
priate management is important to prevent re-bleeding and Early rehabilitation can reduce functional impairment after a
expansion of the hematoma.8 Blood pressure can be controlled stroke. Recent stroke rehabilitation guidelines have been
with IV boluses of labetalol 10 to 80 mg every 10 minutes up to endorsed by the American Heart Association and the American
a maximum of 300 mg or with IV infusions of labetalol (0.5 to Stroke Association. These guidelines recommend that patients
2 mg/minute) or nicardipine (5 to 15 mg/hour). Deep vein receive care in a multidisciplinary setting or stroke unit, receive
thrombosis prophylaxis with intermittent compression stock- early assessment using the NIHSS, and recommend that reha-
ings should be implemented early after admission. In those bilitation is started as soon as possible after the stroke. Other
patients with SAH, once the aneurysm has been treated, heparin recommendations include screening for dysphagia and aggres-
may be instituted.2,3 sive secondary stroke prevention treatments.42
Table 88 provides monitoring guidelines for the acute
stroke patient.
Patients with hemorrhagic stroke are evaluated for surgical treat-
ment of SAH and ICH. In SAH, either clipping of the aneurysm
or coil embolization is recommended within 72 hours after the
initial event to prevent re-bleeding. Coil embolization, also called Patient Care and Monitoring
coiling, is a minimally invasive procedure in which a platinum
coil is threaded into the aneurysm. The exible coil lls up the
space to block blood ow into the aneurysm thereby preventing 1. Assess the patients signs and symptoms including the
re-bleeding. Surgical removal of the blood in patients with ICH time of onset of symptoms and the time of arrival in the
is controversial, as one large randomized trial did not show a emergency department.
benet to removal compared with those treated conservatively 2. Perform thorough neurological and physical examina-
according to the current guidelines.38,39 tions evaluating for a potential cause of the stroke.
3. Perform a CT scan to rule out a hemorrhagic stroke prior
Calcium Antagonists to administering any treatment.
4. Evaluate the inclusion and exclusion criteria for throm-
Oral nimodipine is recommended in subarachnoid hem-
bolytic therapy to determine if it is appropriate for the
orrhage to prevent delayed cerebral ischemia. Delayed cerebral
patient.
ischemia occurs 4 to 14 days after the initial aneurysm rupture
5. Transfer the patient to a stroke center if available and
and is a common cause of neurologic decits and death. A
develop a plan for the acute management of the patient.
meta-analysis of 12 studies was conducted and concluded that
oral nimodipine 60 mg every 4 hours for 21 days following 6. Determine the patients risk factors for stroke.
aneurysmal SAH reduced the risk of a poor outcome and 7. Develop a plan for the long-term management of risk
delayed cerebral ischemia.40 factors in order to prevent a recurrent stroke.
8. Educate the patient on appropriate lifestyle modications
that will reduce stroke risk.
Hemostatic Therapy
9. Educate the patient on their medication regimen and
Recombinant factor VIIa has been shown to have a benet in the stress the importance of compliance.
treatment of ICH. The Recombinant Activated Factor VII
TABLE 88. Monitoring the Stroke Patient
Treatment Parameter(s) Monitoring Frequency Comments

Ischemic Stroke
t-PA BP, neurologic function, Every 15 minutes 1 hour,
bleeding every 0.5 hour 6 hours,
every 1 hour 17 hours;
then every shift
Aspirin Bleeding Daily
Clopidogrel Bleeding Daily
ASA/extended-release Headache, bleeding Daily
dipyridamole
Warfarin Bleeding, INR, Hb/Hct INR daily 3 days; weekly
until stable; then monthly
Hemorrhagic
Stroke
BP, neurologic function, ICP Every 2 hours in ICU May require treatments to
lower BP to less than
180 mm Hg systolic
Nimodipine for SAH BP, neurologic function, Every 2 hours in ICU
uid status
ASA, aspirin; BP, blood pressure; Hb, hemoglobin; Hct, hematocrit; ICP, intracranial pressure; ICU, intensive care unit; INR, International Normalized Ratio;
SAH, subarachnoid hemorrhage; t-PA, tissue plasminogen activator.
ABBREVIATIONS NIHSS: National Institutes of Health Stroke Scale

NINDS: National Institute of Neurological Disorders and
ACE-I: angiotensin-converting enzyme inhibitor Stroke
ADP: adenosine diphosphate NS: normal saline
aPTT: activated partial thromboplastin time PROACT II: Prolyse in Acute Cerebral Thromboembolism II
ARB: angiotensin receptor blocker PT: prothrombin time
ASA: aspirin rt-PA: alteplase
AVM: arteriovenous malformation r-pro UK: prourokinase
BP: blood pressure SAH: subarachnoid hemorrhage
BPH: benign prostatic hypertrophy SBP: systolic blood pressure
CBC: complete blood count TIA: transient ischemic attack
CEA: carotid endarterectomy t-PA: tissue plasminogen activator
CT: computed tomography TTP: thrombotic thrombocytopenic purpura
CVD: cerebrovascular disease
DBP: diastolic blood pressure Reference lists and self-assessment questions and answers are
DVT: deep vein thrombosis available at www.ChisholmPharmacotherapy.com.
ER: extended-release
ESPS2: European Stroke Prevention Study 2 Log into the website: www.pharmacotherapyprinciples.com
FDA: Food and Drug Administration for information on obtaining continuing education credit for
Hb: hemoglobin this chapter.
Hct: hematocrit
IA: intra-arterial
ICA: internal carotid artery
ICH: intracerebral hemorrhage KEY REFERENCES AND READINGS
ICP: intracranial pressure
ICU: intensive care unit Adams HP, Adams RJ, Brott T, et al. Guidelines for the early manage-
INR: International Normalized Ratio ment of patients with ischemic stroke: a scientic statement
IR: immediate-release from the Stroke Council of the American Stroke Association.
IV: intravenous Stroke 2003;34:10561083.
JNC 7: Joint National Committee on the Prevention, Albers GW, Amerenco P, Easton JD, et al. Antithrombotic and throm-
Detection, Evaluation, and Treatment of High Blood bolytic therapy for ischemic stroke: the seventh ACCP confer-
Pressure ence on antithrombotic and thrombolytic therapy. Chest
LMWH: low-molecular-weight heparin 2004;126(3 Suppl):483S512S.
MI: myocardial infarction American Heart Association. Heart Disease and Stroke Statistics
MRI: magnetic resonance imaging 2006 Update. Dallas, TX: American Heart Association; 2006.
Antithrombotic Trialists Collaboration. Collaborative meta-analysis Chaturvedi A, Bruno A, Feasby T, et al. Carotid endarterectomyan
of randomised trials of antiplatelet therapy for prevention of evidence-based review. Neurology 2005;65:794801.
death, myocardial infarction, and stroke in high risk patients. Straus SE, Majumdar SR, McAlister FA. New evidence for stroke pre-
BMJ 2002;324:7186. vention: scientic review. JAMA 2002;288: 13881395.
Broderick JP, Adams HP, Barsan W, et al. Guidelines for the manage- Treib J, Grauer MT, Woessner R, Morganthaler M. Treatment of
ment of spontaneous intracerebral hemorrhage. A statement for stroke on an intensive stroke unit: a novel concept. Intensive
healthcare professions from a special writing group of the Stroke Care Med 2000;26:15981611.
Council, American Heart Association. Stroke 1999;30:905915.
9 HYPERLIPIDEMIA
Matthew K. Ito
LEARNING OBJECTIVES
1. Identify the major components within each lipoprotein and their role in lipoprotein
metabolism and the development of atherosclerosis.
2. Identify the common types of lipid disorders.
3. Determine a patients coronary heart disease risk and corresponding treatment goals
according to the National Cholesterol Education Program Adult Treatment Panel III
guidelines.
4. Recommend appropriate therapeutic lifestyle changes (TLC) and pharmacotherapy
interventions for patients with dyslipidemia.
5. Describe the components of a monitoring plan to assess effectiveness and adverse effects of
pharmacotherapy for dyslipidemias.
6. Educate patients about the disease state, appropriate TLC, and drug therapy required for
effective treatment.
KEY CONCEPTS from atherosclerotic disease, convenient once-daily dosing,

and low risk of side effects.
The risk of atherosclerosis is directly related to increasing lev- Patients with metabolic syndrome have an additional lipid
els of serum cholesterol. parameter that needs to be assessed, namely non-high-density
The National Cholesterol Education Program Adult lipoprotein (non-HDL) cholesterol (total cholesterol minus HDL
Treatment Panel III guidelines have set the optimal level for cholesterol). The target for non-HDL cholesterol is less than the
low-density lipoprotein (LDL) cholesterol for all adults as less patients LDL cholesterol target plus 30 mg/dL (0.78 mmol/L).
than 100 mg/dL (2.59 mmol/L). After assessment and control of LDL cholesterol, patients with
All adults greater than 20 years of age should be screened at serum triglycerides of 200 to 499 mg/dL (2.26 to 5.64
least every 5 years using a fasting blood sample. mmol/L) should be assessed for atherogenic dyslipidemia (low
The benets of lowering LDL cholesterol to as low as 70 HDL cholesterol and increased small-dense LDL particles)
mg/dL (1.81 mmol/L) have been demonstrated in clinical tri- and metabolic syndrome.
als; however, the lowest level at which to treat LDL cholesterol Combination drug therapy is an effective means to achieve
has not yet been determined. greater reductions in LDL cholesterol (statin + ezetimibe or
An adequate trial of therapeutic lifestyle changes should be bile acid resin, bile acid resin + ezetimibe, or three-drug com-
employed in all patients, but pharmacotherapy should be binations) as well as raising HDL cholesterol and lowering
instituted concurrently in higher-risk patients. serum triglycerides (statin + niacin or brate).
Typically, statins are the medications of choice to treat high Reducing LDL cholesterol while substantially raising HDL choles-
LDL cholesterol because of their ability to substantially reduce terol (statin + niacin) appears to reduce the risk of atherosclerotic
LDL cholesterol, ability to reduce morbidity and mortality disease progression to a greater degree than statin monotherapy.
175
The risk of atherosclerosis is directly related to increasing lev- Other major lipids in our body are triglycerides and phospho-
els of serum cholesterol. Hypercholesterolemia (elevation in serum lipids. Since cholesterol is a relatively water-insoluble molecule,
cholesterol) and other abnormalities in serum lipids play a major it is unable to circulate through the blood alone. Cholesterol
role in plaque formation leading to coronary heart disease (CHD) along with triglycerides and phospholipids are packaged in a
as well as other forms of atherosclerosis, such as carotid and large carrier-protein called a lipoprotein (Fig. 91). Lipoproteins
peripheral artery disease (atherosclerosis of the peripheral arter- are water soluble, which allows transportation of the major lipids
ies). This predictive relationship has been demonstrated from in the blood. These lipoproteins are spherical and vary in size
large epidemiologic,1 animal, and genetic studies. Coronary heart (~1,000 to 6 nm) and density (less than 0.94 to 1.21 g/mL)4
disease is the leading cause of death in both men and women in (Table 91). The amount of cholesterol and triglycerides vary by
the United States and most industrialized nations. It is also the lipoprotein size. The major lipoproteins in descending size and
chief cause of premature, permanent disability in the United ascending density are chylomicrons, very low-density lipoprotein
States workforce. Annually, approximately 700,000 Americans will (VLDL), intermediate-density lipoprotein (IDL), low-density
suffer a new heart attack and 500,000 will have a recurrent event. lipoprotein (LDL), and high-density lipoprotein (HDL). When
The average age of a rst heart attack is 66 years for American men clinical laboratories measure and report serum total cholesterol,
and 70 years for women. The direct and indirect cost of CHD to what they are measuring and reporting are total cholesterol mol-
the United States economy is almost $140 billion.2 Clinical trials ecules in all the major lipoproteins. The estimated value of LDL
have consistently demonstrated that lowering serum cholesterol cholesterol is found using the following equation:
reduces atherosclerotic progression and mortality from CHD.
The development of CHD is a lifelong process. Except in LDL cholesterol = total cholesterol
rare cases of severely elevated serum cholesterol levels, years of (HDL cholesterol + triglycerides/5)
poor dietary habits, sedentary lifestyle, and life-habit risk fac-
tors (e.g., smoking and obesity) contribute to the development If serum triglycerides are greater than 400 mg/dL (4.52
of atherosclerosis.3 Unfortunately, many individuals at risk for mmol/L), this formula becomes inaccurate and LDL cholesterol
CHD do not receive lipid-lowering therapy or are not opti- must be directly measured.3
mally treated. This chapter will help identify individuals at risk, Each lipoprotein has various proteins called apolipoproteins
assess treatment goals based on the level of CHD risk, and embedded on the surface (Fig. 9-1). These apolipoproteins
implement optimal treatment strategies and monitoring plans. serve four main purposes, they: (1) are required for assembly
and secretion of lipoproteins (such as apolipoproteins B-48 and
B-100); (2) serve as major structural components of lipoproteins;
PATHOPHYSIOLOGY (3) act as ligands (apolipoprotein B-100 and apolipoprotein E)
for binding to receptors on cell surfaces (LDL receptors); and
Lipid and Lipoprotein Metabolism (4) can be co-factors (such as apolipoprotein C-II) for activa-
Cholesterol is an essential substance manufactured by most cells tion of enzymes (such as lipoprotein lipase [LPL]) involved in
in the body. Cholesterol is used to maintain cell wall integrity the breakdown of triglycerides from chylomicrons and VLDL.
and for the biosynthesis of bile acids and steroid hormones.4 Apolipoproteins A-I and A-II are major structural proteins on
Apolipoprotein FIGURE 91. Lipoprotein structure. Lipoproteins are a

diverse group of particles with varying size and density. They
contain variable amounts of core cholesterol esters and
Triglycerides triglycerides, and have varying numbers and types of surface
Apolipoprotein apolipoproteins. The apolipoproteins function to direct the
processing and removal of individual lipoprotein particles.
(Reprinted from LipoScience, Inc. with permission.)
Cholesterol
esters
Phospholipids
Apolipoprotein
Free cholesterol
CHAPTER 9 / HYPERLIPIDEMIA 177
TABLE 91. Physical Characteristics of Lipoproteins
Composition (%)
Lipoprotein Density Range (g/mL) Size (nm) Cholesterol Triglycerides Apolipoprotein
Chylomicrons Less than 0.95 1001000 37 8595 A-I, A-II, A-IV, B-48, C-I, C-II, E
VLDL Less than 1.006 4050 2030 5065 B-100, C-I, C-II, C-III, E
IDL 1.0061.019 2530 40 20 B-100, E
LDL 1.0191.063 2025 5158 48 B-100
HDL 1.0631.21 610 1825 27 A-I, A-II, C-I, C-II, C-III, E
HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein.
the surface of HDL. Apolipoprotein A-I interacts with adenosine (Fig. 94). Very low-density lipoprotein particles are released
triphosphate (ATP) binding cassette A1 to trafc cholesterol into the circulation where they acquire apolipoprotein E and
from extra-hepatic tissue (such as the arterial wall) to immature apolipoprotein C-II from HDL. Very-low density lipoprotein
or nascent HDL.4 loses its triglyceride content through the interaction with LPL
Cholesterol from the diet as well as from bile enters the small to form VLDL remnant and IDL. Intermediate-density lipopro-
intestine, where it is emulsied by bile salts into micelles (Fig. 92). tein can be cleared from the circulation by hepatic LDL recep-
These micelles interact with the duodenal and jejunal enterocyte tors or further converted to LDL (by further depletion of
surfaces, and cholesterol is transported from the micelles into triglycerides) through the action of hepatic lipases (HL).
these cells by the Niemann-Pick C1 Like 1 (NPC1L1) trans- Approximately 50% of IDL is converted to LDL. Low-density
porter.5 Some cholesterol and most plant sterols, which are lipoprotein particles are cleared from the circulation primarily
structurally similar to cholesterol, are exported back from the by hepatic LDL receptors by interaction with apolipoprotein
enterocyte into the intestinal lumen by the ATP-binding cassette B-100. They can also be taken up by extra-hepatic tissues or
(ABC) G5/G8 transporter. Cholesterol within enterocytes is enter the arterial wall, contributing to atherogenesis.4,6
esteried and packaged into chylomicrons along with triglyc- Cholesterol is transported from the arterial wall or other
erides, phospholipids, and apolipoprotein B-48 as well as extra-hepatic tissues back to the liver by HDL (Fig. 93).
apolipoproteins C and E, which are then released into the lym- Apolipoprotein A-I (derived from the intestine and liver) on nas-
phatic circulation. In the circulation, chylomicrons are con- cent HDL interacts with ABCA1 transporter on extra-hepatic
verted to chylomicron remnants (through loss of triglycerides by tissue. Cholesterol in nascent HDL is esteried by lecithin-
the interaction of apolipoprotein C-II and LPL). During this cholesterol acyltransferase (LCAT) resulting in mature HDL.
process, chylomicrons also interact with HDL particles (Fig. 93) The esteried cholesterol can be transferred as noted above to
and exchange triglyceride and cholesterol content, and HDL apolipoprotein B-containing particles in exchange for triglyc-
particles acquire apolipoproteins A and C. Chylomicron rem- erides. Triglyceride-rich HDL is hydrolyzed by HL, generating
nant particles are then taken up by LDL-related protein (LRP).4 fatty acids and nascent HDL particles, or the mature HDL can
In the liver, cholesterol and triglycerides are incorporated bind to the scavenger receptors (SR-BI) on hepatocytes and
into VLDL along with phospholipids and apolipoprotein B-100 transfer their cholesterol ester content.4
FIGURE 92. Intestinal cholesterol absorption and

Diet Bile transport. Cholesterol from food and bile enter the
gut lumen and are emulsied by bile acids into
micelles. Micelles binding to the intestinal entero-
Brush border cytes, and cholesterol and other sterols are trans-
ported from the micelles into the enterocytes by a
Lipolysis and
Luminal delivery to the liver
sterol transporter. Triglycerides synthesized by
cholesterol FA absorbed fatty acids along with cholesterol and
apolipoprotein B-48 are incorporated into chylomi-
FA crons. Chylomicrons are released into the lymphatic
Micellar
cholesterol
circulation and are converted to chylomicron rem-
NPC1L1 TG nants (through loss of triglyceride), and then taken
and other Transporter
sterols up by the hepatic LDL receptor-related protein
TG (LRP). ABC G5/G8, ATP-binding cassette G5/G8;
CE
CE Apo, apolipoprotein; CE, cholesterol ester; FA, fatty
Fecal Cholesterol acid; NPC1L1, Niemann-Pick C1 Like 1; TG,
cholesterol triglyceride.
and other Apo B-48 Apo B-48
sterols ABC G5/G8
Transporter
Intestinal lumen Enterocyte Lymph
FIGURE 93. Reverse cholesterol trans-

Intestine
Biliary port. Cholesterol is transported from the
cholesterol arterial wall or other extra-hepatic tissues
Cholesterol
back to the liver by HDL. Esteried cho-
lesterol from HDL can be transferred to
LDL receptor apolipoprotein B-containing particles in
SR-B1 exchange for triglycerides. Cholesterol
esters transferred from HDL to VLDL and
Blood
LDL are taken up by hepatic LDL recep-
CE tors or delivered back to extra-hepatic
tissue. ABCA1, ATP-binding cassette A1;
Apo A-1 CE
Mature Apo, apolipoprotein; C, cholesterol; CE,
HDL cholesterol ester; CETP, cholesterol ester
LCAT CE HL transfer protein; CM, chylomicrons; HDL,
C CE TG high-density lipoprotein; HL, hepatic
Transfer
CETP of lipase; LCAT, lecithin cholesterol acyl-
Extrahepatic Nascent Transfer Transfer TG
HDL of of transferase; LDL, low-density lipoprotein;
tissues to
CE TG
tissues SR-BI, scavenger receptors; TG, triglyc-
CM/ CE CE eride; VLDL, very low-density lipoprotein.
Cholesterol VLDL/
LDL TG TG
ABCA1
Transporter
Muscle/heart/
Adipose tissue
Triglycerides
Triglycerides FA
IDL Cholesterol
HL LDL
LPL
Foam cell
Blood
Endothelial
VLDL cell
esis
rogen
Athe
Vessel wall
Cholesterol
Triglycerides Acetyl Co A
Apo B100
CE Apo-B100
HMG Co A HVG Co A
redudase ApoE
Cholesterol Apo C-II
Mevalonic acid LDL receptor
Intestine
(see Figure 9-2)
FIGURE 94. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and
exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors
or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis.
Acetyl CoA, acetyl coenzyme A; Apo, apolipoprotein; C, cholesterol; CE, cholesterol ester; FA, fatty acid; HL, hepatic lipase; HMG CoA,
3-hydroxy-3-methyglutaryl coenzyme A; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-
density lipoprotein; LPL, lipoprotein lipase; VLDL, very low-density lipoprotein.
A variety of genetic mutations occur in the above steps dur- maintain vasomotor tone. Small, denser LDL particles migrate
ing lipoprotein synthesis and metabolism that cause lipid dis- into the arterial wall more readily and are particularly susceptible
orders. The major genetic disorders and their effect on serum to oxidation. The oxidized particles cause an increased expression
lipids are presented in Table 92.4 Disorders that increase of cell-adhesion molecules on vascular endothelial cells leading
serum cholesterol are generally those that affect the number or to recruitment of monocytes into the intima. The monocytes
afnity of LDL receptors (also known as apolipoprotein B-E differentiate into macrophages and express scavenger receptors
receptors) known as familial hypercholesterolemia, or the abil- allowing enhanced uptake of apolipoprotein B-containing
ity of apolipoprotein B-100 to bind to the receptor known as lipoproteins. The macrophages continue to accumulate lipo-
familial defective apolipoprotein B-100. These patients com- proteins and ultimately develop into lipid-laden foam cells.
monly present with corneal arcus of the eye and xanthomas of Accumulation of foam cells leads to formation of a lipid-rich
extensor tendons of the hand and Achilles tendon. Elevations core, which marks the transition to a more complicated athero-
in triglycerides are generally associated with overproduction of sclerotic plaque. Vascular wall remodeling leading to outward
VLDL, mutations in apolipoprotein E, or lack of LPL. Patients growth of the wall occurs to accommodate this lipid-rich core.
with extremely elevated serum triglycerides can develop pan- Thus, the vascular lumen is relatively well preserved and gener-
creatitis and tuberoeruptive xanthomas. Most individuals ally the lesion would not be detected using traditional coronary
have mild to moderate elevations in cholesterol caused by a angiographic techniques. Initially, smooth muscle cells migrate
polygenic disorder. Polygenic hypercholesterolemia is not as and proliferate from the media to the intima forming a protec-
well understood as the single-gene disorders discussed above. tive brous cap which separates the potentially thrombogenic
Polygenic hypercholesterolemia is thought to be caused by var- lipid core from circulating blood. As the plaque matures, inam-
ious, more subtle genetic defects as well as environmental fac- matory cells secrete matrix metalloproteinases that degrade
tors such as diet and lack of physical activity.3 collagen and brin produced by smooth muscle cells that lead to
a weakened brous cap. Ischemic events result when the brous
cap of these unstable plaques rupture and produce an occlusive
Pathophysiology of Coronary Artery Disease
thrombus. In contrast, repeated wound healing secondary to less
The most widely accepted theory of the process of atherosclerosis signicant plaque disruption that causes no symptoms might
is that it is a low-grade inammatory response due to injury of produce a more stable plaque as a consequence of smooth mus-
the vascular endothelium.6 The process begins when lipoproteins cle cell, collagen, and brin accumulation and a resolution of the
migrate between the endothelial cells into the arterial wall lipid core.6 These more stable plaques usually cause luminal
(Fig. 95). The initial lesion, known as a fatty streak, appears to encroachment (detected by traditional coronary angiographic
form after accumulation of lipoproteins within the intima. After techniques) and may produce angina pectoris. Unstable lesions
entering the intima, lipoproteins are then structurally modied usually outnumber the more stable plaques, thus accounting for
by oxidation. Oxidized lipoproteins as well as other cytotoxic a majority of acute coronary syndromes. Evidence demonstrates
agents promote endothelial dysfunction by disturbing the that aggressive lipid lowering does stabilize these vulnerable
production of vasoactive molecules such as nitric oxide that lesions and restores endothelial function.3,6,7
TABLE 92. Selected Characteristics of Primary Dyslipidemias
Estimated
Disorder Frequency Metabolic Defect Main Lipid Parameter
Familial hypercholesterolemia
Homozygous 1/1 million LDL-receptor negative LDL-C greater than 500 mg/dL (12.95 mmol/L)
Heterozygous 1/500 Reduction in LDL receptors LDL-C 250500 mg/dL (6.4812.95 mmol/L)
Familial defective apo B-100 1/1000 Single nucleotide mutation LDL-C 250500 mg/L (6.4812.95 mmol/L)
Polygenic hypercholesterolemia Common Metabolic and environmental LDL-C 160250 mg/dL (4.146.48 mmol/L)
Familial combined dyslipidemia 1/200300 Overproduction of VLDL and/or LDL LDL-C 250350 mg/dL (6.489.07 mmol/L)
TG 200800 mg/dL (2.269.04 mmol/L)
Familial 5% Increase apo B production Apo B greater than 125 mg/dL
hyperapobetalipoproteinemia
Familial dysbetalipoproteinemia 0.5% Apo E2/2 phenotype LDL-C 300600 mg/dL (7.7715.54 mmol/L)
TG 400800 mg/dL (4.529.04 mmol/L)
Familial hypertriglyceridemia
Type IV 1/300 Unknown TG 200500 mg/dL (2.265.65 mmol/L)
Type V 1/205,000 Unknown TG greater than 1000 mg/dL (11.3 mmol/L)
Hypoalphalipoproteinemia 35% Defect in HDL catabolism HDL-C less than 35 mg/dL (0.91 mmol/L)
Apo, apolipoprotein; C, cholesterol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride; VLDL, very low-density lipoprotein.
Lumen Foam cell
Vessel
wall
IDL
LDL
NO
Oxidation Chemotactic
Monocyte
factors Smooth
muscle
MMP cells
Atherosclerotic
lesion
Macrophage
Adhesion
molecules
FIGURE 95. The process of atherogenesis. Atherosclerosis is initiated by the migration of
LDL and remnant lipoprotein particles into the vessel wall. These particles undergo oxida-
tion and are taken up by macrophages in an unregulated fashion. The oxidized particles
participate to induce endothelial cell dysfunction leading to a reduced ability of the
endothelium to dilate the artery and cause a prothrombotic state. The unregulated uptake of
cholesterol by macrophages leads to foam cell formation and the development of a blood
clotfavoring fatty lipid core. The enlarging lipid core eventually causes an encroachment of
the vessel lumen. Early in the process, smooth muscle cells are activated and recruited from
the media to the intima, helping to produce a collagen matrix that covers the growing clot
protecting it from circulating blood. Later, macrophages produce and secrete matrix metal-
loproteinases which degrade the collagen matrix, leading to unstable plaque which may
cause a myocardial infarction. IDL, intermediate-density lipoprotein; LDL, low-density
lipoprotein; MMP, matrix metalloproteinases; NO, nitric oxide.
TREATMENT in patients with established CHD or other atherosclerotic

vascular disease based on the results of two additional trials
In the United States, prevention and treatment of CHD is based published after the 2004 NCEP update.9 These guidelines
primarily on guidelines issued in 2001 by the National suggest it is reasonable to set an LDL cholesterol goal of less
Cholesterol Education Program (NCEP) Expert Panel on than 70 mg/dL (1.81 mmol/L) in all patients with CHD or other
Detection, Evaluation, and Treatment of High Blood Cholesterol forms of atherosclerotic vascular disease. If it is not possible to
in Adults (Adult Treatment Panel III [ATP III]).3 Low-density attain LDL cholesterol less than 70 mg/dL (1.81 mmol/L) due
lipoprotein cholesterol is the primary diagnostic and therapeu- to a high baseline LDL cholesterol, it is generally possible to
tic target. The NCEP ATP III guidelines have set the optimal achieve an LDL cholesterol reduction of greater than 50%
level for LDL cholesterol for all adults as less than 100 mg/dL with more intensive LDL lowering therapy, including combi-
(2.59 mmol/L). The NCEP panel issued an update in 2004 to the nation drug therapy.
ATP III guidelines based on more recent clinical trial evidence.8
The update outlines additional treatment options for certain Guidelines for Treatment
patient populations, mainly those who are at very high risk of
recurrent CHD events. These treatment options emphasize Step 1: Patient Assessment
the benets of diet, exercise, and weight control and the use of Determine lipoprotein prole after fasting for 9 to 12 hours.
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase The NCEP guidelines recommend that all adults greater than
inhibitors (or statins) as rst-line drugs. If statins or other drugs 20 years of age should be screened at least every 5 years using a
used to treat hyperlipidemia are prescribed, doses that reduce LDL fasting blood sample to obtain a lipid prole (total cholesterol, LDL
cholesterol by at least 30% to 40% should be recommended.8 cholesterol, HDL cholesterol, and triglycerides). A fasting lipid
Most recently, the American Heart Association and American prole is preferred so an accurate assessment of LDL cholesterol
College of Cardiology issued guidelines for secondary prevention can be performed. Fasting permits the clearance of triglycerides
TABLE 93. Secondary Conditions and Drugs That May Cause

Clinical Presentation and Diagnosis Hyperlipidemias
LDL HDL
cholesterol Triglycerides cholesterol
Lipid Panel Other Conditions
Patients presenting with a total cholesterol level exceeding Diabetes
200 mg/dL (5.18 mmol/L) or LDL cholesterol exceeding Hypothyroidism
100 mg/dL (2.59 mmol/L) should be evaluated for high Obstructive liver
cholesterol. disease/biliary
Patients with serum triglycerides from 150500 mg/dL cirrhosis
Renal disease
(1.705.65 mmol/L) and serum HDL cholesterol less than
Nephrotic
40 mg/dL (1.04 mmol/L) may have metabolic syndrome syndrome
and need to be evaluated. Chronic renal
failure
Physical Findings
Hemodialysis
Patients with genetic disorders that cause a marked patients
increase in serum LDL cholesterol (greater than 250 mg/dL Obesity
[6.48 mmol/L]) may present with corneal arcus of the eye
Drugs
and xanthomas of extensor tendons of the hand and Estrogen
Achilles tendon. Progestins
Patients with extremely elevated serum triglycerides Protease inhibitors
(greater than 1,000 mg/dL [11.3 mmol/L]) can develop Anabolic steroids
pancreatitis and tuberoeruptive xanthomas. Corticosteroids
Isotretinoin
Indications for Lipid Panel Cyclosporine
All adults greater than 20 years of age should be screened Atypical
at least every 5 years using a fasting blood sample to obtain antipsychotics
a lipid prole (total cholesterol, LDL cholesterol, HDL cho- Thiazide diuretics
lesterol, and triglycerides). A fasting lipid prole is preferred -Blockers
so an accurate assessment of LDL cholesterol can be per- LDL, low-density lipoprotein; HDL, high-density lipoprotein.
formed, and fasting will allow the clearance of triglycerides
carried by chylomicrons from the circulation, allowing
VLDL cholesterol to be determined. be made to correct or control underlying diseases such as
Children between 2 and 20 years old should be screened hypothyroidism and diabetes. Concurrent medications known
for high cholesterol if their parents have premature CHD to induce lipid abnormalities should be evaluated for discon-
or if one of their parents has a total cholesterol greater than tinuation prior to instituting long-term lipid-lowering therapy.3
240 mg/dL (6.22 mmol/L). Early screening will help to iden-
tify children at highest risk of developing CHD in whom Step 3: Identify the Presence of Clinical Atherosclerotic
early education and dietary intervention is warranted.
Disease That Confers High Risk for CHD Events
Indications for Other Tests Individuals with established CHD, other clinical atheroscle-
Conditions that may produce lipid abnormalities (such as rotic disease (CAD), or diabetes have a greater than 20% risk
those listed in Table 93) should be screened for using over a 10-year period of developing CHD.3 The ATP III guide-
appropriate tests. If present, these conditions should be lines set the target LDL cholesterol level at less than 100 mg/dL
properly addressed. (2.59 mmol/L) for high-risk patients who have a history of
one or more of the following:
carried by chylomicrons from the circulation thus allowing Myocardial infarction (MI)
VLDL cholesterol to be determined. Children between 2 and Unstable angina
20 years old should be screened for high cholesterol if their par- Chronic stable angina
ents have premature CHD or if one of their parents has a total Coronary interventions (coronary bypass, percutaneous
cholesterol greater than 240 mg/dL (6.22 mmol/L).3 Early transluminal coronary angioplasty, or stents)
screening will help to identify children at highest risk of devel- Peripheral arterial disease (claudication or ankle-brachial
oping CHD, in whom early education and dietary intervention index less than 0.9)
is warranted. Symptomatic carotid artery disease (stroke or transient
ischemic attack)
Step 2: Rule Out Secondary Causes of Dyslipidemia Diabetes (types 1 and 2)
Certain drugs and diseases can cause abnormalities in serum Multiple risk factors with a Framingham calculated risk
lipids and should be evaluated (Table 93). Every effort should (Fig. 96) greater than 20%
Men Women
Estimate of 10-year risk for men Estimate of 10-year risk for women
(Framingham point scores) (Framingham point scores)
Age Points Age Points
2034 9 2034 7
3539 4 3539 3
4044 0 4044 0
4549 3 4549 3
5054 6 5054 6
5559 8 5559 8
6064 10 6064 10
6569 11 6569 12
7074 12 7074 14
7579 13 7579 15
Points Points
Total Age Age Age Age Age Total Age Age Age Age Age
cholesterol 2039 4049 5059 6069 7079 cholesterol 2039 4049 5059 6069 7079
Less than 160 0 0 0 0 0 Less than 160 0 0 0 0 0
160199 4 3 2 1 0 160199 4 3 2 1 1
200239 7 5 3 1 0 200239 8 6 4 2 1
240279 9 6 4 2 1 240279 11 8 5 3 2
Greater than or Greater than or
equal to 280 11 8 5 3 1 equal to 280 13 10 7 4 2
Points Points
Age Age Age Age Age Age Age Age Age Age
2039 4049 5059 6069 7079 2039 4049 5059 6069 7079
Nonsmoker 0 0 0 0 0 Nonsmoker 0 0 0 0 0
Smoker 8 5 3 1 1 Smoker 9 7 4 2 1
HDL (mg/dL) Points

HDL (mg/dL) Points
Greater than or equal to 60 1
Greater than or equal to 60 1
5059 0
5059 0
4049 1
4049 1
Less than 40 2
Less than 40 2
Systolic BP (mmHg) If untreated If treated
Systolic BP (mmHg) If untreated If treated
Less than 120 0 0
120129 0 1 Less than 120 0 0
130139 1 2 120129 1 3
140159 1 2 130139 2 4
Greater than or equal to160 2 3 140159 3 5
Greater than or equal to 160 4 6
Point total 10-year risk %
Less than 0 Less than 1 Point total 10-year risk %
0 1
1 1 Less than 9 Less than 1
2 1 9 1
3 1 10 1
4 1 11 1
5 2 12 1
6 2 13 2
7 3 14 2
8 4 15 3
9 5 16 4
10 6 17 5
11 8 18 6
12 10 19 8
13 12 20 11
14 16 21 14
15 20 22 17
16 25 23 22
10-year risk _____% 24 27 10-year risk _____%
Greater than or Greater than or
equal to 17 equal to 30 Greater than or Greater than or
equal to 25 equal to 30
FIGURE 96. Framingham point scale for estimating 10-Year CHD risk. The Framingham score is used to determine a patients CHD
risk category when they are found to have two or more CHD risk factors (Table 94). This system assigns points to the following risk
factors: age, total cholesterol level, smoking status, HDL cholesterol level, and systolic blood pressure. The point total corresponds
to the 10-year risk (%) of a CHD event (non-fatal myocardial infarction and coronary death), which serves as a basis for deciding
how intensively to treat hypercholesterolemia and other risk factors. To calculate risk factor using the Framingham Point Scale, go to
the following website: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm. The Systme International units for the correspon-
ding conventional units in the Framingham Point Scale illustration include: (1) total cholesterol (160 mg/dL = 4.14 mmol/L; 160 to
199 mg/dL = 4.14 to 5.15 mmol/L; 200 to 239 mg/dL = 5.18 to 6.19 mmol/L; 240 to 279 mg/dL = 6.22 to 7.23 mmol/L; 280 mg/dL =
7.25 mmol/L) and (2) HDL (60 mg/dL = 1.55 mmol/L; 50 to 59 mg/dL = 1.3 to 1.53 mmol/L; 40 to 49 mg/dL = 1.04 to 1.27
mmol/L; 40 mg/dL = 1.04 mmol/L). BP, blood pressure; CHD, coronary heart disease; HDL, high-density lipoprotein. (From
http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.)
TABLE 95. CHD Risk Factors and Needed Risk Factors for
Patient Encounter 1 Framingham Score Calculation
10-Year Risk Need for Framingham

Risk Prole for CHD Calculation
MN is a 48-year-old man with a history of hypertension and Less than or equal to Less than 10% No
smoking who presents to the clinic for evaluation of his 1 risk factor
cholesterol. He denies having chest pain or history of Greater than or equal 010% Yes
myocardial infarction, stroke, or peripheral artery disease. to 2 risk factors 1020% Yes
He has no siblings and both parents are alive with no his- CAD or CAD Greater than 20% No
tory of CHD. MN says that he smokes about 1 pack of ciga- risk-equivalent
rettes per day. He does not exercise on a regular basis. He Very-high risk Much greater than No
has been fasting for approximately 11 hours. 20%
CAD, clinical atherosclerotic disease; CHD, coronary heart disease.

Can MN be evaluated today for his cholesterol?
Does he have risk factors for CHD?
What additional information do you need to know for the Step 5: If Two or More Risk Factors are Present Without
evaluation of MN? CHD or CHD Risk Equivalent, Assess 10-Year CHD Risk
Listed in Table 95 are the risk groups that require risk calcu-
lations using the Framingham scoring system.3 Since individ-
The benets of lowering LDL cholesterol to as low as uals with two or more risk factors may carry a risk equivalent
70 mg/dL (1.81 mmol/L) have been demonstrated in clinical trials; to individuals with established CHD, and therefore should be
however, the lowest level at which to treat LDL cholesterol has not treated with the same intensity, a scoring system developed
yet been determined. Thus, in patients considered very high risk from the Framingham Coronary Heart Disease Study is used
and those conferring a CHD risk much greater than 20%, an to estimate this 10-year risk (Fig. 96). This system assigns
LDL cholesterol goal of less than 70 mg/dL (1.81 mmol/L) is a points to the following risk factors: age, total cholesterol level,
therapeutic option.7 These individuals are those with established smoking status, HDL cholesterol level, and systolic blood
CAD plus: multiple major risk factors (especially diabetes), pressure. The score is used to determine a patients risk category
severe and poorly controlled risk factors (especially continued and the intensity of treatment to lower their LDL cholesterol.
cigarette smoking), multiple risk factors of metabolic syndrome, To calculate a Framingham score, visit the following website:
and acute coronary syndromes. http://www.nhlbi.nih.gov/guidelines/cholesterol/ index.htm.
Step 4: Determine the Presence of Major Risk Factors
Step 6: Determine Treatment Goals and Therapy
In individuals who do not have established CHD or CHD risk
Treatment goals for LDL cholesterol and thresholds for the
equivalent, the next step is to count major risk factors for CHD
institution of therapeutic lifestyle changes (TLC) and phar-
as presented in Table 94. These risk factors are considered
macotherapy is the next step (Table 96).
independent predictors of CHD. High-density lipoprotein
cholesterol of greater than or equal to 60 mg/dL (1.55 mmol/L)
Step 7: Initiate Therapeutic Lifestyle Changes If LDL Is
is considered a negative risk factor and means 1 risk factor can
Above Goal
be subtracted from the total count.3
Therapeutic lifestyle changes should be the rst approach
TABLE 94. Risk Factors for Coronary Heart Disease tried in all patients (Table 97).3 An adequate trial of TLC
should be employed in all patients, but pharmacotherapy should
Risk Factor Denition be instituted concurrently in higher-risk patients. This includes
Age (years) Male greater than or equal to 45; female dietary restrictions of cholesterol and saturated fats as well as
greater than or equal to 55 regular exercise and weight reduction. In addition, therapeu-
Family history of Male rst-degree relative at less than tic options to enhance LDL cholesterol lowering such as con-
premature 55 years
sumption of plant stanols/sterols (which competitively inhibit
CHD events Female rst-degree relative at less than
65 years incorporation of cholesterol into micelles) and dietary ber
Hypertension SBP greater than or equal to 140 mm Hg should be encouraged. These therapeutic options collectively
DBP greater than or equal to 90 mm Hg may reduce LDL cholesterol by 20% to 25%.
HDL cholesterol Less than 40 mg/dL (1.04 mmol/L)
Cigarette smoking Within the past month
Step 8: Consider Adding Drug Therapy If LDL Is Above
HDL cholesterol greater than or equal to 60 mg/dL (1.55 mmol/L) is con- Threshold Level
sidered a negative risk factor; thus, subtract 1 risk factor from the total Patients unable or unlikely to achieve their LDL cholesterol
from above.
CHD, coronary heart disease; DBP, diastolic blood pressure; HDL, high- goals following a reasonable trial of TLC (typically 12 weeks
density lipoprotein; SBP, systolic blood pressure. for patients without CHD and sooner for those at high risk or
TABLE 96. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III [ATP III]) Treatment Goals for LDL Cholesterol and Thresholds for
Starting Therapeutic Lifestyle Changes and Pharmacotherapy
Initiate Therapeutic
Risk Category LDL cholesterol Goal Lifestyle Changes (TLC) Consider Drug Therapy
High Risk
CHD or CHD risk equivalents Less than 100 mg/dL Greater than or equal to Greater than or equal to
(10-year risk greater than 20%) (2.59 mmol/L) 100 mg/dL (2.59 mmol/L) 100 mg/dL (2.59 mmol/L)
Very-High Risk Optional goal of less than
70 mg/dLa (1.81 mmol/L)
Moderately-High Risk Less than 130 mg/dL Greater than or equal to Greater than or equal to
Greater than or equal to 2 risk (3.37 mmol/L) (Optional 130 mg/dL (3.37 mmol/L) 130 mg/dL (3.37 mmol/L)
factors (10-year risk 10%20%) goal of less than 100 mg/dLa (consider drug options if
[2.59 mmol/L]) LDL cholesterol
100129 mg/dL
[2.593.34 mmol/L)
Moderate Risk Less than 130 mg/dL Greater than or equal to Greater than 160 mg/dL
Greater than or equal to 2 risk (3.37 mmol/L) 130 mg/dL (3.37 mmol/L) (4.14 mmol/L)
factors (10-year risk less than 10%)
Low Risk Less than 160 mg/dL Greater than or equal to Greater than or equal to
(4.14 mmol/L) 160 mg/dL (4.14 mmol/L) 190 mg/dL (4.91 mmol/L)
(consider drug options
if LDL cholesterol
160189 mg/dL
[4.144.89 mmol/L])
a
Optional goals indicated in the NCEP ATP III 2004 update of the guidelines.
CHD, coronary heart disease; LDL, low-density lipoprotein.
with LDL cholesterol greater than 190 mg/dL [4.92 mmol/L] Step 9: Identify Patients with the Metabolic Syndrome
at baseline) are candidates for drug therapy (Table 96). The diagnosis of metabolic syndrome is made when three or
Typically, statins are the medications of choice to treat more of the following risk factors are present:3,10
high LDL cholesterol because of their ability to substantially
reduce LDL cholesterol, ability to reduce morbidity and mortal- Waist circumference greater than 40 inches (101.6 cm) in
ity from atherosclerotic disease, convenient once-daily dosing, men (greater than 35 inches in Asian males), or 35 inches
and low risk of side effects. (88.9 cm) in women (greater than 31 inches in Asian females)
Triglycerides greater than or equal to 150 mg/dL (1.70 mmol/L)
or on drug treatment for elevated triglycerides
TABLE 97. Essential Components of Therapeutic Lifestyle
Changes (TLC)
HDL cholesterol less than 40 mg/dL (1.04 mmol/L) in men
or 50 mg/dL (1.3 mmol/L) in women or on drug treatment
Component Recommendation for reduced HDL cholesterol
LDL-raising nutrients Total fat range should be 2535% for Blood pressure greater than or equal to 130/85 mm Hg or on
most cases drug treatment for hypertension
Saturated fats Less than 7% of total calories and Fasting blood glucose greater than or equal to 100 mg/dL
reduce intake of trans fatty acids (5.55 mmol/L) or on drug treatment for elevated glucose
Dietary cholesterol Less than 200 mg/day
Therapeutic options for Patients with metabolic syndrome are twice as likely to
LDL lowering
Plant stanols/sterols 2 g per day
develop type 2 diabetes and four times more likely to develop
Increased viscous 1025 g per day CHD.3,11 These individuals are usually insulin resistant, obese,
(soluble) ber have hypertension, are in a prothrombotic state, and have
Total calories Adjust caloric intake to maintain atherogenic dyslipidemia characterized by low HDL cholesterol
desirable body weight and and elevated triglycerides, and an increased proportion of their
prevent weight gain LDL particles are small and dense.3
Physical activity Include enough moderate exercise NCEP ATP III identied metabolic syndrome as an impor-
to expend at least 200 kcal tant target for further reducing CHD risk. Treatment of meta-
per day
bolic syndrome starts with increased physical activity, weight
LDL, low-density lipoprotein. reduction (which also enhances LDL cholesterol lowering and
insulin sensitivity), and moderation of ethanol use and carbohy-

drate intake, which effectively reduce many of the associated risk Patient Encounter 1, Part 2:
factors. Each of the risk factors should be addressed independ- Medical History, Physical Exam, and
ently as appropriate, including treatment of hypertension and Diagnostic Tests
use of aspirin in CHD patients to reduce the prothrombotic state.
Patients with metabolic syndrome have an additional lipid PMH
Hypertension for 9 years; history of gout
parameter that needs to be assessed, namely non-HDL cholesterol
(total cholesterol minus HDL cholesterol).3 The target for non-HDL FH
cholesterol is less than the patients LDL cholesterol target plus Father and mother both alive with no history of CHD or
30 mg/dL (0.78 mmol/L). After assessment and control of LDL diabetes.
cholesterol, patients with serum triglycerides between 200 and
SH
499 mg/dL (2.26 and 5.64 mmol/L) should be assessed for athero- Works as a computer programmer and sits at his desk most of
genic dyslipidemia (low HDL cholesterol, increased small-dense the day; does not exercise on a regular basis; drinks alcohol
LDL particles) and metabolic syndrome. Non-HDL cholesterol (2 to 3 beers) mainly on the weekends while watching sports
estimates the cholesterol carried by all apolipoprotein B- on TV
containing lipoprotein particles. Thus, non-HDL cholesterol
Meds
represents the sum of LDL cholesterol, VLDL cholesterol, and
Aspirin 80 mg once daily
other remnant particles. The non-HDL cholesterol goal is 30
Verapamil SR 180 mg once daily
mg/dL (0.78 mmol/L) higher than the LDL cholesterol goal. This
is based on the premise that a VLDL cholesterol level less than ROS
or equal to 30 mg/dL (0.78 mmol/L) is normal. For example, No chest pain, shortness of breath, or dizziness
the LDL cholesterol goal is less than 100 mg/dL (2.59 mmol/L) PE
and the non-HDL cholesterol goal is less than 130 mg/dL
(3.37 mmol/L) for a diabetic patient without a history of CHD. VS: BP 142/86 mm Hg, pulse 71 beats per minute, respira-
tory rate 16 beats per minute, temperature 37C (98.6F),
Two treatment approaches can be considered for achieving the
waist circumference 38 inches (96.52 cm)
non-HDL cholesterol goal: titrating existing LDL-lowering
CV: RRR, normal S1, S2; no murmurs, rubs, or gallops
therapy or adding niacin or a brate to the LDL-lowering Abd: Soft, non-tender, non-distended; positive for bowel
therapy.3 sounds, no hepatosplenomegaly or abdominal aortic
aneurysm
Step 10: Treatment of Elevated Triglycerides Exts: Ankle-brachial index 1.1
Patients with serum triglycerides exceeding 500 mg/dL Neck: No carotid and basilar bruits
(5.65 mmol/L) are at increased risk of pancreatitis. 3 Labs
Reducing triglycerides in these individuals becomes the pri- Total cholesterol 256 mg/dL (6.63 mmol/L), triglycerides
mary target for intervention. Reduction in ethanol and car- 235 mg/dL (2.66 mmol/L), HDL cholesterol 27 mg/dL
bohydrates should be considered and secondary causes (0.70 mmol/L), glucose 115 mg/dL (6.38 mmol/L), all other
(Table 93) should be assessed. When pharmacotherapy is labs within normal limits
instituted, the intensity of therapy should be to reduce
triglycerides to less than 150 mg/dL (1.70 mmol/L). Once Given this additional information, what is your assessment
of MNs CHD risk?
triglycerides are less than 500 mg/dL (5.65 mmol/L), the
Identify your treatment goals for MN.
primary focus of intervention should once again be on LDL
What diagnostic parameters does MN have for the meta-
cholesterol. Niacin, brates, and sh oils are the most effec- bolic syndrome?
tive agents in patients with hypertriglyceridemia.3 What nonpharmacologic and pharmacologic alternatives
are available for MN?
Develop a care plan for MN.
Emerging and Life-Habit Risk Factors
In addition to the ve major risks, the ATP III guidelines rec-
ognize other factors that contribute to CHD risk. These are
classied as life-habit risk factors and emerging risk factors.
Life-habit risk factors, consisting of obesity, physical inac-
tivity, and an atherogenic diet, require direct intervention. predicting CHD risk beyond LDL cholesterol and major CHD
For example, emerging risk factors are lipoprotein(a), risk factors.11 In some patients, emerging risk factors may be
homocysteine, prothrombotic/proinflammatory factors, used to guide the intensity of risk-reduction therapy. Deciding
and C-reactive protein (CRP). C-reactive protein is a when to consider emerging risk factors requires the use of
marker of low-level inammation and appears to help in clinical judgment.
Pharmacotherapy affect intracellular transport, membrane trafcking, and gene

transcription.23 This may explain some of the cholesterol-
Statins (HMG-CoA Reductase Inhibitors) independent benets (so-called pleiotropic effects) of
Statins are very effective LDL-lowering medications and are statins such as reducing lipoprotein oxidation, enhancing
proven to reduce the risk of CHD, stroke, and death. Thus, endothelial synthesis of nitric oxide, and inhibiting thrombo-
NCEP ATP III considers statins the preferred LDL-lowering sis. These pleiotropic effects are thought to contribute to the
medications. Data concerning the efcacy and safety of the rapid/earlier benets of statins on CHD risk while the
statins now go back nearly 25 years. Statins are effective in decrease in serum lipids accounts for the slower late benet.
reducing MIs, strokes, revascularization procedures, cardio- Statins are well tolerated with less than 4% of patients in
vascular deaths, and in some cases, total mortality. This effec- clinical trials discontinuing therapy due to adverse side effects
tiveness has been demonstrated in both genders, the elderly, (Table 99). Elevations in liver function tests (LFTs) and
patients with diabetes and hypertension, those with and with- myopathy, including rhabdomyolysis, are important adverse
out preexisting CHD, and following an acute coronary syn- effects associated with the statins. Liver toxicity, dened as
drome. 1222 Statins inhibit conversion of HMG-CoA to LFT elevations greater than three times the upper limit of
L-mevalonic acid and subsequently cholesterol. Statins lower normal, is reported in less than 2% of patients; however, the
LDL cholesterol levels by approximately 25% to 62% (Table 98). incidence is higher at higher doses and the progression to liver
A substantial reduction in LDL cholesterol occurs at the usual failure is thought to be exceedingly rare. Liver function tests
starting dose and each doubling of the daily dose only pro- should be obtained at baseline and 6 to 12 weeks after starting
duces an additional 6% average reduction (known as the rule therapy or any dose escalation. Annual monitoring of LFTs is
of 6). This is important when considering dose escalation usually sufcient. Myopathy, dened as muscle symptoms
versus adding on an additional LDL-lowering drug. Statins are with creatine kinase (CK; or creatine phosphokinase [CPK])
moderately effective at reducing triglycerides and modestly 10 times the upper limit of normal, is reported to range from
raise HDL cholesterol (Table 98). By inhibiting the synthesis 0% to less than 0.5% for the currently marketed statins at
of L-mevalonic acid, statins in turn inhibit other important Food and Drug Administration (FDA)-approved doses.
by-products in the cholesterol biosynthetic pathway that Rhabdomyolysis, dened as muscle symptoms with marked
TABLE 98. Effects of Lipid-Lowering Drugs on Serum Lipids at FDA-Approved Doses
Lipid-Lowering Drug LDL Cholesterol HDL Cholesterol Triglycerides Total Cholesterol

Statins
Atorvastatin 26% to 60% +5% to +13% 17% to 53% 25% to 45%
Fluvastatin 22% to 36% +3% to +11% 12% to 25% 16% to 27%
Fluvastatin ER 33% to 35% +7% to +11% 19% to 25% 25%
Lovastatin 21% to 42% +2% to +10% 6% to 27% 16% to 34%
Lovastatin ER 24% to 41% +9% to +13% 10% to 25% 18% to 29%
Pravastatin 22% to 34% +2% to +12% 15% to 24% 16% to 25%
Rosuvastatin 45% to 63% +8% to +14% 10% to 35% 33% to 46%
Simvastatin 26% to 47% +8% to +16% 12% to 34% 19% to 36%
Bile Acid Sequestrants
Cholestyramine 15% to 30% +3% to +5% May increase in patients 10% to 25%
with elevated triglycerides
Colesevelam 8% to 15% +3% to +5% 70% to 10%
Colestipol 15% to 30% +3% to +5% 10% to 25%
Cholesterol Absorption
Inhibitor
Ezetimibe 18% +1% to +2% 7% to 9% 12% to 13%
Nicotinic Acid
Niacin ER 5% to 17% +14% to +26% 11% to 38% 3% to 12%
Niacin IR 5% to 25% +15% to +39% 20% to 60% 3% to 25%
Fibric Acid Derivatives
Fenobrate 31% to +45% +9% to +23% 23% to 54% 9% to 22%
Gembrozil 30% to +30% +10% to +30% 20% to 60% 2% to 16%
Combination Products
Niacin ER and lovastatin 30% to 42% +20% to +30% 32 to 44% Not stated
Simvastatin and ezetimibe 46% to 59% +8% to +12% 26% to 25% 34% to 43%
ER, extended-release; FDA, Food and Drug Administration; HDL, high-density lipoprotein; IR, immediate-release; LDL, low-density lipoprotein; SR,
sustained-release.
TABLE 99. Formulation, Dosing, and Common Adverse Effects of Lipid-Lowering Drugs
Lipid-Lowering Usual Adult Maintenance

Drug Dosage Forms Dose Range Adverse Effects
Statins
Atorvastatin 10, 20, 40, 80 mg tablets 10 to 80 mg once daily Most frequent side effects are constipation, abdominal
(at any time of day) pain, diarrhea, dyspepsia, and nausea. Statins
Fluvastatin 20, 40 mg capsules; 80 mg 2040 mg/day as a single should be discontinued promptly if serum
extended-release tablets dose (evening) or 40 mg transaminase levels (liver function tests) rise to
twice daily; 80 mg once 3 times upper limit of normal, or if patient
daily (evening) develops signs or symptoms of myopathy.
Lovastatin 10, 20, 40 mg tablets 10 to 80 mg/day as a single Approximate equivalent doses of HMG-CoA
dose (with evening meal) reductase inhibitors are: atorvastatin 10 mg,
or divided twice daily uvastatin 80 mg, lovastatin 40 mg, pravastatin
with food 40 mg, simvastatin 20 mg, and rosuvastatin 5 mg.
Lovastatin ER 20, 30, 60 mg tablets 20 to 60 mg/day as a
single dose
Pravastatin 10, 20, 40, 80 mg tablets 10 to 80 mg/day as a
single dose at bedtime
Rosuvastatin 5, 10, 20, 40 mg tablets 540 mg/day (at any time of
day). 40 mg reserved for
those who dont achieve
LDL cholesterol goal on
20 mg
Simvastatin 5, 10, 20, 40, 580 mg/day as a single dose
80 mg tablets in the evening, or divided
Bile Acid
Sequestrants
Cholestyramine 4 g packets 424 g/day in two or more Main side effects are nausea, constipation, bloating,
divided doses and atulence, although these may be less with
Colesevelam 625 mg tablets 37504375 mg/day as a colesevelam. Increasing uid and dietary ber
single dose or divided intake may relieve constipation and bloating.
twice daily, with meals Impair absorption of fat-soluble vitamins.
Colestipol 5 g packets 530 g/day as a single dose
or divided
1 g tablets 216 g/day as a single dose
or divided
Cholesterol
Absorption
Inhibitors
Ezetimibe 10 mg tablet 10 mg once daily The overall incidence of adverse events reported
with ezetimibe alone was similar to that reported
with placebo and generally similar between
ezetimibe with a statin and statin alone.
The frequency of increased transaminases
was slightly higher in patients receiving
ezetimibe plus a statin compared with those
receiving statin monotherapy (1.3% versus 0.4%).
Nicotinic Acid
Niacin ER 500, 750, 1000 mg 10002000 mg once Side effects include ushing, itching, gastric distress,
extended-release tablets daily at bedtime headache, hepatotoxicity, hyperglycemia, and
Niacin 50 to 750 mg tabs or caps, 15 g/day in three or more hyperuricemia.
immediate-release divided doses
250 to 750 mg 12 g/day (never exceed
sustained-release 2 g/day due to increased
risk of hepatotoxicity)
Fibric Acid
Derivatives
Fenobrate 54, 160 mg tablets 54160 mg/day Most common side effects are nausea, diarrhea,
Gembrozil 600 mg tablets 1200 mg/day in two doses, abdominal pain, and rash. Increased risk of
30 minutes before meals rhabdomyolysis when given with a statin. Fibric
acids are associated with gallstones, myositis,
and hepatitis.
(Continued )
TABLE 99. Formulation, Dosing, and Common Adverse Effects of Lipid-Lowering Drugs (Continued )
Lipid-Lowering Usual Adult Maintenance

Drug Dosage Forms Dose Range Adverse Effects
Combination
Products
Niacin ER and 500 mg/20 mg, 500 mg/20 mg to See entries on prior page for each drug (niacin ER
lovastatin 750 mg/20 mg, 2000 mg/40 mg daily, and lovastatin)
1000 mg/20 mg tablets at bedtime
Ezetimibe and 10 mg/10 mg, The dosage range is See entries on prior page for each drug (ezetimibe and
simvastatin 10 mg/20 mg, 10/10 mg/day through simvastatin)
10 mg/40 mg, 10/80 mg/day. The
10 mg/80 mg recommended usual
starting dose is
10/20 mg/day.
Initiation of therapy with
10/10 mg/day may be
considered for patients
requiring less aggressive
LDL cholesterol reductions.
ER, extended release; HMG-CoA, 3-hydroxy-3-methyglutaryl coenzyme A; LDL, low-density lipoprotein.
elevation in CK 10 times the upper limit of normal with creati- and at each visit. More frequent monitoring should be done in
nine elevation usually associated with myoglobinuria and higher-risk individuals such as those identied above.
brown urine, is very rare.24 The concern of statin-associated With the exception of pravastatin which is mainly metabo-
myopathy has increased since the voluntary removal of cerivas- lized by isomerization in the gut to a relatively inactive metabo-
tatin from the world market in 2001 because the reported rate of lite, the other statins undergo biotransformation by the
fatal rhabdomyolysis was 16 to 80 times higher than the rate for cytochrome P-450 system. Therefore, drugs known to inhibit
any other statins, and many of these cases were reported in statin metabolism should be used cautiously. The time until
patients treated with concomitant gembrozil.25 The American maximum effect on lipids for statins is generally 4 to 6 weeks.
College of Cardiology/American Heart Association/National
Heart, Lung and Blood Institute published a clinical advisory Cholesterol Absorption Inhibitors
with a focus on myopathy.24 Listed below are the risks associated Ezetimibe is the rst drug in a new class of agents referred to
with statin-induced myopathy published in this report: as cholesterol absorption inhibitors. Ezetimibe blocks biliary
and dietary cholesterol as well as phytosterol (plant sterol)
Small body frame and frailty
Multisystem disease (e.g., chronic renal insufciency, espe-
cially due to diabetes) Patient Encounter 2
Multiple medications
Perioperative periods
Specic concomitant medications or consumptions (check LC is a 51-year-old female with a history of CHD (stent
specic statin package insert for warnings): brates (espe- placement in the left anterior descending coronary artery
cially gembrozil, but other brates too), nicotinic acid 3 years prior) and type 2 diabetes who is referred to you for
(rarely), cyclosporine, azole antifungals such as itraconazole follow-up of her cholesterol. She is taking simvastatin
and ketoconazole, macrolide antibiotics such as erythromy- 20 mg once daily in the evening for her cholesterol, and
cin and clarithromycin, protease inhibitors used to treat metformin 2000 mg once daily in the evening and piogliti-
Acquired Immune Deciency Syndrome, nefazodone (anti- zone 15 mg once daily for diabetes. Her diabetes is well
depressant), verapamil, amiodarone, large quantities of controlled. Her laboratory test results are within normal
limits, except for her fasting lipid prole: total cholesterol
grapefruit juice (usually more than 1 quart per day), and
215 mg/dL (5.57 mmol/L), triglycerides 135 mg/dL (1.53
alcohol abuse (independently predisposes to myopathy) mmol/L), HDL cholesterol 51 mg/dL (1.32 mmol/L), and
LDL cholesterol 137 mg/dL (3.55 mmol/L).
Baseline CK should be obtained in all patients prior to starting
statin therapy. Follow-up CK should only be obtained in patients What is your assessment of LCs cholesterol results?
complaining of muscle pain, weakness, tenderness, or brown Identify treatment goals for LC.
urine. Routine monitoring of CK is of little value in the absence Assess LCs risk for statin-induced side effects.
of clinical signs or symptoms. Patient assessment for symptoms Design a treatment plan for LC.
of myopathy should be done 6 to 12 weeks after starting therapy
absorption by interacting with the NPC1L1 transporter located of patients taking cholestyramine or colestipol report consti-
in the brush border membrane of enterocytes5 (Fig. 92). pation and symptoms such as atulence and bloating. A large
Ezetimibe inhibits 54% of all intestinal cholesterol absorption number of patients stop therapy because of this. Resins should
on average. By reducing the cholesterol content within chy- be started at the lowest dose and escalated slowly over weeks to
lomicrons delivered to the liver, ezetimibe reduces liver choles- months as tolerated until the desired response is obtained.
terol stores, inducing an up-regulation of LDL receptors resulting Patients should be instructed to prepare the powder formula-
in a decrease in serum cholesterol. As a result, ezetimibe also tions in 6 to 8 ounces (approximately 180240 mL) of non-
induces a compensatory increase in cholesterol biosynthesis. carbonated uids, usually juice (enhances palatability) or water.
Since statins inhibit cholesterol biosynthesis, the compensatory Fluid intake should be increased to minimize constipation.
increase in cholesterol biosynthesis by ezetimibe can be blocked Colesevelam is better tolerated with fewer gastrointestinal side
by combining ezetimibe with a statin. effects, although it is more expensive. All resins have the poten-
Ezetimibe reduces LDL cholesterol by an average of 18% tial to prevent the absorption of other drugs such as digoxin,
(Table 98). However, larger reductions can be seen in some warfarin, thyroxine, thiazides, -blockers, fat-soluble vitamins,
individuals, presumably due to higher absorption of choles- and folic acid. Potential drug interactions can be avoided by
terol. These individuals appear to have a blunted response to taking a resin either 1 hour before or 4 hours after these other
statin therapy. Ezetimibe lowers triglycerides by 7% to 9% and agents. Colesevelam appears less likely than the older agents
modestly increases HDL cholesterol. to reduce drug absorption, and the manufacturer does not
Once absorbed, ezetimibe undergoes extensive glucuronida- state that colesevelam has to be dosed hours apart from other
tion in the intestinal wall to the active metabolite (ezetimibe medications.27 The time until maximum effect on lipids for
glucuronide). Ezetimibe and the active metabolite are entero- resins is generally 2 to 4 weeks.
hepatically recirculated back to the site of action, which limits
systemic exposure and may explain the low incidence of adverse
effects (Table 99). Ezetimibe alone or with a statin is con- Niacin
traindicated in patients with active liver disease or unexplained Niacin (vitamin B3) has broad applications in the treatment of
persistent elevations in LFTs. Currently, clinical trials designed lipid disorders when used at higher doses than those used as a
to determine ezetimibes effects on CHD morbidity and mor- nutritional supplement. Niacin inhibits fatty acid release from
tality have not been completed. The time until maximum effect adipose tissue and inhibits fatty acid and triglyceride produc-
on lipids for ezetemibe is generally 2 weeks. tion in liver cells. This results in an increased intracellular
degradation of apolipoprotein B, and in turn, a reduction in
the number of VLDL particles secreted (Fig. 94). The lower
Bile Acid Sequestrants VLDL levels and the lower triglyceride content in these parti-
Cholestyramine, colestipol, and colesevelam are the bile acid- cles leads to an overall reduction in LDL cholesterol as well as
binding resins or sequestrants (BAS) currently available in the a decrease in the number of small, dense LDL particles. Niacin
United States. Resins are highly charged molecules that bind to also reduces the uptake of HDL-apolipoprotein A1 particles
bile acids (which are produced from cholesterol) in the gut. The and increases uptake of cholesterol esters by the liver, thus
resin-bile acid complex is then excreted in the feces. The loss of improving the efciency of reverse cholesterol transport
bile causes a compensatory conversion of hepatic cholesterol to between HDL particles and vascular tissue (Fig. 94). Niacin
bile, reducing hepatocellular stores of cholesterol resulting in an is indicated for patients with elevated triglycerides, low HDL
up-regulation of LDL receptors to replenish hepatocellular stores cholesterol, and elevated LDL cholesterol.3
which then result in a decrease in serum cholesterol. Resins have Several different niacin formulations are available:
been shown to reduce CHD events in patients without CHD.26 niacin immediate-release (IR), niacin sustained-release
Resins are moderately effective in lowering LDL cholesterol (SR), and niacin extended-release (ER).28,29 These formula-
but do not lower triglycerides (Table 98). Moreover, in tions differ in terms of dissolution and absorption rates,
patients with elevated triglycerides, the use of a resin may metabolism, efcacy, and side effects. Limitations of niacin
worsen the condition. This may be due to a compensatory IR and SR are ushing and hepatotoxicity, respectively.
increase in HMG-CoA reductase activity and results in an These differences appear related to the dissolution and
increase in assembly and secretion of VLDL. The increase in absorption rates of niacin formulations and its subsequent
HMG-CoA reductase activity can be blocked with a statin, metabolism. Niacin IR is available by prescription (Niacor)
resulting in enhanced reductions in serum lipids (see section as well as a dietary supplement which is not regulated by
on combination therapy). Resins reduce LDL cholesterol from the FDA.28 Currently, there are no FDA-approved niacin SR
15% to 30%, with a modest increase in HDL cholesterol (3% products, thus, all SR products are available only as dietary
to 5%) (Table 98). Resins are most often used as adjuncts to supplements.
statins in patients who require additional lowering of LDL Niacin IR is usually completely absorbed within 1 to 2 hours;
cholesterol. Since these drugs are not absorbed, adverse effects thus, it quickly saturates a high-afnity, low-capacity metabolic
are limited to the gastrointestinal tract (Table 99). About 20% pathway, and the majority of the drug is metabolized by a
second low-afnity, high-capacity system with metabolites Fibrates are the most effective triglyceride-lowering drugs and
associated with ushing.30 Conversely, absorption of niacin are used primarily in patients with elevated triglycerides and
SR may exceed 12 hours. Because niacin SR is absorbed over low HDL cholesterol.
12 or more hours, the high-afnity pathway metabolizes the Fibrates work by reducing apolipoproteins B, C-III (an
majority of the drug, resulting in the production of metabo- inhibitor of LPL), and E, and increasing apolipoproteins A-I
lites associated with hepatotoxicity. Niacin ER was developed and A-II through activation of peroxisome proliferator-
as a once-daily formulation to be taken at bedtime, with the activated receptors-alpha (PPAR-), a nuclear receptor
goal of reducing the incidence of ushing without increasing involved in cellular function. The changes in these apolipopro-
the risk of hepatotoxicity. Niacin ER (Niaspan) is the only teins result in a reduction in triglyceride-rich lipoproteins
long-acting niacin product approved by the FDA for dyslipi- (VLDL and IDL) and an increase in HDL.
demia. Niacin ER has an absorption rate of 8 to 12 hours, Clinical trials of brate therapy in patients with elevated
intermediate to niacin IR and SR, and therefore balances cholesterol and no history of CHD demonstrated a reduction
metabolism more evenly over the high-afnity, low-capacity in CHD incidence, although less than the reduction attained
pathway and the low-afnity, high-capacity pathway. with statin therapy.35 In addition, a large study of men with
Furthermore, taking niacin ER at bedtime can minimize the CHD, low HDL cholesterol, low LDL cholesterol, and elevated
impact of ushing. triglycerides demonstrated a 24% reduction in the risk of
Niacin use is limited by cutaneous reactions such as death from CHD, non-fatal MI, and stroke with gembrozil.36
ushing and pruritus of the face and body. The use of Fibrates may be appropriate in the prevention of CHD events
aspirin or a non-steroidal anti-inammatory drug 30 min- for patients with established CHD, low HDL cholesterol, and
utes prior to taking niacin can help alleviate these reactions, triglycerides below 200 mg/dL (2.26 mmol/L). However, LDL-
as they are mediated by an increase in prostaglandin D2.3 In lowering therapy should be the primary target if LDL choles-
addition, taking niacin with food and avoiding hot liquids terol is elevated. Evidence of a reduction in CHD risk among
at the time niacin is taken is helpful in minimizing ushing patients with established CHD has not been demonstrated
and pruritus. with fenobrate.
In general, niacin reduces LDL cholesterol from 5% to The bric acid derivatives are generally well tolerated. The
25%, reduces triglycerides by 20% to 50%, and increases HDL most common adverse effects include dyspepsia, abdominal
cholesterol by 15% to 35% (Table 98). Niacin has been pain, diarrhea, atulence, rash, muscle pain, and fatigue
shown to reduce CHD events and total mortality31 as well as (Table 99). Myopathy and rhabdomyolysis can occur, and the
the progression of atherosclerosis when combined with a risk appears to increase with renal insufciency or concurrent
statin.31 statin therapy. If a brate is used with a statin, fenobrate is pre-
Niacin can raise uric acid levels, and in diabetics can raise ferred because it appears to inhibit the glucuronidation of the
blood glucose levels. However, several clinical trials have statin hydroxy and moiety less than gembrozil, allowing
shown that niacin can be used safely and effectively in patients greater renal clearance of the statins.24,37 A CK level should be
with diabetes.33 Due to the high cardiovascular risk of patients checked before therapy is started and if symptoms occur. Liver
with diabetes, the benets of improving the lipid prole dysfunction has been reported, and LFTs should be monitored.
appear to outweigh any adjustment in diabetic medication(s) Fibrates increase cholesterol in the bile and have caused gall-
that is needed.33 bladder and bile duct disorders, such as cholelithiasis and
Niacin should be instituted at the lowest dose and gradu- cholecystitis. Unlike niacin, these agents do not increase glu-
ally titrated to a maximum dose of 2 grams daily for ER and cose or uric acid levels. Fibrates are contraindicated in patients
SR products and no more than 5 grams daily for IR products. with gallbladder disease, liver dysfunction, or severe kidney
FDA-approved niacin products are preferred because of dysfunction. The risk of bleeding is increased in patients tak-
product consistency. Moreover, niacin products labeled as ing both a brate and warfarin. The time until maximum effect
no ush dont contain nicotinic acid and therefore have no on lipids is generally 2 weeks for fenobrate and 3 to 4 weeks
therapeutic role in the treatment of lipid disorders.28 The for gembrozil.
time until maximum effect on lipids for niacins is generally 3
to 5 weeks. Fish Oils
Omega-3 fatty acids (eicosapentaenoic acid and docosa-
Fibrates hexaenoic acid), the predominant fatty acids in the oil of cold-
The predominant effects of brates are a decrease in triglyc- water sh, lower triglycerides by as much as 35% when taken
eride levels by 20% to 50% and an increase in HDL cholesterol in large amounts. Fish oil supplements may be useful for
levels by 9% to 30% (Table 98). The effect on LDL choles- patients with high triglycerides despite diet, alcohol restric-
terol is less predictable. In patients with high triglycerides, tion, and brate therapy. This effect may be modulated thru
however, LDL cholesterol may increase. Fibrates increase the PPAR- and a reduction in apolipoprotein B-100 secretion.
size and reduce the density of LDL particles much like niacin. Omega-3 fatty acids reduce platelet aggregation and have
anti-arrhythmic properties, and therefore their use has been A statin combined with a resin results in similar reductions in
associated with a reduction in MI and sudden cardiac death, LDL cholesterol as those seen with ezetimibe. However, the mag-
respectively.38 nitude of triglyceride reduction is less with a resin compared to
Omega-3 fatty acids are usually started at 1 gram daily, and the ezetimibe, and this should be considered in patients with higher
FDA recommends not exceeding 4 grams daily for the treatment baseline triglyceride levels. In addition, gastrointestinal adverse
of elevated triglycerides. Use of high-quality omega-3 fatty acids events and potential drug interactions limit the utility of this
free of contaminants such as mercury and organic pollutants combination.
should be encouraged when using these agents. Common side Ezetimibe and a resin can also be combined. A study which
effects associated with omega-3 fatty acids are diarrhea and assessed the effects of adding ezetimibe to ongoing resin ther-
excess bleeding. Patients taking anticoagulant or antiplatelet apy showed an additional 19% reduction in LDL cholesterol
agents should be monitored more closely when consuming these and an additional 14% reduction in triglycerides. This combi-
products because excessive amounts of omega-3 fatty acids (for nation was well tolerated.41
example, greater than 3 grams daily) may lead to bleeding and Some patients, in particular those with genetic forms of
may increase the risk of hemorrhagic stroke. hypercholesterolemia (Table 92), will require three or more
drugs to manage their disorder. Regimens using a statin, resin,
and niacin were found to reduce LDL cholesterol up to 75%.42
Combination Therapy
These early studies were conducted with lovastatin, so larger
reductions would be expected with the more potent statins
A large proportion of the United States population
available today.
wont achieve their NCEP cholesterol targets for a variety of
reasons.39 These include inadequate patient adherence,
Combination Therapy for Elevated Cholesterol and
adverse events, inadequate starting doses, lack of dose esca-
Triglyceridemia with or without Low HDL Cholesterol
lation, and lower treatment targets.28,40 Moreover, patients
Fibrates are the most effective triglyceride-lowering agents
with concomitant elevations in triglycerides and/or low
and also raise HDL cholesterol levels. Combination therapy
levels of HDL cholesterol may need combination drug
with a brate, particularly gembrozil, and a statin has been
therapy to normalize their lipid prole. Combination
found to increase the risk for myopathy. Of the 31 rhab-
drug therapy is an effective means to achieve greater reduc-
domyolysis deaths reported with cerivastatin use, 12 involved
tions in LDL cholesterol (statin + ezetimibe or bile acid resin,
concomitant gembrozil.25 Therefore, more frequent moni-
bile acid resin + ezetimibe, or three-drug combinations) as
toring, thorough patient education, and consideration of fac-
well as raising HDL cholesterol and lowering serum triglyc-
tors that increase the risk as reviewed previously should be
erides (statin + niacin or brate).
considered.
Combination Therapy for Elevated LDL Cholesterol Reducing LDL cholesterol while substantially raising HDL
For patients who dont achieve their LDL or non-HDL cho- cholesterol (statin + niacin) appears to reduce the risk of ather-
lesterol goals with statin monotherapy and lifestyle modica- osclerotic disease progression to a greater degree than statin
tions including those unable to tolerate high doses due to monotherapy. Combining niacin with a statin augments the
adverse effects, combination therapy may be appropriate. LDL cholesterollowering potential of niacin while enhancing
Resins or ezetimibe combine effectively with statins to aug- both the HDL cholesterolraising effects and triglyceride
ment LDL cholesterol reduction. When added to a statin, eze- lowering effects of the statin. A statin combined with niacin
timibe can reduce LDL cholesterol levels by an additional 18% appears to offer greater benets for reducing atherosclerosis
to 21% or up to 65% total reduction with maximum doses of progression compared to a statin alone.32 A formulation com-
the more potent statins. Ezetimibe and simvastatin are available bining ER niacin and lovastatin (AdvicorTM) is available and is
as a combination tablet (Vytorin) and indicated as adjunctive indicated for treatment of primary hypercholesterolemia and
therapy to diet for the reduction of elevated total cholesterol, mixed dyslipidemia in patients treated with lovastatin who require
LDL cholesterol, apolipoprotein B, triglycerides, and non- further triglyceride lowering or HDL cholesterol raising and
HDL cholesterol, and to increase HDL cholesterol. The usual may benet from having niacin added to their regimen. The
starting dose is 10 mg/20 mg, and the maximum dose is combination is also indicated for patients treated with niacin
10 mg/80 mg (Table 99). Adverse events are similar to those who require further LDL cholesterol lowering and may bene-
of each product taken separately; however, the percentage of t from having lovastatin added to their regimen. The time
patients with LFT elevations greater than 3 times normal is until maximum effect on lipids for this combination is gener-
slightly higher than with a statin alone, and there appears to ally 3 to 6 weeks.
be a slightly higher risk of myopathy and rhabdomyolysis Niacin can be combined with a brate in patients with
when statins and ezetimibe are combined. The time until high elevations in serum triglycerides. The combination may
maximum effect on lipids for this combination is generally increase the risk of myopathy compared to either agent
2 to 6 weeks. alone.
Compared with monotherapy, combination therapy is rel-

atively unstudied in terms of the effects on CHD event reduc- Patient Care and Monitoring
tion and may reduce patient compliance through increased
side effects and increased costs. When used appropriately
and with proper precautions, however, they are effective in
1. Assess the patient for the presence of CHD or other
normalizing lipid abnormalities, particularly in patients who atherosclerosis disorders.
cannot tolerate adequate doses of statin therapy for more
2. Assess major risk factors for CHD.
severe forms of dyslipidemia.
3. For patients without CHD or CHD risk equivalent, but
two or more major CHD risk factors, perform
Investigational Agents Framingham risk assessment.
There are numerous investigational drugs in development
4. Obtain fasting cholesterol prole and assess any abnor-
for the treatment of lipid disorders and prevention of athero- mal lipid levels.
sclerosis. Many of these will likely be used in combination
5. Obtain a thorough history of prescription, non-
with currently available lipid-modulating drugs. The most
prescription, and natural drug product use. Determine
promising are the cholesterol ester transfer protein (CETP) what treatments for cholesterol the patient has used in the
inhibitors, which have the potential to signicantly raise past (if any). Assess if the patient is taking any medications
HDL cholesterol.43 Other agents in development include that may contribute to his or her abnormal lipid levels.
newer statins; bile acid transport inhibitors; phytostanol 6. Assess concomitant diseases that may contribute to the
analogues; acyl coenzyme A: cholesterol acyltransferase patients abnormal lipid levels.
(ACAT) inhibitors; squalene synthase inhibitors; and newer
7. Assess risk factors for metabolic syndrome.
PPAR-, -, and - agonists, as well as dual PPAR-/ ago-
8. Determine the treatment goal for LDL cholesterol based
nists. In addition, weekly infusions of genetically engineered
on the patients CHD risk and non-HDL cholesterol goal
HDL (Apolipoprotein A1 Milano) in patients with athero-
if patient meets criteria for metabolic syndrome.
sclerosis has been shown to cause signicant reduction in
9. Educate all patients on therapeutic lifestyle changes
atheroma volume compared to placebo after just 5 weeks of
(TLC) and the importance of regular physical activity.
therapy.44
These novel therapies will provide opportunities for devel- 10. For patients exceeding their LDL cholesterol goal,
initiate TLC. Consider starting concurrent pharma-
oping different combination strategies to further reduce the
cotherapy in patients in the high-risk or moderately-
risk of CHD even after adequate treatment with existing
high-risk categories. Pharmacotherapy should be initi-
agents. Well-designed studies using non-invasive imaging ated at a dose to reduce LDL cholesterol by 30% to
technology and long-term follow-up periods are needed to 40% at a minimum.
ensure that there is a favorable risk:benet ratio.
11. Therapeutic lifestyle changes should be continued and
intensied (consider adding plant sterols/stanols and
increase ber) after 6 weeks if not below LDL choles-
terol target. For those patients above their LDL choles-
OUTCOME EVALUATION terol target after adequate trial of TLC (12 to 18 weeks),
pharmacotherapy should be strongly considered.
The successful outcome in cholesterol management is to
12. Institute appropriate pharmacotherapy based on lipid
reduce cholesterol and triglycerides below the NCEP ATP III abnormality. Obtain appropriate baseline labs to moni-
goals in an effort to alter the natural course of atherosclero- tor for adverse drug effects. Assess potential disease and
sis and decrease future cardiovascular events. drug interactions that may affect choice or intensity of
Employ an adequate trial of TLC in all patients, but insti- pharmacotherapy.
tute pharmacotherapy concurrently in higher-risk patients. 13. Monitor response, safety, and adherence after a mini-
When indicated, initiate drug therapy at a dose that will mum of 4 to 6 weeks. Titrate therapy or add a second
reduce LDL cholesterol in the range of 30% to 40%. drug as needed.
Typically, statins are the medications of choice to treat high 14. Once the LDL cholesterol goal is achieved, assess non-
LDL cholesterol because of their ability to substantially reduce HDL cholesterol in those with metabolic syndrome and
LDL cholesterol, ability to reduce morbidity and mortality from intensify LDL-lowering therapy further or consider
atherosclerotic disease, convenient once-daily dosing, and low adding niacin or brate.
risk of side effects. 15. Provide patient education in regard to CHD, hyperlipi-
Employ an individualized patient monitoring plan in an demia, therapeutic lifestyle modications, drug therapy,
effort to minimize side effects and maintain treatment and therapy adherence.
adherence and lipid goals.
ABBREVIATIONS NO: nitric oxide

NPC1L1: Niemann-Pick C1 Like 1
ABC: ATP-binding cassette PPAR-: peroxisome proliferator-activated receptor-alpha
ABCA1: ATP-binding cassette A1 SBP: systolic blood pressure
ACAT: acyl coenzyme A: cholesterol acyltransferase SR: sustained-release
Acetyl: CoA acetyl coenzyme A SR-BI: scavenger receptors
Apo: apolipoprotein TG: triglyceride
ATP: adenosine triphosphate TLC: therapeutic lifestyle changes
ATP III: Adult Treatment Panel III edition VLDL: very low-density lipoprotein
BAS: bile acid sequestrant
BP: blood pressure Reference lists and self-assessment questions and answers are
Bpm: beats per minute available at www.ChisholmPharmacotherapy.com.
C: cholesterol
CAD: clinical atherosclerotic disease Log into the website: www.pharmacotherapyprinciples.com
CE: cholesterol ester for information on obtaining continuing education credit for
CETP: cholesterol ester transfer protein this chapter.
CHD: coronary heart disease
CK: creatine kinase
CM: chylomicrons KEY REFERENCES AND READINGS
CPK: creatine phosphokinase
CRP: C-reactive protein Genest J. Lipoprotein disorders and cardiovascular risk. J Inherit
DBP: diastolic blood pressure Metab Dis 2003;26:267287.
ER: extended-release Libby P. Molecular basis of the acute coronary syndrome. Circulation
FA: fatty acid 1995;91:28442850.
FDA: Food and Drug Administration Grundy SM, Cleeman JI, Bairey Merz CN, et al. for the Coordinating
HDL: high-density lipoprotein Committee of the National Cholesterol Education Program
HMG-CoA: 3-hydroxy-3-methyglutaryl coenzyme A Endorsed by the National Heart, Lung, and Blood Institute,
HL: hepatic lipase American College of Cardiology Foundation, and American
IDL: intermediate-density lipoprotein Heart Association. Update Implications of Recent Clinical Trials
IR: immediate-release for the National Cholesterol Education Program Adult
LCAT: lecithin-cholesterol acyltransferase Treatment Panel III Guidelines. Circulation 2004;110:227239.
LDL: low-density lipoprotein Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI
LFT: liver function test Clinical advisory on the use and safety of statins. J Am Coll
LPL: lipoprotein lipase Cardiol 2002;40:568573.
LRP: LDL-related protein Third Report of the National Cholesterol Education Program
MI: myocardial infarction (NCEP) Expert Panel on Detection, Evaluation, and Treatment
MMP: matrix metalloproteinase of High Blood Cholesterol in Adults (Adult Treatment Panel III)
NCEP: National Cholesterol Education Program nal report. Circulation 2002; 106(25):31433421.
10 HYPOVOLEMIC SHOCK
Bradley A. Boucher and G. Christopher Wood
LEARNING OBJECTIVES
1. List the most common etiologies of decreased intravascular volume in hypovolemic shock
patients.
2. Describe the major hemodynamic and metabolic abnormalities that occur in patients with
hypovolemic shock.
3. Describe the clinical presentation, including signs, symptoms, and laboratory test
measurements, for the typical hypovolemic shock patient.
4. Prepare a treatment plan with clearly dened outcome criteria for a hypovolemic shock
patient that includes both uid management and other pharmacologic therapy.
5. Compare and contrast the relative advantages and disadvantages of crystalloids, colloids,
and blood products in the treatment of hypovolemic shock.
6. Formulate a stepwise monitoring strategy for a hypovolemic shock patient.
KEY CONCEPTS Blood products are indicated in adult hypovolemic shock

patients who have sustained blood loss from hemorrhage
Hypovolemic shock occurs as a consequence of inadequate exceeding 1500 mL.
intravascular volume to meet the oxygen and metabolic needs Vasopressors may be warranted as a temporary measure in
of the body. patients with profound hypotension or evidence of organ
Protracted tissue hypoxia sets in motion a downward spi- dysfunction in the early stages of shock.
ral of events secondary to organ dysfunction and eventual Major treatment goals in hypovolemic shock following
failure if untreated. uid resuscitation are as follows: arterial systolic blood
The overarching goals in treating hypovolemic shock are to pressure greater than 90 mm Hg within 1 hour, organ dys-
restore effective circulating blood volume, as well as man- function reversal, and normalization of laboratory meas-
aging its underlying cause, thereby reversing organ dys- urements as rapidly as possible (less than 24 hours).
function and returning to homeostasis.
Three major therapeutic options are available to clinicians The principal function of the circulatory system is to supply
for restoring circulating blood volume: crystalloids oxygen and vital metabolic substrates to cells throughout the
(electrolyte-based solutions), colloids (large-molecular- body, as well as removal of metabolic waste products.
weight solutions), and blood products. Circulatory shock is a life-threatening condition whereby this
In the absence of ongoing blood loss, administration of 2000 principal function is compromised. When circulatory shock is
to 4000 mL of isotonic crystalloid will normally re-establish caused by a severe loss of blood volume or body water it is
baseline vital signs in adult hypovolemic shock patients. called hypovolemic shock, the focus of this chapter. Regardless
The volume of colloid administered is primarily conned of etiology, the most distinctive manifestations of hypovolemic
to the intravascular space, in contrast to isotonic crystal- shock are arterial hypotension and metabolic acidosis.
loid solutions that distribute throughout the extracellular Metabolic acidosis is a consequence of an accumulation of
uid space. lactic acid resulting from tissue hypoxia and anaerobic
195
metabolism. If the decrease in arterial blood pressure is severe plication, Fig. 101 is benecial in conceptualizing where
and protracted, such hypotension will inevitably lead to severe the major abnormalities occur in patients with circulatory
hypoperfusion and organ dysfunction. Rapid and effective shock as well as predicting the bodys compensatory
restoration of circulatory homeostasis through the use of responses.
blood products, uids, and/or pharmacologic agents is imper- Shock can be effectively categorized by etiology into four
ative to prevent complications of untreated shock and ulti- major types: hypovolemic, obstructive, cardiogenic, and dis-
mately death. tributive (Table 101).2 As noted, all patients with shock have
profound decreases in arterial blood pressure. Understanding
the primary cause of the circulatory abnormality in these
ETIOLOGY AND EPIDEMIOLOGY respective shock states is invaluable to their management.
Hypovolemic shock is caused by a loss of intravascular volume.
Practitioners must have a good understanding of cardiovas- Obstructive shock is caused by an obstruction that directly
cular physiology to diagnose, treat, and monitor circulatory compromises inow or outow of blood from the heart.
problems in critically ill patients. Eugene Braunwald, a Cardiogenic shock is caused by diminished myocardial con-
renowned cardiologist, described the interrelationships tractility resulting in decreased CO. Lastly, distributive shock is
between the major hemodynamic variables (Fig. 101).1 caused by a major decrease in SVR. In all shock types, one
These variables include: arterial blood pressure, cardiac out- would expect a compensatory increase in HR to bolster the
put (CO), systemic vascular resistance (SVR), heart rate fallen arterial blood pressure. The exception is relative brady-
(HR), stroke volume (SV), left ventricular size, afterload, cardia seen in spinal shock resulting from spinal cord injury.
myocardial contractility, and preload. While an oversim- Differentiating between the underlying abnormality and the
A.
Left ventricular Peripheral
Preload size resistance
Stroke Arterial
volume pressure
Myocardial Cardiac
Contractility
fiber shortening output
Heart rate
Afterload
B.
Left ventricular Peripheral
Preload size resistance
Stroke Arterial
volume pressure
Myocardial Cardiac
Contractility
fiber shortening output
Heart rate
Afterload
FIGURE 101. Hemodynamic relationships between key cardiovascular parameters (panel A). Solid lines represent a
direct relationship; the broken line represents an inverse relationship. In panel B, the perturbations typically observed
in hypovolemic shock are highlighted in blue with arrows depicting the likely direction of the pertubation. (Reprinted
from Braunwald E. Regulation of the circulation. I. N Engl J Med 1974;290:1129, with permission.)
CHAPTER 10 / HYPOVOLEMIC SHOCK 197
TABLE 101. Major Shock Classications and Etiologies2,49 restoration of preload becomes an overriding goal in the man-
agement of hypovolemic shock.
I. Hypovolemic The prognosis of shock patients depends on several variables
Hemorrhagic
Trauma
including severity, duration, underlying etiology, preexisting
Gastrointestinal organ dysfunction, and reversibility.2 Data are not readily
Non-hemorrhagic (dehydration) available as to the incidence of hypovolemic shock, although
Vomiting mortality rates have been reported as high as 30% to 40% in
Diarrhea trauma patients.3
II. Cardiogenic
Myocardial infarction
Septal wall rupture
Acute mitral valve regurgitation PATHOPHYSIOLOGY
Myocarditis
Pericardial tamponade
Arrhythmias The total amount of water in a typical 70 kg (154 lb) adult is
III. Obstructive
approximately 42 liters (Fig. 102).4 About 28 of the 42 liters
Pulmonary embolism are inside the cells of the body (intracellular uid) while the
Amniotic uid embolism remaining 14 liters are in the extracellular uid space (uid
Tumor embolism outside of cells: interstitial uid and plasma). Circulating
IV. Distributive blood volume for a normal adult is roughly 5 liters (70
Sepsis mL/kg) and is comprised of 2 liters of red blood cell uid
Anaphylactic
(intracellular) and 3 liters of plasma (extracellular). By def-
Neurogenic (spinal trauma)
inition, hypovolemic shock occurs as a consequence of inade-
quate intravascular volume to meet the oxygen and metabolic
associated compensatory response is also essential in terms of needs of the body. Diminished intravascular volume can result
treatment and monitoring. Hypovolemic shock is considered to from severe external or internal bleeding, profound uid
be essentially a profound decit in preload. Preload is dened losses from gastrointestinal sources such as diarrhea or vom-
as the volume in the left ventricle at the end of diastole. iting, or urinary losses such as diuretic use, diabetic ketoaci-
Decreased preload results in subsequent decreases in SV, CO, dosis, or diabetes insipidus (Table 101).2 Other sources of
and eventually, mean arterial pressure (MAP). As such, intravascular uid loss can occur through damaged skin, as
FIGURE 102. Distribution of body uids

Total body fluids showing the extracellular uid volume, intra-
(42 liters)
cellular body uid volume, and total body
uids in a 70 kg adult. Extracellular volume
(ECV) comprises 14 liters of total body uid
(42 liters). Plasma volume makes up approxi-
Plasma volume Red cell volume mately 3 liters of the 14 liters of ECV.
(3 liters) (2 liters) Intracellular volume accounts for the remain-
ing 28 liters of total body uids with roughly
2 liters being located within the red blood
cells. Blood volume (approximately 5 liters)
is also depicted and is made up of primarily
red blood cells and plasma. (Reprinted from
Guyton AC, Hall JE. Textbook of Medical
Physiology. 8th ed. Philadelphia: Saunders,
Extracellular volume Intracellular volume 1991: 275, with permission.)
(14 liters) (28 liters)
Blood volume
(5 liters)
seen with burns, or via capillary leak into the interstitial Cardiac output is augmented by catecholamine release and
space or peritoneal cavity, as seen with edema or ascites. This uid retention.6 However, when intravascular volume losses
latter phenomenon is often referred to as third spacing exceed 1500 mL, the compensatory mechanisms are inade-
since uid accumulates in the interstitial space dispropor- quate, typically resulting in a fall in CO and arterial blood
tionately to the intracellular and extracellular uid spaces. pressure, while acute losses greater than 2000 mL are life-
Regional ischemia may also develop as blood ow is naturally threatening (35 mL/kg in pediatric patients).6 The decrease
shunted from organs such as the gastrointestinal tract or the in CO results in a diminished delivery of oxygen to tissues
kidneys to more immediately vital organs such as the heart within the body. Oxygen delivery can be further compro-
and brain. mised by inadequate blood hemoglobin levels due to hemor-
Hypovolemic shock symptoms begin to occur with rhage and/or diminished hemoglobin saturation due to
decreases in intravascular volume in excess of 750 mL or impaired ventilation. Decreased delivery of oxygen and
15% of the circulating blood volume (20 mL/kg in pediatric other vital nutrients results in diminished production of the
patients).5 As previously outlined, decreases in preload or energy substrate, adenosine triphosphate (ATP). Lactic acid
left ventricular end-diastolic volumes result in decreases in is then produced as a by-product of anaerobic metabolism
SV. Initially, CO may be partially maintained by compensa- within tissues throughout the body.7 Hyperglycemia pro-
tory tachycardia. Similarly, reex increases in SVR and duced during the stress response from cortisol release is also
myocardial contractility may attenuate arterial hypotension. a contributing factor in the development of lactic acidosis.
This neurohumoral response to hypovolemia is mediated by Lactic acidosis indicates that inadequate tissue perfusion has
the sympathetic nervous system in an attempt to preserve occurred.7 Intracellularly, organelles such as endoplasmic
perfusion to vital organs such as the heart and brain (Fig. 103). reticulum and mitochondria begin to swell. Eventually,
Two major endpoints of this response are to conserve water lysosomal rupture that releases degradative enzymes into
to maximize intravascular volume and to improve tissue the cell and abnormal calcium deposition contribute to cel-
perfusion by increasing blood pressure and CO (oxygen lular damage. Reactive oxygen species may also have a role
delivery). The body attempts to maximize its uid status by in facilitating cellular damage, especially when organs are
decreasing water and sodium excretion through release of reperfused with blood and uids after the initial hemor-
antidiuretic hormone, aldosterone, and cortisol. Blood pres- rhage.2 The degree to which irreparable cellular damage has
sure is maintained by peripheral vasoconstriction mediated occurred will largely determine the reversibility of the
by catecholamine release and the renin-angiotensin system. shock event.
FIGURE 103. Expected neurohumoral response

to hypovolemia. ACTH, adrenocorticotropic
Intravascular volume
hormone; ADH, antidiuretic hormone; CNS,
central nervous system; Na, sodium. (Reprinted
from Jimenez EJ. Shock. In: Civetta JM, Taylor
RW, Kirby RR, eds. Critical Care. New York:
Baroreceptor activity
Lippincott-Raven; 1997: 369, with permission.)
Mechanoreceptor activity
CNS response
Pituitary release Sympathetic nervous

ACTH system stimulation
Neural effects
ADH Epinephrine
Cardiac stimulation
Norepinephrine
Peripheral vasoconstriction
Renin/angiotensin/
aldosterone
Cortisol
Na/Water retention
Na/Water retention
Peripheral vasoconstriction
Protracted tissue hypoxia sets in motion a downward spiral of TABLE 102. Shock Manifestations on Major Organs
events secondary to organ dysfunction and eventual failure if
Heart
untreated.5 Table 102 describes the effects of shock on the bodys
Myocardial ischemia
major organs. Relative failure of more than one organ, regardless Dysrhythmias
of etiology, is referred to as the multiple organ dysfunction Brain
syndrome (MODS). Involvement of the heart is particularly Restlessness, confusion, obtundation
devastating considering the central role it plays in oxygen delivery Global cerebral ischemia
and the potential for myocardial dysfunction to perpetuate the Liver
shock state. Preexisting organ dysfunction can also exacerbate Release of liver enzymes
the effects of hypovolemic shock and its complications. For Biliary stasis
example, acute or chronic heart failure can lead to pulmonary Lungs
edema, further aggravating gas exchange in the lungs and, ulti- Pulmonary edema
Acute respiratory distress syndrome (ARDS)
mately, tissue hypoxia. MODS develops in approximately 20%
Kidneys
of trauma patients who require uid resuscitation. Only about
Oliguria
one-third of early-onset MODS is quickly reversible (within Decreased glomerular ltration
48 hours) with proper uid resuscitation. Thus, it is imperative Acute renal failure
that hypovolemic shock be treated quickly to avoid MODS.8 Gastrointestinal tract
Stress-related mucosal disease
Bacterial translocation
Clinical Presentation and Diagnosis

TREATMENT
General Desired Outcomes

Patients will be in acute distress although symptoms and The overarching goals in treating hypovolemic shock are to
signs will vary depending on the severity of the hypo-
restore effective circulating blood volume, as well as manage its
volemia and whether the etiology is hemorrhagic versus
non-hemorrhagic.
underlying cause. In achieving this goal, the downward spiral of
events that can perpetuate severe or protracted hypovolemic shock
Symptoms is interrupted.2 This is accomplished through the delivery of ade-
Thirst quate oxygen and metabolic substrates such as glucose and elec-
Weakness
trolytes to the tissues throughout the body that will optimally
Lightheadedness
bring about a restoration of organ function and return to home-
Signs ostasis. Evidence of the latter is a return to the patients baseline
Hypotension, arterial SBP (systolic blood pressure) vital signs, relative normalization of laboratory test results,
less than 90 mm Hg or fall in SBP greater than 40 mm Hg and alleviation of the other signs and symptoms of hypo-
Tachycardia
volemic shock previously discussed.9 Concurrent supportive
Tachypnea
Hypothermia
therapy is also warranted to avoid exacerbation of organ dys-
Oliguria function associated with the hypovolemic shock event.
Dark, yellow-colored urine
Skin color: pale to ashen; may be cyanotic in severe cases General Approach to Therapy
Skin temperature: cool to cold
Mental status: confusion to coma Securing an adequate airway and ventilation is imperative in
Pulmonary artery catheter measurements: decreased CO, hypovolemic shock patients consistent with the ABCs (airway,
decreased SV, increased SVR, low PAOP (pulmonary breathing, and circulation) of life support. Any compromise in
artery occlusion pressure) ventilation will only accentuate the tissue hypoxia occurring
Laboratory Tests secondary to inadequate perfusion. Thus, tracheal intubation
Hypernatremia and mechanical ventilation may be needed (Fig. 104).
Elevated serum creatinine Intravenous access is also essential for administration of intra-
Elevated blood urea nitrogen venous uids and medications. Intravenous access can be
Decreased hemoglobin/hematocrit (hemorrhagic hypo- accomplished through the placement of peripheral intra-
volemic shock) venous lines or catheterization with central venous lines if
Hyperglycemia
rapid or large volumes of resuscitative uids are indicated.
Increased serum lactate
Decreased arterial pH
While primarily facilitating uid administration, the intra-
venous lines provide access for blood samples for obtaining
1
Moderate to severe
hypovolemia
2
No 3
Adequate airway Go to 4
Intubate patient
and ventilation
Yes
5
4
Yes
Is SBP less than 90 mmHg Administer 10002000 ml of normal saline or Go to 6
(MAP less than 60 mmHg)? lactated Ringers (adults), 20 ml/kg (pediatrics)
(or 5 ml/kg 6% hetastarch)
No
7
6 Yes
Transfuse 2 units (1020 ml/kg) type O PRBCs. Go to 8
Is the patient bleeding? Provide emergent hemorrhage control
No
8
Perform physical examination
Obtain history
Obtain IV access for
fluid delivery.
Obtain blood for
laboratory tests.
Bladder catherization
ECG monitoring
9
Is patient
hemodynamically 10
Yes Administer 10002000 ml of normal saline or
unstable? Go to 9
[SBP less than 90 mmHg, lactated Ringers (adults), 20 ml/kg (pediatrics)
PAOP 1418 mmHg, (or 5 ml/kg 5% hydroxyethyl starch)
(CVP less than 8 cmH2O
if available)]
No
13
11 12 Insert PA catheter pr CVP
Yes
Evidence of cerebral or Begin dopamine 10 mcg/kg/minute or catheter for monitoring if not yet
myocardial ischema? norepinephrine 2 mcg/minute available
Go to 9
No
14
Monitor normalization of
organ function. Begin
stress ulcer prophylaxis,
antithrombotic therapy if
no evidence of ongoing
bleeding.
FIGURE 104. Treatment algorithm for the management of moderate to severe hypovolemia. BP, blood pressure; CVP, central venous
pressure; ECG, electrocardiogram; MAP, mean arterial pressure; PA, pulmonary artery; PAOP, pulmonary artery occlusion pressure;
PRBCs, packed red blood cells; SBP, systolic blood pressure.
appropriate laboratory tests. Placement of an arterial catheter seen, but it could be that more severely ill patients have less
is advantageous to allow for accurate and continual monitoring physiologic reserve and less room for error and benet from
of blood pressure, as well as arterial blood gas (ABG) sam- the therapeutic decisions that come from detailed PA catheter
pling. A bladder catheter should be inserted for ongoing mon- data.15 The goal of resuscitating patients to supra-normal
itoring of urine output. Baseline laboratory tests that should hemodynamic values (e.g., cardiac index [CI] greater than
be done immediately include: complete blood cell counts with 4.5 L/minute per square meter) has also been controversial,
differentials, platelet count, serum chemistry prole, liver but does not appear to be benecial for most patients.16 An alter-
enzymes, prothrombin and partial thromboplastin times, and native to the PA catheter is placement of a central venous
serum lactate. A urinalysis and an ABG should also be obtained catheter that typically resides in the superior vena cava to
and ongoing electrocardiogram (ECG) monitoring should be monitor central venous pressure (CVP). While central venous
performed. In addition to restoring circulating blood volume, catheters are less expensive and more readily placed, they are not
it is necessary to prevent further losses from the vascular particularly accurate in monitoring effective uid resuscitation.
space. This is especially true with hemorrhagic hypovolemic
shock where identifying the bleeding site and achievement of
hemostasis are critical in the successful resuscitation of the Fluid Therapy
patient. This frequently involves surgical treatment of hemor- Three major therapeutic options are available to clinicians
rhages. Similarly, other types of shock may also require inter- for restoring circulating blood volume: blood products, crystal-
ventions that treat the underlying cause of hypovolemia, such loids (electrolyte-based solutions), and colloids (large-molecular-
as epinephrine to treat anaphylactic shock. weight solutions). Blood products are used only in instances
Upon stabilization, placement of a pulmonary artery (PA) involving hemorrhage (or severe preexisting anemia), thus
catheter may be indicated based on the need for more exten- leaving crystalloids and colloids as the mainstay of therapy in
sive cardiovascular monitoring than is available from non- all types of hypovolemic shock, along with adjunctive vaso-
invasive measurements such as vital signs, cardiac rhythm, pressor support. The aggressiveness of uid resuscitation (rate
and urine output.9,10 Key measured parameters that can be and volume) will be dictated by the severity of the hypo-
obtained from a PA catheter are the pulmonary artery occlu- volemic shock and the underlying cause. Warming of all uids
sion pressure, which is a measure of preload, and CO. From to 37C (98.6F) prior to administration is an important con-
these values and simultaneous measurement of HR and blood sideration to prevent hypothermia, since hypothermia will have
pressure (BP), one can calculate the left ventricular SV and a negative impact on the success of the resuscitation effort.17
SVR.10 Placement of a PA catheter should be reserved for
patients at high risk of death due to the severity of shock or
Crystalloids
preexisting medical conditions such as heart failure.11 Use of
Conventional, balanced crystalloids are uids with (1) elec-
PA catheters in broad populations of critically ill patients is
trolyte composition that approximates plasma, such as lac-
somewhat controversial because clinical trials have not shown
tated Ringers (LR), or (2) a total calculated osmolality similar
consistent benets with their use.1214 However, critically ill
to that of plasma (280 to 295 mOsm/kg), such as 0.9% sodium
patients with a high severity of illness may have improved out-
chloride (also known as normal saline [NS] or 0.9% NaCl)
comes from PA catheter placement. It is not clear why this was
(Table 103).18 Thus, conventional crystalloids will distribute
in normal proportions throughout the extracellular uid
Patient Encounter, Part 1 space upon administration. In other words, expansion of the
intravascular space will only increase by roughly 200 to 250 mL
for every liter of isotonic crystalloid uid administered.18
Hypertonic crystalloid solutions such as 3% NaCl or 7.5%
TJ is a 21-year-old male who is admitted to the emergency NaCl have osmolalities substantially higher than plasma.
department (ED) after being stabbed in the leg during an The effect observed with these uids is a relatively larger
assault. The paramedics report a large amount of blood loss at volume expansion of the intravascular space. By compari-
the scene from a probable blood vessel injury. The acute son to conventional crystalloids, administration of 1 liter of
bleeding has been partially stabilized with pressure but the
3% sodium chloride will result in an intravascular space
patient has just lost consciousness. The initial diagnosis by the
ED team is hypovolemic shock. A physical exam is being per-
increase of 1000 mL.18 This increase is a result of the uid
formed and blood samples are being sent to the laboratory. administered as well as osmotic drawing of intracellular
uid into the intravascular and interstitial spaces. This
What type of hypovolemic shock does TJ have? occurs because the hypertonic saline increases the osmolal-
What signs and symptoms of hypovolemic shock would ity of the intravascular and interstitial uid compared to the
you expect to see in TJ? intracellular uid. Hypertonic saline also has the potential
What laboratory abnormalities might be expected in TJ? for decreasing the inammatory response.19 Despite these
theoretical advantages, data are lacking demonstrating
TABLE 103. Composition of Common Resuscitation Fluids18
Lactate Osmolality
Fluid Na mEq/La Cl mEq/La K mEq/La Mg mEq/Lb Ca mEq/Lb mEq/La Other pH mOsm/kgc
0.9 NaCl 154 154 5.0 308
3% NaCl 513 513 5.0 1027
7.5% NaCl 1283 1283 5.0 2567
Lactated Ringers 130 109 4 3 28
Hextend 143 124 3 0.9 5 28 Hetastarch 6 g/dL 5.9 307
Hetastarch 154 154 Hetastarch 6 g/dL 5.5 310
Pentastarch 154 154 Pentastarch 10 g/dL 5.0 326
5% Albumin 130160 130160 Albumin 5 g/dL 6.9
(50 g/dL)
25% Albumin 130160 130160 Albumin 25 g/dL 6.9
(250 g/L)
5% Plasma 130160 130160 0.25 Plasma Proteins 7.0
protein 5 g/dL (50 g/L)
fraction (88% albumin)
(PPF)
Dextran 40 154 154 Dextran 10 g/dL
(avg. molecular
weight 40 kDa)
Dextran 70 154 154 Dextran 6 gm/dL 5.5 308
(avg. molecular
weight 70 kDa)
Dextran 75 154 154 Dextran 6 gm/dL 5.5 308
(avg. molecular
weight 75 kDa)
a
For these values, mEq/L = mmol/L; e.g., 154 mEq/L Na = 154 mmol/L.
b
For these values, mEq/L 0.5 = mmol/L; e.g., 0.9 mEq/L Mg = 0.45 mmol/L Mg.
c
For this value, mOsm/kg = mmol/kg; e.g., 308 mOsm/kg = 308 mmol/kg.
avg., average; Ca, calcium; Cl, chloride; K, potassium; kDa, kilodalton; Mg, magnesium; Na, sodium.
superiority of hypertonic crystalloid solutions compared hyponatremia and/or hyperkalemia. Alternatively, NS can cause
with isotonic solutions.20 Crystalloids are generally advocated hypernatremia and hypokalemia. While LR does contain lac-
as the initial resuscitation uid in hypovolemic shock because tate, it does not result in increases in serum lactate when used
of their availability, low cost, and equivalent outcomes com- for uid replacement.25 This is likely because the exogenous
pared with colloids.9 A reasonable initial volume of an iso- lactate is used as a metabolic substrate. Overall, there is no
tonic crystalloid (0.9% NaCl or LR) in adult patients is 1000 clear cut advantage when comparing NS and LR. Clinician
to 2000 mL administered over the rst hour of therapy. preference and the patients serum electrolyte concentrations
Ongoing external or internal bleeding will require more will usually guide selection.
aggressive uid resuscitation. In the absence of ongoing
blood loss, administration of 2000 to 4000 mL of isotonic crys- Colloids
talloid will normally re-establish baseline vital signs in adult Understanding the effects of colloid administration on circulat-
hypovolemic shock patients.2 Selected populations, such as burn ing blood volume necessitates a review of those physiologic
patients, may require more aggressive uid resuscitation, while forces that determine uid movement between capillaries and
other patient subsets such as those with cardiogenic shock or the interstitial space throughout the circulation (Fig. 105).4
heart failure may warrant less aggressive uid administration Relative hydrostatic pressure between the capillary lumen and
to avoid over-resuscitation.21 In hemorrhagic shock patients, the interstitial space is one of the major determinants of net
approximately three to four times the shed blood volume of uid ow into or out of the circulation. The other major
isotonic crystalloids is needed for effective resuscitation.21,22 determinant is the relative colloid osmotic pressure between
Side effects from crystalloids primarily involve uid over- the two spaces. Administration of exogenous colloids results
load and electrolyte disturbances of sodium, potassium, and in an increase in the intravascular colloid osmotic pressure. In
chloride.23 Dilution of coagulation factors can also occur resulting the case of isosomotic colloids (5% albumin, 6% hetastarch,
in a dilutional coagulopathy.24 Two clinically signicant rea- and dextran products), initial expansion of the intravascular
sons LR is different from NS is that LR contains potassium space is essentially that of the volume of colloid administered.
and has a lower sodium content (130 versus 154 mEq/L or In the case of hyperoncotic solutions such as 25% albumin,
mmol/L). Thus, LR has a greater potential than NS to cause uid is pulled from the interstitial space into the vasculature
For years within the critical care literature a controversy

known as the colloid versus crystalloid debate raged over the
Capillary Plasma colloid
pressure osmotic pressure
relative merits of the two types of resuscitation uids. At the cen-
ter of the debate was what the goal of uid resuscitation in shock
should be: immediate expansion of the intravascular space with
colloids versus expansion of the entire extracellular uid space
with crystalloids. A meta-analysis showed no difference in out-
comes between crystalloids and albumin.27 However, the balance
Interstitial Interstitial fluid was tipped in favor of those advocating crystalloids after a meta-
fluid pressure colloid osmotic pressure analysis performed by the Cochrane group revealed a relative
increase in mortality in all shock patients receiving albumin ver-
FIGURE 105. Operative forces at the capillary membrane sus crystalloids.28 This increased risk was not statistically signif-
tending to move uid either outward or inward through the icant when only comparing studies of hypovolemic shock
capillary membrane. In hypovolemic shock, one therapeutic patients.28 A more recent randomized controlled study involving
strategy is the administration of colloids that can sustain and/or
6997 critically ill patients [Saline versus Albumin Fluid
draw uid from the interstitial space by increasing the plasma
colloid osmotic pressure. (Reprinted from Guyton AC, Hall JE. Evaluation (SAFE) Study] challenged the overall Cochrane nd-
Textbook of Medical Physiology. 8th ed. Philadelphia: Saunders, ings by demonstrating no difference in mortality between
1991: 174, with permission.) patients receiving saline versus albumin.28,29 Largely in response
to the SAFE trial, the Food and Drug Administration (FDA)
issued a revised notice to health care providers in May 2005
declaring albumin safe for use in most critically ill patients.
resulting in an increase in the intravascular volume that is Burn, traumatic brain injury, and septic shock patients were
much greater than the original volume of the 25% albumin excluded from the SAFE trial; however, based on previous data
that was administered. While theoretically attractive, hyper- there does not appear to be a clear-cut overall advantage for
oncotic solutions should not be used for hypovolemic shock either crystalloids or colloids in these patient groups.30 Thus,
since the expansion of the intravascular space is at the expense while the debate is not fully resolved, most clinicians today pre-
of depletion of the interstitial space. The effects of colloids on fer using crystalloids based on their availability and inexpensive
intravascular volume are a consequence of their relatively cost compared with colloids.21,31
large molecular size (greater than 30 kilodaltons [kDa]), limiting Generally, the major adverse effects associated with col-
their passage across the capillary membrane in large amounts loids are uid overload, dilutional coagulopathy, and anaphy-
except under conditions in which capillary permeability may lactoid/anaphylactic reactions.24,32 Although derived from
be increased such as during a capillary leak. Examples of the pooled human plasma, there is no risk of disease transmission
latter, situations in which colloids may be less effective as from commercially available albumin or PPF products since
intravascular volume expanders, include any condition they are heated and sterilized by ultraltration prior to distri-
involving the systemic inammatory response syndrome bution.24 Because of direct effects on the coagulation system
(SIRS) such as trauma, sepsis, and pancreatitis.2 Nonetheless, with the hydroxyethyl starch and dextran products, they
under circumstances in which capillary permeability is should be used cautiously in hemorrhagic shock patients. This
normal, colloids can be thought of as sponges drawing is another reason why crystalloids may be preferred in hemor-
uid into the intravascular space from the interstitial space. rhagic shock. Furthermore, hetastarch can result in an
Thus, the volume of colloid administered remains primarily increase in amylase not associated with pancreatitis. As such,
conned to the intravascular space, in contrast to isotonic crys- the adverse-effect proles of the various uid types should
talloid solutions that distribute throughout the extracellular also be considered when selecting a resuscitation uid.
uid space. Eventually, the exogenous colloids will migrate to
the interstitial space diminishing the expansion in intravascu- Blood Products
lar volume. Exogenous colloids available in the United States Blood products are indicated in hypovolemic shock patients
include 5% albumin, 25% albumin, 5% plasma protein frac- who have sustained blood losses from hemorrhage exceeding
tion (PPF), 6% hetastarch, 10% pentastarch, 10% dextran 40, 1500 mL (30 to 35 mL/kg). This, in fact, is the only setting in
6% dextran 70, and 6% dextran 75 (Table 103). The rst three which freshly procured whole blood is administered. In vir-
products are derived from pooled human plasma. Hetastarch tually all other settings, blood products are given as the indi-
and pentastarch are semisynthetic hydroxyethyl starches derived vidual components of whole blood units, such as packed red
from amylopectin. The dextran products are semisynthetic blood cells (PRBCs), fresh frozen plasma (FFP), platelets,
glucose polymers that vary in terms of the average molecular cryoprecipitate, and concentrated coagulation factors.33,34
weight of the polymers. Superiority of one colloid solution This includes ongoing resuscitation of hemorrhagic shock,
over another has not been clearly established.26 when PRBCs can be transfused to increase oxygen-carrying
capacity in concert with crystalloid solutions to increase blood analyses of rFVIIa will be needed because of the very high
volume. In patients with documented coagulopathies, FFP for acquisition costs of the drug.
global replacement of lost or diluted clotting factors, or platelets
for patients with severe thrombocytopenia (less than 20,000 Pharmacologic Therapy
cells/m3 [20 103/L or 20 109/L]) should be administered.34
Type O blood or universal donor blood is given in emergent Vasopressor Therapy
cases of hemorrhagic shock. Thereafter, blood that has been Vasopressor is the term used to describe any pharmacologic
typed and cross-matched with the recipients blood is given. The agent that can induce arterial vasoconstriction through stimula-
traditional threshold for PRBC transfusion in hypovolemic tion of the 1-adrenergic receptors. While replenishment of
shock has been a serum hemoglobin of less than 10 g/dL (100 g/L intravascular volume is undoubtedly the cornerstone of hypo-
or 6.2 mmol/L) and hematocrit less than 30%.35 However, a volemic shock therapy, use of vasopressors may be warranted as a
more restrictive transfusion threshold of 7 g/dL (70 g/L or temporary measure in patients with profound hypotension or evi-
4.34 mmol/L) appears to be safe for critically ill patients after dence of organ dysfunction in the early stages of shock.2,9,42 Often
they have received appropriate uid resuscitation and have no vasopressors are used concurrently with uid administration.
signs of ongoing bleeding. Traditional risks from allogenic blood Table 104 is a list of those vasopressors used in the management
product administration include hemolytic and non-hemolytic of hypovolemic shock. Dopamine or norepinephrine may be
transfusion reactions and transmission of blood-borne infec- preferred over epinephrine because epinephrine has an increased
tions in contaminated blood. However, recent large studies have potential for causing cardiac arrhythmias and impaired abdo-
also shown that transfusions are associated with higher mor- minal organ (splanchnic) circulation.43 In cases involving con-
tality, possibly because of adverse immune and inammatory current heart failure, an inotropic agent such as dobutamine may
effects.36,37 Based on limitations of homologous blood donations, be needed, in addition to the use of a vasopressor. Patients with
intraoperative salvage techniques can be employed in patients spinal shock may require some level of vasopressor and/or
with massive hemorrhage in an effort to conserve blood.5,38 inotropic support even after adequate uid resuscitation.
Due to blood shortages and associated risks with transfusions, Vasopressors are almost exclusively administered as contin-
there are ongoing research efforts concerning the development uous infusions because of their very short half-lives and the
of red blood cell substitutes as a possible therapy alternative. need for close titration of their dose-related effects. Starting
Products that have reached clinical trials include peruorocar- doses should be at the lower end of the dosing range followed
bon emulsions and hemoglobin-based oxygen carriers by rapid titration upward if needed to maintain adequate blood
(HBOCs).39,40 These blood products have several advantages pressure. Monitoring of end-organ function such as adequate
over PRBCs including greater availability (because donors urine output can also be used to monitor therapy. Once blood
arent needed), increased shelf-life, absence of infectious risks, pressure is restored, vasopressors should be weaned and dis-
and no need for cross-matching. As such, red blood cell substi- continued as soon as possible to avoid any untoward events.
tutes have the potential to serve as temporizing measures in The most signicant systemic adverse events associated with
hypovolemic shock patients until conventional red blood cell vasopressors are excessive vasoconstriction resulting in
transfusions can be administered or in instances in which avail- decreased organ perfusion and potential to induce arrhythmias
ability of donated PRBCs is extremely limited. Nonetheless, lack (Table 104). Central venous catheters should be used to mini-
of adequate efcacy data and additional side effects associated mize the risk of local tissue necrosis that can occur with extra-
with each of the respective red blood cell substitutes have pre- vasation of peripheral intravenous catheters.42
cluded their approval in the United States at present.
Research also continues into the use of recombinant acti- Treatment of Lactic Acidosis
vated factor VII (rFVIIa) as an adjunctive agent to treat Lactic acidosis, which typically accompanies hypovolemic shock
uncontrolled hemorrhage. Initial experiences with rFVIIa as a consequence of tissue hypoxia, is best treated by reversal of
show that it can decrease transfusions, though large studies the underlying cause. Administration of alkalizing agents such as
have not been performed.41 Ultimately, pharmacoeconomic sodium bicarbonate has not been demonstrated to have any
TABLE 104. Vasopressor Drugs
Potential to Cause
Drug Usual IV Dose Adrenergic Effects Arrhythmias
1 1 Dopaminergic
Dopamine 1020 mcg/kg per minutea +++ ++ +++ +++
Norepinephrine 0.580 mcg/minute +++ ++ 0 ++
Epinephrine 1200 mcg/minute ++ +++ 0 +++
Phenylephrine 0.59 mcg/kg per minute +++ 0 0 0
IV, intravenous.
a
Note: Lower dosages of dopamine may not produce desired 1-adrenergic (vasopressor) effects.
benecial effects44 and may actually worsen intracellular acido- Supportive Care Measures
sis.45 Nonetheless, administration of sodium bicarbonate, 100 to
Since gastrointestinal ischemia is a common complication of
150 mEq intravenously, can be considered when the pH is below
hypovolemic shock, prevention of stress-related mucosal dis-
7.1.2 An alternative to sodium bicarbonate is the proton accep-
ease should be instituted as soon as the patient is stabilized. The
tor tromethamine (i.e., tris-hydroxymethyl aminomethane, or
most common agents used for stress ulcer prophylaxis are the
THAM). THAM has the advantage over sodium bicarbonate in
histamine2-receptor antagonists and proton pump inhibitors.
buffering lactic acidosis without increasing sodium concentra-
Prevention of thromboembolic events is another secondary
tions or fostering the production of additional carbon dioxide.46,47
consideration in hypovolemic shock patients. This can be
This could be particularly advantageous in hypovolemic shock
accomplished with the use of external devices such as sequen-
patients with respiratory failure who may have a difcult time
tial compression devices and/or antithrombotic therapy such as
clearing carbon dioxide from their lungs. However, there are no
the low-molecular-weight heparin products or unfractionated
large studies evaluating THAM for treating metabolic acidosis.
heparin. Patients with adrenal insufciency due to preexisting
If used, the initial dose of THAM can be determined by the fol-
disease, glucocorticoid use, or critical illness may have refrac-
lowing equation: amount (in milliliters) of 0.3 mol/L THAM =
tory hypotension despite resuscitation. Such patients should
lean body weight (kg) base decit (mmol/L).47 THAM should
receive appropriate glucocorticoid replacement therapy.
not be used in patients with renal failure.
OUTCOME EVALUATION
Patient Encounter, Part 2: Physical Successful treatment of hypovolemic shock is measured by

Exam, Diagnostic Tests, and Initial the restoration of blood pressure to baseline values and reversal
Treatment of associated organ dysfunction. The likelihood of a successful
uid resuscitation will be directly related to the expediency of
PMH treatment. Therapy goals include:
Non-contributory
Meds Arterial systolic blood pressure greater than 90 mm Hg (MAP
None greater than 60 mm Hg) within 1 hour;
Organ dysfunction reversal evident by increased urine output
SH
to greater than 0.5 mL/kg per hour (1.0 mL/kg per hour in
Occasional alcohol use (per family)
pediatrics), return of mental status to baseline, and normaliza-
FH tion of skin color and temperature over the rst 24 hours;
Non-contributory Heart rate should begin to decrease reciprocally to increases in
PE the intravascular volume within minutes to hours;
Ht 510 (178 cm), Wt 85 kg (187 lb) Normalization of laboratory measurements expected within
VS: BP 80/40 mm Hg, pulse 130/minute, respiratory rate hours to days following uid resuscitation. Specically, nor-
22 beats per minute, temperature 35C (95F), urine output: malization of base decit and serum lactate is recommended
none since catheterization 10 minutes ago. within 24 hours to potentially decrease mortality;48 and
Neurologic: Recent loss of consciousness, had been con- Achievement of PAOP to a goal pressure of 14 to 18 mm Hg
scious but confused during transport to the ED, pupils equal occurs (alternatively CVP 8 to 15 mm Hg).
and reactive
Pulmonary: Normal breath sounds, undergoing tracheal
intubation for mechanical ventilation
Patient Encounter, Part 3: Care
CV: ECG shows sinus tachycardia, otherwise normal
Plan/Ongoing Therapy
Abd: Within normal limits
Exts: Stab wound to left thigh with some ongoing bleeding
Pertinent labs One hour after the initial uid bolus and transfusion TJs
pH 7.18, PCO2 45 mm Hg (5.985 kPa), PaO2 70 mm Hg vital signs are:
(9.31 kPa), HCO3 18 mEq/L (18 mmol/L), lactate 7.0 mg/dL BP 85/50 mm Hg, HR 120 beats per minute, RR 20/minute,
(0.777 mmol/L), SCr 1.7 mg/dL (150 mol/L), Hgb 7 g/dL urine output: 5 mL in the past hour. Pertinent new labs: pH 7.2,
(70 g/L or 4.34 mmol/L), Hct 21% lactate 3.8 mg/dL (0.422 mmol/L). The bleeding has stopped.
What are the rst nonpharmacologic steps in treating TJ? What is your assessment of TJs condition compared to
Identify treatment goals for TJ in the next 24 hours. 1 hour ago?
What initial pharmacologic/uid therapy is required at What therapy is required at this time?
this time? Describe monitoring over the next 24 hours for TJ.
Patient Care and Monitoring per minute or norepineprhine 2 mcg/minute. Titrate

dosage every 5 minutes as needed. Wean and discon-
tinue vasopressor as soon as the goal arterial blood pres-
sure has been achieved.
1. Does the patient have an adequate airway and ventilation
(hemoglobin saturation greater than 92%)? If not, trained 7. Has the goal arterial blood pressure been achieved? If
emergency personnel should consider performing tra- not, give additional uid therapy hourly blending crys-
cheal intubation with initiation of mechanical ventilation. talloids and isooncotic colloids based on inadequate
blood pressure response.
2. Is there a detectable blood pressure? If yes, obtain his-
tory, perform physical examination, obtain blood for 8. Is the patient hemodynamically stable? If not, admit to
baseline laboratory tests, and monitor ECG. If not, begin the intensive care unit for ongoing treatment and moni-
isotonic crystalloid uid resuscitation immediately (see toring. A PA catheter (or CVP catheter) should be
step 4 below). inserted by trained medical personnel. Monitor PAOP to
a goal pressure of 14 to 18 mm Hg and minimum car-
3. Monitor the following serial laboratories for comparison to diac index of 2.2 L/minute per square meter (alterna-
baseline values every 6 hours in the rst 24 hours and tively CVP 8 to 15 cm H2O).
daily thereafter until normalized: sodium, serum creatinine,
blood urea nitrogen, serum lactate, glucose, bilirubin, 9. Is the arterial pH less than 7.1? If yes, consider admin-
hemoglobin, hematocrit, platelets, prothrombin time, istration of sodium bicarbonate 100 to 150 mEq intra-
partial thromboplastin time, arterial blood gases, and pH. venously as slow infusion. Alternatively, consider use of
tromethamine intravenously.
4. Is the systolic blood pressure less than 90 mm Hg (MAP
less than 60 mm Hg)? If yes, start aggressive uid therapy 10. Monitor normalization of organ function to baseline
beginning with 1000 to 2000 mL lactated Ringers over state including mental status, urine output to greater
1 hour in adults (20 mL/kg in pediatrics). Monitor blood than 0.5 mL/kg per hour (1 mL/kg per hour in pediatric
pressure at least every 15 minutes (or continuously via patients), normal skin color and temperature, and normal-
an arterial catheter). ization of base decit and/or lactate. Begin supportive
care measures including stress ulcer prophylaxis and
5. Is the patient bleeding? If yes, transfuse 5 to 10 mL/kg antithrombotic therapy if there is no evidence of ongoing
PRBCs (note: 1 unit PRBCs will provide approximately 3% bleeding.
increase in hematocrit or 1 g/dL [10 g/L or 0.62 mmol/L]
increase in hemoglobin). Do not allow hemoglobin con- 11. Has the underlying cause of the hypovolemic shock
centrations to fall below 7 g/dL (70 g/L or 4.34 mmol/L) been addressed to prevent its recurrence? If not, treat as
(hematocrit 20%). Conventional goal hemoglobin con- necessary.
centration is 10 g/dL (100 g/L or 6.2 mmol/L) (alterna- 12. Is there any evidence of adverse events from the resus-
tively hematocrit greater than or equal to 30%). Provide citation therapies employed such as uid overload,
emergent control of ongoing hemorrhaging. electrolyte disturbances, transfusion reactions, and/or
6. Is there evidence of cerebral or myocardial ischemia? If alterations in coagulation? If yes, manage the particular
yes, begin vasopressor therapy of dopamine 10 mcg/kg adverse event accordingly.
ABBREVIATIONS ECV: extracellular volume

ED: emergency department
ABCs: airway, breathing, and circulation FDA: Food and Drug Administration
ABG: arterial blood gas FFP: fresh frozen plasma
ACTH: adrenocorticotropic hormone HBOC: hemoglobin-based oxygen carrier
ADH: antidiuretic hormone HCO3: bicarbonate
ARDS: acute respiratory distress syndrome Hct: hematocrit
ATP: adenosine triphosphate Hgb: hemoglobin
BP: blood pressure HR: heart rate
bpm: beats per minute IV: intravenous
Ca: calcium K: potassium
CI: cardiac index kDa: kilodalton
Cl: chloride LR: lactated Ringers
CNS: central nervous system MAP: mean arterial pressure
CO: cardiac output Mg: magnesium
CVP: central venous pressure MODS: multiple organ dysfunction syndrome
ECG: electrocardiogram Na: sodium
NaCl: sodium chloride KEY REFERENCES AND READINGS

NS: normal saline
PA: pulmonary artery Jimenez EJ. Shock. In: Civetta JM, Taylor RW, Kirby RR, eds. Critical
PaO2: partial pressure of arterial oxygen Care. New York: Lippincott-Raven; 1997: 359387.
PAOP: pulmonary artery occlusion pressure Kelley DM. Hypovolemic shock: an overview. Crit Care Nurs Q
PCO2: partial pressure of carbon dioxide 2005;28:219.
PPF: plasma protein fraction Kline JA. Shock. In: Marx JA, Hockberger RS, Walls RM, et al, eds.
PRBCs: packed red blood cells Rosens Emergency Medicine. Concepts and Clinical Practice.
rFVIIa: recombinant activated factor VII Philadelphia: Mosby; 2002: 3347.
RR: respiratory rate Moore FA, McKinley BA, Moore EE. The next generation in shock
SAFE: Saline versus Albumin Fluid Evaluation Study resuscitation. Lancet 2004;363:19881996.
SBP: systolic blood pressure Mullins RJ. Management of shock. In: Mattox KL, Feliciano DV, Moore
SCr: serum creatinine EE, eds. Trauma. New York: McGraw-Hill; 2000: 195232.
SIRS: systemic inammatory response syndrome
SV: stroke volume
SVR: systemic vascular resistance
THAM: tris-hydroxymethyl aminomethane (tromethamine)


this chapter.
Section 2. Respiratory Disorders
11 ASTHMA
W. Greg Leader
LEARNING OBJECTIVES
1. Explain the pathophysiology of asthma.

2. Identify the goals of asthma management.
3. Classify asthma severity based on asthma symptoms.
4. Recommend environmental control strategies for patients with identied allergies.
5. Educate patients on the use of inhaled drug delivery devices, peak ow monitors, and
asthma education plans.
6. Develop a therapeutic plan for patients with chronic asthma that maximizes patient
response while minimizing adverse drug events and other drug-related problems.
7. Evaluate current asthma therapy and make changes when necessary.
8. Develop a therapeutic plan for treating patients with acute asthma.
KEY CONCEPTS Excessive use of inhaled short-acting 2-agonists is an indica-

tor of inadequately controlled asthma.
Asthma is a chronic inammatory disorder of the airways in
which many cells and cellular elements play a role. Asthma is a chronic inammatory disorder of the airways
Therapy for chronic asthma is directed at suppressing the in which many cells and cellular elements play a role, in partic-
underlying inammatory response and normalizing pul- ular, mast cells, eosinophils, T lymphocytes, macrophages,
monary function. neutrophils, and epithelial cells. In susceptible individuals,
Classication of asthma severity is based on daytime and this inammation causes recurrent episodes of wheezing,
nighttime symptoms, physical activity, lung function, vari- breathlessness, chest tightness, and coughing, particularly at
ability in peak expiratory ow (PEF), and use of reliever night or in the early morning. These episodes are usually asso-
medications. ciated with widespread but variable airow obstruction that is
Direct airway administration of asthma medications through often reversible spontaneously or with treatment. The inam-
inhalation is the most efcient route and minimizes systemic mation also causes an associated increase in existing airway
adverse effects. hyperresponsiveness to a variety of stimuli.1 Additionally, it is
Inhaled short-acting 2-agonists are the most effective now recognized that airway remodeling may occur, resulting
agents for reversing acute airway obstruction caused by in a xed or irreversible airway defect.2,3
bronchoconstriction. Asthma is a diverse disease that presents in a heterogeneous
In persistent asthma, inhaled corticosteroids provide the most manner. Severity of chronic disease ranges from mild with
comprehensive control of the inammatory process. intermittent symptoms to severe and disabling if left untreated.
Intensity of pharmacologic therapy is based on the severity of Despite variances in the underlying severity of chronic asthma,
the disease. all asthmatics are at risk of severe acute disease when exposed
Adding a long-acting inhaled 2-agonist to low-dose inhaled to the appropriate trigger or if inadequately treated. The
corticosteroids is equally or more effective than doubling the National Asthma Education and Prevention Program (NAEPP)
inhaled corticosteroid dose or adding other long-term con- Expert Panel Report 21 and its subsequent update2 provide
trol medications and decreases the potential for adverse guidelines for the diagnosis and management of asthma. These
effects. guidelines emphasize the importance of treating underlying
209
210 SECTION 2 / RESPIRATORY DISORDERS
airway inammation as a means of controlling persistent induce a type 2 T-helper CD4+ (TH2) response. Antigens are
asthma and preventing acute exacerbations of the disease. taken up by antigen-presenting cells,6 and presentation of anti-
gens to T lymphocytes causes activation of the TH2 type
response, leading to B-cell production of antigen-specic
EPIDEMIOLOGY AND ETIOLOGY immunoglobulin E (IgE) and proinammatory cytokines and
chemokines that recruit and activate eosinophils, neutrophils,
Asthma is the most common chronic disease of childhood, and and alveolar macrophages.6,7 Further exposure to the antigen
it causes signicant morbidity and mortality in both adults and results in cross-linking of cell-bound IgE in mast cells and
children. Approximately 20 million people in the United States basophils, causing the release or generation of inammatory
carried the diagnosis of asthma in 2002, with Puerto Ricans, non- mediators such as histamine, cysteinyl leukotrienes (C4, D4, and
Hispanic blacks, and Native Americans having a signicantly E4), and prostaglandins. Activation and degranulation of mast
higher prevalence than non-Hispanic whites.4 Approximately cells and basophils results in an early phase response that
12 million workdays and 15 million schooldays are missed involves an acute bronchoconstriction that usually lasts approx-
yearly due to asthma. In 2002, there were 1.9 million emergency imately 1 hour after allergen exposure.6 This early phase
department visits and 484,000 hospitalizations for asthma. response can be blocked by pretreatment with an inhaled 2-
Children younger than 4 years of age have the highest rate of agonist or cromolyn.
emergency department visits and hospitalizations. There were In the late phase response, activated airway cells release
approximately 4600 asthma-related deaths in 2002, but the inammatory cytokines and chemokines, recruiting inam-
annual mortality rate appears to be decreasing.4 matory cells into the lungs. The late phase response occurs 4
Asthma is also a signicant economic burden in the United to 6 hours after the initial allergen challenge and results in a
States, costing $12.7 billion in 1998 with direct medical expendi- less intense bronchoconstriction as well as increased airway
tures accounting for 58% of the cost or approximately $7.4 bil- hyperresponsiveness and airway inammation.6
lion.5 Hospital and emergency department care accounted for
45.1% of the direct medical expenditures, with prescription
drugs and physician ofce visits accounting for 43.3% and Airway Inammation and Hyperresponsiveness
11.6%, respectively. Costs appear to increase with disease severity, TH2 lymphocytes are one of the primary factors initiating
and it has been suggested that fewer than 20% of asthma patients and perpetuating the inammatory response.7 In addition,
account for more than 80% of direct medical expenditures.5 proinammatory mediators such as the leukotrienes gener-
Asthma results from a complex interaction of genetic and ated during mast cell degranulation can increase vascular
environmental factors; however, the underlying cause is not well permeability, leading to airway edema and increased mucus
understood. There appears to be an inheritable component, as production.8 Eosinophilic inltration of the airways is a
the presence of asthma in a parent is a strong risk factor for the hallmark of asthma, and activated eosinophils can cause
development of asthma in a child. This risk increases when a bronchoconstriction and AHR.9
family history of atopy is also present.1,3 Approximately 50% of Airway hyperresponsiveness is dened as the exaggerated
asthma can be attributed to atopy, and atopic asthma is more ability of the airways to narrow in response to a variety of stim-
common in children than adults.3 Furthermore, atopy in child- uli. Although AHR exists in patients without asthma, it is a
hood asthma is the strongest prognostic factor for continued characteristic feature of asthma and appears to be directly
asthma as an adult.1,3 related to airway inammation and the severity of asthma.1,3
Genetic factors cannot explain the recent rapid rise in asthma Treatment of airway inammation with inhaled corticosteroids
prevalence. Asthma appears to require both genetic predisposi- attenuates AHR in asthma but does not eliminate it.1
tion and environmental exposure. Many patients with occupa- Clinically, AHR manifests as increased variability of airway
tional asthma develop the disease late in life upon exposure to function. Although not commonly used to diagnose asthma,
specic allergens in the workplace. Environmental inuences in AHR can be evaluated clinically using a methacholine or hista-
utero or in infancy may contribute to the development of mine bronchoprovocation test.
asthma. Maternal smoking during pregnancy or exposure to
secondhand smoke after birth increases the risk of childhood
asthma.3 Adult-onset asthma is not uncommon and may be Airway Obstruction
related to atopy, nasal polyps, aspirin sensitivity, occupational
Airway obstruction manifests itself as symptoms such as chest
exposure, or a recurrence of childhood asthma.
tightness, cough, and wheezing. Airway obstruction can be
caused by multiple factors including airway smooth muscle con-
PATHOPHYSIOLOGY striction, airway edema, mucus hypersecretion, and airway
remodeling. Airway smooth muscle tone is maintained by an
Asthma is characterized by inammation, airway hyperrespon- interaction between sympathetic, parasympathetic, and non-
siveness (AHR), and airway obstruction. Inhaled antigens adrenergic mechanisms. Acute bronchoconstriction usually
CHAPTER 11 / ASTHMA 211
results from preformed or generated mediators such as hista-

mine and cysteinyl leukotrienes released during mast cell and Clinical Presentation of Chronic
basophil degranulation that act directly on the airways.3 Asthma
Inammatory mediators such as histamine, leukotrienes, and
bradykinin increase microvascular permeability leading to
General
mucosal edema, which causes the airway to become more rigid
Asthma severity ranges from normal pulmonary function and
and limits airow.10 These changes exaggerate the consequences symptoms only with acute exacerbations to signicantly
of acute bronchoconstriction. In asthmatics, there is an decreased pulmonary function with continuous symptoms.
increased number and volume of mucous glands with increased
Symptoms
mucus secretion.11 Extensive mucus plugging has been demon-
Symptoms may include dyspnea, cough, wheezing, and
strated in patients who have died from acute asthma and is likely chest tightness. These symptoms may be continual,
a cause of persistent airway obstruction in severe acute attacks. episodic, seasonal, or occur in association with known
Although airway obstruction in asthma has generally been triggers.
considered reversible, some asthmatics have an irreversible or Symptoms may occur more often at night, early in the
xed obstruction. The process that produces the structural air- morning, or with exercise.
way changes leading to this xed obstruction has been termed Patients with mild intermittent asthma may be
airway remodeling and is characterized by airway epithelial symptom-free and have normal pulmonary function
damage, subepithelial brosis, airway smooth muscle hypertro- between exacerbations.
phy and hyperplasia, increased mucus production, and Signs
increased vascularity of the airways.3,11 Airway remodeling may Patients may have end-expiratory wheezing and dry cough.
be caused by repetitive injury to the airways, by an abnormal Laboratory Tests
injury-repair cycle of dysfunctional epithelial cells, or in Increased serum concentrations of IgE or eosinophils may
response to the chronic inammatory process. Structural airway help conrm the diagnosis of asthma but are not diagnos-
changes can be demonstrated early in asthma, may be present in tic for asthma.
newly diagnosed asthmatics, and has been seen prior to the Other Diagnostic Tests
onset of asthma.11 Spirometry, an objective measure of pulmonary function,
can be used to assist in conrming the diagnosis of asthma.
The primary pulmonary function tests used to assist in the
CLINICAL PRESENTATION AND DIAGNOSIS diagnosis of asthma are the forced expiratory volume in
1 second (FEV1), forced vital capacity (FVC), and peak expi-
Factors Affecting Asthma Severity ratory ow (PEF). Values used to support a diagnosis of
asthma include:
Major factors that may contribute to the severity of asthma
include allergens typically associated with atopy; chemical Decreased FEV1/FVC (less than 80%, but may be normal
exposures in occupational environments; and exposure to between exacerbations) demonstrates airway obstruction.
tobacco smoke, irritants, and indoor and outdoor pollution. A greater than or equal to 12% (at least 200 mL) improve-
Other factors include concurrent disease states or medications ment in FEV1 after an inhaled bronchodilator demonstrates
that may worsen asthma severity. a reversible obstruction. A 2- to 3-week course of oral corti-
Up to 80% of asthmatics have symptoms of rhinitis, and costeroids may be necessary to demonstrate reversibility in
inammation of the upper airways may increase AHR.1,3 airway obstruction.
A greater than or equal to 15% decrease in FEV1 after an
Treatment of rhinitis with intranasal corticosteroids may
exercise test is diagnostic for exercise-induced asthma.
improve asthma symptoms and is recommended for asthma
patients with rhinitis. Assessment of diurnal variation of PEF may be useful in
Acute and chronic sinusitis can also aggravate asthma, and patients who have asthma symptoms and normal spirometry.
antibiotic therapy of sinusitis may improve asthma symptoms.3 When spirometry is equivocal, a 20% or greater decrease in
Nasal polyps are associated with aspirin-sensitive asthma, and FEV1 after the administration of methacholine is diagnostic
adult patients with nasal polyps should be counseled against for asthma. A negative bronchoprovocation test with metha-
using non-steroidal anti-inammatory medications.1,3 choline may help rule out asthma.
Gastroesophageal reux has been associated with increased A positive allergen test may help guide nonpharmacologic
asthma symptoms, especially nighttime symptoms. therapy but is not diagnostic for asthma.
Non-selective -blockers, including those in ophthalmic
preparations, may cause asthma symptoms, and these agents is dose related, the lowest effective dose should be used. -
should be avoided in asthmatics unless the benets of therapy Blockers may inhibit -agonist reversal of bronchospasm, and a
outweigh the risks.1 In asthmatic patients requiring -blocker larger dose of -agonist or the use of an anticholinergic agent
therapy, a 1-selective agent should be chosen. Because selectivity may be necessary to reverse bronchospasm.
Clinical Presentation of Acute Asthma Patient Encounter, Part 1
General RB is a 13-year-old African-American female who presents

Acute asthma can present rapidly (within 3 to 6 hours) but with complaints of shortness of breath when she exercises.
more commonly, deterioration occurs over several hours, days, She has joined the cross-country team, and she is having
or even weeks. Typically there is gradual deterioration over trouble keeping up with the other girls on the team because
several days followed by a more rapid deterioration over 2 to she gets extremely short of breath 5 or 10 minutes into her
3 days. Acute asthma can be a life-threatening event, and run; her chest begins to feel tight, and she coughs. The
severity does not correspond to severity of the chronic disease. symptoms usually go away 30 minutes to an hour after she
stops running. She also wakes up at night approximately
Symptoms once a week because she is having trouble catching her
The patient usually presents with complaints of dyspnea, breath.
cough, shortness of breath, and chest tightness.
Because of their inability to breathe, patients are gener- What information is suggestive of asthma?
ally anxious and may be agitated. In severe acute asthma, How would you classify this patients asthma severity?
patients may be unable to communicate in complete What additional information do you need to know before
sentences. creating a treatment plan for this patient?
Mental status changes may indicate impending
respiratory failure.
Signs
The patient usually has tachypnea and may have tachycardia. There is little evidence for other food allergies as a routine cause
Wheezing may vary from end-expiratory wheezing in of worsening asthma symptoms.1,3
mild exacerbations to wheezing throughout inspiration Viral infections are the most common cause of increased
and expiration in severe exacerbations. asthma symptoms and asthma exacerbations.
Bradycardia and absence of wheezing may indicate
impending respiratory failure.
Patients may also present with hyperination, use of TREATMENT OF ASTHMA
accessory muscles to breathe, pulsus paradoxus,
diaphoresis, and cyanosis. Desired Outcomes
Laboratory Tests
Arterial blood gases for evaluating partial arterial pressure Chronic Asthma
of carbon dioxide (PCO2) should be considered for patients Therapy for chronic asthma is directed at suppressing the
in severe distress, suspected hypoventilation, or when PEF underlying inammatory response and normalizing pulmonary
or FEV1 is less than or equal to 30% after initial treatment. function. The goals of treatment for chronic asthma are to: (1)
A complete blood count with differential should be prevent chronic and troublesome symptoms; (2) maintain
obtained in patients with fever or purulent sputum. normal or near normal pulmonary function; (3) maintain
Serum electrolytes should be obtained, because frequent normal activity levels, including exercise and other physical
2-agonist administration may decrease serum potassium,
activities; (4) prevent recurrent exacerbations of asthma and
magnesium, and phosphate.
minimize the need for emergency department visits or hospi-
Other Diagnostic Tests talizations; (5) provide optimal pharmacotherapy with mini-
Patients may present with PEF rates greater than 80% and mal or no adverse effects; and (6) meet patients and families
oxygen saturation greater than 95% in mild exacerbations expectations of and satisfaction with asthma care.1
to PEF rates less than 50%, oxygen saturations less than
Because of the varying presentation of asthma, treatment
91%, partial arterial oxygen pressures (PaO2) less than
guidelines for asthma therapy should serve as a guide for ther-
50 mm Hg (less than 6.65 kPa), and PCO2 greater than 42
mm Hg (greater than 5.59 kPa) in a severe exacerbation. apy with the therapeutic plan individualized for each patient
A chest x-ray should be performed when pneumonia is to achieve these goals.
suspected.
Acute Severe Asthma
Worsening or acute asthma can be a life-threatening situation,
The ingestion of sultes can also worsen asthma. These and appropriate outcomes require rapid assessment and
agents are often found in processed potatoes, shrimp, dried appropriate intensication of therapy. Mortality associated
foods, beer, and wines. Patients sensitive to sultes should be with asthma exacerbations is usually related to an inappropri-
warned not to ingest these products, as they have been known ate assessment of the severity of the exacerbation resulting in
to cause severe exacerbations, particularly in severe asthmatics. insufcient treatment or referral for medical care.12 The goals
of therapy are to: (1) correct signicant hypoxemia; (2) rapidly Nonpharmacologic Therapy
reverse airow obstruction; and (3) reduce the likelihood of
Patients should play an active role in their therapy. The devel-
recurrent severe airow obstruction.1
opment of a health care providerpatient partnership is vital
Because of the signicance of the event, patients may be
to the success of any treatment plan. Goals for asthma treat-
more open to education about asthma after resolution of the
ment should be shared with the patient and family, and the
exacerbation. Health care professionals should use this oppor-
patient and health care provider should jointly agree on the
tunity to provide information to help prevent future episodes,
patients personal treatment goals.
including recognition of early indicators of an exacerbation
Nonpharmacologic therapy should be incorporated into
and a process to appropriately intensify pharmacotherapy
each step of therapy. Patient education should occur early in
during the early stages of future exacerbations, including an
the disease process, include all members of the health care
individualized written asthma action plan.
team, and be tailored to meet individual patient needs.1
Patients should be taught basic facts about asthma, including
General Approach to Treatment the difference between the asthmatic and normal lung, what
happens to the lung during an asthma attack, how medications
In chronic asthma, classication of asthma severity is work, environmental control measures, and self-management
based on daytime and nighttime symptoms, physical activity, of asthma, including skills for self-monitoring of pulmonary
lung function (PEF or FEV1), PEF variability, and reliever med- function, symptoms of asthma deterioration, and when and
ication use. Because lung function is difcult to measure in how to take rescue actions.
preschool children (children 5 years of age or younger), it can- Patients must understand the role of long-term control
not be used to classify disease severity in this age group. and quick relief medications in their asthma treatment plan.
Chronic asthma is classied as mild intermittent asthma, or The importance of understanding asthma as a chronic disease
mild, moderate or severe persistent asthma (Table 111). and the need for daily treatment with long-term control med-
Treatment of asthma involves avoidance of triggers known ications should be stressed. Additionally, the importance of
to precipitate or worsen asthma and the use of long-term proper use of medication delivery devices should be continu-
control and quick relief medications. Long-term control ally reinforced. Basic education should be provided over sev-
medications include inhaled corticosteroids, inhaled long- eral visits with the health care provider.
acting 2-adrenergic agonists, oral theophylline, and oral
leukotriene modifying agents. In patients with severe asthma, sys- Risk Factor Avoidance
temic corticosteroids may be used as a long-term control medica- Patients who smoke should be strongly encouraged to quit;
tion. Quick relief medications include short-acting 2-agonists, cigarette smoking decreases the efcacy of inhaled cortico-
anticholinergics, and systemic corticosteroids. A stepwise steroids and can trigger an acute asthmatic response.3 All
approach to therapy is recommended to achieve the treatment patients should also avoid secondhand smoke. Parents of chil-
goals2 (Table 111). dren with asthma should be instructed not to smoke in the
In acute severe asthma, the severity of an exacerbation is not home and not to allow others to smoke in the home. Patients
dependent upon the classication of the patients chronic should also avoid outdoor activities when air quality is poor
asthma, as even patients with mild intermittent asthma can have and avoid exposure to other irritants such as hairspray, paint,
life-threatening acute exacerbations. Treatment of acute or exhaust fumes, and smoke from any re.
worsening asthma primarily involves pharmacologic treatment. Patients sensitive to specic allergens should be educated
Early and aggressive treatment is necessary for quick resolu- on ways to avoid them. Environmental controls to reduce the
tion.1,3 Important elements of an early treatment plan include: allergen load in the patients home may reduce asthma symp-
(1) a written action plan; (2) recognition of early indicators of toms, school absences because of asthma, and unscheduled
an acute exacerbation, including asthma symptoms as well as wors- clinic and emergency visits for asthma.13 Patients allergic to
ening PEF or FEV1; (3) appropriate intensication of pharma- warm-blooded pets should remove them from the home if
cotherapy, which may include a short course of oral corticosteroids; possible or at least keep them out of the bedroom. However,
and (4) removal of triggers or irritants that may be contributing to allergens may remain in the home for months after the pet is
the acute exacerbation. removed.1
Treatment of severe acute asthma includes the use of oxygen Patients allergic to cockroach antigens should ensure that
for the rapid reversal of hypoxemia, a short-acting 2-agonist to food and garbage are not left exposed and cockroach popula-
reverse airway constriction, and a systemic corticosteroid to tions are controlled. For patients with house dust mite aller-
attenuate the inammatory response.1 Close monitoring of gies, essential measures to reduce the allergen load include
objective measures such as FEV1 or PEF is important to quan- encasing the mattress and pillow in allergen-impermeable
tify the response to therapy. Because recovery from exacerba- covers and washing the patients bed sheets and covers in hot
tions is often gradual, intensied therapy should be continued water [130F (54C)] weekly. Dust mite exposure may also be
for several days. minimized by removing carpets from the bedroom, removing
214
TABLE 111. Classication of Severity and Stepwise Approach For Managing Asthma
Clinical Features Medication Required to Maintain Medication Required to Maintain Long-Term

Severity Classication Before Treatment Long-Term Control: Adults and Control: Children 5 Years of
(Prior to Treatment) or Adequate Controla,b,c Children Older Than 5 Years of Age Age and Younger
Step 4: Severe persistent Daytime Symptoms Preferred Treatment Preferred Treatment
Continual symptoms High-dose inhaled corticosteroids High-dose inhaled corticosteroids
Limited physical activity AND AND
Nighttime Symptoms Long-acting inhaled 2-agonists Long-acting inhaled 2-agonists
Frequent AND if needed AND if needed
Exacerbations Corticosteroid tablets or syrup long term Corticosteroid tablets or syrup long term
Frequent (2 mg/kg per day; generally do not exceed (2 mg/kg per day; generally do not exceed
Lung Function 60 mg/day); make repeated attempts to 60 mg/day); make repeated attempts to
FEV1 or PEF less than or equal to 60% pre- reduce systemic corticosteroids and reduce systemic corticosteroids and maintain
dicted; PEF variability greater than 30% maintain control with high-dose inhaled control with high-dose inhaled corticosteroids
corticosteroids
Step 3: Moderate persistent Daytime Symptoms Preferred Treatment Preferred Treatment
Daily symptoms Low- to medium-dose inhaled Low-dose inhaled corticosteroids and long-
Daily use of inhaled short-acting corticosteroids and long-acting inhaled acting inhaled 2-agonists
2-adrenergic agonists 2-agonists OR
Nighttime Symptoms Alternate Treatment Medium-dose inhaled corticosteroids
Greater than 1 time per week Increase inhaled corticosteroid dose into Alternate Treatment
Exacerbations the medium-dose range Low-dose inhaled corticosteroids and either
Affect activity; occur greater than or OR leukotriene receptor antagonist or theo-
equal to 2 times per week; exacerba- Low- to medium-dose inhaled corticos- phylline
tions may last days teroids and either leukotriene modier or If needed (particularly in patients with recurring
Lung Function theophylline severe exacerbations):
FEV1 or PEF greater than 60% but less If needed (particularly in patients with recur- Preferred Treatment
than 80% predicted; PEF variability ring severe exacerbation): Medium-dose inhaled corticosteroids and
greater than 30% Preferred Treatment long-acting 2-agonists
Increase inhaled corticosteroids within Alternative Treatment
medium-dose range and add long-acting Medium-dose inhaled corticosteroids and
2 agonist either a leukotriene receptor antagonist or
Alternative Treatment theophylline
Increase inhaled corticosteroids within
medium-dose range and add either
Step 2: Mild persistent Daytime Symptoms leukotriene modier or theophylline
Symptoms greater than 2 times per week Preferred Treatment Preferred Treatment
but less than 1 time per day Low-dose inhaled corticosteroids Low-dose inhaled corticosteroids (with nebu-
Nighttime Symptoms Alternative Treatment lizer or MDI with holding chamber with or
Greater than 2 times per month Cromolyn, leukotriene modiers, without facemask or DPI)
Exacerbations nedocromil OR sustained-release Alternative Treatment
May affect activity theophylline adjusted to a serum Cromolyn (nebulizer is preferred or MDI with
Lung Function concentration of 515 mcg/mL holding chamber) OR leukotriene receptor
FEV1 or PEF greater than or equal to (2883 mol/L) antagonists
80%; PEF variability 2030%
Step 1: Mild intermittent Daytime Symptoms No daily medications needed No daily medications needed
Symptoms less than or equal to 2 times Severe exacerbations may occur, separated
per week by long periods of normal lung function; a
Asymptomatic or normal PEF between course of systemic corticosteroids is
exacerbations recommended
Nighttime Symptoms
Less than or equal to 2 times per month
Exacerbations
Brief (from a few hours to a few days);
intensity may vary
Lung Function
Quick Relief for All Patientsc FEV1 or PEF greater than or equal to Short-acting bronchodilator: 24 puffs Bronchodilators as needed for symptoms;
80% PEF variability less than 20% short-acting inhaled 2-agonist as needed intensity of treatment depends on the severity
for symptoms of the exacerbation
Intensity of treatment depends on severity Preferred Treatment
of exacerbation: up to 3 treatments at Short-acting inhaled 2-agonist by nebulizer
20-minute intervals or a single nebulizer or facemask and spacer/holding chamber
treatment as needed; a course of systemic Alternative Treatment
corticosteroids may be needed Oral 2-agonist
Use of short-acting 2-agonist greater than With viral respiratory infection:
2 times a week in intermittent asthma Bronchodilator every 46 hours up to 24 hour
(daily or increasing use in persistent (longer with physician consult); in general,
asthma) may indicate the need to initiate repeat no more than once every 6 weeks
or increase long-term-control therapy Consider systemic corticosteroid if exacer-
bation is severe or patient has a history of
previous severe exacerbations
Use of short-acting 2-agonist greater than 2
times a week in intermittent asthma (daily or
increasing use in persistent asthma) may indi-
cate the need to initiate or increase long-
term-control therapy
Notes:
The stepwise approach is intended to assist, not replace, the clinical decision making required to meet individual patient needs.
There are very few studies on asthma therapy for infants.
Gain control as quickly as possible (a short course of systemic corticosteroids may be required.); then step down to the least medication necessary to maintain control.
Minimize use of short-acting inhaled 2-agonists. Overreliance on short-acting inhaled 2-agonists (e.g., use of short-acting inhaled 2-agonists every day, increasing use or lack of
expected effect, or use of approximately one canister a month even if not using it every day) indicates inadequate control of asthma therapy and the need to initiate or intensify
long-term control therapy.
Provide education on self-management or parent education on asthma management and controlling environmental factors that make asthma worse (e.g., allergens and irritants).
Consultation with an asthma specialist is recommended for patients with moderate or severe persistent asthma. Consider consultation for patients with mild, persistent asthma.
a
The presence of one of the features of severity is sufcient to place a patient in that category. An individual should be assigned the most severe grade to which any feature occurs. The characteristics
noted in this table are general and may overlap because asthma is highly variable. Furthermore, an individuals classication may change over time.
b
Accurate assessment of FEV1 or PEF may not be possible in children less than 5 years of age.
c
Patients at any level can have mild, moderate, or severe exacerbations. Some patients with intermittent asthma experience severe and life-threatening exacerbations separated by long periods of
normal lung function and no symptoms.
FEV1, forced expiratory volume in 1 second; PEF, peak expiratory ow; MDI, metered-dose inhaler; DPI, dry powder inhaler.
Adapted from NHLBI. National Asthma Education and Prevention Program, Expert Panel Report 2. Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 97-4051. Bethesda,
MD: United States Department of Health and Human Services, 1997, and National Institutes of Health. National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program.
Expert Panel Report. Guidelines for the Diagnosis and Management of Asthma. Update on Selected Topics 2002. http://www.nhlbi.nih.gov/guidelines/astham/asthmafullrpt.pdf; accessed August 2005;
with permission.
215
carpets laid over concrete slabs, and avoiding sleeping or lying steps for the appropriate use of inhaled delivery devices.
on upholstered furniture. Reducing indoor humidity to less Inhaled asthma medications are available in metered-dose
than 50% helps control dust mite populations and decreases inhalers (MDIs), dry powder inhalers (DPIs), and nebulized
exposure to indoor mold. Patients allergic to outdoor aller- solutions.
gens should stay indoors during times of peak allergen levels. Patients switched from an MDI to a DPI should be coun-
Asthma patients should receive the inuenza vaccine every seled that the DPI requires a rapid and forceful inhalation as
year.1 Although the pneumococcal vaccine may decrease the compared to the slow inhalation used for an MDI. Patients
risk of invasive pneumococcal disease in asthmatics, current using a DPI should also be counseled not to exhale into the
guidelines do not include the routine administration of this device, as it will cause a loss of dose or decreased drug deliv-
vaccine to asthma patients.1,14 ery. Because delivery technique with inhalers deteriorates over
time, the health care provider should take every opportunity
Drug Delivery Devices to reinforce appropriate inhaler technique.
Direct airway administration of asthma medications Patients should also be educated to keep track of inhaler
through inhalation is most efcient and minimizes systemic use. Many DPIs have a built-in counter or device to notify the
adverse effects. Poor inhaler technique can result in increased patient of how many doses are remaining (e.g., Diskus and
oropharyngeal deposition of the drug with decreased ef- Twisthaler) or that the inhaler is approaching empty (e.g.,
cacy and increased adverse effects. Figure 111 provides Turbuhaler).
Steps for Using Your Inhaler
Please demonstrate your inhaler technique at every visit.

1. Remove the cap and hold inhaler upright.
2. Shake the inhaler.
3. Tilt your head back slightly and breathe out slowly.
4. Position the inhaler in one of the following ways (A or B is optimal, but C is acceptable for those who have difficulty with A or B.
C is required for breath-activated inhalers):
A Open mouth with inhaler 1 to B Use spacer/holding chamber (that is C In the mouth. Do not use for D NOTE: Inhaled dry powder capsules
2 inches away. recommended especially for young children corticosteroids. require a different inhalation technique.
and for people using corticosteroids). To use a dry powder inhaler, it is im-
portant to close the mouth tightly around
the mouthpiece of the inhaler and to
inhale rapidly.
5. Press down on the inhaler to release medication as you start to breathe in slowly.
6. Breathe in slowly (3 to 5 seconds).
7. Hold your breath for 10 seconds to allow the medicine to reach deeply into your lungs.
8. Repeat puff as directed. Waiting 1 minute between puffs may permit second puff to penetrate your lungs better.
9. Spacers/holding chambers are useful for all patients. They are particularly recommended for young children and
older adults and for use with corticosteroids.
Avoid common inhaler mistakes. Follow these inhaler tips:
Breathe out before pressing your inhaler.
Inhale slowly.
Breathe in through your mouth, not your nose.
Press down on your inhaler at the start of inhalation (or within the first second of inhalation).
Keep inhaling as you press down on inhaler.
Press your inhaler only once while you are inhaling (one breath for each puff).
Make sure you breathe in evenly and deeply.
NOTE: Other inhalers are becoming available in addition to those illustrated above. Different types of inhalers require different techniques.
FIGURE 111. Steps for using your inhaler. (From Kelly HW, Sorkness CA. Asthma. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.)
Spacers or holding chambers decrease the need for coordi- NAEPP recommends PEF be measured daily in the morning
nation of actuation of MDI devices with inhalation, decrease on waking, prior to taking a bronchodilator.1
oropharyngeal deposition of drug, and increase pulmonary Because PEF values in patients do not always correlate well
drug delivery.15,16 These devices are equipped with a mouth- with predicted PEF values, daily PEF values should be compared
piece or a facemask allowing the use of an MDI in children to the patients personal best PEF. Personal best PEF should be
less than 5 years of age. Patients using a spacer or holding established over a 2- to 3-week period when the patient is receiv-
chamber should be counseled to place only one puff of the ing optimal treatment.1,3 During this time, the patient should
drug into the chamber at a time, because actuating the MDI measure PEF at least twice a day, in the morning and early after-
more than once into the chamber before inhalation decreases noon, and before and after a dose of bronchodilator if the
drug delivery.15 Additionally, patients should be instructed not patient is taking one. At each time period, the patient should
to delay inhalation after actuation of the MDI, as a 10- to record the best of three attempts. The highest PEF recorded dur-
20-second delay in inhalation may also signicantly decrease ing this 2- to 3-week period is the patients personal best. If the
drug delivery. Taking multiple breaths after a single actuation patients personal best is less than 80% of predicted values or if
is appropriate and does not decrease drug efcacy.15 peak ow variability is greater than 20%, more aggressive ther-
Although nebulizers have often been used for drug delivery apy (including a short course of oral corticosteroids) may be
in children, their use is expensive and time consuming. required to adequately assess the patients personal best.3
Nebulizers may atomize drug using compressed air or oxygen Subsequent evaluation of PEF is done in relation to its vari-
(jet nebulizers) or by high-frequency vibration (ultrasonic ability from the patients best. Consistent PEF measurements
nebulizers). Ultrasonic nebulizers should not be used for less than 80% of personal best indicate the need for intensify-
drugs in suspension, as they are ineffective in delivering the ing therapy and a PEF measurement less than 50% indicates a
suspended particles.16 severe exacerbation. The NAEPP recommends that these zones
be associated with a trafc light system to assist the patient in
Asthma Self-Management
their use.1 PEF measurements in the range of 80% to 100% of
Asthma self-management plans give patients the freedom to personal best are in the green zone and indicate that current
adjust therapy based on personal assessment of disease severity therapy is acceptable. A PEF in the range of 50% to 79% of per-
and a pre-agreed upon action plan. Furthermore, because most sonal best is in the yellow zone and indicates caution. PEF
asthma exacerbations occur at home or in the community, measurements in the yellow zone may indicate an impending
these plans allow for the rapid initiation of patient-specic exacerbation and based on his or her self-management plan,
therapy. Asthma self-management plans reduce morbidity the patient should increase the use of relief medication, inten-
and the need for medical services.17 For self-management sify inhaled corticosteroid therapy, or begin a short course of
plans to be effective, patients should be given a written action oral corticosteroids. A PEF less than 50% is in the red zone and
plan that is part of a global educational program.3 signals a medical alert. Patients should use their short-acting
Patients should be educated to assess asthma severity by eval- 2-agonist immediately and consult their asthma action plan.
uating key asthma symptoms and monitoring PEF. Early signs of
asthma deterioration include increasing nocturnal symptoms, Pharmacologic Therapy
increasing use of short-acting inhaled 2-agonists, or symptoms
that do not respond to increased use of short-acting inhaled 2- Beta2-Adrenergic Agonists
agonists. Patients with moderate to severe persistent asthma 2-Agonists relax airway smooth muscle by directly stimulat-
should monitor PEF every day.1 Measurement of PEF may be ing 2-adrenergic receptors.18 They also increase mucociliary
particularly important for the patient who is a poor judge of clearance and stabilize mast cell membranes. Inhalation, oral,
symptoms or whose perceptions of decreased airow do not and injectable dosage forms are available, and the inhalation
correlate with objective measures of airow.3 dosage forms are most commonly used. Oral 2-agonists
Measurement of PEF is highly dependent upon patient should not be used in acute asthma because of a delayed onset
effort and technique; therefore, the health care provider of action compared to the inhaled route.1 Inhaled 2-agonists
should educate the patient on the proper technique for meas- are classied as either short- or long-acting based on their
uring PEF and review this technique on a regular basis. To use duration of action.
the peak ow meter properly, the patient should be instructed
to move the indicator to the bottom of the numerical scale; Short-Acting Inhaled Beta2-Agonists
stand up; take a deep breath completely lling their lungs; Inhaled short-acting b2-agonists are the most effective
place the mouthpiece in the mouth being careful to close their agents for reversing acute airway obstruction caused by bron-
lips around it and not to obstruct the hole with their tongue; choconstriction and are the drugs of choice for treating acute
and blow out as hard and fast as they can in a single blow.1 severe asthma and symptoms of chronic asthma.1 Short-acting
This effort should be repeated three times, with the highest inhaled 2-agonists have an onset of action of less than 5 min-
value of the three recorded in the patients PEF diary. The utes and a duration of action of 4 to 6 hours. 2-Agonists have
signicantly better bronchodilating activity in acute asthma asthma symptoms. Salmeterol is a partial agonist with an
than theophylline or anticholinergic agents. onset of action of approximately 30 minutes. Because of this
Adverse effects of the inhaled 2-agonists include tachycar- delayed onset of action, patients should be cautioned not to
dia, tremor, and hypokalemia, which are usually not problem- use salmeterol as a quick relief medication. Formoterol is a full
atic. Because of increased adverse effects, oral 2-agonists should agonist that has an onset of action similar to that of albuterol,
be avoided in patients who are able to use inhaled medications. but it is not currently indicated for the treatment of acute
Albuterol (also known as salbutamol outside the United bronchospasm.
States), the most commonly used inhaled short-acting 2- Inhaled long-acting 2-agonists are indicated for add-
agonist, is a racemic mixture (50:50) of albuterol enan- on therapy for asthma not controlled on low to medium
tiomers. The R-enantiomer is the active component whereas the doses of inhaled corticosteroids. Adding a long-acting
S-enantiomer is inactive or may be associated with unwanted effects. inhaled 2-agonist is at least as effective as doubling the dose
Levalbuterol, the pure R-enantiomer of albuterol, is available as a of an inhaled corticosteroid with respect to improving lung
solution for nebulization and as an MDI dosage form. function and symptom scores and decreasing nocturnal symp-
Comparative studies show similar efcacy and safety between toms, reliever medication use, and asthma exacerbations.2
levalbuterol and albuterol, but the acquisition cost of leval- Addition of a long-acting inhaled 2-agonist to inhaled corti-
buterol is substantially higher. costeroid therapy also reduces the amount of inhaled corti-
Other commonly used short-acting inhaled 2-agonists costeroids necessary for asthma control.2,21 Combined therapy
include pirbuterol and terbutaline. Non-selective 2-agonists with a long-acting inhaled 2-agonist and an inhaled corticos-
such as metaproterenol are no longer commonly used due to teroid is also superior to the combination of a leukotriene
the potential for increased adverse effects. Although not modier or theophylline with an inhaled corticosteroid.2,2224
equivalent on a milligram basis, the inhaled short-acting 2- Although both formoterol and salmeterol are effective as
agonists are equally potent when given in equivalent doses. add-on therapy for moderate persistent asthma, neither agent
Doses for use as quick relief drugs in chronic asthma are pro- should be used as monotherapy for chronic asthma. Patients
vided in Table 112. Usual rescue doses may be doubled for treated with salmeterol alone are at greater risk of worsening
mild exacerbations. Because of previous -agonist use by the asthma than those treated with inhaled corticosteroids.25,26
patient and the underlying inammatory process in acute Salmeterol is also available in a xed ratio combination
severe asthma, the dose-response curve for 2-agonists is product containing uticasone, and a new drug application
shifted to the right, and the duration of action is decreased; has been led for a xed combination product containing
therefore, larger doses of short-acting inhaled 2-agonists may budesonide and formoterol. Combination products have the
need to be administered more often.18 potential advantage of increasing patient adherence due to the
Inhaled short-acting 2-agonists may be administered decreased number of inhalers and inhalations; however, these
through a nebulizer or an MDI. Compared to nebulization, products offer less exibility with respect to dosage adjust-
administration through an MDI with a spacer is quicker and at ments when necessary.
least as effective with fewer adverse effects. In infants and young
children, short-acting 2-agonists administered by MDI should Corticosteroids
be administered through a spacer with a facemask, and in older Corticosteroids are the most potent anti-inammatory agents
children and adults through a spacer with a mouthpiece. In the available for the treatment of asthma. The efcacy of cortico-
case of crying infants and patients unwilling to use an MDI steroids is due to their ability to affect multiple inammatory
with a spacer, short-acting 2-agonists may be administered via pathways, resulting in the suppression of inammatory cell acti-
nebulization connected to oxygen. Infants should receive nebu- vation and function, prevention of microvascular leakage,
lization via a facemask that ts over the nose and mouth. decreased mucus production, and upregulation of 2-adrenergic
Continuous nebulization is as effective as intermittent nebu- receptors.10,18 Clinically, corticosteroids decrease airway
lization with fewer adverse effects.19 inammation, decrease AHR, decrease mucus production and
In patients hospitalized because of asthma, patient-initiated secretion, and improve the response to 2-agonists.18
(on-demand) therapy may result in decreased nebulized doses, Corticosteroids for the treatment of asthma are available in
decreased adverse effects, and shorter hospital stays than ther- inhaled, oral, and injectable dosage forms.
apy given regularly at 4-hour intervals.20 In patients admitted
to the intensive care unit and placed on mechanical ventila- Inhaled Corticosteroids
tion, 2-agonists can be delivered via an MDI or nebulization In persistent asthma, inhaled corticosteroids provide the most
through the ventilatory circuit. comprehensive control of the inammatory process and are the cor-
nerstone of therapy.2 Inhaled corticosteroids are more effective
Long-Acting Inhaled Beta2-Agonists than cromolyn, leukotriene modiers, nedocromil, and theo-
Salmeterol and formoterol are long-acting inhaled 2-agonists phylline in reducing markers of inammation and AHR, improv-
that provide up to 12 hours of bronchodilation after a single ing lung function, and preventing emergency department visits
dose. Both agents are approved for the chronic prevention of and hospitalizations due to asthma exacerbations.2,25 The primary
TABLE 112. Usual Dosages for Selected Quick-Relief Medications
Medication Dosage Form Adult Dose Child Dosea

Short-Acting Inhaled
b2-Agonists
Albuterol MDI: 90 mcg/puff 200 puffs 2 puffs 5 minutes before exercise 12 puffs 5 minutes before exercise
2 puffs 34 times a day as needed 2 puffs 34 times a day as needed
Albuterol HFA MDI: 90 mcg/puff 200 puffs
Levalbuterol HFA MDI: 45 mcg/puff 200 puffs 2 puffs every 46 hours (1 puff every 2 puffs every 46 hours (1 puff every
4 hours may be sufcient in some 4 hours may be sufcient in some
patients) patients)
Albuterol nebulizer 5 mg/mL (5%) 1.255 mg in 3 mL of saline every 0.05 mg/kg (minimum of 1.25 mg,
solution 2.5 mg/3 mL 48 hours maximum of 2.5 mg) in 3 mL of
1.25 mg/3 mL saline every 46 hours
0.63 mg/3 mL
Levalbuterol 0.31 mg/3 mL 0.632.5 mg every 48 hours 0.025 mg/kg (minimum of 0.63 mg;
(R-albuterol) 0.63 mg/3 mL maximum of 1.25 mg every
nebulizer 1.25 mg/3 mL 48 hours
solution
Anticholinergics
Ipratropium MDI CFC: 18 mcg/puff, 23 puffs every 6 hours 12 puffs every 6 hours
200 puffs
MDI HFA: 17 mcg/puff,
200 puffs
Nebulizer solution: 0.25 mg every 6 hours 0.250.5 mg every 6 hours
0.25 mg/mL (0.25%)
Ipratropium with MDI: 18 mcg/puff of 23 puffs every 6 hours 12 puffs every 8 hours
albuterol ipratropium bromide and
90 mcg/puff of albuterol
Nebulizer solution: 3 mL every 46 hours 1.53 mL every 48 hours
0.5 mg/3 mL ipratropium
bromide and 2.5 mg/3 mL
albuterol
Systemic
Corticosteroids
Methylprednisolone 2-, 4-, 8-, 16-, 32-mg tablets Short course burst to achieve Short-course burst to achieve
Prednisolone 5-mg tablets control; 4060 mg/day as single or control; 12 mg/kg per day,
5 mg/5 mL two divided doses for 310 days maximum of 60 mg/day for
15 mg/5 mL 310 days
Prednisone 1-, 2.5-, 5-, 10-, 20-,
50-mg tablets
5 mg/mL
5 mg/5 mL
Methylprednisolone Repository injection: 240 mg intramuscularly once 7.5 mg/kg intramuscularly once
acetate 40 mg/mL
80 mg/mL
a
Children less than or equal to 12 years of age.
CFC, chlorouorocarbon propellant; HFA, hydrouoroalkane propellant; MDI, metered-dose inhaler.
Adapted from National Institutes of Health, National Heart Lung and Blood Institute. National Asthma Education and Prevention Program.
Expert Panel Report. Guidelines for the Diagnosis and Management of Asthma. Update on Selected Topics 2002; http://www.nhlbi.nih.gov/
guidelines/asthma/asthmafullrpt.pdf; accessed August 2005, used with permission.
advantage of the use of inhaled corticosteroids compared to Inhaled corticosteroids appear to have a at dose-response
systemic corticosteroids is the targeted delivery of drug to the curve, with a two-fold increase in dose having a limited addi-
lungs, which decreases the risk of systemic adverse effects. tional effect on asthma control.3,27 Although a four-fold increase
Inhaled corticosteroids are not equivalent on a milligram basis; in inhaled corticosteroid dose has been shown to improve
however, equivalent doses have been approximated (Table 113). asthma control, this signicantly increases the risk of systemic
Low to moderate doses have been shown to be safe and effective adverse effects.2,28 These agents are generally effective when
in all age groups. Although some effect is seen from inhaled cor- given twice daily and may be effective when given once daily for
ticosteroids within 12 hours, 2 weeks of therapy is necessary to mild asthma; however, dosing four times a day may be required
see signicant clinical effects, and longer treatment periods to achieve asthma control in patients with severe asthma.3
may be necessary to see the full effect of these agents on airway Local adverse effects of inhaled corticosteroids include oral
inammation and remodeling. candidiasis and dysphonia. The incidence of local adverse
TABLE 113. Estimated Comparative Dosages for Inhaled Corticosteroids
Medication Agea Low Daily Dose Medium Daily Dose High Daily Dose
Beclomethasone Adult 80240 mcg 240480 mcg Greater than 480 mcg
MDI (HFA): 4080 mcg/puff Child 80160 mcg 160320 mcg Greater than 320 mcg
Budesonide Adult 200600 mcg 6001200 mcg Greater than 1200 mcg
DPI: 200 mcg/inhalation Child 200400 mcg 400800 mcg Greater than 800 mcg
Budesonide solution for inhalation Child 0.5 mg 1 mg 2 mg
250 mcg or 500 mcg/2 mL
Flunisolide Adult 5001000 mcg 10002000 mcg Greater than 2000 mcg
MDI (CFC): 250 mcg/puff Child 500750 mcg 10001250 mcg Greater than 1250 mcg
Fluticasone Adult 88264 mcg 264660 mcg Greater than 660 mcg
MDI: 44, 110, or 220 mcg/puff Child 88176 mcg 176440 mcg Greater than 440 mcg
Mometasone furoate Adult 200400 mcg 400800 mcg Greater than 800 mcg
DPI: 200 mcg/inhalation Child
Triamcinolone acetonide MDI Adult 4001000 mcg 10002000 mcg Greater than 2000 mcg
(CFC): 100 mcg/puff Child 400800 mcg 8001200 mcg Greater than 1200 mcg
a
Children less than or equal to 12 years of age
CFC, chlorouorocarbon; DPI, dry powder inhaler; HFA, hydrouoroalkane propellant; MDI, metered-dose inhaler.
National Institutes of Health. National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program.
Expert Panel Report. Guidelines for the Diagnosis and Management of Asthma. Update on Selected Topics 2002.
http://www.nhlbi.nih.gov/guidelines/astham/asthmafullrpt.pdf; accessed August 2005; and Kelly HW, Sorkness CA. Asthma. In:
DiPro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw Hill;
2005:527.
effects can be reduced by using a spacer or holding chamber and Systemic Corticosteroids
by having the patient rinse their mouth with water and expecto- Systemic corticosteroids are effective as both long-term
rate after using the inhaled corticosteroids. Systemic absorption control and rescue medications; however, due to the poten-
occurs via the pulmonary and oral routes. Although only a frac- tial for serious adverse effects, systemic corticosteroids
tion of the drug is delivered to the lungs, 100% of the drug should only be used for long-term control of asthma in
reaching the lungs is absorbed systemically.1,3 For most delivery patients who have failed other therapies. Serious adverse
devices, the majority of the drug is deposited in the oropharyn- effects include hypothalamic-pituitary-adrenal suppres-
geal cavity and swallowed. Systemic exposure to swallowed drug sion, growth retardation, osteoporosis, aseptic necrosis of
is primarily determined by the degree of rst-pass metabolism the bone, psychiatric disturbances, sodium and water
of the agent. Because spacers and holding chambers decrease retention, hyperkalemia, hyperglycemia, immunosuppres-
oral deposition and increase pulmonary delivery, these devices sion, impaired wound healing, glaucoma, posterior subcap-
may increase the systemic effects of inhaled corticosteroids.15,16 sular cataracts, skin thinning and easy bruising, central
Additionally, changes in drug delivery devices [e.g., from a CFC redistribution of fat, and moon facies.
to a hydrouoroalkane (HFA) propellant or from an MDI to a If it is necessary to use systemic corticosteroids for long-term
DPI] may also alter pulmonary drug deposition with a resulting control therapy, once-daily or every-other-day therapy should
change in efcacy or systemic adverse effects.3 be used and repeated attempts should be made to decrease the
Systemic adverse effects are dose-dependent and are rare at dose or discontinue the drug. Withdrawal of chronic therapy
low to medium doses; however, high-dose inhaled cortico- may precipitate adrenal failure or unmask underlying inam-
steroids have been associated with adrenal suppression, decreased matory disorders such as Churg-Strauss syndrome.
bone mineral density, skin thinning, and easy bruising.3,29 Systemic corticosteroids are the cornerstone of the treat-
Growth suppression in children may occur even with low-dose ment of worsening asthma not responding to bronchodilators
inhaled corticosteroids; however, suppression appears to occur and acute severe asthma. For patients with worsening asthma
primarily in the rst year of treatment and may be due to not responding to bronchodilators, a short course or burst
delayed growth with the potential of future catch-up growth.30 of systemic corticosteroids is effective for gaining control and
Because all inhaled corticosteroids are equally effective preventing progression.1,3 The short course should be contin-
if given in equipotent doses, product selection should be ued until the PEF reaches 80% of personal best or symptoms
individualized based on the available dosage form, delivery resolve. Three to ten days of therapy are usually sufcient, but
device, and patient preference. In infants, administration may longer therapy may be required.1
require the use of a nebulizer or spacer/holding chamber with In acute severe asthma, systemic corticosteroids should be
a facemask. Caregivers should use a soft, damp cloth to wipe given to all patients who do not respond to initial bron-
the face of infants receiving an inhaled corticosteroid via a chodilator therapy and all patients with moderate to severe
facemask to prevent topical candidiasis.18 exacerbations. Corticosteroids attenuate the inammatory
response and increase the response to 2-agonists. They speed There is no evidence that intravenous corticosteroid
recovery from the exacerbation, decrease hospital admissions, administration is more effective than oral administration,
and reduce relapse rates. Their onset of effects is delayed, and and the oral route is preferred in acute severe asthma.3 There
a clinical response may not be seen for 4 to 12 hours.18 For this are also few data to guide selection of initial corticosteroid
reason, systemic corticosteroids should be started early in the doses. Recommended doses for acute severe asthma are shown
course of acute exacerbations or worsening asthma. in Table 115, page 227; however, recent data indicate that
TABLE 114. Usual Doses for Long-Term Control Medications

Inhaled Corticosteroids
See Table 113
Systemic Corticosteroids
Methylprednisolone 2-, 4-, 8-, 16-, 32-mg tablets 7.560 mg daily in a single dose 0.252 mg/kg daily
in the morning or every in a single dose in the
Prednisolone 5-mg tablets other day as needed for morning or every
5 mg/5 mL control other day as
15 mg/5 mL needed for control
Prednisone 1-, 2.5-, 5-, 10-, 20-,
50-mg tablets
5 mg/mL
5 mg/5 mL
Long-Acting Inhaled
b2-Agonists
Salmeterol DPI 50 mcg/blister 1 blister every 12 hours 1 blister every 12 hours
Formoterol DPI 12 mcg/single-use capsule 1 capsule every 12 hours 1 capsule every 12 hours
Cromolyn and Nedocromil
Cromolyn MDI 1 mg/puff 24 puffs 34 times a day 12 puffs 34 times a day
Nebulizer: 20 mg/ampule 1 ampule 34 times a day 1 ampule 34 times a day
Nedocromil MDI 1.75 mg/puff 24 puffs 24 times a day 12 puffs 24 times a day
Leukotriene Modiers
Montelukast 4 mg/pack granules 10 mg at bedtime (greater than 4 mg at bedtime
4- or 5-mg chewable tablet 14 years of age) (12 mo5 years,
10-mg tablet granules; 25 years
of age, chewable
tablet)
5 mg at bedtime
(614 years of age)
Zarlukast 10- or 20-mg tablet 20 mg twice a day 10 mg twice a day
(711 years of age)
Zileuton 300- or 600-mg tablet 600 mg four times a day
Methylxanthine
Theophylline Liquids, sustained-release Starting dose: 10 mg/kg per Starting dose: 10 mg/kg
tablets, capsules day up to 300 mg maximum; per day; usual
usual maximum dose is maximum dose is:
800 mg/day Less than 1 year of age:
(0.2 age in weeks) +
5 = dose in mg/kg per day
Greater than or equal to
1 year of age: 16 mg/kg
per day up to 300 mg
maximum
Miscellaneous
IgE monoclonal antibody Lyophilized powder for Dosed every 2 or 4 weeks
reconstitution with sterile based on patient weight and
water: 150 mg/vial baseline total IgE concentrations
a
DPI, dry powder inhaler; MDI, metered-dose inhaler.
Adapted from National Institutes of Health, National Heart Lung and Blood Institute. National Asthma and Education Prevention Program.
http://www.nhlbi.nih.gov/guidelines/asthma/asthmafullrpt.pdf; accessed August 2005; used with permission.
methylprednisolone 60 to 80 mg/day (or equivalent) is ade- Use of zileuton is uncommon due to the need for dosing four
quate for hospitalized patients, and doses as low as 40 mg/day times a day, potential drug interactions, and the potential for
(or equivalent) are probably adequate.3 No advantage has hepatotoxicity with the resulting need for frequent monitoring
been shown for higher doses in acute severe asthma.1,3 of liver enzymes. In patients started on zileuton, serum alanine
Although the optimal duration of systemic corticosteroids aminotransferase concentrations should be monitored before
is unknown, therapy should be continued until PEF is greater treatment begins, monthly for the rst 3 months, every 2 to 3
than or equal to 80% of predicted or personal best. According months for the remainder of the rst year, and then periodically
to the NAEPP, the usual regimen is to continue frequent mul- thereafter for as long as the patient continues to receive the med-
tiple doses until the patients FEV1 or PEF improves to 50% of ication. Zileuton also inhibits the cytochrome P-450 (CYP)
predicted and then decrease the frequency to twice daily. In mixed function enzyme system and has been shown to decrease
general, the duration of therapy ranges from 3 days for mild the clearance of theophylline, R-warfarin and propranolol.34
exacerbations to 14 days for severe exacerbations. It is not nec- The leukotriene inhibitors zarlukast and montelukast are
essary to taper the systemic steroid dose in patients receiving generally well tolerated and dosed twice and once a day,
short bursts of systemic corticosteroid therapy, as the adrenal respectively. Signicant increases in hepatic enzymes have
suppression that occurs is transient and rapidly reversible.18 been reported in postmarketing studies for zarlukast but not
montelukast.34 Zarlukast also inhibits the CYP2C9 and
Anticholinergics CYP3A4 isoenzymes and may increase prothrombin times in
Anticholinergic agents act by inhibiting the effects of acetyl- patients receiving warfarin. The International Normalized
choline on muscarinic receptors in the airways. They only pro- Ratio should be monitored if warfarin and zarlukast are used
tect against cholinergic-mediated bronchoconstriction and are concomitantly. Erythromycin and theophylline may decrease
not as effective as bronchodilators as are 2-agonists in asthma.18 zarlukast concentrations, whereas aspirin may increase zar-
Administration can be associated with bothersome adverse lukast concentrations. It is not clear if these interactions are
effects such as blurred vision, dry mouth, urinary retention, and clinically important. Montelukast does not appear to inhibit
constipation. However, the anticholinergic agents currently the cytochrome P-450 enzymes, but drugs that induce
available for inhalation are quaternary amines that are not CYP3A4 may decrease montelukast concentrations.
absorbed systemically and have limited adverse effects. Both of these agents have been associated with rare reports
Ipratropium is the most commonly used anticholinergic for of Churg-Strauss syndrome. This syndrome may result from
treating bronchoconstriction in asthma. It is available as an the corticosteroid dose reduction, as it has also been reported
MDI and solution for nebulization. Ipratropium has an onset of when systemic corticosteroids have been reduced or with-
action of approximately 30 minutes and a duration of action of drawn in conjunction with the initiation of high-potency
4 to 8 hours. Care should be taken not to spray the metered-dose inhaled corticosteroids.35
inhaler into or allow the nebulized solution to get in the
patients eyes, as it can cause mydriasis and blurred vision. Cromolyn and Nedocromil
The addition of ipratropium bromide to inhaled 2-agonist Cromolyn and nedocromil are inhaled anti-inammatory
therapy in acute severe asthma improves pulmonary function agents that block both the early- and late-phase response.
and decreases hospitalization rates in both adult and pediatric Both agents are considered alternative therapies to inhaled
patients.31 The benet of combining ipratropium and corticosteroids for the treatment of mild persistent asthma;
albuterol appears to be greatest in moderate to severe exacer- however, both are less effective than low doses of inhaled cor-
bations, and the combination should be considered rst-line ticosteroids.2,30 The exact mechanism of action of these agents
therapy in severe exacerbations. is not understood, but they appear to inhibit mast cell media-
Tiotropium is a long-acting inhaled anticholinergic available tor release as well as modulate other inammatory responses.3
in a DPI; it has an onset of action of approximately 30 minutes Patients receiving these agents may notice improvement in
and a duration of action longer than 24 hours.32 Because pure 1 to 2 weeks, but maximal benet may not be seen for 4 to 6
asthmatics were excluded from clinical trials for tiotropium, a weeks. Cromolyn and nedocromil appear to be similar in ef-
paucity of data exist concerning its use in asthma. cacy to the leukotriene antagonists and theophylline for per-
sistent asthma.18 Both agents are well tolerated with adverse
Leukotriene Modiers effects limited to cough and wheezing. Bad taste and headache
Leukotriene modiers either inhibit 5-lipoxygenase (zileuton) have also been reported with nedocromil. One dose of cro-
or competitively antagonize the effects of leukotriene D4 molyn or nedocromil prior to exercise or allergen exposure
(montelukast and zarlukast). These agents improve FEV1 will provide effective prophylaxis for 1 to 2 hours. Cromolyn
and decrease asthma symptoms, rescue drug use, and exacer- and nedocromil are not as effective as albuterol for prophy-
bations due to asthma. Although these agents offer the con- laxis of exercise-induced asthma.
venience of oral therapy for asthma, they are signicantly less In addition to their decreased efcacy compared to corti-
effective than low doses of inhaled corticosteroids.2,33 costeroids, a primary drawback to the use of these agents is
the need to dose them four times a day until symptoms stabi- greater than 150 mg should be administered as separate injec-
lize, after which the dosage frequency can be reduced to three tions at multiple sites. The most common adverse effects are
times a day for cromolyn and twice a day for nedocromil.18 injection site reactions and include bruising, redness, pain,
stinging, itching, and burning. Anaphylactic reactions are rare.
Methylxanthines
Theophylline is also considered an alternative to inhaled cor-
Treatment of Chronic Asthma
ticosteroids for the treatment of mild persistent asthma; how-
ever, limited efcacy compared to inhaled corticosteroids, a The intensity of pharmacologic therapy is based on the
narrow therapeutic index with life-threatening toxicity, and severity of the disease, and the least amount of medications
multiple clinically important drug interactions have severely necessary to meet the goals of asthma therapy should be
limited its use. Theophylline causes bronchodilation through used.1,3 Stepwise therapy for the treatment of chronic asthma
inhibition of phosphodiesterase and antagonism of adenosine based on disease severity is shown in Table 111.
and appears to have anti-inammatory and immunomodula-
tory properties as well.36 Mild Intermittent Asthma
Target serum theophylline concentrations are 5 to 15 mg/L In patients with mild intermittent asthma, long-term control
(28 to 83 mol/L). Adverse effects generally are not problem- medications are not necessary, and patients should use a
atic at serum concentrations below 15 mg/L (83 mol/L), but short-acting inhaled 2-agonist to prevent or treat symp-
the increased risk of adverse effects outweighs the increase in toms.2 This classication includes patients with exercise-
bronchodilation in most patients above 15 mg/L (83 mol/L).36 induced asthma, seasonal asthma, or asthma symptoms asso-
Headache, nausea, vomiting, and irritability may occur at ciated with infrequent trigger exposure. Patients can pre-treat
serum concentrations less than 20 mg/L (110 mol/L) but are with two puffs of cromolyn or nedocromil prior to exposure
rare when the dose is started low and increased slowly. More to a known trigger. The treatment of choice for exercise-
serious adverse effects, including cardiac arrhythmias, induced asthma is two inhalations of albuterol 5 minutes
seizures, toxic encephalopathy, and death can occur at higher prior to exercise.1 Cromolyn and nedocromil are less effective
concentrations.18 Arrhythmias and seizures may occur with- than albuterol for prophylaxis of exercise-induced asthma.
out nausea and vomiting, particularly in chronic toxicity.
Theophylline is primarily metabolized by CYP1A2 and Persistent Asthma
CYP3A4 and is involved in a large number of disease and drug Patients who use their short-acting inhaled 2-agonist more
interactions. Theophylline exhibits non-linear pharmacokinet- than twice a week should be treated as mild persistent asthma,
ics in the therapeutic range; therefore, serum concentration and consideration should be given to treating those with a his-
changes due to dosage adjustments and drug interactions may tory of severe exacerbations as having moderate persistent
not always be predictable.18,36 Theophylline also exhibits inter- asthma.2,3
patient variability in hepatic clearance, and therefore patients Patients with persistent asthma require daily long-term con-
receiving theophylline should have their serum theophylline trol therapy (Table 114). The NAEPP recommends that long-
concentrations monitored. term control therapy be initiated one step above the severity
classication to gain quick control, and once the asthma is con-
Omalizumab trolled, therapy should be stepped down to the least amount
Omalizumab is a recombinant humanized monoclonal anti- of medication necessary to maintain control.1 This may
IgE antibody that inhibits binding of IgE to receptors on mast require high-dose inhaled corticosteroids or a short course of
cells and basophils, resulting in the inhibition of mediator systemic corticosteroids. However, initiating treatment at a
release and attenuation of the early- and late-phase allergic moderate dose of inhaled corticosteroids may be as effective
response. It may be a treatment option for moderate to severe as initiating therapy with a high-dose inhaled corticosteroid
persistent asthmatics 12 years of age or older whose asthma is and may decrease the chances of overmedication.3,38 Therapy
not controlled by inhaled corticosteroids and who have a pos- should be evaluated on a regular basis, and a gradual step
itive skin test or in vitro reactivity to perennial allergens.37 down in long-term control therapy should be initiated when
Omalizumab signicantly decreases inhaled corticosteroid possible.1 Inhaled corticosteroids are the long-term control
use, number and length of exacerbations, and increases medication of choice at all levels of severity and in all age
asthma-related quality of life.37 groups.2 Cromolyn, leukotriene modiers, nedocromil, and
Omalizumab is given as a subcutaneous injection, and the theophylline are non-preferred alternatives to inhaled corti-
dose is based on the patients weight and initial total IgE serum costeroids.
concentration. The dosage should not be adjusted based on
subsequent total serum IgE measurements. Drug clearance Mild Persistent Asthma
appears to depend on patient weight, and dosage should be In mild persistent asthma, daily use of a low-dose inhaled corti-
adjusted if there is a signicant change in body weight. Doses costeroid is the preferred treatment in all age groups. Cromolyn,
nedocromil, and leukotriene modiers should be reserved for

patients who cannot take inhaled corticosteroids.2,25 Patient Encounter, Part 2: The Medical
History, Physical Exam, and Diagnostic
Moderate Persistent Asthma Tests
The addition of a long-acting inhaled b2-agonist to low-
PMH
dose inhaled corticosteroids is the preferred treatment of moder-
Allergic rhinitis for 6 years
ate asthma in adults and school-age children.2 Although efcacy Bronchitis 3 times in the last 6 years, last episode 6 months ago
data in pre-school children are lacking, the combination is Hospitalized with viral lower respiratory tract infections
one of the preferred treatments for moderate persistent twice at ages 2 and 4
asthma in this age group as well. Medium-dose inhaled cor-
ticosteroids have also been shown to be effective in pre- FH
Mother had asthma as a child, but outgrew it and has had
school children and are also a preferred treatment in this age
no problems with it since she was 12 or 13 years old; both
group.2 In some patients with moderate persistent asthma,
her mother and father have allergic rhinitis
particularly those with risks for severe exacerbations, the
combination of a medium-dose inhaled corticosteroid plus a SH
long-acting inhaled 2-agonist may be preferred for asthma Only child who lives at home with her mother and father in
control.2 a two-bedroom duplex built on a concrete slab; neither the
patient nor her parents smoke or drink alcohol; they have
no animals inside or outside the home
Severe Persistent Asthma
Patients with severe persistent asthma should receive high- Meds
dose inhaled corticosteroids, a long-acting inhaled 2-agonist, Fexofenadine SR 180 mg PO daily
and if needed, systemic corticosteroids.2 Because of the signif-
ROS
icant adverse effects seen with long-term therapy, efforts
Unremarkable except as described above
should be made to optimize other therapies in an attempt to
discontinue or limit systemic corticosteroid therapy. The PE
Global Initiative for Asthma guidelines suggest adding a General appearance: Small for her age but appears to be
leukotriene modier or theophylline as an alternative to start- well nourished and healthy
ing systemic corticosteroids.3 VS: Blood pressure 112/68 mm Hg, pulse 78 beats per
Leukotriene modiers may permit dose reduction of minute, respiratory rate 18/minute, temperature 37.0C
inhaled corticosteroids in moderate and severe asthmatics, (98.7F), Ht 46 (137 cm), Wt 62 lb (28 kg)
improve surrogate markers of inammation in patients treated Chest: CTA bilaterally, no wheezing
with inhaled corticosteroids plus a long acting 2-agonist, and CV: RRR, S1 and S2 normal, no rubs, gallops, or murmurs
improve asthma control in patients not controlled on low to Exts: No clubbing, cyanosis, or edema
high doses of inhaled corticosteroids.3,39 Thus, addition of a Labs
leukotriene modier should be considered for patients not con- Normal except for an eosinophil count of 7% of the total
trolled by high-dose inhaled corticosteroids and an inhaled white blood cell count
long-acting 2-adrenergic agonist before starting systemic cor-
Pulmonary function tests
ticosteroids.3 In patients in whom systemic corticosteroids are
FEV1: 1.6 L (90% predicted)
necessary for asthma control, the lowest effective dose should FVC: 1.75 L (92% predicted)
be used, and repeated attempts should be made to wean the FEV1/FVC: 0.914
patient from systemic corticosteroids or decrease the dose. Post-bronchodilator FEV1: 1.73 L (8.1% increase)
All patients with chronic asthma should be prescribed a FEV1 after exercise 1.23 L (23.1% decrease)
short-acting inhaled -agonist to treat symptoms; however,
use of these agents should be minimized. Excessive use of Given this additional information, what is your assess-
inhaled short-acting 2-agonists is an indicator of inadequately ment of the patients condition?
controlled asthma, and long-term control therapy should be Identify your treatment goals for this patient.
intensied. Excessive use can be demonstrated by daily use of What nonpharmacologic and pharmacologic alternatives
are feasible for this patient?
these agents, use of more than one canister a month, increas-
Outline a treatment plan for this patient that includes
ing use, or lack of expected effect.2 Additionally, failure to have
nonpharmacologic therapy, pharmacologic therapy, and
a rapid and sustained response to these agents in worsening a monitoring plan. Justify your therapeutic selections.
asthma indicates the need for further medical attention and
intensication of therapy.3 Use of an inhaled short-acting 2-
agonist more than twice a week to treat symptoms is cause to
consider stepping up long-term control therapy.10
FIGURE 112. Home manage-

Assess severity ment of acute asthma exacer-
Measure PEF: Value less than 50% bation. Patients at risk for
personal best or predicted suggests
severe exacerbation.
asthma-related death should
receive immediate clinical
Note signs and symptoms: Degrees of attention after initial treatment.
cough, breathlessness, wheeze, and PEF, peak expiratory ow.
chest tightness correlate imperfectly
with severity of exacerbation. (From Kelly HW, Sorkness CA.
Accessory muscle use and Asthma. In: DiPiro JT, Talbert
suprasternal retractions suggest RL, Yee GC, et al, (eds.)
severe exacerbation.
Pharmacotherapy: A
Pathophysiologic Approach.
Initial treatment
6th ed. New York: McGraw-Hill;
Inhaled short-acting 2-agonist:
Up to three treatments of 24 2005: 516, with permission.)
puffs by MDI at 20-minute
intervals or single nebulizer
treatment.
Good response Incomplete response

Poor response
Mild Exacerbation Moderate Exacerbation
PEF greater than 80% predicted or Severe Exacerbation
PEF 50%80% predicted or personal
personal best PEF less than 50% predicted or personal
best
No wheezing or shortness of breath best
Persistent wheezing and shortness
Response to 2-agonist sustained for 4 hours Marked wheezing and shortness of breath
of breath
Add oral corticosteroid.
May continue 2-agonist every Add oral corticosteroid.
Repeat 2-agonist immediately.
3 4 hours for 24 48 hours. Continue 2-agonist.
If distress is severe and non-
For patients on inhaled
responsive, call your doctor and
corticosteroids, double dose for
Contact clinician urgently (this proceed to emergency department;
710 days.
day) for instructions. consider calling ambulance or 9-1-1.
Contact clinician for follow-up

instructions. Proceed to emergency department.
Treatment of Acute Severe Asthma incomplete responses should start a short course of oral pred-
nisone. Corticosteroid therapy should continue until PEF is at
The optimal treatment of acute severe asthma depends on the
least 80% of predicted or personal best.40 Short-acting 2-agonist
severity of the exacerbation (Figs. 112 and 113). The patients
therapy can be continued at two to four inhalations every 3 to
condition usually deteriorates over several hours, days, or weeks;
4 hours for several days until symptoms resolve. Continued
however, rapid deterioration can occur in some patients.3
reliance on short-acting 2-adrenergic agonists for prolonged
Gradual deterioration may indicate failure of long-term con-
periods indicates a need to seek medical care.
troller therapy. Patients with rapid deterioration usually respond Patients with incomplete responses should contact their
well to bronchodilator therapy.40 Severity at the time of the eval- health care provider immediately for instructions, while those
uation can be estimated by signs and symptoms, but patient with a poor response should proceed directly to the emer-
response 30 minutes after inhalation of a bronchodilator is the gency department.1 In the emergency department, baseline
best predictor of outcome.12 PEF measurements and oxygen saturation should be moni-
Starting therapy at home allows for rapid initiation and early tored. PEF should be monitored before and 15 to 20 minutes
assessment of response. Patients should follow their written after bronchodilator administration. Treatment should be ini-
action plan as symptoms intensify or lung function deteriorates. tiated as soon as lung function is assessed (Fig. 113). Dosages
An algorithm for the initial treatment of an asthma exacerbation for emergency department and hospital use of quick relief
at home is shown in Fig. 112. Based on the initial response to medications are shown in Table 115.
2-agonist therapy, the severity of the exacerbation can be Patients with an oxygen saturation less than 90% (less than
assessed, and treatment can be appropriately intensied.1 95% in children, pregnant women, and patients with co-existing
Patients with a good response to therapy should consider heart disease) should receive oxygen with the dose adjusted to
intensication of anti-inammatory therapy.1 Although keep oxygen saturation above these levels.3,12,40 Hypoxemia
guidelines recommend doubling the previous inhaled corti- usually results from a ventilation/perfusion mismatch, and low
costeroid dose, this may not be necessary for mild exacerba- oxygen levels (less than 30% of the fraction of inspired air)
tions.3,41,42 Treatment selection should be individualized based administered by nasal cannula or facemask are sufcient to
on what has worked for the patient previously. reverse hypoxemia in most patients.
Patients with mild exacerbations whose response to inhaled Infants and young children may present with dehydration due
short-acting 2-agonists lasts less than 1 hour and patients with to increased respiratory losses and decreased intake.1,3 Rehydration
Initial assessment
History, physical examination (auscultation, use of accessory muscles, heart rate,
respiratory rate), PEF or FEV1, oxygen saturation, and other tests as indicated
FEV1 or PEF greater than 50% FEV1 or PEF less than 50% (severe exacerbation) Impending or actual respiratory arrest
Inhaled 2-agonist by metered-dose inhaler or Inhaled high-dose 2-agonist and anticho-linergic by Intubation and mechanical ventilation with 100%
nebulizer, up to three doses in first hour nebulization every 20 minute or continuously for 1 hour O2
Oxygen to achieve O2 saturation greater than or Oxygen to achieve O2 saturation greater than or equal to Nebulized 2-agonist and anticholinergic
equal to 90% 90% Intravenous corticosteroid
Oral systemic corticosteroids if no immediate Oral systemic corticosteroid
response or if patient recently took oral systemic
corticosteroid Admit to hospital intensive care (see
Repeat assessment box below)
Symptoms, physical examination, PEF, O2
saturation, other tests as needed
Moderate exacerbation Severe exacerbation

FEV1 or PEF 50% 80% predicted/personal best FEV1 or PEF less than 50% predicted/personal best
Physical exam: moderate symptoms Physical exam: severe symptoms at rest, accessory
Inhaled short-acting 2-agonist every 60 minutes muscle use, chest retraction
History: high-risk patient
Systemic corticosteroid
No improvement after initial treatment
Continue treatment 13 hours, provided there
is improvement Inhaled short-acting 2-agonist, hourly or
continuous + inhaled anticholinergic
Oxygen
Systemic corticosteroid
Good response Incomplete response Poor response

FEV1 or PEF greater than or equal to 70% FEV1 or PEF greater than or equal FEV1 or PEF less than 50%
Response sustained 60 minute after last treatment to 50% but less than 70% PCO2 greater than or equal to 42 mm Hg
No distress Mild-to-moderate symptoms Physical exam: symptoms severe, drowsiness,
Physical exam: normal confusion
Individualized decision re:
hospitalization (see text)
Admit to hospital ward

Inhaled 2-agonist + inhaled
anticholinergic
Discharge home Systemic (oral or intravenous)
Continue treatment with inhaled 2-agonist corticosteroid Admit to hospital intensive care
Continue course of oral systemic corticosteroid Oxygen Inhaled 2-agonist hourly or continuously +
Patient education Monitor FEV1 or PEF, O2 inhaled anticholinergic
Review medicine use saturation, pulse Intravenous corticosteroid
Review/ initiate action plan Oxygen
Improve
Recommend close medical follow-up Possible intubation and mechanical ventilation
Discharge home
Continue treatment with inhaled
2-agonist
Continue course of oral systemic
corticosteroid
Patient education
Review medicine use
Review/initiate action plan
Recommend close medical
follow-up
FIGURE 113. Emergency department and hospital-based management of asthma exacerbation. FEV1, forced expiratory volume
in 1 second; PCO2, partial arterial pressure of carbon dioxide; PEF, peak expiratory ow; O2, oxygen. (From Kelly HW, Sorkness CA.
Asthma. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill;
TABLE 115. Dosages of Selected Medications for Asthma Exacerbations in Emergency Medical Care or Hospital

Short-Acting Inhaled
b2-Agonists
Albuterol Nebulizer solution:
5 mg/mL (5%) 2.55 mg every 20 minutes for 0.15 mg/kg (minimum dose 2.5 mg) every
2.5 mg/3 mL 3 doses, then 2.510 mg every 20 minutes for 3 doses, then 0.150.3 mg/kg
1.25 mg/3 mL 14 hours as needed, or up to 10 mg every 14 hours as needed, or
0.63 mg/3 mL 1015 mg/hour continuously 0.5 mg/kg per hour by continuous nebulization
MDI: 90 mcg/puff 48 puffs every 20 minutes up to 48 puffs every 20 minutes for 3 doses, then
4 hours, then every 14 hours every 14 hours inhalation maneuver; use
as needed spacer/holding chamber
Levalbuterol Nebulizer solution 1.252.5 mg every 20 minutes for 0.075 mg/kg (maximum dose 1.25 mg) every
0.31 mg/3 mL 3 doses, then 1.255 mg every 20 minutes for 3 doses, then 0.0750.15 mg/kg,
0.63 mg/3 mL 14 hours as needed or up to 5 mg, every 14 hours as needed or
1.25 mg/3 mL 57 mg/hour continuously 0.25 mg/hour by continuous nebulization
MDI: 45 mcg/puff See albuterol dose; thought to be See albuterol dose; thought to be twice as
twice as potent as albuterol on a potent as albuterol on a mg basis
mg basis
Anticholinergics
Ipratropium Nebulizer solution 0.5 mg every 30 minutes for 3 doses 0.25 mg every 20 minutes for 3 doses, then
bromide 0.25 mg/mL then every 24 hours as needed every 24 hours
MDI CFC: 18 mcg/puff 48 puffs as needed 48 puffs as needed
MDI HFA: 17 mcg/puff
Ipratropium Nebulizer solution:
with albuterol 0.5 mg ipratropium 3 mL every 30 minutes for 3 doses, 1.5 mL every 20 minutes for 3 doses,
bromide and then every 24 hours as needed then every 24 hours
2.5 mg albuterol
per 3-mL vial
MDI: 18 mcg of 48 puffs as needed 48 puffs as needed
ipratropium bromide
and 90 mcg
of albuterol per puff
Systemic
Corticosteroids
Methylprednisolone Tablets: 2, 4, 8, 16, 32 mg 120180 mg/day in 3 or 4 divided doses 1 mg/kg every 6 hours for 48 hours, then
Injection: 40-mg, for 48 hours, then 6080 mg/day 12 mg/kg per day (maximum of 60 mg/day)
125-mg, 500-mg, 1-g, until PEF reaches 70% of predicted in 2 divided doses until PEF 70% of predicted
and 2-g vials or personal best or personal best
Prednisolone Tablets: 5 mg
Oral liquid: 5 mg/5 mL,
15 mg/5 mL
Prednisone Tablets: 1, 2.5, 5, 10,
20, 50 mg
Oral liquid: 5 mg/mL,
5 mg/5 mL
a
CFC, chlorouorocarbon; HFA, hydrouoroalkane; MDI, metered-dose inhaler; PEF, peak expiratory ow.
Adapted from: National Institutes of Health, National Heart Lung and Blood Institute. National Asthma and Education Prevention Program.
http://www.nhlbi.nih.gov/guidelines/asthma/asthmafullrpt.pdf; accessed August 2005; used with permission.
therapy is appropriate and should be guided by an assessment of especially compared to previous exacerbations; (3) all current
uid status from urine output, urine specic gravity, mucous medications and time of last dose; and (4) identication of
membrane moisture, and serum electrolytes.1,18 Dehydration is risk factors for fatal asthma. These risk factors include a past
not problematic in older children and adults; therefore, aggressive history of severe asthma, use of more than two canisters of a
rehydration is not recommended. short-acting 2-adrenergic agonists in a month, current use of
After the initiation of treatment, the health care profes- systemic corticosteroids or recent withdrawal from corticos-
sional should conduct an initial history that includes: (1) the teroids, cardiopulmonary comorbidities, serious psychiatric
time of onset of symptoms; (2) severity of the symptoms, or psychosocial problems, low socioeconomic status and
urban residence, illicit drug use, and sensitivity to the mold of the risk to the fetus, asthma exacerbations should be man-
allergen Alternaria.1 aged aggressively. Albuterol is the drug of choice for the treat-
A focused physical exam should be conducted that includes ment of asthma symptoms and exacerbations in pregnancy.43
the general presentation (level of alertness, uid status, pres-
ence of cyanosis, and use of accessory muscles), auscultation Exercise-Induced Asthma
of the lungs, heart rate, and respiratory rate. Exercise is one of the most common precipitants of asthma
Routine antibiotic use is not warranted because the pri- symptoms, and exercise-induced asthma is commonly seen in
mary infectious agents associated with asthma exacerbations children and adolescents. Exercise may be a precipitant in up to
are viruses.2,3 Antibiotics should be reserved for situations 90% of the population with asthma and may be the rst precip-
when bacterial infection is strongly suspected (e.g., fever and itant noticed in an asthma patient.18 Shortness of breath, wheez-
purulent sputum, pneumonia, and suspected sinusitis). ing, or chest tightness usually occur during or shortly after vig-
Theophylline is not recommended for treatment of acute orous exercise and resolve within 30 to 60 minutes.
asthma.2 It provides no additional benet when optimal Patients with exercise-induced asthma should warm-up
inhaled bronchodilators are used and increases the risk of prior to vigorous exercise and cover their mouth and nose with
adverse events. Similarly, although magnesium has bron- a scarf or mask during cold weather. Increased physical condi-
chodilator activity, it offers no signicant benets when opti- tioning and gradually decreasing the intensity of exercise prior
mal bronchodilator therapy is used.12,40 to stopping may also help prevent bronchospasm. Pre-treatment
Heliox is a mixture of helium and oxygen that results in a with albuterol 5 minutes prior to exercise is the treatment of
lower density of inspired air, thereby improving oxygen delivery. choice and will protect against bronchospasm for 2 to 3 hours.1
Heliox does not appear to have any signicant adverse effects, Pretreatment with cromolyn sodium or nedocromil is also effec-
but it does limit oxygen ow to approximately 30% and there- tive in preventing bronchospasm, but it is not as effective as
fore is not useful in patients needing higher concentrations of albuterol.18 Pretreatment with salmeterol or formoterol can pro-
oxygen.12,40 tect against bronchospasm for up to 12 hours; however, toler-
Patients who do not respond adequately to intensive therapy ance to the bronchoprotective effects occurs with repeated use
in the emergency department within 3 to 4 hours should be and a more reasonable expectation for protection is for 6 to
admitted to the hospital. Patients responding to therapy in the 9 hours. Pretreatment with a leukotriene modier and regular
emergency department with a sustained response to inhaled treatment with inhaled corticosteroids also prevents bron-
2-agonists (PEF greater than 60%) that lasts at least an hour can chospasm associated with exercise. Consideration should be
be discharged home.1,12 It is important to ensure that the patient given to initiating long-term control therapy in mild intermit-
has an inhaled short-term 2-agonist, is restarted on mainte- tent asthmatics using multiple weekly doses of a bronchodilator
nance medications, and receives a 3- to 10-day course of oral cor- to prevent asthma symptoms associated with exercise.3
ticosteroids. Prior to discharge, the health care provider should
instruct the patient on what to do if asthma symptoms worsen, Aspirin Sensitivity
review medication use, and instruct the patient to schedule a Patients with aspirin-sensitive asthma are usually adults and
follow-up visit with their health care provider in 3 to 5 days.1 often present with the triad of rhinitis, nasal polyps, and
asthma. In this population, acute asthma may occur within
Special Populations minutes of ingesting aspirin or another non-steroidal anti-
inammatory agent. Although acetaminophen is thought to be
Pregnancy safe in this population, doses larger than 1 gram may cause
Approximately 4% to 8% of pregnant women are affected by acute asthmatic reactions in some patients, and the incidence of
asthma with roughly one-third of them experiencing worsen- asthma is signicantly greater in frequent users of acetamino-
ing asthma during pregnancy.43 Because inadequate control of phen compared to non-users.44,45 Patients with aspirin-sensitive
asthma is a greater risk to the fetus than is the risk of asthma asthma may be able to tolerate cyclooxygenase-2 inhibitors;
medication use, it is safer for pregnant women to have their however, given the potentially serious adverse events that could
asthma appropriately treated with medications than to risk occur in aspirin-sensitive asthmatics, the rst dose of a
worsening asthma.43 Goals for asthma therapy in pregnancy cyclooxygenase-2 inhibitor should be given under the observa-
are the same as those for the general population, and recent tion of a health care provider with rescue drugs available.44
guidelines propose a stepwise approach to asthma therapy in
pregnancy that is similar to the guidelines for the general pop-
OUTCOME EVALUATION
ulation with respect to preferred therapies for each step.43
Because budesonide has the most safety data in humans, it
Chronic Asthma
is the preferred inhaled corticosteroid and is the only inhaled
corticosteroid classied as pregnancy category B; however, Monitor symptoms such as wheezing, shortness of breath,
there are no data indicating that other inhaled corticosteroids chest tightness, cough, and nocturnal awakenings due to
contribute to increased risk to the mother or fetus.43 Because asthma symptoms. Daytime symptoms should occur no
more frequently than twice a week, and nocturnal symptoms

should occur twice a month or less. Patients with more fre- Patient Encounter, Part 3
quent symptoms should have their long-term control med-
ications increased to the next step of therapy.
Monitor and maintain PEF above 80% of personal best; PEF
Follow-Up
variability should be less than 20%. Patients with PEF rates
Six months later, RBs mother brings her back for a check-up.
consistently greater than 80% over several months should be The patient has been using her albuterol inhaler 3 to 4 times
evaluated for a step down in long-term control therapy. a week to treat symptoms, and she is waking up about twice
Patients with a PEF less than 80% of personal best should a month with shortness of breath. She has developed a sore
begin to monitor PEF twice daily and consult their asthma mouth. White patches on the back of her tongue and the
action plan. Patients with a PEF less than 50% of personal best inside of her cheek are observed on examination.
should immediately use their short-acting inhaled 2-agonist Meds
and consult their asthma action plan. Qvar 84 mcg/puff, 1 puff 4 times a day
Monitor patient activity levels. Inability of a patient to perform Proventil HFA 2 puffs PRN for symptoms
routine physical activities indicates inappropriate therapy, and Flonase 1 puff in each nostril daily
long-term control medications should be increased according
to the next step of therapy. What further information do you need before altering this
Monitor frequency of patient exacerbations. Frequent exac- patients therapy?
erbations, unscheduled clinic visits, emergency department How would you counsel this patient to prevent further
visits, and hospitalizations due to asthma may indicate a adverse reactions?
Assuming that the patient is currently using her medica-
non-adherent patient or the need to step up long-term con-
tions appropriately, how would you adjust this patients
trol medications.
medication?
Monitor patient use of long-term control medications to
ensure adherence to the medication plan. Patients not adher-
ing to the long-term control medication regimen should be
re-educated on the importance of these medications for Patient Care and Monitoring
asthma control.
Monitor use of short-acting inhaled 2-agonists. Use of these
agents more than twice a week in intermittent asthma may
indicate the need to initiate long-term control therapy. Use Chronic Asthma
1. Obtain a thorough medical history focusing on disease
of more than one canister per a month indicates the need to
states that may worsen the severity of asthma.
step up long-term control therapy.
Monitor for adverse events from medications, including can- 2. Ask the patient about the frequency and severity of
symptoms, when symptoms occur, and whether or not
didiasis and dysphonia from inhaled corticosteroids.
the symptoms are associated with exposure to known
allergens. Ask the patient about previous emergency
department visits and hospitalizations due to asthma.
Acute Severe Asthma
3. Use the patients symptoms and pulmonary function tests
Monitor PEF, which should increase to greater than 60% of to classify disease severity.
personal best or predicted after the rst three doses of an 4. Explain the goals of therapy to the patient and ask if (s)he
inhaled short-acting 2-agonist. has any personal therapeutic goals.
Monitor patients for hypoxemia. Oxygen saturation should 5. Develop a patient education plan that ts the patients
be greater than 90% in adults and greater than 95% in chil- needs. Educate about the differences between the asth-
dren, pregnant women, and patients with co-existing cardio- matic and normal lung and what happens to the lung
vascular disease. during an asthma attack. Counsel the patient on how
In patients with severe exacerbations, monitoring of PCO2 their medications work and differentiate between long-
should be considered. Patients with acute asthma usually term control and quick relief medications.
have a respiratory alkalosis, and a normal or increased PCO2 6. Provide the patient with a specic allergen avoidance
indicates the potential for respiratory failure. plan and counsel all patients to avoid secondhand
Monitor serum potassium in patients receiving high-dose or tobacco smoke.
continuous nebulization of a short-acting 2-agonist. Serum 7. Demonstrate the appropriate use of drug delivery devices
potassium concentrations should be obtained upon admis- and peak ow meters; then have the patient perform these
sion, and if hypokalemic, every 4 hours (after each 30 to 40 activities for you. If the task is performed incorrectly,
mEq or mmol of replacement) until the patients potassium demonstrate the skill again, emphasizing the incorrect step
is stable. Potassium should be monitored every 3 to 6 and have the patient re-demonstrate the skill.
months after discharge. (Continued )
ABBREVIATIONS
Patient Care and Monitoring (Continued )
AHR: airway hyperresponsiveness
8. Prepare a patient-specic self-monitoring plan and CFC: chlorouorocarbon
review it with the patient. Educate the patient on the CYP: cytochrome P-450 isoenzyme
signs and symptoms of asthma deterioration and when DPI: dry powder inhaler
and how to take rescue actions. FEV1: forced expiratory volume in 1 second
9. Assess the patients adherence to long-term control FVC: forced vital capacity
therapy. If the patient is non-adherent, stress the HFA: hydrouoroalkane
importance of adherence to this therapy. Evaluate IgE: immunoglobulin E
the complexity of the patients treatment plan and MDI: metered-dose inhaler
simplify it as much as possible. Determine whether NAEPP: National Asthma Education and Prevention Program
the patient would benefit from an inhaled PaO2: partial arterial oxygen pressure
corticosteroid/inhaled long-acting 2-agonist PCO2: partial arterial pressure of carbon dioxide
combination product. PEF: peak expiratory ow
10. Assess the patient for adverse effects, particularly can- TH2: type 2 T helper CD4+ cell
didiasis and dysphonia associated with inhaled
corticosteroids. Reference lists and self-assessment questions and answers are
11. Evaluate therapy on a regular basis. Assess the patients available at www.ChisholmPharmacotherapy.com.
control of asthma by evaluating symptoms, PEF diary
entries, and rescue medication use. Step long-term con- Log into the website: www.pharmacotherapyprinciples.com
trol therapy up or down based on these parameters. for information on obtaining continuing education credit for
Before stepping up therapy, reassess the patients inhaler this chapter.
technique to assure appropriate drug delivery.
Acute Severe Asthma
1. Assess the patients PEF. KEY REFERENCES AND READINGS
2. Assess whether or not the patient can use an MDI with a
Currie GP, Devereux GS, Lee DKC, Ayres JG. Recent developments in
spacer or holding chamber. If the patient cannot use the
asthma management. BMJ 2005;330:585589.
device, determine whether someone can assist the patient
de Benedictis FM, Selvaggio D. Use of inhaler devices in pediatric
with the inhaler device, or whether a nebulizer is necessary.
asthma. Pediatr Drugs 2000;5:629638.
3. Initiate therapy with a short-acting 2-agonist and 2 to Kelly HW. What is new with the 2-agonists: Issues in the manage-
6 L/minute of oxygen if needed. ment of asthma. Ann Pharmacother 2005;39:931938.
4. Perform a brief medical history to determine the time of Lemanske RF Jr, Busse WW. 6. Asthma. J Allergy Clin Immunol 2003;
symptom onset, symptom severity, symptom severity in 111:S502S519.
relation to previous exacerbations, current medications, McFaddden ER Jr. Acute severe asthma. Am J Respir Crit Care Med
previous emergency department visits or hospitalizations 2003;168:740759.
due to asthma, previous history of respiratory failure, and National Institutes of Health, National Heart Lung and Blood
psychiatric or psychological disorders. Institute. Global Initiative for Asthma. Global Strategy for
5. Assess the patients general appearance, use of accessory Asthma Management and Prevention. Revised 2004. NHLBI/
muscles, respiratory rate, heart rate, lung sounds, pulsus WHO Workshop Report. NIH Publication No. 02-3659.
paradoxus, PEF, and oxygen saturation. Bethesda, MD: United States Department of Health and Human
6. Reassess pulmonary function every 20 to 30 minutes. If Services, http://www.ginasthma.org; accessed March 2006.
there was not an immediate response to the inhaled short National Institutes of Health, National Heart Lung and Blood Institute.
acting 2-agonist, initiate systemic corticosteroid therapy. National Asthma Education and Prevention Program. Expert
If the patient is not improving, add ipratropium to the Panel Report. Guidelines for the Diagnosis and Management of
patients therapy and continue with a high-dose inhaled Asthma. Update on Selected Topics 2002. http://www.nhlbi.nih.
short-acting 2-agonist. gov/guidelines/asthma/asthmafullrpt.pdf; accessed March 2006.
7. Assess the patient for hospitalization or discharge home. NHLBI, National Asthma Education and Prevention Program Expert
Panel Report 2. Guidelines for the Diagnosis and Management
8. If the patient is discharged home, ensure that the patient
of Asthma. NIH Publication No. 97-4051. Bethesda, MD:
has a short-acting 2-agonist, review the appropriate
United States Department of Health and Human Services, 1997.
technique for inhaler use with the patient, and ensure
Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults. A review.
that the patient has a prescription for 3 to 10 days of oral
Chest 2004;125:10811102.
corticosteroids.
9. Restart the patient on maintenance therapy. Instruct the
patient on what to do if asthma should worsen and to
follow-up with his/her health care provider in 3 to 5 days.
12 CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Tara R. Whetsel and Nicole D. Verkleeren
LEARNING OBJECTIVES
1. Describe the pathophysiology of chronic obstructive pulmonary disease (COPD).

2. Identify signs and symptoms of COPD.
3. List the treatment goals for a patient with COPD.
4. Design an appropriate COPD treatment regimen based on patient-specic data.
5. Develop a monitoring plan to assess effectiveness and adverse effects of pharmacotherapy
for COPD.
6. Formulate an appropriate education plan for a patient with COPD.
KEY CONCEPTS reversible. It is caused by exposure to noxious particles or

gases, most commonly cigarette smoke. It is a major cause of
Inammation plays a key role in the pathophysiology of COPD, morbidity and mortality and a leading cause of disability in
but it differs from that seen in asthma; therefore, the use of and the United States.
response to anti-inammatory medications are different. COPD includes chronic bronchitis and emphysema. Chronic
An integrated approach of health maintenance (e.g., smoking bronchitis is dened clinically as a chronic productive cough for
cessation), drug therapy, and supplemental therapy (e.g., oxy- at least 3 months in each of two consecutive years in a patient in
gen and pulmonary rehabilitation) should be used in a step- whom other causes have been excluded.1 Emphysema is dened
wise manner. pathologically as the presence of permanent enlargement of the
Smoking cessation is the only intervention known to slow the airspaces distal to the terminal bronchioles, accompanied by
rate of decline in pulmonary function in patients with COPD. destruction of their walls without obvious brosis.1 The major
Bronchodilators are the mainstay of treatment for sympto- risk factor for both conditions is cigarette smoking, and many
matic COPD. They reduce symptoms and improve exercise patients share characteristics of each condition. Therefore, new
tolerance and quality of life. consensus guidelines have moved away from using these subsets
In symptomatic patients with severe COPD and frequent and instead focus on chronic airow limitation.
exacerbations, regular treatment with inhaled corticosteroids The Global Initiative for Chronic Obstructive Lung Disease
decreases the number of exacerbations per year and improves (GOLD) is an expert panel of health professionals who have
health status; however, corticosteroids do not slow the long- developed a consensus document with recommendations for
term decline in pulmonary function. the diagnosis and care of patients with COPD.2 The online
Antibiotics should be used in patients with COPD exacerba- document is updated annually and is commonly referred to as
tions who have either of the following characteristics: (1) at the GOLD guidelines. The American Thoracic Society (ATS)
least two of three cardinal symptoms: increased dyspnea, spu- and the European Respiratory Society (ERS) have jointly pub-
tum volume, or sputum purulence; or (2) a severe exacerba- lished standards for the diagnosis and treatment of patients
tion requiring mechanical ventilation. with COPD.1 The ATS/ERS guidelines provide more specic
recommendations on oxygen therapy, pulmonary rehabilita-
Chronic obstructive pulmonary disease (COPD) is a progres- tion, and other treatment issues than the broader GOLD
sive disease characterized by airow limitation that is not fully guidelines.
231
EPIDEMIOLOGY AND ETIOLOGY
In 2001, 12.1 million United States adults 25 years of age and

older reported having COPD.3 The true prevalence is larger;
COPD is underdiagnosed because many patients have few or
no symptoms in the early stages.
COPD is the fourth leading cause of death in the United
States; in 2000, 119,000 adults died from the disease.3 In 2002,
COPD was estimated to cost the United States $32.1 billion,
with direct medical costs accounting for $18 billion of the
total.3 Morbidity, mortality, and costs are all expected to
increase over the next decade.
Exposures and host factors play a role in the development of
COPD. Cigarette smoking is the leading cause of COPD and
accounts for 80% to 90% of cases in developed countries.4
Occupational exposure to dusts and chemicals (vapors, irritants,
and fumes) also plays a role. Environmental air pollution has
been implicated as an etiologic factor, but its exact role is
unclear. Not all smokers develop clinically signicant COPD,
which suggests that genetic susceptibility plays a role. The best FIGURE 121. Pathophysiology of chronic obstructive
pulmonary disease.
documented genetic factor is a rare hereditary deciency of a
The physiologic abnormalities usually develop in this order.
1-antitrypsin (AAT). Severe deciency of this enzyme results in
premature and accelerated development of emphysema. Asthma
and airway hyperresponsiveness have been identied as risk fac- Eosinophils may be increased in some patients, particularly
tors, but how they inuence the development of COPD is during exacerbations. Activated inammatory cells release a
unknown. Failure to reach maximal lung function, due to recur- variety of mediators, most notably leukotriene B4, interleukin-
rent infections or exposure to tobacco smoke during childhood, 8, and tumor necrosis factor- (TNF-). Various proteinases,
may also increase the risk of COPD. such as elastase, cathepsin G, and proteinase-3, are secreted by
activated neutrophils. These mediators and proteinases are
capable of sustaining inammation and damaging lung
PATHOPHYSIOLOGY structures.
Proteinases and antiproteinases are part of the normal pro-
COPD is characterized by pathologic changes in the central air- tective and repair mechanisms in the lungs. The imbalance of
ways, peripheral airways, lung parenchyma, and pulmonary proteinase-antiproteinase activity in COPD is a result of either
vasculature. Chronic inammation in the lung from repeated increased production or activity of destructive proteinases or
exposure to noxious particles and gases is primarily responsible inactivation or reduced production of protective antipro-
for these changes.2 An imbalance between proteinases and teinases. AAT (an antiproteinase) inhibits trypsin, elastase, and
antiproteinases in the lung and oxidative stress are also several other proteolytic enzymes. Deciency of AAT results in
thought to be important in the pathogenesis of COPD. These unopposed proteinase activity, which promotes destruction of
processes may be a result of ongoing inammation or may arise alveolar walls and lung parenchyma, leading to emphysema.
from environmental (e.g., oxidants in cigarette smoke) or Markers of oxidative stress (e.g., hydrogen peroxide, nitric
genetic (e.g., AAT deciency) factors (Fig. 121).2 In addition to oxide, and isoprostane F2-III) have been found in the epithelial
these destructive processes, chronic inammation and exposure uid, breath, and urine of cigarette smokers and patients with
to noxious particles and gases disrupts or impairs the normal COPD.2 Increased oxidative stress contributes to COPD in a
protective and repair mechanisms. variety of ways. Oxidants (e.g., reactive oxygen species, super-
Inammation is present in the lungs of all smokers. It is oxide, and nitric oxide) can react with and damage a variety of
unclear why only 15% to 20% of smokers develop COPD, but molecules leading to cell dysfunction and damage to the lung
susceptible individuals appear to have an exaggerated inam- extracellular matrix. Oxidative stress promotes inammation and
matory response.5 The inammation of COPD differs from contributes to the proteinase-antiproteinase imbalance by reduc-
that seen in asthma, so the use of anti-inammatory medica- ing antiproteinase activity. In addition, oxidants constrict airway
tions and the response to those medications are different. The smooth muscle, contributing to reversible airway narrowing.
inammation of asthma is mainly mediated through eosinophils In the central airways (the trachea, bronchi, and bronchioles
and mast cells. In COPD the primary inammatory cells greater than 2 to 4 mm in internal diameter), inammatory cells
include neutrophils, macrophages, and CD8+ T lymphocytes. and mediators stimulate mucus-secreting gland hyperplasia
CHAPTER 12 / CHRONIC OBSTRUCTIVE PULMONARY DISEASE 233
and mucus hypersecretion. Mucus hypersecretion and ciliary

dysfunction lead to chronic cough and sputum production. Clinical Presentation of Chronic
The major site of airow obstruction is the peripheral airways Obstructive Pulmonary Disease
(small bronchi and bronchioles with an internal diameter less
than 2 mm). Three mechanisms are postulated to be involved in
General
the narrowing of these small airways.2 Airways may be blocked
Patients with COPD are initially asymptomatic. The dis-
by inammatory exudates and mucus hypersecretion. Loss of ease is usually not diagnosed until declining lung func-
elasticity and destruction of alveolar attachments leads to loss tion leads to signicant symptoms and prompts patients
of support and closure of small airways during expiration. to seek medical care.
Inltration of inammatory cells, increased smooth muscle tis-
Symptoms
sue, and brosis cause thickening of airway walls. Of these
The onset of symptoms is variable but often does not
mechanisms, the structural changes in the airway walls are the
occur until the forced expiratory volume in one second
most important cause of xed airow obstruction. (FEV1) has fallen to approximately 50% of predicted.2
As airow obstruction worsens, the rate of lung emptying is Initial symptoms include chronic cough (duration greater
slowed and the interval between inspirations does not allow than 3 months), which may be intermittent at rst;
expiration to the relaxation volume of the lungs. This leads to chronic sputum production; and dyspnea on exertion.
pulmonary hyperination, which initially only occurs during As COPD progresses, dyspnea at rest develops and the
exercise, but later is also seen at rest. Hyperination contributes ability to perform activities of daily living declines.
to the discomfort associated with airow obstruction by atten- Signs
ing the diaphragm and placing it at a mechanical disadvantage. Observation of the patient may reveal use of accessory
In advanced COPD, airow obstruction, damaged bronchi- muscles of respiration (manifested as paradoxical move-
oles and alveoli, and pulmonary vascular abnormalities lead to ments of the chest and abdomen, in a see-sawtype
impaired gas exchange. This results in hypoxemia and eventu- motion), pursed-lips breathing, and hyperination of the
ally hypercapnia. Hypoxemia is initially present only during chest with increased anterior-posterior diameter (barrel
exercise but occurs at rest as the disease progresses. Inequality chest).
in the ventilation/perfusion ratio (VAQ) is the major mecha- On auscultation of the lungs, patients may have distant
breath sounds, wheezing, a prolonged expiratory phase
nism behind hypoxemia in COPD.
of respiration, and rhonchi.
Pulmonary hypertension develops late in the course of
In advanced COPD, signs of hypoxemia may include
COPD, usually after the development of severe hypoxemia. It cyanosis and tachycardia.
is the most common cardiovascular complication of COPD Signs of cor pulmonale include increased pulmonic com-
and can result in cor pulmonale, or right-sided heart failure. ponent of the second heart sound, jugular venous disten-
Hypoxemia plays the primary role in the development of pul- tion (JVD), lower extremity edema, and hepatomegaly.
monary hypertension by causing vasoconstriction of the pul-
Laboratory Tests
monary arteries and by promoting vessel wall remodeling. Hematocrit may be elevated and may exceed 55%
Destruction of the pulmonary capillary bed by emphysema (polycythemia).
further contributes by increasing the pressure required to per- Arterial blood gases (ABGs) should be obtained in patients
fuse the pulmonary vascular bed. Cor pulmonale is associated with an FEV1 less than 40% predicted or signs or symp-
with venous stasis and thrombosis that may result in pul- toms suggestive of cor pulmonale or respiratory failure.2
monary embolism. Another important systemic effect is the COPD patients characteristically exhibit normal or
progressive loss of skeletal muscle mass, which contributes to increased arterial carbon dioxide tension (PaCO2) and
exercise limitations and declining health status. decreased arterial oxygen tension (PaO2).
An 1-antitrypsin level should be obtained in younger
patients (less than 45 years old) presenting with COPD
DIAGNOSIS signs and symptoms, especially if there is a strong family
history of emphysema.
A suspected diagnosis of COPD should be based on the patients
symptoms and/or history of exposure to risk factors.
Spirometry is required to conrm the diagnosis. The presence It is important to distinguish COPD from asthma because
of a postbronchodilator FEV1/FVC ratio less than 70% [the ratio treatment and prognosis differ. Differentiating factors include
of FEV1 to forced vital capacity (FVC)] conrms the presence of age of onset, smoking history, triggers, occupational history, and
airow limitation that is not fully reversible.1,2 Spirometry results degree of reversibility measured by pre- and postbronchodilator
can further be used to classify COPD severity (Table 121). spirometry. In some patients a clear distinction between asthma
Full pulmonary function tests (PFTs) with lung volumes and dif- and COPD is not possible. Management of these patients
fusion capacity and arterial blood gases are not necessary to should be similar to that of asthma. Bronchiectasis, cystic
establish the diagnosis or severity of COPD. brosis, obliterative bronchiolitis, congestive heart failure, and
TABLE 121. GOLD Classication of COPD Severitya
Stage Category FEV1/FVC FEV1 Symptoms

0 At risk Greater than Greater than or equal Chronic cough and
or equal to 70% to 80% predicted sputum production
I Mild Less than 70% Greater than or equal With or without chronic
to 80% predicted cough and sputum production
II Moderate Less than 70% 50%79% With or without chronic
predicted cough and sputum production
III Severe Less than 70% 30%49% With or without chronic
predicted cough and sputum production
IV Very severe Less than 70% Less than 30% predicted
or less than 50% predicted
plus chronic
respiratory failureb
a
Classication based on postbronchodilator FEV1.
b
Respiratory failure: Arterial partial pressure of oxygen (PaO2) less than 60 mm Hg with or without arterial partial pressure of
carbon dioxide (Paco2) greater than 50 mm Hg while breathing air at sea level. FEV1, forced expiratory volume in one second;
FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease.
Adapted from GOLD Science Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive
pulmonary disease. Updated 2005. Available at: www.goldcopd.com. Used with permission.
tuberculosis are other possible differential diagnoses that are General Approach to Treatment
usually easier to distinguish from COPD. Chest radiography or
high-resolution computed tomography (CT) along with
An integrated approach of health maintenance (e.g.,
smoking cessation), drug therapy, and supplemental therapy
patient presentation help rule out these other lung diseases.
(e.g., oxygen and pulmonary rehabilitation) should be used in a
stepwise manner. Table 122 provides an overview of the man-
TREATMENT agement of stable COPD.
Desired Outcomes
The goals of COPD management include: (1) smoking cessa- Nonpharmacologic Therapy
tion; (2) reducing symptoms; (3) minimizing the rate of
decline in lung function; (4) maintaining or improving Smoking Cessation
quality of life; (5) preventing and treating exacerbations; and Smoking cessation is the only intervention known to
(6) limiting complications. slow the rate of decline in pulmonary function in patients with
COPD.6,7 Stopping smoking can also reduce cough and spu-
tum production and decrease airway reactivity. Therefore, it
is a critical part of any treatment plan for patients with
COPD. Unfortunately, achieving and maintaining cessation
is a major challenge. A clinical practice guideline from the
A 49-year-old man with a past medical history of hyper- United States Public Health Service recommends a specic
tension presents to the clinic complaining of shortness of action plan depending on the current smoking status and
breath that began about 3 to 4 years ago. His symptoms desire to quit (Fig. 122).8 Brief interventions are effective
have gradually gotten worse since then. He is now unable and can increase cessation rates signicantly. The ve As
to walk 100 yards without having to stop and rest. He also and the ve Rs can be used to guide brief interventions
has a daily cough that is usually productive of yellowish (Table 123).
sputum. He smokes about 11/2 packs of cigarettes a day and All tobacco users should be assessed for their readiness
has done so for the past 30 years. He also drinks on aver-
to quit and appropriate strategies implemented. Those who
age 6 to 7 beers a day. He does not have any signicant
are ready to quit should be treated with a combination of
occupational exposures to dust, gases, or fumes.
counseling on behavioral and cognitive strategies and
What information is suggestive of COPD? pharmacotherapy (nicotine replacement therapy, sus-
What risk factors does he have for COPD? tained-release bupropion, or varenicline). In COPD
What additional information do you need to know before patients, the likelihood of sustained abstinence is higher
creating a treatment plan for this patient? with nicotine replacement therapy than with sustained-
release bupropion.9
TABLE 122. Treatment Algorithm for Stable Chronic

Does patient now
Obstructive Pulmonary Disease
use tobacco?
GOLD Stage Recommended Therapy2 If yes If no
0: At Risk Avoidance of risk factor(s), especially smoking Is patient now Did patient once
cessation; inuenza vaccination willing to quit? use tobacco?
ADD
I: Mild Short-acting inhaled bronchodilator when If yes If no If yes If no
needed (e.g., ipratropium, albuterol, or Provide Promote Prevent No
combination inhaler) appropriate motivation relapse intervention
ADD tobacco to quit required
II: Moderate Pulmonary rehabilitation dependence encourage
Inhaled LABD on a scheduled basis treatments continued
(e.g., tiotropium,a salmeterol, or formoterol) abstinence
FIGURE 122. Algorithm for routine assessment of tobacco use

Inadequate response to LABD? status. (Reproduced from Treating Tobacco Use and Dependence
Clinicians Packet. A How-To Guide for Implementing the Public
Yes Health Service Clinical Practice Guideline, March 2003. United
States Public Health Service. Available at: www.surgeongeneral.gov/
Use alternative class or combine classes of tobacco/clinpack.html.)
inhaled LABD
Inadequate response to LABD?

length of an effective program is 2 months; the longer the pro-
Yes gram, the more sustained the results.10 It is important for
Add/substitute oral theophylline
patients to continue with a home exercise program to maintain
the benets gained from the pulmonary rehabilitation program.
ADD
III: Severe Inhaled corticosteroids if repeated Long-Term Oxygen Therapy
exacerbationsb Long-term administration of oxygen (greater than 15 hours
ADD
IV: Very severe Long-term oxygen if chronic respiratory
per day) to patients with chronic respiratory failure has been
failure shown to reduce mortality and improve quality of life.1,2
Consider surgical treatment Oxygen therapy should be initiated in stable patients with
a very severe COPD (GOLD stage IV) who are optimized on
Albuterol should be used as rescue therapy for patients treated with
tiotropium.
b
Dened as three exacerbations in the past 3 years by GOLD and as at
least one exacerbation requiring a course of oral corticosteroids or
antibiotics within the last year by ATS/ERS. Other authorities dene fre-
quent exacerbations as at least two within the past year. TABLE 123. Components of Brief Interventions for Tobacco
ATS, American Thoracic Society; ERS, European Respiratory Society;
LABD, long-acting bronchodilator. Users
The 5 As for Brief Intervention

Ask: Identify and document tobacco use status for every patient
Pulmonary Rehabilitation at every visit.
Advise: Urge every tobacco user to quit.
Pulmonary rehabilitation results in signicant and clinically
Assess: Is the tobacco user willing to make a quit attempt at this
meaningful improvements in dyspnea, exercise capacity, time?
health status, and health care utilization.10 It should be con- Assist: Use counseling and pharmacotherapy to help patients
sidered for patients with COPD who have dyspnea or other willing to make a quit attempt.
respiratory symptoms, reduced exercise capacity, a restriction Arrange: Schedule follow-up contact, preferably within the rst
week after the quit date.
in activities because of their disease, or impaired health status.1
A comprehensive pulmonary rehabilitation program should The 5 Rs to Motivate Smokers Unwilling to Quit at Present
Relevance: Tailor advice and discussion to each smoker.
include exercise training, nutrition counseling, and education. Risks: Help the patient identify potential negative consequences
It should cover a range of non-pulmonary problems including of tobacco use.
exercise deconditioning, relative social isolation, altered mood Rewards: Help the patient identify the potential benets of
states (especially depression), muscle wasting, and weight loss. quitting.
Rehabilitation programs may be conducted in the inpatient, Roadblocks: Help the patient identify barriers to quitting.
Repetition: Repeat the motivational message at every visit.
outpatient (most common), or home setting. The minimum
drug therapy and meet one of the following criteria: (1) A Beta2-Agonists
resting PaO2 at or below 55 mm Hg (7.32 kPa) or oxygen sat- 2-Agonists cause airway smooth muscle relaxation by stimulat-
uration (SaO2) at or below 88%; (2) PaO2 between 55 and 60 ing adenyl cyclase to increase the formation of cyclic adenosine
mm Hg (7.32 and 7.98 kPa) or SaO2 of 89% and evidence of monophosphate (cAMP). Other non-bronchodilator effects have
pulmonary hypertension, peripheral edema suggesting con- been observed, such as improvement in mucociliary transport,
gestive heart failure, or polycythemia.1,2 but their signicance is uncertain.11 2-Agonists are available in
The dual-prong nasal cannula is the standard means of inhalation, oral, and parenteral dosage forms; the inhalation
delivering continuous ow oxygen. The goal of therapy is to route is preferred because of fewer adverse effects.
increase the baseline oxygen saturation to at least 90% These drugs are also available in short-acting and long-acting
and/or PaO2 to at least 60 mm Hg (7.98 kPa), allowing ade- formulations (Table 124). The short-acting 2-agonists include
quate oxygenation of vital organs. The ow rate, expressed as albuterol, levalbuterol, pirbuterol, and terbutaline. They are used
liters per minute (L/minute), must be increased during exer- as rescue therapy for acute symptom relief. Most COPD
cise and sleep and can be adjusted based on pulse oximetry. patients need continuous bronchodilator therapy on a sched-
Hypoxemia also worsens during air travel; patients requiring uled basis every day. For these patients, short-acting 2-agonists
oxygen should generally increase their ow rate by 2 L/minute are inconvenient because of the need for frequent dosing. In
during ight.1 addition, short-acting 2-agonists have been associated with a
Oxygen therapy should be continued indenitely if it was slight, but statistically signicant, loss of effectiveness when used
initiated while the patient was in a stable state (rather than regularly for more than 3 months (tachyphylaxis).12
during an acute episode). Withdrawal of oxygen because of Long-acting 2-agonists include salmeterol and formoterol.
improved PaO2 in such a patient may be detrimental. Salmeterol is a partial agonist with a slower onset of action than
short-acting 2-agonists. Formoterol is a more complete agonist
Surgery and has an onset of action similar to that of albuterol. Full ago-
Bullectomy, lung volume reduction surgery, and lung trans- nists (formoterol) produce greater response at full receptor
plantation are surgical options for very severe COPD. These capacity than partial agonists (salmeterol). Bronchodilator
procedures may result in improved spirometry, lung vol- effects of salmeterol and formoterol last at least 12 hours, allow-
umes, exercise capacity, dyspnea, health-related quality of ing for twice-daily dosing. Long-acting bronchodilators are
life, and possibly survival. Patient selection is critical because superior to scheduled short-acting bronchodilators on impor-
not all patients benet. Refer to the ATS/ERS COPD stan- tant clinical outcomes, including frequency of exacerbations,
dards for a detailed discussion of appropriate selection of degree of dyspnea, and health-related quality of life.11 For symp-
surgical candidates.1 tomatic patients, these are preferred over short-acting agents for
maintenance therapy. Patients should also have a short-acting
Pharmacologic Therapy of Stable COPD 2-agonist such as albuterol available for as-needed use (rescue
medication).
The medications available for COPD are effective for reducing
Adverse effects of 2-agonists are dose-related and include
or relieving symptoms, improving exercise tolerance, reducing
palpitations, tachycardia, and tremor. Sleep disturbance may
the number and severity of exacerbations, and improving
also occur and appears to be worse with higher doses of
quality of life. No medications presently available have been
inhaled long-acting 2-agonists. Increasing doses beyond
shown to slow the rate of decline in lung function.
those clinically recommended is without benet and could be
Bronchodilators associated with increased adverse effects.
Bronchodilators are the mainstay of treatment for sympto-
matic COPD. They reduce symptoms and improve exercise tol- Anticholinergics
erance and quality of life.2 They can be used as needed for Ipratropium and tiotropium are inhaled anticholinergic med-
symptoms or on a scheduled basis to prevent or reduce symp- ications commonly used for COPD. They produce bronchodi-
toms. Bronchodilator drugs commonly used in COPD include lation by competitively blocking muscarinic receptors in
2-agonists, anticholinergics, and theophylline. The choice bronchial smooth muscle. They may also decrease mucus
depends on availability, individual response, and preferences. secretion, although this effect is variable. Tiotropium dissoci-
The inhaled route is preferred, but attention must be paid to ates from receptors extremely slowly resulting in a half-life
proper inhaler technique training. Long-acting inhaled bron- longer than 36 hours, allowing for once-daily dosing.
chodilators are more effective and convenient but more Ipratropium has an elimination half-life of about 2 hours,
expensive than short-acting inhaled bronchodilators. necessitating dosing every 6 to 8 hours.
Combination therapy improves efcacy and is preferred over Tiotropium provides the most consistent improvements on
increasing the dose of a single agent, especially since the dose- the widest range of outcomes among all the bronchodilators.
response relationship using FEV1 as the outcome is relatively It has been shown to be superior to ipratropium and salme-
at for single-agent therapy. terol in improving lung function and superior to ipratropium
TABLE 124. Maintenance Medications for COPD
Medication Onset Peak Duration Usual dose

Short-Acting Albuterol
b2-Agonists Nebulization 515 minutes 0.52 hours 26 hours 2.5 mg every 68 hours (max:
30 mg/day)
Inhalation 515 minutes 0.52 hours 26 hours MDI (90 mcg/puff) 12 puffs every
46 hours (max: 1080 mcg/day)
Oral 730 minutes 23 hours 46 hours 24 mg three to four times a day
ER: 812 hours ER: 48 mg every 12 hours
(max: 32 mg/day)
Levalbuterol
Nebulization 1020 minutes 1.5 hours 58 hours 0.631.25 mg three times a day,
68 hours apart (max: 3.75 mg/day)
Inhalation 510 minutes 11.5 hours 36 hours MDI (45 mcg/puff) 12 puffs every
Pirbuterol
Inhalation 5 minutes 0.51.5 hours 45 hours MDI (200 mcg/puff) 12 puffs every
Terbutaline
Oral 0.52 hours 13 hours 68 hours 2.55 mg three times a day, 6 hours
apart (max: 15 mg/day)
Long-Acting Formoterol
b2 Agonists Inhalation 13 minutes 13 hours 12 hours Powder (12 mcg/inhalation)
1 inhalation every 12 hours
(max: 24 mcg/day)
Salmeterol
Inhalation 10 minutes2 hours 25 hours 12 hours Powder (50 mcg/inhalation)
(max: 100 mcg/day)
Short-Acting Ipratropium
Anticholinergic Nebulization 130 minutes 1.52 hours 46 hours 500 mcg every 68 hours
(max: 2000 mcg/day)
Inhalation 130 minutes 1.52 hours 46 hours MDI (18 mcg/puff) 2 puffs four times
a day (max: 216 mcg/day)
Long-Acting Tiotropium
Anticholinergic Inhalation 30 minutes 14 hours 24 hours Powder (18 mcg/inhalation)
(max: 18 mcg/day)
Methylxanthine Theophylline
Oral 0.52 hours Up to 24 hours, 624 hours 400600 mg/day divided every
depending on 624 hours based on
formulation formulation
Adjust dose to serum concentrations
of 515 mcg/mL (2883 mol/L)
Inhaled Beclomethasone 17 days 14 weeks MDI (40, 80 mcg/puff) 40160 mcg
Corticosteroids twice a day (max: 640 mcg/day)
Budesonide 17 days 12 weeks Powder (200 mcg/inhalation)
12 inhalations twice a day
(max: 1600 mcg/day)
Fluticasone 17 days 12 weeks MDI (44, 110, 220 mcg/puff)
88440 mcg twice a day
(max: 1760 mcg/day)
Triamcinolone 17 days 12 weeks MDI (100 mcg/puff) 2 puffs three
to four times a day or 4 puffs
twice a day (max: 1600 mcg/day)
MDI, metered-dose inhaler; ER, extended-release.

in relieving symptoms, reducing exacerbation frequency, and leads to fewer exacerbations than either drug alone.18 A com-
improving health status.13,14 Because of its superior efcacy, bination of all three bronchodilator classes (2-agonist, anti-
tiotropium is considered rst-line therapy for all COPD cholinergic, and theophylline) can be used if the response to a
patients with persistent symptoms (e.g., dyspnea, need for res- two-drug combination is inadequate. However, this approach
cue medication more than twice a week, and night waking). has not been evaluated adequately in clinical trials.
The largest drawback to widespread use of tiotropium is the
high cost of therapy. Patients using tiotropium as maintenance Corticosteroids
therapy should be prescribed albuterol as their rescue therapy. In symptomatic patients with severe COPD (FEV1 less
The combination of ipratropium and tiotropium is not recom- than 50% predicted) and frequent exacerbations, regular treatment
mended because of the risks of excessive anticholinergic effects. with inhaled corticosteroids decreases the number of exacerbations
Inhaled anticholinergics are well tolerated with the most per year and improves health status; however, corticosteroids do
common adverse effect being dry mouth. Occasional metallic not slow the long-term decline in pulmonary function.2,1923 A
taste has also been reported with ipratropium. Other anti- combination inhaler device is recommended when using a
cholinergic adverse effects include constipation, tachycardia, long-acting 2-agonist with an inhaled corticosteroid [e.g.,
blurred vision, and precipitation of narrow-angle glaucoma Advair (uticasone/salmeterol)]. Patients should be reassessed
symptoms. Urinary retention could be a problem, especially 6 to 8 weeks after initiating inhaled corticosteroids to determine
for those with concurrent bladder outlet obstruction. whether there has been a positive response. A positive response
is indicated by an increase in FEV1 of 15% or more, improve-
Theophylline ment in symptoms, and/or improvement in 6-minute walking
Theophylline is a non-specic phosphodiesterase inhibitor distance.24 Treatment should be discontinued if no substantial
that increases intracellular cAMP within airway smooth mus- clinical or physiologic improvement is seen.1,24
cle resulting in bronchodilation. It has a modest bronchodila- Upon discontinuation of inhaled corticosteroids some
tor effect in patients with COPD, and its use is limited due to patients may experience deterioration in lung function and an
a narrow therapeutic index, multiple drug interactions, and increase in dyspnea and mild exacerbations; it is reasonable to
adverse effects. Theophylline should be reserved for patients reinstitute the medication in these patients.25 Completion of
who cannot use inhaled medications or who remain sympto- ongoing clinical trials assessing mortality should help to clar-
matic despite appropriate use of inhaled bronchodilators. ify the role of corticosteroid treatment of COPD.
Theophyllines bronchodilatory effects are dependent upon The most common adverse effects from inhaled cortico-
achieving adequate serum concentrations, and therapeutic steroids include oropharyngeal candidiasis and hoarse voice.
drug monitoring is needed to optimize therapy because of wide These can be minimized by rinsing the mouth after use and by
interpatient variability. If theophylline is used, serum concen- using a spacer device with metered-dose inhalers. Increased
trations in the range of 5 to 15 mcg/mL (28 to 83 mol/L) pro- bruising and decreased bone density have also been reported;
vide adequate clinical response with a greater margin of safety the clinical importance of these effects remains uncertain.1,2,19
than the traditionally recommended range of 10 to 20 mcg/mL Long-term use of oral corticosteroids should be avoided
(55 to 110 mol/L). The most common adverse effects include due to an unfavorable risk/benet ratio. The steroid myopathy
heartburn, restlessness, insomnia, irritability, tachycardia, and that can result from long-term use of oral corticosteroids
tremor. Dose-related adverse effects include nausea and vom- weakens muscles, further decreasing the respiratory drive in
iting, seizures, and arrhythmias. patients with advanced disease.
Tobacco smoke contains chemicals that induce the
Immunizations
cytochrome P-450 isoenzymes 1A1, 1A2, and 2E1. Theophylline
Serious illness and death in COPD patients can be reduced by
is metabolized by 1A2 and 2E1, and therefore smoking leads to
about 50% with annual inuenza vaccination. The optimal
increased clearance and subsequently decreased plasma levels of
time for vaccination is usually from early October through
the drug.15 Because most patients with COPD are current or
mid-November. All patients with COPD should also receive a
past smokers, it is important to assess current tobacco use and
one-time vaccination with the pneumococcal polysaccharide
adjust the theophylline dose as required based on altered plasma
vaccine, even though sufcient data supporting its use in COPD
theophylline levels if tobacco use changes.
patients are lacking.1,2 Patients over 65 years of age should be
revaccinated if it has been more than 5 years since initial vacci-
Combinations of Bronchodilators nation and they were less than 65 years of age at the time.
Patients with COPD often need maintenance treatment with
two or three bronchodilators. Combining albuterol plus ipra- Alpha1-Antitrypsin Augmentation Therapy
tropium, a long-acting 2-agonist plus theophylline, or a long- The American Thoracic Society and the European Respiratory
acting 2-agonist plus tiotropium produces a greater Society have published standards for the diagnosis and manage-
change in spirometry than either drug alone. 1,2,16,17 ment of individuals with AAT deciency.26 They recommend
Administering a long-acting 2-agonist plus ipratropium intravenous augmentation therapy for individuals with AAT
deciency and moderate airow obstruction (FEV1 35% to 60%

predicted). In these patients, augmentation therapy appears to Patient Encounter, Part 2: The Medical
reduce overall mortality and slow the decline in FEV1, although History, Physical Exam, and Diagnostic
large randomized controlled trials have not been conducted. Tests
Augmentation therapy consists of weekly transfusions of pooled
PMH
human AAT with the goal of maintaining adequate plasma levels
Hypertension for 6 years, currently controlled
of the enzyme. The benets of augmentation therapy are unclear
in patients with severe (FEV1 less than 35% predicted) or mild SH
(FEV1 greater than 60% predicted) airow obstruction. Patient works as an accountant; married with two children
Augmentation therapy is not recommended for individuals with FH
AAT deciency who do not demonstrate lung disease. Father with emphysema and lung cancer. There is no family
history of type 2 diabetes or heart disease
Other Pharmacologic Therapies Meds
Leukotriene modiers (e.g., zarlukast and montelukast) have Lisinopril 40 mg PO once daily
not been adequately evaluated in COPD patients and are not Hydrochlorothiazide 25 mg PO once daily
recommended for routine use. Small, short-term studies ROS
showed improvement in pulmonary function, dyspnea, and () skin rash; () nasal congestion, drainage; () chest pain,
quality of life when leukotriene modiers were added on to paroxysmal nocturnal dyspnea, orthopnea; (+) shortness of
inhaled bronchodilator therapy.27,28 Additional long-term breath, cough, intermittent wheezing; () hemoptysis; () heart-
studies are needed to clarify their role. burn, reux symptoms, N/V/D, change in appetite, change in
Nedocromil, a mast cell stabilizer, has not been adequately bowel habits; () joint pain or swelling; () pedal edema
tested in COPD patients and is not included in the GOLD PE
recommendations. VS: blood pressure 134/82 mm Hg, pulse 80 beats per minute,
N-acetylcysteine has antioxidant and mucolytic activity, respiratory rate 20/minute, temperature 35.8C, Wt 132 lb
which makes it a promising agent for COPD treatment, but (60 kg), Ht 64 in. (163 cm), body mass index 22.7 kg/m2
clinical trials have produced conicting results. One of the HEENT: EOMI; mucosal membranes are moist; no evidence
largest trials found N-acetylcysteine to be ineffective at reduc- of JVD; no palpably enlarged cervical lymph nodes
Lungs: Barrel-shaped chest; hyperresonant percussion noted
ing the decline in lung function and preventing exacerba-
bilaterally; lung sounds are fairly distant, no rhonchi or crackles.
tions.29 Routine use cannot be recommended at this time. CV: RRR, normal S1, S2; no murmur, gallop, or rub
Prophylactic, continuous use of antibiotics has no effect on Abd: Soft, non-tender, no hepatosplenomegaly
the frequency of exacerbations; antibiotics should only be used Exts: No cyanosis, edema, or nger clubbing; evidence of
for treating infectious exacerbations. Antitussives are con- onychomycosis on all ngernails
traindicated because cough has an important protective role.
PFTs
Opioids may be effective for dyspnea in advanced disease but Prebronchodilator Postbronchodilator
may have serious adverse effects; they may be used to manage Actual % Predicted Actual % Predicted
symptoms in terminal patients.
FVC (L) 4.4 107% 4.0 97%
FEV1 (L) 1.68 50% 1.59 47%
Pharmacologic Therapy of COPD Exacerbations FEV1/FVC (%) 39%
An exacerbation is a sustained worsening of the patients symp- Chest x-ray: Hyperlucency and hyperination of the lungs
suggestive of emphysematous change
toms from his or her usual stable state that is beyond normal day-
to-day variations. It is acute in onset and sufcient to warrant a
Given this additional information, what is your assessment
change in management. Commonly reported symptoms are of the patients condition?
worsening of dyspnea, increased sputum production, and change This patients COPD can be classied as what stage?
in sputum color. The most common causes of an exacerbation What are the treatment goals for this patient?
are respiratory infection and air pollution, but the cause cannot What nonpharmacologic and pharmacologic alternatives
be identied in about one-third of severe exacerbations.2 are feasible for this patient?
Treatment depends on the symptoms and severity of the Develop a treatment plan for this patient.
exacerbation. Mild exacerbations can often be treated at home
with an increase in bronchodilator therapy with or without
oral corticosteroids (Fig. 123). Antibiotics are indicated only emergency department or hospital. Management should consist
if there are clinical signs of airway infection (e.g., increased of controlled oxygen therapy, bronchodilators, oral or intra-
volume and change in color of sputum and/or fever). venous corticosteroids, antibiotics if indicated, and considera-
Moderate to severe exacerbations require management in the tion of mechanical ventilation (non-invasive or invasive).
Antibiotics
Initiate or increase bronchodilator therapy
Consider antibiotics The role of bacterial infections in COPD exacerbations is con-
troversial, and there are limited data on the efcacy of antibi-
otics in treating COPD exacerbations. Recent studies suggest
Reassess within hours that bacteria cause 40% to 50% of acute exacerbations.31
Antibiotics should be used in patients with COPD exacerba-
tions who have either of the following characteristics: (1) at least
Resolution or improvement
No resolution or improvement two of three cardinal symptoms: increased dyspnea, sputum
of signs and symtoms
volume, or sputum purulence; or (2) a severe exacerbation
requiring mechanical ventilation.2
Continue management
Step down when possible
Add oral corticosteroids The predominant bacterial organisms in patients with mild
exacerbations are Streptococcus pneumoniae, Haemophilus
inuenzae, and Moraxella catarrhalis. In patients with more
Review long-term
management
Reassess within hours severe underlying COPD, other bacteria, such as enteric gram-
negative bacilli (Escherichia coli, Klebsiella pneumoniae, and
Enterobacter cloacae) and Pseudomonas aeruginosa may be
Worsening of signs/symptoms more common. Selection of empiric antibiotic therapy should
be based on the most likely organism(s) thought to be respon-
sible for the infection and on local resistance patterns. A risk
Refer to hospital stratication approach has been advocated to help guide
antibiotic selection.1,2,31 This approach is based on risk factors
FIGURE 123. Algorithm for the management of an exacerbation found to be predictive of treatment failure or early relapse.
of COPD at home. (Reproduced from GOLD Science Committee. Patients at risk for poor outcome are candidates for more
Global strategy for the diagnosis, management, and prevention of aggressive initial antibiotic treatment. Table 125 provides rec-
chronic obstructive pulmonary disease. Updated 2005. Available ommended antibiotic treatment based on this risk stratication
at: www.goldcopd.com. Used with permission.) approach.2,31 Antibiotic treatment for most patients should be
maintained for 3 to 10 days, until the patient has been afebrile for
3 consecutive days. Exacerbations due to certain infecting organ-
isms (P. aeruginosa, E. cloacae, and methicillin-resistant
Bronchodilators Staphylococcus aureus), while not common, require more
Albuterol is the preferred bronchodilator for treatment of acute lengthy courses of therapy (21 to 42 days) when they occur. If
exacerbations because of its rapid onset of action. Ipratropium there is worsening clinical status or inadequate clinical
can be added to allow for lower doses of albuterol, thus reduc- response in 48 to 72 hours, re-evaluate the patient, consider
ing dose-dependent adverse effects such as tachycardia and sputum Grams stain and culture if not already obtained, and
tremor. Delivery can be through metered-dose inhaler (MDI) adjust antimicrobial therapy. If Grams stain and culture results
and spacer or nebulizer. The nebulizer route is preferred in are available, narrow the antibiotic therapy according to cul-
patients with severe dyspnea and/or cough that would limit tured organism(s) and sensitivities. If no cultures have been
delivery of medication through an MDI with spacer. If response obtained, or cultures remain negative, consider additional
is inadequate, theophylline can be considered; however, clinical antibiotics and/or change to antibiotics with a broader spec-
evidence supporting its use is lacking. trum of activity.
Oral Corticosteroids Oxygen

Systemic corticosteroids shorten the recovery time, help to The goal of oxygen therapy is to maintain PaO2 above 60 mm Hg
restore lung function more quickly, and may reduce the risk of (8 kPa) or SaO2 above 90% in order to prevent tissue hypoxia
early relapse.30 The GOLD guidelines recommend that corti- and preserve cellular oxygenation.1 Increasing the PaO2 much
costeroids be considered in addition to bronchodilators in all further confers little added benet and may increase the risk
hospitalized patients and in outpatients with baseline FEV1 less of CO2 retention, which may lead to respiratory acidosis. An
than 50% predicted.2 Other authorities recommend cortico- arterial blood gas should be obtained after 1 to 2 hours to
steroids for all patients experiencing a COPD exacerbation.1 assess for hypercapnia.
Oral prednisone 30 to 40 mg/day for 10 to 14 days is recom- In advanced COPD, caution should be used since overly
mended. Prolonged treatment does not result in greater efcacy aggressive administration of oxygen to patients with chronic
and increases the risk of adverse effects. If inhaled cortico- hypercapnia may result in respiratory depression and respira-
steroids are part of the patients usual treatment regimen, they tory failure. In these patients, mild hypoxemia, rather than
should be continued during systemic therapy. carbon dioxide accumulation, triggers their drive to breathe.
TABLE 125. Recommended Antibiotic Therapy in Acute Exacerbations of COPD
Patient Characteristics Likely Pathogens Recommended Antibioticsa,b

Uncomplicated exacerbation Streptococcus pneumoniae, Oral:
Not requiring hospitalization Haemophilus inuenzae, Macrolide (azithromycin, clarithromycin)
Less than 3 exacerbations per year Moraxella catarrhalis Second- or third-generation cephalosporin
No comorbid illness (cefuroxime, cefpodoxime, cefdinir,
FEV1 greater than 50% predicted cefprozil)
No recent antibiotic therapy Doxycycline
Ketolide (telithromycin)
-Lactam/-lactamase inhibitor (amoxicillin-
clavulanate)
Intravenous:
Not recommended
Complicated exacerbation Above organisms plus: drug-resistant Oral:
FEV1 less than 50% predicted pneumococci, -lactamase- -Lactam/-lactamase inhibitor
Comorbid cardiac disease producing H. influenzae and (amoxicillin-clavulanate)
Greater than or equal to 3 exacerbations M. catarrhalis, Escherichia coli, Fluoroquinolone with enhanced pneumococ-
per year Proteus spp., Enterobacter spp., cal activity (levooxacin, gemioxacin,
Antibiotic therapy in the previous 3 months Klebsiella pneumoniae moxioxacin)
Intravenous:
-lactam/-lactamase inhibitor (ampicillin-
sulbactam)
Second- or third-generation cephalosporin
(cefuroxime, ceftriaxone)
Fluoroquinolone with enhanced pneumococ-
cal activity (levooxacin, moxioxacin)
Complicated exacerbation with risk factors Above organisms plus: P. aeruginosa Oralc:
for P. aeruginosa Antipseudomonal uoroquinolone
Recent hospitalization (ciprooxacin, high-dose levooxacin)
Greater than or equal to 4 courses of antibi- Intravenous:
otics in the last year Antipseudomonal -lactamase resistant
Very severe COPD (GOLD stage IV) penicillin (piperacillin-tazobactam)
Previous isolation of P. aeruginosa Third- or fourth-generation cephalosporin
with antipseudomonal activity
(ceftazidime, cefepime)
Antipseudomonal uoroquinolone
(ciprooxacin, high-dose levooxacin)
a
Antibiotics indicated if patient has at least two of three cardinal symptoms: increased dyspnea, sputum volume, or sputum purulence; or a severe exac-
erbation requiring mechanical ventilation.
b
Trimethoprim-sulfamethoxazole, amoxicillin, rst-generation cephalosporins, and erythromycin are not recommended due to susceptibility and resist-
ance patterns of the likely infectious organisms.
c
Double coverage (e.g., use of two antipseudomonal antibiotics) should be considered for likely pseudomonal infection. Additional antipseudomonal
antibiotic choices to add for double coverage include aminoglycosides, imipenem, meropenem, and aztreonam.
COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in one second.
Assisted Ventilation per minute.2 Invasive mechanical ventilation should be used in

Mechanical ventilation can be administered as follows: (1) inva- patients with more severe symptoms and in those failing NPPV.
sive (conventional) mechanical ventilation through an endotra-
cheal tube; (2) non-invasive mechanical ventilation using either
negative (e.g., iron lungnot recommended) or positive pressure OUTCOME EVALUATION
devices. Non-invasive positive pressure ventilation (NPPV) is pre-
ferred whenever possible. NPPV improves signs and symptoms, Monitor the patient for improvement in symptoms (dyspnea,
decreases the length of hospital stay, and most importantly, cough, sputum production, and fatigue).
reduces mortality.32 Appropriate patients to consider for NPPV Changes in FEV1 should not be the main outcome assessed.
include those with the following characteristics: (1) moderate to FEV1 changes are weakly related to symptoms, exacerba-
severe dyspnea with use of accessory muscles and paradoxical tions, and health-related quality of life (outcomes that are
abdominal motion; (2) moderate to severe acidosis (pH between important to patients).
7.25 and 7.35) and hypercapnia (PaCO2 between 45 and 60 mm The Medical Research Council (MRC) dyspnea scale can be
Hg [68 kPa]); and (3) respiratory rate between 25 and 35 breaths used to monitor physical limitation due to breathlessness
(Table 126). The scale is simple to administer and correlates and after any dosage adjustment. Routine levels are not neces-
well with scores of health status.33 sary unless toxicity is suspected or disease has worsened.
The BODE Index is a validated predictor of mortality and is a
better predictor than FEV1 alone.34 It is a composite score TABLE 126. Medical Research Council (MRC) Dyspnea Scale
derived from body mass index or BMI (B), FEV1 or degree of
airow obstruction (O), modied Medical Research Council Modied Statement about
(MMRC) dyspnea scale (D), and 6-minute walking distance Grade Gradea Perceived Breathlessnessb
(E, exercise capacity). All of these variables predict important 1 0 I only get breathless with strenuous
outcomes such as health-related quality of life, the rate of exac- activity.
2 1 I get short of breath when hurrying
erbations, and the risk of death. The composite score is based
on the level or up a slight hill.
on a 10-point scale in which higher scores indicate a higher risk 3 2 I walk slower than people of the
of death (Table 127). The BODE Index can be used clinically same age on the level because
to monitor disease progression. Its usefulness in measuring of breathlessness or I have to stop
outcomes of drug therapy, pulmonary rehabilitation, and the for breath after a mile or so on
the level at my own pace.
degree of health care resource utilization needs further study.
4 3 I stop for breath after walking 100 yards
Assess quality of life using the St. Georges Respiratory or after a few minutes on the level.
Questionnaire, which has been validated and is specic for 5 4 I am too breathless to leave the
COPD patients.35 house or I get breathless while
Monitor theophylline levels with goal serum concentrations in dressing.
the range of 5 to 15 mcg/mL (28 to 83 mol/L). Trough levels a
The modied grade is used in the BODE index.
should be obtained 1 to 2 weeks after initiation of treatment b
The last statement to which the patient answers yes is their grade.
Patient Care and Monitoring 6. Provide patient education about the disease state and
therapeutic plan:
What COPD is and the natural course of the disease
Smoking cessation counseling
1. Assess the patients symptoms and history of exposure to Role of regular exercise and healthy eating
risk factors. For new patients obtain a detailed medical his- How and when to take medications; importance of adher-
tory including: ence to the medication plan; adverse effects and how to
Past medical history, especially history of respiratory minimize them
conditions Signs and symptoms of an exacerbation and what to do
Immunization status (pneumococcal and inuenza) if one occurs
Family history of COPD or other chronic respiratory Advanced directives and end-of-life issues for patients
disease with more severe disease
History of exacerbations or previous hospitalizations 7. Determine the follow-up period based on patient status
for respiratory disorders and needs (typically 3 to 6 months).
Impact of disease on the patients life, including limita- 8. Follow-up visits should include:
tion of activity, missed work, and feelings of depression
Assessment of tobacco use and/or quit attempts
or anxiety
Assessment of change in symptoms. Obtain spirometry if
2. Obtain spirometry measurements to assess airow limita- there is a substantial increase in symptoms or a complication
tion and aid in severity classication and treatment deci- Review of drug therapy (dosages, adherence, inhaler
sions. Measure arterial blood gases if FEV1 is less than 40% technique, effectiveness, adverse effects, and drug
predicted or if the patient has clinical signs suggestive of interactions)
respiratory failure or right heart failure. Evaluation of exacerbation frequency, severity, and
3. Obtain a thorough history of prescription, non-prescription, likely causes
and dietary supplement use. Assess inhaler technique and 9. Perform spirometry at least annually to assess disease
adherence to the medication regimen. Ask the patient progression.
about effectiveness of medications at controlling symptoms
10. Provide annual inuenza vaccination.
and adverse effects.
11. Assess inhaler technique at every visit. Have the patient
4. Ask current tobacco users about daily quantity, past quit demonstrate proper use of each device using a placebo
attempts, and current readiness to quit.
inhaler or personal inhaler. Proper use of these devices is
5. Design a therapeutic plan including lifestyle modications critical for therapeutic success.
(e.g., smoking cessation) and optimal drug therapy. Consider
need for pulmonary rehabilitation, oxygen therapy, and/or
surgery.
TABLE 127. The BODE Index
Points on BODE Indexa

Variable 0 1 2 3
FEV1 (% of predicted) Greater than or 5064 3649 Less than or
equal to 65 equal to 35
Distance walked in Greater than or 250349 150249 Less than or
6 minute (meters) equal to 350 equal to 149
MMRC dyspnea scale 01 2 3 4
Body mass index (kg/m2) Greater than 21 Less than or
equal to 21
a
The cutoff values for the assignment of points are shown for each variable.
FEV1, forced expiratory volume in one second; MMRC, modied Medical Research Council. From Celli BR, Cote CG, Marin
JM, et al. The body-mass index, airow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary
disease. N Engl J Med 2004;350:10051012. Copyright 2004 Massachusetts Medical Society. All rights reserved. Used with
permission.
AAT: 1-antitrypsin Alpha-1 Antitrypsin Deciency Task Force. American Thoracic

ABG: arterial blood gas Society/European Respiratory Society Statement: Standards for
ATS: American Thoracic Society the diagnosis and management of individuals with alpha-1 anti-
BMI: body mass index trypsin deciency. Am J Respir Crit Care Med 2003;168:818900.
cAMP: cyclic adenosine monophosphate American Thoracic Society/European Respiratory Society Task
COPD: chronic obstructive pulmonary disease Force. Standards for the diagnosis and management of patients
CT: computed tomography with COPD [Internet]. Version 1.2. New York: American
ERS: European Respiratory Society Thoracic Society; 2004 (updated September 8, 2005). Available
FEV1: forced expiratory volume in one second at: www-test.thoracic.org/copd/. Accessed January 25, 2006.
FVC: forced vital capacity Cooper CB, Tashkin DP. Recent developments in inhaled therapy in
GOLD: Global Initiative for Chronic Obstructive Lung Disease stable chronic obstructive pulmonary disease. BMJ 2005;330:
JVD: jugular venous distention 640644.
LABD: long-acting bronchodilator GOLD Science Committee. Global strategy for the diagnosis, man-
MDI: metered-dose inhaler agement, and prevention of chronic obstructive pulmonary dis-
MMRC: modied Medical Research Council ease. Updated 2005. Available at: www.goldcopd.com. Accessed
MRC: Medical Research Council January 26, 2006.
NPPV: non-invasive positive pressure ventilation Hogg JC. Pathophysiology of airow limitation in chronic obstruc-
PaCO2: partial pressure of arterial carbon dioxide tive pulmonary disease. Lancet 2004;364:709721.
PaO2: partial pressure of arterial oxygen Rennard SI. Treatment of stable chronic obstructive pulmonary
PFT: pulmonary function test disease. Lancet 2004;364:791802.
PO: orally Sethi S, Murphy TF. Acute exacerbations of chronic bronchitis: new
SaO2: arterial oxygen saturation developments concerning microbiology and pathophysiology
TNF-: tumor necrosis factor- impact on approaches to risk stratication and therapy. Infect
VA/Q: ventilation/perfusion ratio Dis Clin North Am 2004;18:861882.
Tashkin DP, Cooper CB. The role of long-acting bronchodilators in
Reference lists and self-assessment questions and answers are the management of stable COPD. Chest 2004;125:249259.
available at www.ChisholmPharmacotherapy.com. Treating Tobacco Use and DependenceClinicians Packet. A how-to
guide for implementing the Public Health Service Clinical Practice
Guideline, March 2003. United States Public Health Service.
Available at: www.surgeongeneral.gov/tobacco/clinpack.html.
for information on obtaining continuing education credit for Accessed January 25, 2006.
this chapter.
13 CYSTIC FIBROSIS
Kimberly J. Novak
LEARNING OBJECTIVES
1. Explain the pathophysiology of cystic brosis (CF) and its multiorgan system involvement.
2. Describe the common clinical presentation and diagnosis of CF.
3. Consider long-term treatment goals with respect to clinical course and prognosis of CF.
4. Identify nonpharmacologic therapies for CF management.
5. Recommend appropriate pharmacologic therapies for chronic CF management.
6. Design appropriate antibiotic regimens for acute pulmonary exacerbations of CF.
7. Employ pharmacokinetic principles when calculating drug doses in CF patients.
8. Formulate monitoring plans for acute and chronic CF pharmacologic therapies.
KEY CONCEPTS Antibiotic regimens in severe CF exacerbations include an intra-

venous antipseudomonal -lactam plus an aminoglycoside.
In CF, the cystic brosis transmembrane regulator (CFTR) chlo- CF patients have a larger volume of distribution and enhanced
ride channel is dysfunctional and usually results in decreased total body clearance of many antibiotics, which often results in
chloride secretion and increased sodium absorption, leading to the need for higher doses to attain target levels.
altered viscosity of uid excreted by the exocrine glands and Titration of pancreatic enzyme doses is based on control of
mucosal obstruction. steatorrhea, stool output, and abdominal symptoms.
Pulmonary disease is characterized by thick mucus secretions, Because CF-related diabetes (CFRD) results from insulin
impaired mucus clearance, chronic airway infection and colo- insufciency, exogenous insulin replacement is required.
nization, obstruction, and an exaggerated neutrophil-dominated
inammatory response. Cystic brosis (CF) is an inherited multiorgan system disorder
Maximizing nutritional status through pancreatic enzyme affecting children and an ever-growing adult population. It is the
replacement and vitamin and nutritional supplements is nec- most common life-threatening genetic disease among
essary for normal growth and development and for maintain- Caucasians and the major cause of severe chronic lung disease
ing long-term lung function. and pancreatic insufciency in children. The disease generally
Airway clearance therapy is a necessary routine for all CF manifests as mucosal obstruction of exocrine glands caused by
patients to clear secretions and control infection. It is typically defective ion transport within epithelial cells. Due to the array of
performed once or twice daily for maintenance care and three affected organ systems and complicated medical therapies,
or four times per day for acute exacerbations. appropriate CF treatment necessitates multidisciplinary team
Antibiotic therapy is indicated in three distinct situations over collaboration.
the course of CF: (1) early eradication and delay of colonization;
(2) suppression of bacterial growth once colonization occurs;
and (3) reduction of bacterial load in acute overgrowth. EPIDEMIOLOGY AND ETIOLOGY
Antibiotic selection is based on periodic culture and sensitivity
data, typically covering all organisms identied over the preceding In the United States, CF most commonly occurs in the Caucasian
year. If no culture data are available, empiric antibiotics should population, ranging from 1 in 1900 to 3700 individuals. CF
cover the most likely organisms for the patients age group. is less common in Hispanics (1 in 9000), African-Americans
245
(1 in 15,000), and Asian Americans (1 in 32,000).1 CF is inher- mucus secretions, impaired mucus clearance, chronic airway infection
ited as an autosomal recessive trait, and approximately 1 in 25 and colonization, obstruction, and an exaggerated neutrophil-
Caucasians are heterozygous carriers. For example, offspring of dominated inammatory response.4 Over time, chronic obstruction
a carrier couple (each parent being heterozygous) have a one in and inammation lead to air trapping, atelectasis, mucus plug-
four chance of having the disease (homozygous), a one in two ging, bronchiectasis, cystic lesions, pulmonary hypertension,
chance of being a carrier (heterozygous), and a one in four and eventual respiratory failure. In the United States CF popula-
chance of receiving no trait. The gene mutation is found on the tion, pulmonary function declines at an average yearly rate of
long arm of chromosome 7 and encodes for the cystic brosis 2%, as measured by forced expiratory volume in 1 second
transmembrane regulator (CFTR) protein, which functions as a (FEV1). The rate in an individual patient may be higher or lower
chloride channel to transport water and electrolytes. Over 1000 depending on severity of CFTR dysfunction and comorbidities.
mutations have been described in the CF gene; however, the Patients may show a slow steady decline over time, or they may
F508 mutation is the most common and is present in 70% to have stable lung function for several years and then experience
90% of CF patients in the United States.2 periods of sharp decline.1 In the upper airways, sinusitis and
nasal polyps are also common, and microbial colonization is
similar to that of the lungs.
PATHOPHYSIOLOGY Bacterial pathogens are often acquired in an age-dependent
sequence, and prevalence is tracked in the Cystic Fibrosis
CF is a disease of exocrine gland epithelial cells where CFTR is Foundation Patient Registry. Early infection is most often
largely expressed. Normally, these cells transport chloride caused by Staphylococcus aureus and non-typeable Haemophilus
through CFTR chloride channels with sodium and water inuenzae (and thus is not prevented by childhood H. inuenzae
accompanying this ux across the cell membrane (Fig. 131). type b immunization). Pseudomonas aeruginosa infection also
CFTR is regulated by protein kinases in response to varying lev- occurs early in life and is the most signicant CF pathogen
els of the intracellular second messenger cyclic-3, 5-adenosine among all age groups. P. aeruginosa expresses extracellular tox-
monophosphate (cAMP). CFTR also downregulates the epithe- ins that perpetuate lung inammation. Mucoid strains of P.
lial sodium channel, regulates calcium-activated chloride and aeruginosa produce an alginate biolm layer that interferes with
potassium channels, and may function in exocytosis and forma- antibiotic penetration. Other organisms identied later in the
tion of plasma membrane molecular complexes and proteins disease course include Stenotrophomonas maltophilia, Alcaligenes
important in inammatory responses.2 In CF, the CFTR chlo- xylosoxidans, Burkholderia cepacia, fungi including Candida and
ride channel is dysfunctional and usually results in decreased chlo- Aspergillus species, and non-tuberculous mycobacteria.1 Other
ride secretion and increased sodium absorption, leading to altered organisms may also present chronically or intermittently.
viscosity of uid excreted by the exocrine glands and mucosal Similarly, cultured organisms may represent an initial infec-
obstruction. tion, chronic colonization, or microbial overgrowth in an acute
exacerbation.
Pulmonary System
Chronic lung disease is a hallmark of CF, leading to death in Gastrointestinal System
90% of patients.3 Pulmonary disease is characterized by thick Gastrointestinal involvement may present initially as small
bowel obstruction shortly after birth (known as meconium
ileus) due to abnormally thick meconium that cannot be
Lumen Submucosa passed. Older CF patients may develop distal intestinal
obstruction syndrome (DIOS), formerly called meconium
Na+
Cl (cAMP) K+ ileus equivalent, which occurs due to fecal impaction in the
2 Cl terminal ileum and cecum.
Cl (Ca2+) Maldigestion due to pancreatic enzyme insufciency is pres-
Na+ ent in about 85% to 90% of CF patients.5 Thick pancreatic secre-
Na+
K+ tions and cellular debris obstruct the pancreatic ducts and lead
to brosis. Volume and concentration of pancreatic enzymes
and bicarbonate are reduced, leading to maldigestion of fat and
FIGURE 131. Electrolyte transport in the airway epithelial protein. Subsequently, absorption of fat-soluble vitamins (A, D,
cell. Ca, calcium; cAMP, cyclic-3, 5-adenosine monophos- E, and K) is often impaired. Maldigestion is characterized by
phate; Cl, chloride; Na, sodium; K potassium. (From Milavetz abdominal distention, numerous large foul-smelling loose stools
G, Smith JJ. Cystic brosis. In: DiPiro JT, Talbert RL, Yee GC, (steatorrhea), atulence, and malnourishment and hunger
et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach.
despite voracious intake. Maldigestion is progressive and may
6th ed. New York: McGraw-Hill; 2005: 592, with permission.)
develop later in a previously pancreatic sufcient patient.
CHAPTER 13 / CYSTIC FIBROSIS 247
Other complications may include gastroesophageal reux, nutrition and decreased body mass; (3) physical inactivity;
dysmotility, intussusception, volvulus, atresia, rectal pro- (4) corticosteroid therapy; and (5) delayed puberty. Chronic
lapse, and complications related to corrective surgery for pulmonary infection, through release of inammatory
meconium ileus.6 cytokines, can cause increased bone resorption and decreased
Hepatobiliary disease occurs due to bile duct obstruction formation. Osteopenia, osteoporosis, pathologic fractures,
from abnormal bile composition and ow. Hepatomegaly, and kyphosis can then occur.10
splenomegaly, and cholecystitis may be present. Hepatic Episodic or chronic arthritis and hypertrophic pulmonary
steatosis may also be present due to effects of malnutrition. osteoarthropathy may also occur due to immune complex
The progression from cholestasis (impaired bile ow) to formation in response to chronic inammation.11 Digital
portal fibrosis and to focal and multilobar cirrhosis, clubbing is commonly observed and is a marker for hypoxia.
esophageal varices, and portal hypertension takes several
years. Many patients are compensated and asymptomatic
but may be susceptible to acute decompensation in the event Hematologic System
of extrinsic hepatic insult from viruses, medications, or
Anemia may be present in some patients due to impaired
other factors.7
erythropoietin regulation, nutritional factors (vitamin E and
iron malabsorption), or chronic inammation. With chronic
Endocrine System pulmonary disease, increased cytokine production can lead to
shortened red blood cell survival, reduced erythropoietin
CF-related diabetes shares characteristics of both type 1 and
response, and impaired mobilization of iron stores.
type 2 diabetes mellitus but is categorized separately. The pri-
Additionally, with chronic hypoxia, normal hemoglobin
mary cause of CFRD is insulin deciency resulting from both
and hematocrit values may represent relative anemia.12
reduced functional pancreatic islet cells and increased islet
Increased red blood cell production is a physiologic response
amyloid deposition. Insulin secretion is delayed in response to
to hypoxia; however, this response may be blunted in CF and
glucose challenge, and absolute insulin secretion over time is
may result in symptoms of anemia despite normal lab values.
reduced. Some insulin resistance may also be present in
Abnormal bleeding may also be observed as a result of vita-
CFRD; however, sensitivity may be increased in CF patients
min K malabsorption or antibiotic-associated depletion of
without diabetes.8
gastrointestinal ora and vitamin K synthesis.
Postprandial hyperglycemia is common, but because some
basal insulin secretion is maintained, fasting hyperglycemia is
less severe and ketosis is rare.5 Diet, acute and chronic infec-
tion, and corticosteroid use lead to uctuations in glucose tol- Miscellaneous Systems
erance over time.8 CFRD is associated with greater nutritional Abnormally high concentrations of sodium and chloride are
failure, increased pulmonary disease, and earlier death. The found in sweat due to impaired reabsorption within the sweat
average age of onset is 18 to 21 years; but underdiagnosis is duct from loss of CFTR channels. Patients are usually asympto-
thought to be common. matic (other than a characteristic salty taste to the skin).2 In rare
instances such as hot weather or excessive sweating during phys-
Reproductive System ical activity, patients may become dehydrated and experience
symptoms of hyponatremia (nausea, headache, lethargy, and
CF patients often experience delayed puberty. In females, confusion). Similar CFTR defects are also seen in the salivary
menarche occurs 18 months later than average, and menstrual glands, manifested by increased saliva viscosity and impaired
irregularity is common. Females also have reduced fertility salivary function.
due to increased viscosity of cervical mucus. Due to increas-
ing life expectancy, pregnancy is becoming more common;
however, outcomes depend on pre-partum nutritional and
CLINICAL PRESENTATION AND DIAGNOSIS
pulmonary status.
Almost all males with CF are azoospermic due to congenital
Diagnosis
absence of the vas deferens with resultant obstruction; however,
conception still occurs occasionally. Conception can also occur Diagnosis of CF is based on two separate elevated sweat chloride
through application of assisted reproductive technologies.9 concentrations of greater than or equal to 60 mEq/L (or
mmol/L) obtained through pilocarpine iontophoresis (referred
to as the sweat test). Genetic testing (CFTR mutation analysis)
Musculoskeletal System
may be performed to conrm the diagnosis, screen in utero, or
Several factors contribute to development of bone disease in CF: detect carrier status. More than 70% of diagnoses are made by
(1) malabsorption of vitamins D and K and calcium; (2) poor 12 months of age and almost all are made by age 12.
Clinical Presentation of Cystic Fibrosis Decreased vitamin K levels may result in elevated pro-
thrombin time (PT) and International Normalized Ratio
(INR).
There may be glucose intolerance, as indicated by
General blood glucose between 140 and 199 mg/dL (7.77 to
CF is usually diagnosed in neonates or during 11.04 mmol/L) 2 hours after an oral glucose tolerance
early childhood. Some patients may present much later in test.
life due to less severe symptoms or misdiagnosis. Patients may have CFRD, as indicated by blood glucose
greater than or equal to 200 mg/dL (greater than or equal to
Symptoms
11.1 mmol/L) 2 hours after an oral glucose tolerance test.
Pulmonary symptoms may include chronic cough, sputum
Some patients have CFRD with fasting hyperglycemia
production, and decreased exercise tolerance.
(fasting blood glucose greater than or equal to 126 mg/dL
Patients with intestinal obstruction may complain of
(greater than or equal to 6.99 mmol/L) regardless of the
abdominal pain, abdominal distention, and/or decreased
postglucose challenge level).
bowel movements.
Serum aspartate aminotransferase, alanine aminotransferase,
Maldigestion may be manifested by the presence of numer-
alkaline phosphatase, -glutamyl transferase, and bilirubin
ous large foul-smelling loose stools (steatorrhea) and atu-
may be elevated in patients with hepatobiliary disease.
lence.
White blood cell count with an associated increase in
Patients with vitamin A deciency may report visual distur-
polymorphonuclear (PMN) leukocytes and bands may
bances, night blindness, and dry skin.
occur in acute pulmonary infection; however, infection
Acute infection may be marked by increased cough,
may occur without these laboratory abnormalities.
changes in sputum (darker and thicker), dyspnea, and fever.
Signs
Other Tests
Signs of obstructive airway disease include tachypnea, dys-
Pulmonary function tests (PFTs) indicate decreased
pnea, cyanosis, wheezes, crackles, sternal retractions, digi-
forced expiratory volume in 1 second (FEV1), decreased
tal clubbing, and barrel chest.
forced vital capacity (FVC), and increased residual vol-
Infants and children with maldigestion may have evidence
ume. Values are typically worse during acute pulmonary
of failure to thrive (below age-based normals in both height
exacerbations.
and weight), and adults may be near or below their ideal
Chest x-ray or chest computed tomography scan may
body weight despite apparent adequate caloric intake.
reveal inltrates, atelectasis, bronchiectasis, and mucus
Salty taste to the skin may be noticed.
plugging.
Biliary cirrhosis may be asymptomatic or evidenced by
Intestinal obstruction may be manifested as meconium
hepatomegaly, splenomegaly, or prolonged bleeding.
ileus, distal intestinal obstruction syndrome, or intus-
Recurrent pancreatitis (usually in pancreatic-sufcient
susception on abdominal x-ray or computed tomogra-
patients) may present with episodes of epigastric abdomi-
phy scan. Rectal prolapse may be noted on physical
nal pain, persistent vomiting, and fever.
exam.
Laboratory Tests In recurrent pneumonia or sinusitis, P. aeruginosa, S.
Maldigestion results in decreased serum levels of the fat- aureus, S. maltophilia, and other CF-related organisms may
soluble vitamins A, D, E, and K. be isolated in sputum, throat, or sinus cultures.
lung disease, less frequent Pseudomonas infection, and less

Clinical Course and Prognosis severe pancreatic insufciency.5 Life expectancy and quality of
life are expected to continue to increase with aggressive treat-
Life expectancy has greatly increased from a predicted survival
ment strategies, lung transplantation when appropriate, and
of 16 years in 1970 to more than 40 years for patients born in
new therapies being investigated.
the 1990s.5 The average age of patients in the Cystic Fibrosis
Foundation Registry is now more than 16 years, and many are
TREATMENT
living far into adulthood. More than 40% of CF patients in the
2004 Registry annual report are over 18 years old, and the old-
Desired Outcomes
est is age 74.13
The clinical course varies greatly among patients because Therapeutic outcomes in CF care relate to both chronic and
of the multiple genetic mutations and heterogeneous prole acute treatment goals. With chronic management, the pri-
of the F508 mutation. Some patients develop severe lung mary goals are to delay disease progression and optimize
disease early in childhood and reach end-stage lung disease by quality of life. Maximizing nutritional status through pan-
their teens, whereas others maintain near-normal lung func- creatic enzyme replacement and vitamin and nutritional sup-
tion into adulthood. Newly-diagnosed adults tend to present plements is necessary for normal growth and development and
with chronic respiratory symptoms but usually have milder for maintaining long-term lung function. Reduction of airway
mobilize secretions. Patients may also be taught autogenic

Patient Encounter, Part 1 drainage, which consists of deep breathing exercises followed by
forced cough.
Several devices are also available to promote airway clear-
ance. Flutter valve devices employ oscillating positive expira-
Jessica is an 18-month-old female who is brought to her
tory pressure (OPEP) to cause vibratory air ow obstruction
pediatrician because of difculty gaining weight. Her
mother states that Jessica has had four to ve loose stools and an internal percussive effect to mobilize secretions.
daily ever since I can remember. She was previously diag- Intrapulmonary percussive ventilation (IPV) provides contin-
nosed with reux and milk allergy. Oral ranitidine and uous oscillating pressures during inhalation and exhalation.
elimination of cows milkbased dairy products have not Finally, the most commonly used technique is high-frequency
helped. Jessica is plotted on the growth chart at less than chest compression (HFCC) with an inatable vest that pro-
the third percentile for both height and weight. Mom also vides external oscillation. Vest therapy is often preferred by
reports that she has been treated in the emergency depart- patients because they can independently perform the therapy
ment for pneumonia twice since birth. Mom is concerned even from an early age.5,14
since her mothers older sister died from some strange If performed appropriately, airway clearance techniques
wasting illness when she was a young child.
provide similar clearance results, so choice should be based on
patient preference and compliance. Airway clearance therapy
What information is consistent with a diagnosis of CF?
What other information would you like to gather? is typically performed once or twice daily for maintenance
How would you pursue making the diagnosis of CF? care and is increased to three or four times per day for acute
exacerbations. Inhaled medications are usually given with the
therapies and will be discussed in a later section.
inammation and infection and aggressive preventive thera-
pies minimize acute pulmonary exacerbations and delay Nutrition
pulmonary decline. In pulmonary exacerbations, therapy is Most CF patients have an increased caloric need due to
directed toward reducing acute airway inammation and increased energy expenditure through increased work of breath-
obstruction. This is accomplished through more aggressive ing and increased basal metabolism. Prevention of malnutrition
air clearance regimens and antibiotic therapy with a goal of requires early nutritional intervention. In patients with mild
returning lung function to pre-exacerbation levels or greater. lung disease and well-controlled absorption, required caloric
intake is approximately 100% to 120% of the recommended
daily allowance (RDA) for age.15 As lung disease progresses,
caloric requirements increase.
The intensity of the daily chronic maintenance regimen varies Nutrition in malnourished patients consists of baseline
based on patient age, baseline lung function, other organ system required calories plus additional calories for weight gain. Even
involvement, and social factors such as time available for therapy with aggressive diet and oral supplements, the caloric require-
and patient-selected care choices. Generally, with more severe ment may not be achieved. Placement of a gastrostomy or
lung disease and multiorgan system involvement, therapies jejunostomy tube to allow for nighttime bolus or continuous
become more complicated and time intensive. Additionally, formula feeds in addition to daytime meals may be required to
therapy is intensied when pulmonary symptoms are increased meet caloric goals.5 Patients with continued malabsorption on
with acute exacerbations or even mild viral upper respiratory ill- appropriate pancreatic enzyme supplementation or diabetes are
ness such as the common cold. The approach to treatment is especially challenging due to their unique caloric needs.
best described by the organ system affected. Collaboration with a dietician specially trained in CF nutrition
is essential.
Airway Clearance Therapy
Airway clearance therapy is a necessary routine for all CF Pulmonary System
patients to clear secretions and control infection, even at diagnosis
prior to becoming symptomatic. Waiting until development of a Treating Obstruction and Inammation
rst pneumonia or until daily symptoms are present delays Airway clearance therapy is usually accompanied by bron-
benets and may contribute to a faster pulmonary decline. chodilator treatment [albuterol (also known as salbutamol out-
The traditional form of chest physiotherapy (CPT) is known side the United States) by nebulizer or metered-dose inhaler] to
as percussion and postural drainage. Areas of the patients stimulate mucociliary clearance and prevent bronchospasm
chest, sides, and back are rapidly clapped by hand in different associated with other inhaled agents. A mucolytic agent may be
patient positions, followed by cough or forced expiration to administered to reduce sputum viscosity and enhance clearance.
Dornase alfa (Pulmozyme ) is a recombinant human (rh) Azithromycin is a macrolide antibiotic commonly used in CF
DNase that selectively cleaves extracellular deoxyribonucleic as an anti-inammatory agent. The exact mechanism for this
acid (DNA). This DNA is released during neutrophil degrada- activity is unclear, but azithromycin has been shown to improve
tion and contributes to the high viscosity of CF sputum. overall lung function. Proposed mechanisms include interfer-
Nebulization of dornase alfa 2.5 mg once or twice daily ence with Pseudomonas alginate biolm production, bactericidal
improves daily pulmonary symptoms and function, reduces activity during stationary Pseudomonas growth, neutrophil
pulmonary exacerbations, and improves quality of life.16 N- inhibition, interleukin-8 reduction, and reduction in sputum
acetylcysteine and hypertonic saline are other mucolytic agents viscosity.22,23 Due to its long tissue half-life, azithromycin is typ-
that are occasionally used; however, they are not preferred agents ically dosed 3 days per week (Monday, Wednesday, and Friday),
due to a greater incidence of bronchospasm and unpleasant with a dose of 500 mg for patients weighing at least 40 kg and
odor and taste.5 250 mg for patients weighing 25 to 39 kg. Alternatively, patients
Many patients with CF also have a reactive airways component may take 500 mg or 250 mg either every day or only Monday
or concurrent asthma and benet from long-acting 2-agonists.5 through Friday, based on the same weight parameters. To mini-
Patients with recurrent wheezing or dyspnea who have demon- mize the risk of selecting for macrolide-resistant non-tubercu-
strated improvement with albuterol should be considered for lous mycobacteria, patients should have a screening acid-fast
maintenance therapy, as should patients with bronchodilator- bacillus sputum culture obtained prior to starting therapy and
responsive pulmonary function tests. Inhaled corticosteroids then every 6 months. Conrmed mycobacterial colonization is
may also attenuate reactive airways and reduce airway inam- usually a contraindication to chronic azithromycin therapy.17
mation in some patients. While many patients appear to respond
clinically to these agents, clear benet in CF has not been estab- Antibiotic Therapy
lished.1,17 Drug delivery to the site of inammation is limited by Antibiotic therapy is used in three distinct clinical settings
the severity of lung disease, which may prevent maximal efcacy within the course of CF. First, in early lung disease, the primary
in CF. CF patients who are on inhaled corticosteroids and/or goals are to detect infection early and institute appropriate antibi-
long-acting 2-agonists should be advised to administer these otic therapy to eradicate infection and delay colonization. Second,
medications after airway clearance therapies to optimize drug once colonization is present, chronic maintenance antibiotics are
delivery. Montelukast, antihistamines, and/or intranasal steroids used to suppress bacterial growth. Third, in acute exacerbations,
are sometimes used for CF patients with a reactive airways or intensive antibiotics are administered in an attempt to drastically
allergic rhinitis component to their disease. reduce bacterial load and return lung function to pre-exacerbation
Several systemic therapies aim at reducing airway inamma- levels or greater.1 Antibiotic selection is based on periodic culture
tion. Long-term oral corticosteroids, namely prednisone and and sensitivity data, typically covering all organisms identied over
prednisolone, have been shown to reduce airway inammation the preceding year. If no culture data are available, empiric antibi-
and improve lung function; however, benecial effects diminish otics should cover the most likely organisms for the patients age
upon discontinuation. Concern for long-term adverse effects group. Due to altered pharmacokinetics and microorganism
including diabetes, osteoporosis, cataracts, cushingoid effects, resistance, care must be taken to ensure that optimal doses are
growth suppression, and infection limits their use as mainte- prescribed (Table 131).
nance therapy.17 In clinical practice, systemic steroids may be Severity of pulmonary symptoms also guides selection of
added for short courses in acute exacerbations or for longer antibiotic regimens for treatment of acute exacerbations. If
treatment of the allergic response to Aspergillus colonization symptoms are recent in onset and/or mild in severity (e.g., slight
(allergic bronchopulmonary aspergillosis or ABPA); however, increase in cough and sputum production without fever),
dose and duration of therapy should be minimized.1,18 patients may be treated with oral and inhaled antibiotics for 14
High-dose ibuprofen to achieve peak concentrations of 50 to to 21 days on an outpatient basis. Outpatient uoroquinolone
100 mcg/mL (243 to 485 mol/L) has been shown to slow pro- use is common among CF patients infected with P. aeruginosa,
gression of disease. At high doses, ibuprofen inhibits the lipoxy- even in children. Despite concerns regarding cartilage and ten-
genase pathway, reducing neutrophil migration and function as don toxicity in animal studies, clinical practice has not shown an
well as release of lysosomal enzymes. At the lower concentrations increased risk in children.23
achieved with analgesic dosing, neutrophil migration increases, To prevent development of resistance and promote synergy,
potentially increasing inammation.19,20 The greatest benet inhaled tobramycin or colistin is usually added to an oral uo-
with high-dose ibuprofen is in children 5 to 13 years of age with roquinolone for P. aeruginosa coverage.1,3 Methicillin-sensitive
mild lung disease (FEV1 greater than 60%). A dose of 20 to 30 S. aureus (MSSA) may be treated with oral amoxicillin-clavulanic
mg/kg given twice daily is usually needed to attain these levels, acid, dicloxacillin, rst- or second-generation cephalosporins,
but serum concentration monitoring is necessary due to interpa- trimethoprim-sulfamethoxazole, or clindamycin, depending on
tient variability.19 Due to the need for therapeutic drug monitor- sensitivity. Likewise, methicillin-resistant S. aureus (MRSA) may
ing and concerns regarding long-term safety and tolerability, only be treated with oral trimethoprim-sulfamethoxazole, clin-
a few CF centers currently prescribe high-dose ibuprofen.1,17 damycin, minocycline, or linezolid. H. inuenzae often produces
TABLE 131. Antibiotic Dosing in Cystic Fibrosisa -lactamases but can usually be treated with amoxicillin-clavulanic
acid, a cephalosporin, or trimethoprim-sulfamethoxazole. Oral
Pediatric Adult trimethoprim-sulfamethoxazole or minocycline may be used to
Dose (mg/kg Maximum Interval
Antibiotic per day) Daily Dose (Hours)
treat S. maltophilia.
For more severe infections or patients failing outpatient ther-
Intravenous
apy, intravenous (IV) antibiotic therapy is started and continued
Tobramycin, 10 None 812
gentamicinb for 2 to 3 weeks. Most patients are admitted to the hospital for
Amikacinb 30 None 812 initiation of IV antibiotics; however, depending on the availabil-
Ceftazidime 150 6g 8 ity of home health services, patients may be discharged to nish
Cefepime 150 6g 8 their course or even receive their entire course at home.
Piperacillin- 400 16 g 6
Typical regimens for severe infections include an antipseudomonal
tazobactam
Ticarcillin- 400 12 g 6 b-lactam plus an aminoglycoside for added synergy and delay of
clavulanate resistance development.1,3 Cephalosporins tend to be better tol-
Meropenem 120 6g 8 erated and offer the benet of administration every 8 hours.
Aztreonam 200 8g 6 Extended-spectrum penicillins have been associated with a
Ciprooxacin 30 1.2 g 812
higher incidence of allergy. Aztreonam offers the added ben-
Levooxacin 750 mg 24
Nafcillin 200 12 46 et of little cross-reactivity in penicillin- or cephalosporin-
Vancomycinb 4060 None 812 allergic patients; however, it has no gram-positive coverage.
Linezolid 2030 1.2 g 812 Meropenem should be reserved for organisms resistant to all
Colistin 58 480 mg 8 other antibiotics to minimize development of resistance in
Chloramphenicolb 6080 4g 6
the carbapenem drug class, as it is the last line of defense
Oral against extended-spectrum -lactamase (ESBL)-producing
Amoxicillin 4590 4g 12
clavulanic acid
organisms.
Dicloxacillin 100 2g 6 Intravenous tobramycin is generally the rst-line aminogly-
Cephalexin 50100 4g 68 coside. Isolates are usually resistant to gentamicin, and amikacin
Cefuroxime 30 1g 12 is reserved for tobramycin-resistant strains. Pharmacokinetic
Trimethoprim- 1020 640 mg 612 goals are listed in Table 132. In general, higher peak serum con-
sulfamethoxazolec
Clindamycin 30 1.8 g 68
centrations are targeted in CF. As a result, lower serum trough
Ciprooxacin 40 2g 12 levels are desirable to reduce toxicity.
Levooxacin 750 mg 24 Some centers use once-daily aminoglycoside dosing to
Minocyclined 4 200 mg 12 achieve higher peaks and minimize troughs. Since aminogly-
Linezolid 2030 1.2 g 812 cosides exhibit concentration-dependent killing, once-daily
Inhaled dosing may optimize this effect; however, time below the min-
Tobramycin 160600 mg/day 600 mg 12
imum inhibitory concentration (MIC) is prolonged with once-
Colistin 75150 mg/day 300 mg 12
daily administration, possibly leading to loss of synergy for a
a
All doses assume normal renal and hepatic function. Consult a spe- substantial portion of the dosing interval. With once-daily admin-
cialized drug reference for dosage adjustment if function is impaired.
b
Empiric starting doses only. Adjust dose per therapeutic drug monitoring.
istration, tobramycin is typically dosed at 10 to 15 mg/kg per day
c
Dose based on trimethoprim component. and amikacin at 35 mg/kg per day. Long-term studies are
d
Children greater than 8 years of age. needed to examine the efcacy and resistance patterns associ-
ated with once-daily aminoglycosides in the CF population.1,3
TABLE 132. Pharmacokinetic Goals in Cystic Fibrosis
Traditional Units of SI Units of

Measurement Measurement
Goal Peaka Goal Troughb Goal Peaka Goal Troughb
Antibiotic (mcg/mL) (mcg/mL) (mol/L) (mol/L)
Tobramycin, gentamicin 1012 Less than 1.5 21.425.7 Less than 3.2
Amikacin 3040 Less than 5.0 35.146.8 Less than 5.85
Vancomycin c 1015 c 710.35
a
Peaks calculated 30 minutes after end of infusion for aminoglycosides. Higher peaks may be targeted
with corresponding lower trough concentrations for aminoglycosides.
b
Troughs calculated immediately prior to the time the dose is due.
c
Not routinely measured.
Routine use of once-daily aminoglycosides in CF is not rec- with increased sputum production, and concomitant use of
ommended and should be limited to adults and older teens, IV aminoglycosides may increase risk of toxicity.
in whom the time below the MIC can be minimized. Due to
a shorter half-life, once-daily aminoglycoside dosing does Pharmacokinetic Considerations
not appear to be optimal for use in younger children. CF patients have larger volumes of distribution of many
Most other serious gram-negative infections are also treated antibiotics due to an increased ratio of lean body mass to total
with combination therapy. S. maltophilia is highly resistant and body mass and lower fat stores. CF patients also have an
is most often treated with trimethoprim-sulfamethoxazole or enhanced total body clearance, although the exact mechanism
ticarcillin-clavulanate. A. xylosoxidans and B. cepacia are also has not been determined. Increased renal clearance, increased
highly resistant and may have minimal therapeutic options. In glomerular ltration rate, decreased protein binding,
some cases, uoroquinolones may be substituted for amino- increased tubular secretion, decreased tubular reabsorption,
glycosides based on sensitivity data or if renal dysfunction is extrarenal elimination, and increased metabolism have all
present. Due to excellent bioavailability, oral uoroquinolones, been proposed as possible reasons for the increased clearance.
trimethoprim-sulfamethoxazole, minocycline, and linezolid As a result of these pharmacokinetic changes, higher doses
should be used whenever possible. Due to toxicity risk, colistin of aminoglycosides are needed to achieve target serum levels and
and chloramphenicol are reserved for life-threatening, highly promote adequate tissue penetration. Higher doses of -lactam
resistant infections. Additional combinations of two or three antibiotics are also needed to achieve and sustain levels above
drugs may be used for highly-resistant organisms based on the MIC. Trimethoprim-sulfamethoxazole displays enhanced
synergy studies that test susceptibility of different antibiotic renal clearance and hepatic metabolism in the CF population.
combinations. Fluoroquinolones and vancomycin have fewer pharmacoki-
Inpatient treatment of methicillin-resistant S. aureus can netic deviations in the CF population; however, higher doses
consist of IV vancomycin or oral agents as described above, are typically needed to attain inhibitory serum and tissue con-
depending on the severity of infection and concomitant centrations against CF pathogens.26
organisms. IV vancomycin may also be converted to oral step- Although most CF patients have shorter half-lives and
down therapy upon discharge. larger volumes of distribution than non-CF patients, some
Chronic maintenance antibiotic therapy may be used in patients exhibit decreased clearance. Possible causes include
patients with Pseudomonas colonization in an attempt to pre- concomitant use of nephrotoxic medications, presence of
vent bacterial overgrowth. Some centers advocate regular diabetic nephropathy, history of transplantation (with immuno-
scheduled CF clean-outs with IV or oral antibiotics regard- suppressant use and/or procedural hypoxic injury), and age-
less of symptoms.5 However, long-term systemic antibiotics related decline in renal function in older adult patients.
are not recommended due to emergence of resistant isolates.1 Additionally, CF patients are repeatedly exposed to multiple
Chronic or rotating inhaled antibiotic maintenance therapy courses of IV aminoglycosides, which can result in decreased
has become a more common practice for preventing, treating, renal function. Evaluation of previous pharmacokinetic
and suppressing P. aeruginosa colonization. parameters and trends, along with incorporation of new
Inhaled tobramycin (TOBI) is typically administered to health information, is key to providing appropriate dosage
patients 6 years of age and older in alternating 28-day cycles of recommendations.
300 mg nebulized twice daily, followed by a 28-day washout or
off period to minimize development of resistance. Long- Gastrointestinal System
term intermittent administration improves pulmonary func- Pancreatic enzyme replacement is the mainstay of gastroin-
tion, decreases microbial burden, and reduces the need for testinal therapy. Most enzyme products are formulated as cap-
hospitalization for IV therapy.24,25 Due to minimal systemic sules containing enteric-coated microspheres or microtablets
absorption, pharmacokinetic monitoring is not necessary to avoid inactivation of enzymes in the acidic stomach; instead,
with normal renal function. Lower doses of nebulized they dissolve in the more alkaline environment of the duode-
tobramycin solution for injection have been used in younger num. Capsules may be opened and the microbeads swallowed
children, and studies are underway using 300 mg twice daily with food, as long as they are not chewed. A powder form is
in children under age 6. available for patients unable to swallow the capsules or
Nebulized colistin using the IV formulation may be an microbeads, but bioavailability is poor. While products may
option in patients with tobramycin-resistant strains or intol- contain similar enzyme ratios, they are not bioequivalent and
erance to inhaled tobramycin. Due to an increased risk of cannot be substituted. Generic enzyme products generally dis-
bronchoconstriction after colistin inhalation, patients should play poor dissolution and should not be used.5 Table 133 lists
pre-treat with albuterol and administer the rst doses under commonly used enzyme replacement products.
medical observation.1,5 Pancreatic enzyme doses are initiated at 500 to 1000 units/kg
Inhaled antibiotics are typically stopped during an acute per meal of lipase component with half-doses given with
exacerbation requiring IV therapy. Drug delivery is reduced snacks. Infants are typically started at 1500 to 2500 units of
TABLE 133. Common Pancreatic Enzyme Replacement Ursodiol may slow progression of liver disease. It improves
Products bile ow and may displace toxic bile acids that accumulate in a
cholestatic liver, stimulate bicarbonate secretion into the bile,
Lipase Amylase Protease
Trade Namea (Units) (Units) (Units)
offer a cytoprotective effect, and reduce elevated liver tests.
Ursodiol is typically dosed at 15 to 20 mg/kg per day in two
Enteric-Coated
divided doses and may be rounded to the nearest tablet size.5,7
Creon 5 5,000 16,600 18,750
Creon 10 10,000 33,200 37,500 Treatment of distal intestinal obstruction syndrome (DIOS)
Creon 20 20,000 66,400 75,000 consists of oral or nasogastric administration of polyethylene
Pancrease 4,500 20,000 25,000 glycol electrolyte (PEG) solutions. Enemas may also be used to
Pancrease MT 4 4,000 12,000 12,000 facilitate stool clearance. IV uids are often required to correct
Pancrease MT 10 10,000 30,000 30,000
dehydration due to vomiting or decreased oral intake. Re-
Pancrease MT 16 16,000 48,000 48,000
Pancrease MT 20 20,000 56,000 44,000 evaluation of enzyme compliance and dosing is essential to
Pancreacarb MS-4 4,000 25,500 25,000 prevent further episodes. Patients with recurrent symptoms
Pancreacarb MS-8 8,000 40,000 45,000 may require daily PEG administration (Miralax).5 Severe presen-
Ultrase 4,500 20,000 25,000 tations of DIOS or initial meconium ileus may require surgical
Ultrase MT 12 12,000 39,000 39,000
resection.
Ultrase MT 18 18,000 58,500 58,500
Ultrase MT 20 20,000 65,000 65,000
Endocrine System
Non-Enteric Coated
Patients with mild CFRD may be managed with dietary modi-
Viokase 87 tablet 8,000 30,000 30,000
Viokase 16 tablet 16,000 60,000 60,000 cation if their nutritional status will allow carbohydrate con-
Viokase powder 16,800 70,000 70,000 trol. However, most patients present with poor nutrition and
(amount per 0.7 g) weight loss and require more aggressive treatment. Because
a
The number after a trade name refers to the number of thousands of
CFRD results from insulin insufciency, exogenous insulin
units of lipase contained per dosage form. replacement is required in most cases. Many patients can be suc-
cessfully managed by meal coverage with short- or rapid-acting
insulin (regular, lispro, or aspart) dosed by carbohydrate count-
lipase per 120 mL of formula or breast milk. Capsules may be ing. Patients with fasting hyperglycemia or patients receiving
opened and beads divided to obtain appropriate doses. nighttime tube feedings typically also require longer-acting
Enzymes should be taken at the beginning or divided through- basal insulin. Regular home glucose monitoring is essential to
out the meal and must be given with any fat-containing snack. appropriate therapy. Little information is available regarding
They should not be mixed with alkaline or hot foods, as use of oral antidiabetic agents in CFRD, and routine use is not
enzymes may be denatured. recommended.5,8
Titration of pancreatic enzyme doses is based on control of
Musculoskeletal System
steatorrhea, stool output, and abdominal symptoms. Doses up
to 2500 units/kg per meal may be needed. Higher doses CF patients with low bone mineral density and low serum
should be used with caution due to the risk of brosing vitamin D levels may improve bone health through supple-
colonopathy.5,6 Patients who respond poorly to maximal doses mental vitamin D analogs beyond those found in standard CF
of one product may benet from changing to another prod- vitamins. The optimal dose and analog have not been deter-
uct.6 Patients may also benet from addition of a histamine mined. For ergocalciferol, a minimum of 400 IU and 800 IU
H2-receptor antagonist or proton pump inhibitor to boost
effective enzyme dose if duodenal pH is not alkaline enough Patient Encounter, Part 2
to neutralize residual gastric acid. Antacid therapy is also often
used to treat concomitant gastroesophageal reux, which is
common in the CF population.5,6
Fat-soluble vitamin supplementation is usually required in Laboratory testing conrms the diagnosis of CF, and Jessica
has been referred to her regional CF center for treatment.
pancreatic insufciency. Specially-formulated products for CF
Additional stool studies indicate the presence of severe fat
patients (ADEKs and Vitamax) are usually sufcient to maldigestion. The pulmonologist indicates that she would
attain normal serum vitamin levels at a dose of 1 tablet daily like to start Jessica (weight 8.2 kg) on pancreatic enzyme
for younger children and 2 tablets daily for teenagers and replacement therapy.
adults. Additional supplementation may be needed in uncon-
trolled malabsorption or for replacement of severe vitamin What formulation and dose would you recommend?
deciency.5,15 Appetite stimulants such as cyproheptadine may How would you administer the enzymes?
be an option for promoting nutrition and weight gain, but How would you titrate the dose?
efcacy has not been established.
should be taken daily by infants and patients over 1 year of Obtain serum drug levels for aminoglycosides and/or van-
age, respectively. Total weekly doses of 12,000 IU for children less comycin and perform pharmacokinetic analysis. Adjust the
than 5 years of age and 50,000 IU for patients 5 years of age dose, if needed, according to the parameters in Table 132.
and older may be required to achieve target vitamin D con- Obtain follow-up trough levels at weekly intervals or sooner
centrations. Supplemental calcium should be provided if 1300 if renal function is unstable. Follow serum creatinine levels if
to 1500 mg of elemental calcium intake cannot be achieved renal function is unstable. Hearing tests may be scheduled
through diet. yearly or per patient preference.
Antiresorptive agents (oral or IV bisphosphonates) may be
used to treat adult CF patients with osteoporosis. Remaining
upright for 30 minutes may be difcult in patients needing to Gastrointestinal System
perform airway clearance therapy, so once-weekly dosing should
Monitor short- and long-term nutritional status through
be considered. A high incidence of gastroesophageal reux and
evaluation of height, weight, and body mass index. Ideally,
presence of cirrhosis-associated esophageal varices may also
parameters should be near the normals for non-CF patients.
complicate therapy and increase the risk of erosive esophagitis.
Evaluate the patients stool patterns. Steatorrhea indicates
IV pamidronate, dosed at 30 mg every 3 months, has increased
suboptimal enzyme replacement or non-compliance. Infants
bone mineral density in adult CF patients. Studies using IV bis-
should have two to three well-formed stools daily, while
phosphonates in children with CF are underway.
older children and adults may have one or two stools.
Androgen replacement in male CF patients with docu-
Monitor efcacy of vitamin supplementation through yearly
mented hypogonadism may also benet bone health but
serum vitamin levels. Obtain levels more frequently if an
should be decided on an individual basis.10,27
identied deciency is being treated.
Short courses of non-steroidal anti-inammatory drugs
(NSAIDs) can be used to treat CF-related arthritis and hyper-
trophic pulmonary osteoarthropathy.5 The impact on neu-
Endocrine System
trophil recruitment in the lung with long-term NSAID therapy
at lower analgesic doses is unknown. Monitor blood glucose several times daily in patients with
CFRD or those taking systemic corticosteroids. Follow gly-
Future Direction of Therapy cosylated hemoglobin levels on an outpatient basis to assess
Signicant strides have been made in past decades with develop- long-term glucose control. Levels may be falsely low in CF
ment of new therapies that have led to the ever-lengthening CF due to a shorter red blood cell half-life.
life-span. Since the discovery of the CF gene and the CFTR pro-
tein defect, research has focused on gene therapy as a way to
restore normal CFTR function through DNA transfer.
Pharmacologic approaches are being investigated to correct Patient Encounter, Part 3
dysfunctional CFTR by suppressing premature stop codons in
the CFTR gene and to activate alternative chloride channels,
effectively bypassing dysfunctional CFTR. Additional research is
being conducted with anti-inammatory therapies, anti- At Jessicas follow-up appointment 1 month later, her
pseudomonal vaccines, and development of exogenous cationic weight is up to 8.8 kg. Her mother reports that she seems to
antimicrobial peptides to mimic those found naturally in the have caught a cold and has been coughing quite a bit of
late and has not been eating as well as usual. In clinic, the
lung.1 Development of more effective systemic and inhaled
following vitals are noted: respiratory rate 40/minute, tem-
antibiotic agents continues to be a major focus as well. perature 38.3C (101F), and oxygen saturation 92%. The
throat culture from her previous visit was positive for S.
aureus (sensitive to cefazolin, nafcillin, trimethoprim-
OUTCOME EVALUATION sulfamethoxazole, clindamycin, vancomycin, and linezolid;
resistant to erythromycin) and P. aeruginosa (sensitive to
Pulmonary System ceftazidime, cefepime, piperacillin, aztreonam, meropenem,
ciprooxacin, tobramycin, and amikacin; resistant to
Monitor for changes in pulmonary symptoms such as cough, gentamicin).
sputum production, respiratory rate, and oxygen saturation.
Symptoms of an acute exacerbation should improve with What antibiotic(s) and dose(s) would you recommend for
antibiotics and aggressive airway clearance therapy. outpatient therapy?
Pulmonary function tests should be markedly increased What antibiotic(s) and dose(s) would you recommend for
after 1 week and trend back to pre-exacerbation levels after inpatient therapy?
2 weeks of therapy. If improvement lags, 3 weeks of therapy Develop a monitoring plan to assess antibiotic response.
may be needed.
ABBREVIATIONS
ABPA: allergic bronchopulmonary aspergillosis
cAMP: cyclic-3,5-adenosine monophosphate
CF: cystic brosis
1. Perform a thorough history of prescription, non- CFRD: cystic brosisrelated diabetes
prescription, and alternative medications. CFTR: cystic brosis transmembrane regulator
Assess adherence to the prescribed regimen, including CPT: chest physiotherapy
timing of inhaled medications with respect to airway DIOS: distal intestinal obstruction syndrome
clearance therapies and timing of enzymes and insulin DNA: deoxyribonucleic acid
with regard to meals. Is the patient taking any medica- ESBL: extended-spectrum -lactamase
tions not prescribed by the CF center team? FEV1: forced expiratory volume in 1 second
2. Is the patient on all appropriate maintenance medica- FVC: forced vital capacity
tions? Are medications at the appropriate doses for HFCC: high-frequency chest compression
weight and/or age? If the patient is admitted, are main- INR: International Normalized Ratio
tenance medications ordered? IPV: intrapulmonary percussive ventilation
3. Evaluate the medication regimen for drug interactions, IV: intravenous
adverse reactions, and allergies. MIC: minimum inhibitory concentration
MRSA: methicillin-resistant Staphylococcus aureus
4. Assess pulmonary symptoms. Review the incidence and MSSA: methicillin-sensitive Staphylococcus aureus
quality of cough, dyspnea, respiratory rate, sputum pro- NSAID: non-steroidal anti-inammatory drug
duction, and fever. Are the patients PFTs decreased? Is OPEP: oscillating positive expiratory pressure
there an oxygen requirement? PEG: polyethylene glycol
5. Review culture and sensitivity history over the last 1 to 2 PFT: pulmonary function test
years. What antibiotics were used in the past, and did the PT: prothrombin time
patient appear to respond better to a particular regimen? RDA: recommended daily allowance
Is the patient currently on antibiotics, and if so, are the
symptoms improving? Recommend an appropriate antibi- Reference lists and self-assessment questions and answers are
otic regimen based on culture and sensitivity data. available at www.ChisholmPharmacotherapy.com.
6. Review the pharmacokinetic history. Are there any pos-
sible changes in clearance since the last antibiotic Log into the website: www.pharmacotherapyprinciples.com
course? Will the patient be discharged home on IV for information on obtaining continuing education credit for
antibiotics? Can the IV regimen be simplied or made
this chapter.
more convenient for home administration? Recommend
appropriate doses based on the patients clearance and
an appropriate but convenient schedule.
KEY REFERENCES AND READINGS
7. Perform pharmacokinetic adjustments as necessary.
Recommend a monitoring plan for the antibiotic
Cystic Fibrosis Foundation website: www.cff.org.
course. Are any other laboratory tests necessary? Are
Gibson RL, Burns JL, Ramsey BW. State of the art: pathophysiology
signs of toxicity present?
and management of pulmonary infections in cystic brosis. Am
8. Assess nutritional status. Is the patient gaining or main- J Respir Crit Care Med 2003;168:918951.
taining weight according to age? Are any oral supple- Rowe SM, Miller SM, Sorscher EJ. Mechanisms of disease: cystic
ments or tube feedings being used? brosis. N Engl J Med 2005;352:19922001.
9. Assess gastrointestinal symptoms. What is the quantity Yankaskas JR, Marshall BC, Suan JD, et al. Cystic brosis adult care
and quality of bowel movements? Does the patient consensus conference report. Chest 2004;125:1S39S.
have bloating, atulence, or abdominal pain?
10. Assess quality-of-life measures such as physical, psy-
chological, and social well-being.
11. Understand that CF therapy is complicated, and recom-
mend regimens to ease the care burden if possible.
12. Educate the patient and family, stressing the importance
of adherence to the regimen.
Section 3. Gastrointestinal Disorders
14 GASTROESOPHAGEAL REFLUX DISEASE

Dianne B. Williams and Marie A. Chisholm-Burns
LEARNING OBJECTIVES
1. Explain the underlying causes of gastroesophageal reux disease (GERD).

2. Differentiate between typical, atypical, and complicated symptoms of GERD.
3. Determine which diagnostic test should be recommended based on the patients clinical
presentation.
4. Identify the desired therapeutic outcomes for patients with GERD.
5. Recommend appropriate lifestyle modications and pharmacotherapy interventions for
patients with GERD.
6. Discuss other nonpharmacologic interventions that may be appropriate for patients with
GERD.
7. Formulate a monitoring plan to assess the effectiveness and safety of pharmacotherapy for
GERD.
8. Educate patients on appropriate lifestyle modications and drug therapy issues including
compliance, adverse effects, and drug interactions.
KEY CONCEPTS Anti-reux surgery or endoscopic therapies offer an alter-

native treatment for refractory GERD or when pharmaco-
GERD can be divided into three distinct categories: erosive logic management is undesirable.
esophagitis, non-erosive reux disease, and Barretts esophagus. Many patients with GERD experience relapse if medication
Patients with GERD may display symptoms described as is withdrawn, and long-term maintenance treatment is
(1) typical, (2) atypical, or (3) complicated. required in such patients.
Patients presenting with uncomplicated, typical symptoms Patient medication proles should be reviewed for drugs
of reux (heartburn and regurgitation) do not usually that may aggravate GERD.
require invasive esophageal evaluation.
The goals of treatment of GERD are to alleviate symptoms, Gastroesophageal reux disease (GERD) refers to symptoms
decrease the frequency of recurrent disease, promote heal- or mucosal damage that result from abnormal reux of gastric
ing of mucosal injury, and prevent complications. contents into the esophagus.1 GERD can be divided into
Treatment for GERD involves one or more of the following three distinct categories: (1) erosive esophagitis, (2) non-erosive
modalities: (1) lifestyle changes and patient-directed ther- reux disease, and (3) Barretts esophagus.2 Erosive esophagitis
apy; (2) pharmacologic intervention primarily with acid- occurs when the esophagus is repeatedly exposed to reuxed
suppressing agents; (3) anti-reux surgery, or (4) endoscopic material for prolonged periods (Fig. 141). The inammation
therapies. that occurs progresses to erosions of the squamous epithelium.
Acid-suppressing therapy is the mainstay of GERD treat- Non-erosive reux disease, also referred to as symptomatic
ment and should be considered for anyone not respond- GERD or endoscopy-negative reux disease, is associated with
ing to lifestyle changes and patient-directed therapy after severe reux symptoms with normal endoscopic ndings.
2 weeks. Barretts esophagus is a complication of GERD characterized
257
258 SECTION 3 / GASTROINTESTINAL DISORDERS
FIGURE 141. Endoscopic images of the esophagus. Left: Image taken during an endoscopy of the esophagus revealing normal
smooth squamous cell lining. Right: Narrowed esophageal lumen (stricture) due to chronic GERD with inammation and scarring.
The surrounding esophageal lining has ulcerations and erosions from chronic acid injury. (From Barretts esophagus website:
http://www.barrettsinfo.com.; reprinted with permission.)
by replacement of the normal squamous epithelial lining of of GERD. Aggressive factors that may promote esophageal
the esophagus by specialized columnar-type epithelium. damage upon reux into the esophagus include gastric acid,
Barretts esophagus is more likely to occur in patients with a pepsin, bile acids, and pancreatic enzymes. Therapeutic regi-
long history (years) of symptomatic reux and may be a risk mens for GERD are designed to maximize normal mucosal
factor for developing adenocarcinoma of the esophagus. defense mechanisms and attenuate the aggressive factors.
EPIDEMIOLOGY AND ETIOLOGY Lower Esophageal Sphincter Pressure

GERD is prevalent in patients of all ages. Although mortality The lower esophageal sphincter is a manometrically-dened
associated with GERD is rare, symptoms can signicantly zone of the distal esophagus with an elevated basal resting
decrease quality of life. The true prevalence and incidence of pressure. The sphincter is normally in a tonic, contracted
GERD are unknown because: (1) many patients do not seek state, preventing the reux of gastric material from the stom-
medical treatment; (2) symptoms do not always correlate well ach. It relaxes on swallowing to permit the free passage of food
with disease severity; and (3) there is no gold standard for into the stomach.
diagnosing the disease. The prevalence of erosive esophagitis Mechanisms by which defective lower esophageal sphincter
increases in adults older than 40 years of age. However, non- pressure may cause gastroesophageal reux are three-fold.
erosive reux disease may begin approximately a decade sooner. First, and probably most important, reux may occur after
There does not appear to be a major difference in incidence spontaneous transient lower esophageal sphincter relaxations
between men and women except for its association with preg- that are not associated with swallowing.4 Esophageal disten-
nancy and possibly the non-erosive reux disease seen in tion, vomiting, belching, and retching can cause relaxation of
females. Although gender does not play a major role in the devel- the lower esophageal sphincter. These transient relaxations,
opment of GERD, it is an important factor in the development which are normal postprandially, may play an important role
of Barretts esophagus, which occurs more frequently in males. in intermittent non-erosive reux.5 Transient decreases in
sphincter pressure are responsible for approximately 65% of
the reux episodes in patients with GERD.
PATHOPHYSIOLOGY Second, reux may occur after transient increases in intra-
abdominal pressure (stress reux).3 An increase in intra-
The retrograde movement of acid or other noxious substances abdominal pressure such as that occurring during straining,
from the stomach into the esophagus is a major factor in the bending over, coughing, eating, or a Valsalva maneuver may
development of GERD.3 Commonly, gastroesophageal reux is overcome a weak lower esophageal sphincter, and thus may
associated with defective lower esophageal sphincter pressure lead to reux.
or function. Problems with other normal mucosal defense Third, the lower esophageal sphincter may be atonic, thus
mechanisms such as anatomic factors, esophageal clearance, permitting free reux. Although transient relaxations are
mucosal resistance, gastric emptying, epidermal growth factor, more likely to occur when there is normal lower esophageal
and salivary buffering may also contribute to the development sphincter pressure, the latter two mechanisms are more likely
CHAPTER 14 / GASTROESOPHAGEAL REFLUX DISEASE 259
TABLE 141. Foods and Medications that may Worsen GERD peristalsis in response to esophageal distention and gravita-
Symptoms tional effects.
Swallowing contributes to esophageal clearance by increas-
Decreased Lower Esophageal Sphincter Pressure
Foods
ing salivary ow. Saliva contains bicarbonate that buffers the
Fatty meal Garlic residual gastric material on the surface of the esophagus. The
Carminatives (peppermint, spearmint) Onions production of saliva decreases with increasing age, making it
Chocolate Chili peppers more difcult to maintain a neutral intra-esophageal pH.
Coffee, cola, tea Therefore, esophageal damage due to reux occurs more
Medications
Anticholinergics Isoproterenol
often in the elderly and patients with Sjgrens syndrome or
Barbiturates Narcotics (meperidine, xerostomia. Swallowing is also decreased during sleep, which
Benzodiazepines (e.g., diazepam) morphine) contributes to nocturnal GERD in some patients.
Caffeine Nicotine (smoking)
Dihydropyridine calcium channel Nitrates
blockers Phentolamine Mucosal Resistance
Dopamine Progesterone
Estrogen Theophylline The esophageal mucosa and submucosa consist of mucus-
Ethanol secreting glands that contain bicarbonate. Bicarbonate moving
Direct Irritants to the Esophageal Mucosa from the blood to the lumen can neutralize acidic reuxate in
Foods the esophagus. When the mucosa is repeatedly exposed to the
Spicy foods Tomato juice reuxate in GERD, or if there is a defect in the normal
Orange juice Coffee
Medications
mucosal defenses, hydrogen ions diffuse into the mucosa,
Alendronate Quinidine leading to the cellular acidication and necrosis that ulti-
Aspirin Potassium chloride mately cause esophagitis.3
Iron
Non-steroidal anti-inammatory drugs
Gastric Emptying
Adapted from Williams DB, Schade RR. Gastroesophageal reux dis-
ease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Gastric volume is related to the amount of material ingested,
Pathophysiologic Approach. 6th ed. McGraw-Hill, New York: McGraw-
Hill; 2005: 615, with permission. rate of gastric secretion, rate of gastric emptying, and amount
and frequency of duodenal reux into the stomach. Delayed
when the lower esophageal sphincter pressure is decreased by gastric emptying can lead to increased gastric volume and
such factors as fatty foods, gastric distention, smoking, or contribute to reux. An increase in gastric volume may
medications.3 Certain foods and medications may worsen increase both the frequency of reux and the amount of gas-
esophageal reux by decreasing lower esophageal sphincter tric uid available to be reuxed. Factors that increase gastric
pressure or by irritating the esophageal mucosa (Table 141).6 volume and/or decrease gastric emptying, such as smoking
and high-fat meals, are often associated with gastroesophageal
reux. This partially explains the prevalence of postprandial
Anatomic Factors gastroesophageal reux.
Disruption of the normal anatomic barriers by a hiatal her-
nia was once thought to be a primary etiology of gastroe-
Composition of Reuxate
sophageal reux and esophagitis. It is now believed that lower
esophageal sphincter pressure is a more important factor The composition, pH, and volume of the reuxate are aggres-
related to symptoms in patients with hiatal hernia. Although sive factors associated with gastroesophageal reux.
anatomic factors are considered signicant by some clinicians, Duodenogastric reux esophagitis or alkaline esophagitis
the diagnosis of hiatal hernia is generally considered a sepa- refers to esophagitis induced by the reux of bilious and pan-
rate entity with which reux may or may not simultaneously creatic uid. Although bile acids have both a direct irritant
occur. effect on the esophageal mucosa and an indirect effect of
increasing hydrogen ion permeability of the mucosa, symp-
toms are more often related to acid reux than to bile reux.
Esophageal Clearance
The percentage of time that esophageal pH is below 4 is
Many patients with GERD produce normal amounts of acid, greater for patients with severe disease than for those with
but the acid produced spends too much time in contact with mild disease.
the esophageal mucosa. The contact time is dependent on the The pathophysiology of GERD is a complex process. It is
rate at which the esophagus clears the noxious material, as difcult to determine which occurs rst: gastroesophageal
well as the frequency of reux. The esophagus is cleared by reux leading to defective peristalsis with delayed clearing, or
primary peristalsis in response to swallowing, or by secondary an incompetent lower esophageal sphincter pressure leading
Esophageal clearance Esophageal mucosal resistance

Clinical Presentation of GERD
Bethanechol Alginic acid
Cisapride (limited access) Sucralfate
LES pressure
Bethanechol Typical Symptoms
Metoclopramide
Cisapride
Heartburn is the hallmark symptom of GERD and is gen-
Gastric emptying (limited access) erally described as a substernal sensation of warmth or
Metoclopramide burning rising up from the abdomen that may radiate to
Cisapride
(limited access) the neck. It may be waxing and waning in character.
Regurgitation is also very common.
Gastric acid Symptoms may be worse after a fatty meal, when bending
Antacids over, or when lying in a recumbent position.1
H2 receptor antagonists
(Cimetidine, famotidine,
Other symptoms include water brash (hypersalivation)
nizatidine, ranitidine) and belching.
Proton pump inhibitors
Lansoprazole Atypical Symptoms
Omeprazole Atypical symptoms include non-allergic asthma, chronic cough,
Pantoprazole
Rabeprazole hoarseness, pharyngitis, chest pain, and dental erosions.
In some cases, these extra-esophageal symptoms may be
FIGURE 142. Therapeutic interventions in the management of the only ones present, making it more difcult to recog-
gastroesophageal reux disease. Pharmacologic interventions nize GERD as the cause, especially when endoscopic
are targeted at improving defense mechanisms or decreasing studies are normal.
aggressive factors. LES, lower esophageal sphincter. (Adapted It is important to distinguish GERD symptoms from those
from Williams DB, Schade RR. Gastroesophageal reux disease. of other diseases, especially when chest pain or pul-
In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: monary symptoms are present.
A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill;
2005: 617, with permission.) Complicated Symptoms
These include continual pain, dysphagia (difculty swal-
lowing), odynophagia (painful swallowing), bleeding,
to gastroesophageal reux. Understanding factors associated unexplained weight loss, and choking.
with the development of GERD is essential to providing effec- These symptoms may be indicative of complications of
tive treatment (Fig. 142). GERD such as Barretts esophagus, esophageal strictures,
or esophageal cancer.

Diagnosis of GERD
Patients with GERD may display symptoms described The most useful tool in the diagnosis of GERD is the clinical
as (1) typical, (2) atypical, or (3) complicated (see Clinical history, including both the presenting symptoms and associ-
Presentation Box).7 ated risk factors. Patients presenting with uncomplicated,
Complications of GERD
The severity of symptoms of gastroesophageal reux does not
always correlate with the degree of esophagitis, but it does
correlate with the duration of reux. Patients who are not
adequately treated for GERD can develop complications from A 42-year-old man with a history of diabetes and hypertension
long-term acid exposure. Long-term, recurrent reux symptoms presents complaining of heartburn. He reports a burning
that are not adequately treated may lead to Barretts esophagus sensation in his upper chest and some regurgitation of sour-
and may be an independent risk factor for esophageal adeno- tasting material into his throat. The symptoms began about
carcinoma.8 Esophageal strictures (Fig. 141) may be present 1 month ago, occur about twice a week, and are associated
in patients presenting with dysphagia. with heavy meals and lying down after eating. He says that he
The use of non-steroidal anti-inammatory drugs or smokes about one pack of cigarettes per day and drinks coffee
aspirin is an additional risk factor that may contribute to the and alcohol-containing beverages on most days.
development or worsening of esophageal strictures. These What information is suggestive of GERD?
complicated symptoms must be distinguished from other Does he have any factors contributing to GERD?
esophageal disorders such as esophageal diverticulum, achalasia, What additional information do you need before creating
obstruction, esophageal spasm, esophageal infections, sclero- a treatment plan for this patient?
derma, and malignancy.
typical symptoms of reux (heartburn and regurgitation) do not TREATMENT

usually require invasive esophageal evaluation. These patients
generally benet from a trial of lifestyle modications and Desired Outcomes
empiric acid-suppressing therapy.1 A clinical diagnosis of
GERD can be assumed in patients who respond to appropriate The goals of treatment of GERD are to alleviate symptoms,
therapy. decrease the frequency of recurrent disease, promote healing of
More specic diagnostic tests may be warranted in patients mucosal injury, and prevent complications.
not responding to empiric (prescription) therapy, those with
complicated or alarmsymptoms (e.g., weight loss or dysphagia), General Approach to Treatment
or those with long-standing symptoms who are at risk for
Barretts esophagus. Treatment for GERD involves one of the following
More denitive diagnostic tests include endoscopy (via modalities: (1) lifestyle changes and patient-directed therapy;
endoscope or PillcamTM ESO capsule), 24-hour ambulatory (2) pharmacologic intervention primarily with acid-suppressing
pH monitoring, diagnostic proton pump inhibitor (PPI) agents; (3) anti-reux surgery, or (4) endoscopic therapies. The
administration, or esophageal manometry. rst therapeutic option used depends upon the patients con-
Upper gastrointestinal endoscopy is the preferred diag- dition (i.e., frequency of symptoms, degree of esophagitis, and
nostic test for assessing the mucosa for esophagitis and presence of complications; Table 142).
Barretts esophagus.1 It enables visualization and biopsy of Acid-suppressing therapy is the mainstay of GERD treat-
the esophageal mucosa. Endoscopy should be considered ment and should be considered for anyone not responding to
upon initial presentation in any patient who presents with lifestyle changes and patient-directed therapy after 2 weeks. PPIs
complicated symptoms and those at risk for Barretts provide the greatest relief of symptoms and highest rates of
esophagus.1 healing, especially in patients with erosive disease or moderate
The PillcamTM ESO allows for visualization of the esopha- to severe symptoms.
gus via a camera-containing capsule that is swallowed by the Maintenance therapy is generally necessary to control
patient. Sensors are placed on the chest and are connected to symptoms and to prevent complications. GERD that is refrac-
a data collector that downloads images of the esophagus. The tory to adequate acid suppression is rare. In these cases, the
entire procedure takes less than 15 minutes and can be done diagnosis should be conrmed through further diagnostic
in the physicians ofce. The camera-containing capsule is tests before long-term, high-dose therapy or anti-reux sur-
eliminated in the stool. gery or endoscopic therapies are considered.1
24-Hour ambulatory pH monitoring may be the only way
to objectively prove that symptoms are reux-related in
patients with atypical symptoms or non-erosive reux disease. Nonpharmacologic Therapy
Ambulatory pH monitoring may also be useful in patients
whose symptoms are not improving on adequate doses of Nonpharmacologic treatment of GERD includes lifestyle
acid-suppressing therapy. modications, anti-reux surgery, or endoscopic therapies.
The empiric use of a standard-dose (or double-dose) PPI
as a therapeutic trial may be used in diagnosing GERD. This Lifestyle Modications
approach is less expensive, more convenient, and more readily Although most patients do not respond to lifestyle changes
available than ambulatory pH monitoring. Problems with this alone, the importance of maintaining these lifestyle changes
diagnostic approach include lack of a standardized dosing throughout the course of GERD therapy should be stressed to
regimen and duration of the diagnostic trial. patients on a routine basis. The most common lifestyle
Esophageal manometry involves placing a multi-lumen changes that a patient should be educated about include:
tube into the stomach. Pressures are measured as the tube is (1) losing weight; (2) elevating the head of the bed; (3) eating
pulled back across the lower esophageal sphincter, esopha- smaller meals and avoiding meals 3 hours before sleeping;
gus, and pharynx. Manometry may be useful in determining (4) avoiding foods or medications that exacerbate GERD;
which surgical procedure is best for a given patient. A newer (5) smoking cessation; and (6) avoiding alcohol.
tubeless pH monitoring system does not require full A meal high in fat decreases lower esophageal sphincter
manometry. pressure for 2 hours or more postprandially. In contrast, a
Barium radiography involves the ingestion of barium fol- high-protein, low-fat meal elevates lower esophageal sphincter
lowed by x-rays of the esophagus. It is more cost effective than pressure. Elevating the head of the bed about 6 to 10 inches
endoscopy but is no longer recommended for routine diagnosis with an under-mattress foam wedge (not just elevating the
of GERD. Barium radiography lacks the sensitivity and speci- head with pillows) decreases nocturnal esophageal acid con-
city needed to determine the presence of mucosal injury, tact time and should be recommended.3
especially in less severe cases, and it cannot distinguish Patient medications and food histories should be evaluated to
between Barretts esophagus and esophagitis. identify potential factors that may exacerbate GERD symptoms
TABLE 142. Therapeutic Approach to GERD
Patient Presentation Recommended Treatment Regimen Comments

Intermittent, mild heartburn A. Lifestyle modications Start lifestyle changes initially and continue
PLUS throughout the treatment course.
B. Antacids If symptoms are unrelieved with lifestyle changes
Magnesium/aluminum hydroxide 30 mL and over-the-counter medications after 2 weeks,
after meals and at bedtime as needed begin therapy with a standard dose acid-suppressing
Antacid/alginic acid (Gaviscon) 2 tablets agent.
or 15 mL after meals and at bedtime
AND/OR
C. Patient-directed therapy
Over-the-counter H2RAs (each taken up to
twice daily)
- Cimetidine 200 mg
- Famotidine 10 mg
- Nizatidine 75 mg
- Ranitidine 75 mg
OR
Over-the-counter PPI (taken once daily)
- Omeprazole 20 mg
Symptomatic GERD A. Lifestyle modications For typical symptoms, treat empirically with standard
PLUS doses of acid-suppressing therapy.
B. Standard dose acid-suppressing therapy Mild GERD can usually be treated effectively with
H2RAs (taken twice daily) for 612 weeks H2RAs. Patients with moderate to severe symptoms
- Cimetidine 400 mg should receive a PPI as initial therapy. If symptoms
- Famotidine 20 mg are relieved, treat recurrences on an as-needed
- Nizatidine 150 mg basis.
- Ranitidine 150 mg If symptoms recur frequently, consider maintenance
therapy with the lowest effective dose.
OR Most patients require standard doses for maintenance
PPIs (taken once daily) for 48 weeks therapy.
- Esomeprazole 20 mg
- Lansoprazole 1530 mg
- Omeprazole 20 mg
- Pantoprazole 40 mg
- Rabeprazole 20 mg
Healing of erosive A. Lifestyle modications For atypical symptoms, give a trial of a PPI or H2RA.
esophagitis or treatment PLUS If symptoms are relieved, consider maintenance
of moderate to severe B. PPIs (taken once-twice daily) for 416 weeks therapy.
symptoms or complications - Esomeprazole 2040 mg PPIs are the most effective maintenance therapy in
- Lansoprazole 30 mg patients with atypical symptoms, complicated
- Omeprazole 20 mg symptoms, or erosive disease.
- Rabeprazole 20 mg Patients not responding to acid-suppressing therapy,
- Pantoprazole 40 mg including those with persistent atypical symptoms,
may be candidates for anti-reux surgery or
endoscopic therapies.
H2RA, histamine2-receptor antagonist; PPI, proton pump inhibitor.

Adapted from Williams DB, Schade RR. Gastroesophageal reux disease. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy:
A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 618, with permission.
(Table 141).6,9,10 Patients should be closely monitored for Anti-Reux Surgery

symptoms when medications known to worsen GERD are Surgical intervention is a viable alternative for selected
started. patients with well-documented GERD.1 The goal of surgery is
to re-establish the anti-reux barrier, to position the lower
Anti-Reux Surgery and Endoscopic Therapies esophageal sphincter within the abdomen where it is under
Anti-reux surgery or endoscopic therapies offer alterna- positive (intra-abdominal) pressure, and to close any associ-
tive treatments for refractory GERD or when pharmacologic ated hiatal defect.11 It should be considered in patients who
management is undesirable. (1) fail to respond to pharmacologic treatment; (2) opt for
surgery despite successful treatment because of lifestyle For symptomatic relief of mild GERD, low-dose, non-
considerations including age, time, or expense of medications; prescription H2RAs may be benecial. For patients not
(3) have complications of GERD (Barretts esophagus or responding to patient-directed therapy with over-the-
strictures); or (4) have atypical symptoms and reux docu- counter agents after 2 weeks, standard-dose acid-suppressing
mented on 24-hour ambulatory pH monitoring.11 therapy is warranted. Although higher doses of H2RAs may
provide greater symptomatic and endoscopic healing rates,
limited information exists regarding the safety of these regi-
Endoscopic Therapies12 mens and they can be less effective and more costly than
Three endoscopic approaches to the management of GERD once-daily PPIs.
are available. They include: (1) application of radiofrequency Because all H2RAs have similar efcacy, selection of the
energy to the lower esophageal sphincter area; (2) endoscopic specic agent should be based on factors such as differences in
suturing to produce a plication; and (3) endoscopic injection dosage regimen, safety prole, and cost. In general, H2RAs are
of a biopolymer at the gastroesophageal junction.1 More stud- well tolerated. Patients should be monitored for adverse
ies and experience are needed to determine their exact role in effects and potential drug interactions. Cimetidine may
the management of GERD. inhibit the metabolism of certain medications such as theo-
phylline, warfarin, phenytoin, nifedipine, or propranolol. An
alternate H2RA should be selected if the patient is taking any
Pharmacologic Therapy of these medications.
Antacids and AntacidAlginic Acid Products

Proton Pump Inhibitors
Antacids are an appropriate component of treating mild
The PPIs esomeprazole, lansoprazole, omeprazole, pantopra-
GERD, as they are clearly effective for immediate, sympto-
zole, and rabeprazole block gastric acid secretion by inhibiting
matic relief. They are often used concurrently with other acid-
gastric H+/K+-adenosine triphosphatase in gastric parietal
suppressing therapies. Patients who require frequent use of
cells.14 This produces a profound, long-lasting antisecretory
antacids for chronic symptoms should be treated with pre-
effect capable of maintaining the gastric pH above 4, even
scription acid-suppressing therapy.
during acid surges seen postprandially.3,5
An antacid product combined with alginic acid (Gaviscon)
The PPIs are superior to H2RAs in patients with moderate
is not a potent neutralizing agent but forms a highly viscous
to severe GERD. This includes not only patients with erosive
solution that oats on the surface of the gastric contents. This
esophagitis or complicated symptoms (Barretts esophagus or
viscous solution serves as a protective barrier for the esopha-
strictures), but also those with non-erosive reux disease who
gus against reux of gastric contents. It also reduces the fre-
have moderate to severe symptoms. Symptomatic relief is seen
quency of the reux episodes.13
in approximately 83% of patients and healing rates at 8 weeks
Dosage recommendations for antacids vary and range
as judged by endoscopy are 78%.1
from hourly dosing to administration on an as-needed basis.
Whether PPIs can reverse Barretts esophagus remains a
In general, antacids have a short duration of action, which
topic for debate. The use of high-dose omeprazole (40 mg twice
requires frequent administration throughout the day to pro-
daily) caused partial regression of Barretts esophagitis, but no
vide continuous acid neutralization.
change was noted in patients receiving ranitidine 150 mg twice
Antacids also have clinically signicant drug interactions
daily.14 Others propose that islands of normal squamous cells
with tetracycline, ferrous sulfate, isoniazid, quinidine, sul-
that appear in patients with Barretts esophagus after high-dose
fonylureas, and quinolone antibiotics. Antacid-drug interac-
PPIs may be covering gastric mucosa and may mask the devel-
tions are inuenced by antacid composition, dose, dosage
opment of cancerous changes in the mucosa.15 It is unknown
schedule, and formulation.
whether regression of Barretts esophagus reduces the risk of
adenocarcinoma, but aggressive therapy to suppress acid reux
H2-Receptor Antagonists early in the disease may help prevent Barretts esophagus.
The histamine2-receptor antagonists (H2RAs) cimetidine, Comparable daily doses of PPIs are omeprazole 20 mg =
famotidine, nizatidine, and ranitidine decrease acid secretion esomeprazole 20 mg = lansoprazole 30 mg = rabeprazole
by inhibiting the histamine2-receptors in gastric parietal cells. 20 mg = pantoprazole 40 mg. The PPIs degrade in acidic envi-
When given in divided doses, they are effective for patients ronments and are therefore formulated in delayed-release cap-
with mild to moderate GERD.1 Standard doses provide symp- sules or tablets.16 Lansoprazole, esomeprazole, and omeprazole
tomatic improvement in about 60% of patients after 12 weeks contain enteric-coated (pH-sensitive) granules in a capsule
of therapy.1 Healing rates per endoscopy tend to be lower form. For patients unable to swallow the capsule or in pedi-
(50%).1 Response to the H2RAs is dependent on (1) the sever- atric patients, the contents of the capsule can be mixed in
ity of disease, (2) the dosage regimen used, and (3) the dura- applesauce or placed in orange juice. If a patient has a naso-
tion of therapy. gastric tube, the contents of an omeprazole capsule can be
mixed in 8.4% sodium bicarbonate solution. Esomeprazole Prokinetic Agents

can be mixed with water. Lansoprazole is contained in a packet The prokinetic agents include cisapride, metoclopramide, and
for oral suspension and a delayed-release orally disintegrating bethanechol. The inferior efcacy and side-effect proles of
tablet. While lansoprazole dosage forms are benecial for metoclopramide and bethanechol limit their use in the treat-
those who cannot swallow the capsule, such as elderly or pedi- ment of GERD. Metoclopramide may cause tardive dyskinesia,
atric patients, they should not be placed into nasogastric tubes especially with long-term use. In contrast, cisapride has com-
due to potential clogging. Patients taking pantoprazole or parable efcacy to H2RAs in patients with mild esophagitis.
rabeprazole should be instructed not to crush, chew, or split Unfortunately, cisapride is no longer available for routine use
the delayed-release tablets. because of life-threatening arrhythmias that may occur when
Pantoprazole, lansoprazole, and esomeprazole are available given with certain medications and other disease states.
in intravenous formulations, which offer an alternative route
for patients unable to take oral medications. The intravenous Mucosal Protectants
product is not more effective than the oral forms and is sig- Sucralfate, a non-absorbable aluminum salt of sucrose octa-
nicantly more expensive. sulfate, has very limited value in the treatment of GERD and
Patients should be instructed to take their PPI in the morn- is not routinely recommended.
ing, 15 to 30 minutes before breakfast to maximize efcacy,
because these agents inhibit only actively secreting proton
Combination Therapy
pumps.5,17 While usually given prior to breakfast, patients
with nighttime symptoms may benet from taking their PPI Two agents of different therapeutic classes should not be rou-
prior to the evening meal.1 If a second dose is needed, it tinely used together unless a patient has esophagitis with
should be administered before the evening meal and not at known motor dysfunction occurring concurrently. In this
bedtime.1 Regardless of the time of day, PPIs should be given case, an acid-suppressive agent and a prokinetic agent may be
prior to a meal to gain the most benet. appropriate. Only modest improvements have been shown
The PPIs are generally well tolerated, and the choice of a when a prokinetic agent is combined with a standard dose of
particular agent is often based on cost. All PPIs can decrease an H2RA. Therefore, patients not responding to standard
the absorption of drugs (such as ketoconazole or itraconazole) H2RA doses should have the dose increased, or they should be
that require an acidic environment to be absorbed. All PPIs switched to a PPI instead of adding a prokinetic agent.
are metabolized by the cytochrome P-450 system to some Monotherapy with a PPI is not only more effective in
extent, specically by the CYP2C19 and CYP3A4 enzymes. patients not responding to an H2RA or prokinetic agent alone,
However, no interactions with lansoprazole, pantoprazole, but it also improves compliance with once-daily dosing and is
or rabeprazole have been seen with CYP2C19 substrates ultimately more cost-effective.
such as diazepam, warfarin, or phenytoin.18 Esomeprazole
does not appear to interact with warfarin or phenytoin.
Maintenance Therapy
Pantoprazole is metabolized by a cytosolic sulfotransferase
and is therefore less likely to have signicant drug interac- Many patients with GERD relapse if medication is with-
tions than other PPIs.17 drawn, and long-term maintenance treatment is required in such
While generally not of major concern, omeprazole may patients.1 Candidates for maintenance therapy include patients
inhibit the metabolism of warfarin, diazepam, and phenytoin; whose symptoms return once therapy is discontinued or
lansoprazole may decrease theophylline concentrations. Drug decreased, patients with complications such as Barretts esopha-
interactions with omeprazole are of particular concern in gus or strictures, and perhaps patients with atypical symptoms.
patients who are considered slow metabolizers, as are approx- The goal of maintenance therapy is to improve quality of
imately 3% of the Caucasian population. Unfortunately, it is life by controlling symptoms and preventing complications.
unclear which patients have the polymorphic gene variation These goals cannot generally be achieved by decreasing the
that makes them slow metabolizers.17 The metabolism of dose or switching to a less potent acid-suppressing agent.
esomeprazole may also be altered in patients with this poly- Most patients require standard doses to prevent relapses.21
morphic gene variation. Patients on potentially interacting Patients should be counseled on the importance of complying
drugs should be monitored for development of drug-related with lifestyle changes and long-term maintenance therapy to
problems. prevent recurrence or worsening of disease.
Prolonged hypergastrinemia leading to the development The H2RAs may be effective maintenance therapy for
of colonic polyps and potentially adenocarcinoma in rats was patients with mild disease.5 The PPIs are rst choice for main-
a concern that has proven to be unfounded with long-term tenance treatment of moderate to severe GERD.22 Preliminary
use in humans.19 The FDA has stated that there is insufcient data suggest that on demand maintenance therapy may be
evidence linking PPI use to atrophic gastritis, intestinal meta- effective for some patients.1 With on-demand therapy,
plasia, or gastric cancer.20 patients takes their PPIs only when symptoms occur. However,
patients with more severe disease and/or complications Special Population Considerations
should be maintained on standard daily doses of PPIs for
maximum benet. Patients with Atypical GERD Symptoms
Long-term use of higher PPI doses is not indicated unless Patients presenting with atypical symptoms may require higher
the patient has complicated symptoms, has erosive esophagitis doses and longer treatment courses than patients with typical
per endoscopy, or has had further diagnostic evaluation to symptoms. These patients are best diagnosed with ambulatory
determine degree and frequency of acid exposure. Anti- pH testing or an empiric trial with a PPI.23 These tests can con-
reux surgery and endoscopic therapies may be viable alter- rm reux in patients who have persistent symptoms without
natives to long-term drug use for maintenance therapy in evidence of mucosal damage by endoscopy.1 In patients pre-
selected patients. senting with non-cardiac chest pain, a short course (1 to 8 weeks)
of omeprazole 20 mg twice daily has been advocated.23
In patients with asthma, anti-reux medications may
Patient Encounter, Part 2: The Medical improve asthma symptoms and even decrease asthma med-
History, Physical Exam, and Diagnostic ication use but cause little or no improvement in lung
Tests function.24 A trial of 3 months has been advocated using
twice-daily proton pump inhibitor therapy for asthma
PMH symptoms thought to be associated with GERD. Omeprazole
Type 2 diabetes mellitus since age 36; it is often not well doses as high as 60 mg daily have been used.23 In patients
controlled because of poor patient compliance with chronic cough, 24-hour ambulatory pH testing is the
Hypertension x 3 years, currently controlled preferred approach for evaluation of GERD when available
History of hepatitis B
because many patients do not have erosive disease by
FH endoscopy.25 Maintenance therapy is generally indicated in
Father died of MI at the age of 68 years; mother is still alive patients who respond to the therapeutic trial or have evi-
with history of colon cancer and diabetes dence of reux. Anti-reux surgery or endoscopic therapies
SH may be indicated in selected patients not responding to
Works as a laborer in a warehouse; drinks alcohol most medical management.
days but denies any alcohol-related problems
Meds Patients with Endoscopy-Negative Reux Disease
Metformin 1000 mg orally twice daily Although endoscopy is the best diagnostic tool to evaluate the
Hydrochlorothiazide 25 mg orally once daily integrity of the esophageal mucosa, it cannot prove that the
Nifedipine XL 60 mg orally once daily patients symptoms are caused by GERD. Patients with typical
Regular insulin 4 units SC 3 times daily with meals symptoms and increased acid exposure may have no evidence
Insulin glargine 20 units SC at bedtime of esophageal damage. Many patients with persistent, severe
ROS symptoms but normal endoscopy require therapy similar to
(+) Heartburn, regurgitation; () chest pain, nausea, vomiting, those with positive endoscopic ndings.
diarrhea, weight loss, change in appetite, shortness of breath Patients presenting with normal esophageal mucosa on
or cough, difculty or painful swallowing endoscopy may undergo 24-hour ambulatory pH testing or a
PE therapeutic trial with a PPI to further conrm the diagnosis of
VS: Blood pressure 134/84 mm Hg, pulse 82 beats per minute, GERD.
respiratory rate 16/minutes, temperature 37C (98.6F)
CV: RRR, normal S1, S2; no murmurs, rubs, or gallops Pediatric Patients with GERD
Abdomen: Soft, non-tender, non-distended; (+) bowel Gastroesophageal reux occurs in approximately 18% of
sounds, () hepatosplenomegaly, heme () stool infants. As in adults, transient lower esophageal sphincter
Endoscopy: Diffuse erythema and several isolated erosions relaxations appear to be the most common cause of GERD.26
in the distal esophagus; no evidence of ulceration, obstruc- This is due to developmental immaturity of the lower
tion, or stricture esophageal sphincter.27 Other causes include impaired lumi-
nal clearance of gastric acid, neurologic impairment, and type
Given this additional information, what ndings are con-
of infant formula.
sistent with a diagnosis of GERD?
Could any of the medications listed aggravate GERD Most infants have physiologic reux with no clinical con-
symptoms in this patient? sequence.26 Complications, although rare, include distal
Identify your treatment goals for this patient. esophagitis, failure to thrive, esophageal strictures, and
What nonpharmacologic and pharmacologic options are Barretts esophagus.27
possible for this patient? Uncomplicated GERD usually resolves by 12 to 18 months
of life and responds to supportive therapy, including dietary
adjustments such as smaller meals, more frequent feedings, OUTCOME EVALUATION

or thickened infant formula. Postural management (e.g.,
positioning the infant in an upright position, especially Monitor for symptom relief and the presence of complicated
after meals), and reassurance for the parents may also be symptoms, such as difculty swallowing, painful swallowing,
helpful.27 Medical therapy may be indicated if there is no or unexplained weight loss.
improvement. Record the frequency and severity of symptoms by inter-
The combination of a prokinetic agent and acid-suppress- viewing the patient after 6 to 8 weeks of acid-suppressing
ing drug is used commonly in pediatric patients with GERD.27 therapy. Continued symptoms may indicate the need for
Monotherapy with an H2RA is also used frequently; ranitidine long-term maintenance therapy.
2 to 4 mg/kg/day is effective in neonates and pediatric Monitor for adverse drug reactions, drug-drug interactions,
patients. and compliance with the therapeutic regimen initially and
Use of PPIs is becoming more common in pediatrics. any time there is a change in symptoms or medications.
Lansoprazole is FDA-approved for treating symptomatic and Educate patients about symptoms that suggest the presence
erosive GERD in patients 1 through 11 years of age. The recom- of complications requiring immediate medical attention,
mended dose is 15 mg once daily for children weighing less than such as dysphagia or odynophagia.
or equal to 30 kg and 30 mg once daily for those weighing Refer patients who present with atypical symptoms such as
greater than 30 kg. Although omeprazole is not FDA- cough, non-allergic asthma, or chest pain to their physician
approved for use in children, evidence supports its effective- for further diagnostic evaluation.
ness in children with GERD. A common dose for esophagitis
is omeprazole 1 mg/kg/day (given once or twice daily).28
Although no major adverse events have been noted in chil- Patient Care and Monitoring
dren receiving PPIs for up to 7 years, the safety of prolonged
use in children is unknown.28 There are no data evaluating the
use of esomeprazole, pantoprazole, or rabeprazole in treating 1. Assess patient symptoms to determine if further diagnostic
GERD in children. evaluation is necessary. Does the patient have any
GERD-related complications such as difculty swallow-
Elderly Patients with GERD ing, painful swallowing, or unexplained weight loss?
Older individuals have decreased host defense mechanisms 2. Perform a thorough medication history (non-
such as slowed gastric emptying and decreased saliva produc- prescription, prescription, and natural drug products), food,
and patient history to determine exacerbating factors.
tion. They may present with atypical symptoms such as chest
3. Determine what treatments have been helpful in the past.
pain, asthma, hoarseness, coughing, wheezing, or poor denti-
4. Instruct the patient to avoid foods that aggravate GERD
tion. These patients often do not seek medical attention
symptoms.
because they believe their symptoms are part of the normal
5. Educate the patient on lifestyle modications to
aging process. improve symptoms.
A PPI may be warranted in patients older than 60 years of
6. Review the results of diagnostic tests.
age.29 Proton pump inhibitors are the most useful option
7. Recommend appropriate therapy and develop a plan to
because they have superior efcacy and are dosed once daily. assess effectiveness.
Elderly patients may be sensitive to the central nervous system 8. Evaluate the patient for the presence of adverse drug
effects of metoclopramide and H2RAs. reactions, drug allergies, and drug interactions.
9. Stress the importance of compliance with the therapeutic
regimen.
10. Determine if long-term maintenance treatment is
necessary.
Patient Encounter, Part 3: Creating a 11. Assess improvement in quality-of-life measures such as
Care Plan physical, psychological, and social functioning and
well-being.
12. Provide patient education on disease, lifestyle modica-
Based on the information presented, create a care plan tions, and drug therapy:
for this patients GERD. Your plan should include: (1) a What causes GERD and what are things to avoid?
statement of the drug-related needs and/or problems; What are possible complications of GERD?
(2) the goals of therapy; (3) a patient-specic detailed When should medications be taken?
therapeutic plan; and (4) a plan for follow-up to deter- What potential adverse effects may occur?
mine whether the goals have been achieved and adverse Which drugs may interact with their therapy?
effects avoided. What warning signs should be reported to the physician?
ABBREVIATIONS Horn J. The proton-pump inhibitors: Similarities and differences.

Clin Ther 2000;22:266280.
GERD: gastroesophageal reux disease Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gas-
H2RA: histamine2-receptor antagonist troesophageal reux as a risk factor for esophageal adenocarci-
LES: lower esophageal sphincter noma. N Engl J Med 1999;340:825831.
PPI: proton pump inhibitor Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole,
pantoprazole, and rabeprazole in the treatment of acid-related
Reference lists and self-assessment questions and answers are disorders. J Am Pharm Assoc 2000;40:5262.
available at www.ChisholmPharmacotherapy.com. Wong WM, Wong BCY. Denition and diagnosis of gastroesophageal
reux disease. J Gastroenterol Hepatol 2004;19:S26S32.
this chapter.
DeVault KR, Castell DO. Updated guidelines for the diagnosis and treat-
ment of gastroesophageal reux disease. Am J Gastroenterol
2005;100:190200.
15 PEPTIC ULCER DISEASE
Jeffrey J. Fong and John W. Devlin
LEARNING OBJECTIVES
UPON COMPLETION OF THE CHAPTER THE READER WILL BE ABLE TO:
1. Recognize differences between ulcers induced by Helicobacter pylori (HP) and non-
steroidal anti-inammatory drugs (NSAIDs) in terms of risk factors, pathogenesis, signs and
symptoms, clinical course, and prognosis.
2. Identify desired therapeutic outcomes for patients with HP-associated ulcers and NSAID-
induced ulcers.
3. Identify factors that guide selection of an HP eradication regimen and improve compliance
with these regimens.
4. Determine the appropriate management for a patient taking a non-selective NSAID who is
at high risk for ulcer-related gastrointestinal complications or who develops an ulcer.
5. Devise an algorithm for evaluation and treatment of a patient with signs and symptoms
suggestive of an HP-associated or NSAID-induced ulcer.
6. Given patient-specic information and the prescribed drug treatment regimen, formulate a
monitoring plan for a patient who is receiving drug therapy to either eradicate HP or to treat
an active NSAID-induced ulcer or gastrointestinal complication.
KEY CONCEPTS and a non-selective NSAID in reducing the incidence of ulcers,

and questions regarding their long-term cardiovascular safety
Patients with peptic ulcer disease should avoid exposure to remain.
factors known to worsen the disease, exacerbate symptoms, or Low-dose maintenance therapy with a proton pump inhibitor
lead to ulcer recurrence [e.g., non-steroidal anti-inammatory or histamine2-receptor antagonist is only indicated for
drug (NSAID) use or cigarette smoking]. patients who fail HP eradication, have HP-negative ulcers, or
Reliance on conventional antiulcer drug therapy as an alterna- develop severe complications related to their ulcer disease.
tive to Helicobacter pylori (HP) eradication is discouraged
because it is associated with a higher incidence of ulcer recur- Peptic ulcer disease (PUD) refers to an ulcer that forms on the
rence and side effects. muscular mucosa in the wall of the gastrointestinal tract. These
Eradication therapy with a proton pump inhibitorbased three- ulcerations are usually located in the duodenum or stomach but
drug regimen should be considered for all patients who test can be found elsewhere in the gastrointestinal tract. Peptic ulcer
positive for HP and have an active ulcer or a documented his- disease is common and may adversely affect quality of life unless
tory of either an ulcer or ulcer-related complication. Different properly diagnosed and treated. The high prevalence and relapse
antibiotics should be used if a second course of HP eradication rate associated with PUD pose a substantial economic burden.
therapy is required. Peptic ulcers are most commonly caused by one of three etio-
In patients at risk for NSAID-induced ulcers, proton pump logies: (1) HP infection, (2) use of NSAIDs; or (3) stress-related
inhibitors (PPIs) at standard doses reduce the risk of both mucosal damage (SRMD). A number of pathophysiologic vari-
gastric and duodenal ulcers as effectively as misoprostol and ables can be used to distinguish these three common types of
are generally better tolerated. peptic ulcer (Table 151). This chapter will focus on strategies
Selective cyclooxygenase-2 (COX-2) inhibitors have not been to optimize pharmacotherapy for patients with PUD related to
shown to be any more effective than the combination of a PPI HP or NSAID therapy.
269
TABLE 151. Characteristics of Common Causes of Peptic Ulcer Disease
H. pylori NSAID SRMD

Onset Chronic Chronic Acute
Primary location of damage Duodenum Stomach Stomach
Presence of symptoms Frequent Rare Rare
Primary mechanism for ulceration Infection resulting in Loss of defense Loss of defense
inammatory state mechanisms mechanisms
Depth of ulcers Supercial Deep Supercial
Dependence on acid for mucosal damage Greater Lesser Lesser
Characterization of GI bleeding Minor Major Major
Responsive to acid-suppressive therapy No Yes Yes
GI, gastrointestinal; H. pylori, Helicobacter pylori; NSAID, non-steroidal anti-inammatory drug; SRMD, stress-related mucosal damage.
Stress-related mucosal damage occurs most frequently in most common causes of PUD.3 While HP causes gastritis in
critically ill patients and is thought to be caused by factors all infected patients, only a small proportion of patients actu-
such as compromised mesenteric perfusion rather than HP or ally develop PUD.
NSAIDs. Its onset is usually acute, and in a small proportion Helicobacter pylori normally resides in the human stomach
of patients may progress to deep ulceration and hemorrhage. and is transmitted via the fecal-oral route or through ingestion
Less common causes of peptic ulceration include Zollinger- of fecal-contaminated water or food. Infection with HP is
Ellison syndrome (ZES), cancer chemotherapy, radiation, and more common in developing countries because of crowded
vascular insufciency. ZES is caused by a gastrin-producing conditions and the presence of contaminated food and water.
tumor called a gastrinoma and results in gastric acid hyper- HP colonization does not necessarily reect an active infection
secretion. High-dose oral proton pump inhibitor (PPI) ther- since the organism can attach itself to the gastric epithelium
apy is the initial treatment of choice for ZES; intermittent
intravenous PPI therapy may be required for any patient in
whom oral therapy is contraindicated.1
Patient Encounter 1

PUD Secondary to Helicobacter pylori
Approximately, 25 million Americans are affected by PUD, with A 51-year-old woman presents to the emergency department
the lifetime prevalence estimated to be 12% in men and 10% in complaining of abdominal pain for the past 3 days and dark
women.2 Annual direct and indirect costs associated with PUD tarry stools over the past 2 days. She states that she has never
in the United States are estimated to be more than $9 billion. had these symptoms before and that she has been feeling
Despite the widespread use of conventional anti-ulcer therapy weak and tired for the past 2 weeks. She denies having bright
that effectively reduces gastric acid secretion, ulcers frequently red blood in her stools or vomiting. She does not take any
recur, with 1-year recurrence rates (after ulcer initial healing) prescription medications and only takes extra-strength aceta-
estimated to range from 60% to 100%.1 minophen for occasional headaches.
Helicobacter pylori infection and NSAID use account for PMH
most cases of PUD. The relatively high incidence of PUD in Hypertension 10 years
the elderly may be due to higher NSAID use. Although hospi- FH
talizations related to PUD have decreased over the past two Mother died of a stroke at age 81, father died of pneumonia
decades, the incidence of PUD-related complications such as at age 71
bleeding and perforation remain unchanged.
SH
In general, ulcers related to HP infection more commonly Denies alcohol, tobacco, or illicit drug use
affect the duodenum whereas ulcers related to NSAIDs more
frequently affect the stomach. However, ulcers may be found in Allergies: No known drug allergies
either location from either cause. Gastric ulcers (GUs) tend to Meds
occur much later in life than duodenal ulcers (DUs), with the Acetaminophen extra-strength 2 tablets every 6 hours as
peak incidence of GU occurring in patients over 60 years of needed for occasional headache
age. Malignancy is more commonly found with GU than DU.
Which signs and symptoms are suggestive of PUD?
Helicobacter pylori What are this patients risk factors for PUD?
What additional information do you need to know before
Since its discovery nearly 25 years ago, the role of HP in PUD creating a treatment plan for this patient?
has been increasingly recognized, and it is now one of the
CHAPTER 15 / PEPTIC ULCER DISEASE 271
without invading cells. Cellular invasion by HP is necessary for TABLE 152. Established Risk Factors for Ulcers and
an active infection, which is usually asymptomatic and leads to Gastrointestinal Complications Related to
chronic active gastritis. NSAID Use
Age over 60
Non-steroidal Anti-Inammatory Drugs Concomitant anticoagulant use
Preexisting coagulopathy (elevated INR or thrombocytopenia)
NSAIDs are one of the most widely used classes of medica-
Concomitant corticosteroid therapy
tions in the United States, particularly in the elderly.4 More Previous peptic ulcer disease or upper gastrointestinal bleeding
than 20,000 deaths occur in the United States per year as a Cardiovascular disease and other comorbid conditions
direct result of adverse events related to NSAID use. Chronic Multiple NSAID use (e.g., low-dose aspirin in conjunction with
NSAID ingestion leads to symptoms of nausea and dyspepsia another NSAID)
Duration of NSAID use (greater than 1 month)
in nearly half of patients. Peptic ulceration occurs in up to
High-dose NSAID use
30% of patients who use NSAIDs chronically, with gastroin- NSAID-related dyspepsia
testinal bleeding or perforation occurring in 1.5% of patients
who develop an ulcer. NSAID-related peptic ulcers usually INR, International Normalized Ratio; NSAID, non-steroidal anti-
inammatory drug.
occur in the stomach; duodenal ulcers are much less common.
Risk factors for NSAID-induced peptic ulcers and complica-
risk in a patient taking an NSAID (e.g., rheumatoid arthritis,
tions are presented in Table 152. Several important principles
tobacco smoking, alcohol consumption) remain unproven
should be considered when estimating the risk for developing
and thus should not generally be considered independent risk
PUD in a patient taking an NSAID (1) risk factors are generally
factors for NSAID-induced ulceration.5
additive; (2) some risk factors (e.g., corticosteroid therapy) are
not by themselves a risk factor for ulceration but increase
PUD risk substantially when combined with NSAID therapy;
Other Causative Factors
and (3) many of the risk factors postulated to increase PUD Cigarette smoking is associated with a higher prevalence of
ulcers and may also impair healing of ulcers that develop.6 The
exact mechanism(s) for the detrimental effects of smoking on
the gastric mucosa are unclear but may involve increased pepsin
Patient Encounter 2
secretion, duodenogastric reux of bile salts, elevated levels of
free radicals, and reduced bicarbonate and prostaglandin pro-
duction.7,8 It is unknown whether nicotine or one of the many
PUD Secondary to NSAID use other ingredients found in cigarettes is responsible for these
A 65-year-old man with a history of osteoarthritis and deleterious effects.
chronic obstructive pulmonary disease (COPD) comes to Until the discovery of HP, psychological stress was consid-
your clinic complaining of burning abdominal pain. The ered one of the primary causes of PUD. Although psychoso-
pain has worsened over the past 2 weeks; it is worse at cial factors such as life stress, baseline personality patterns,
night and after meals. and depression may inuence PUD prevalence, a clear causal
PMH relationship has not been demonstrated.
Osteoarthritis for 5 years, started diclofenac within the past Dietary factors such as coffee, tea, cola, beer, and a highly-
2 months spiced diet may cause dyspepsia, but they have not been shown
COPD for 15 years to independently increase PUD risk. Although caffeine increases
FH gastric acid secretion and alcohol ingestion causes acute gastri-
Non-contributory tis, there is inconclusive evidence to conrm that either of these
SH
substances are independent risk factors for peptic ulcers.
Tobacco 1 pack per day 40 years; drinks 2 beers/day
Meds PATHOPHYSIOLOGY
Ipratropium metered dose inhaler (MDI) 2 puffs every 6 hours
Albuterol MDI 2 puffs every 4 hours as needed Ulcer formation is the net result of a lack of homeostasis
Prednisone 10 mg daily between factors within the gastrointestinal tract responsible
Diclofenac 75 mg two times a day for the breakdown of food (e.g., gastric acid and pepsin) and
Aspirin 81 mg daily factors that promote epithelial defense and repair (e.g., bicar-
bonate, mucus secretion, and prostaglandins).
Which signs and symptoms are suggestive of PUD?
What are this patients risk factors for PUD? Gastric Acid and Pepsin
creating a treatment plan for this patient? Hydrochloric acid and pepsin are the primary substances that
cause gastric mucosal damage in PUD. Three different stimuli
(i.e., histamine, acetylcholine, and gastrin) are responsible for bacterium with multiple agella that initially inhabits the gas-
acid secretion through their interactions with the histaminic, tric antrum but migrates to the more proximal sections of the
cholinergic, and gastrin receptors on the surface of parietal stomach over time. The motility provided by the agella allows
cells. Gastric acid output occurs in two stages: (1) basal acid it to penetrate the mucous gel barrier, thus permitting a direct
output (BAO), which reects the baseline output of acid dur- interaction with epithelial cellsthe site where acute infec-
ing the fasting state; and (2) maximal acid output (MAO), tion occurs. HP is able to survive in the acidic conditions of
which occurs in response to meals. Basal acid secretion follows the stomach because of its ability to induce a transient
a circadian cycle in which it is highest at night and lowest in hypochlorhydria via production of urease, an enzyme that
the morning and is modulated by the effects of acetylcholine hydrolyzes urea into carbon dioxide and ammonia.
and histamine acting on the parietal cell. A number of host and pathogenic factors contribute to the
Food can cause maximal gastric acid secretion in two ways. ability of HP to cause gastroduodenal mucosal injury includ-
In the cephalic phase of acid secretion, the vagus nerve stimu- ing: (1) direct mucosal damage; (2) alterations to host inam-
lates acid secretion in response to the sight, smell, or taste of matory responses; and (3) hypergastrinemia leading to a state
food. In both the gastric and intestinal phases of acid secretion, of elevated acid secretion. Bacterial-surface adhesion compo-
the physical distention caused by food in the gastric fundus nents facilitate binding of HP to epithelial cells, and vacuolat-
and small intestine induces gastrin secretion resulting in acid ing cytotoxin (vac A) facilitates the binding of HP to the cell
production. After stimulation by histamine, acetylcholine, and membrane, thus enabling the HP organism better access to
gastrin, acid is secreted by the H+-K+-ATPase (proton) pump, nutrients. The cag pathogenicity island (cag-PAI) leads to the
located on the luminal side of parietal cells. Acid secretion in release of cytokines thus leading to a chronic inammatory
PUD is usually normal or slightly elevated. NSAID ingestion state in HP-infected patients.3 The complex interplay between
usually does not affect acid secretion, whereas HP infection bacterial virulence factors and an enhanced inammatory
usually leads to a slight increase in acid output. This is in con- response results in a chronic HP infection that elevates acid
trast to ZES, in which acid secretion is substantially elevated. production and reduces various protective factors.
Pepsinogen released during food digestion is converted to
pepsin in the presence of an acidic environment and plays a
key role in the initiation of protein digestion, proteolysis of Non-steroidal Anti-Inammatory Drugs
collagen, and as a signal for the release of other digestive Non-selective NSAIDs [those that inhibit both cyclooxygenase-1
enzymes such as gastrin and cholecystokinin. The proteolytic and -2 (COX-1 and COX-2)] cause gastric mucosal damage by
activity of pepsin appears to inuence ulcer formation. two primary mechanisms: (1) a direct toxic interaction; and
(2) systemic pharmacologic actions.
Direct irritation of the mucosal lining by NSAIDs occurs
Mucosal Defense and Repair
because NSAIDs are weak acids. Topical irritation is therefore
Several defense and repair mechanisms are responsible for pre- most pronounced with more acidic NSAIDs such as aspirin.
venting mucosal damage and subsequent ulcer formation. While the direct irritant effects of NSAIDs play a contributory
Mucus gel, through its buffering action, is the primary source role in the development of NSAID-induced gastritis, this
of defense for the gastric epithelial surface against gastric acid. mechanism generally plays a minor role in the evolution of
It allows an acidic environment to be maintained in the lumen NSAID-induced PUD.
but a near neutral pH to be maintained on the epithelial lining. The systemic effects of NSAIDs are the primary cause of
On the epithelial lining, a number of protective mechanisms PUD. Cyclooxygenase (COX) is the rate-limiting enzyme in the
are responsible for the repair of damaged cells, production of prostaglandin synthesis pathway (Fig. 151). Inhibition of
defense mechanisms, and the promotion of epithelial growth. prostaglandin production is the primary therapeutic effect of
Prostaglandins, one of the most important epithelial NSAIDs. COX is responsible for the conversion of arachidonic
growth factors, inhibit gastric acid secretion and have numer- acid to prostaglandins (PGs) such as PGG2 and PGH2. There are
ous mucosal protective effects, the most important of which two forms of the COX enzyme, cyclooxygenase-1 (COX-1) and
include the stimulation of both mucus and phospholipid pro- cyclooxygenase-2 (COX-2). COX-1 is routinely found in body
duction, promotion of bicarbonate secretion, and increased tissues that produce prostaglandins for normal physiologic
mucosal cell turnover. Damage to the mucosal defense system is maintenance. In contrast, COX-2 is an inducible enzyme
the primary method by which HP or NSAIDs cause peptic ulcers. that is expressed during states in which cytokines and
inammatory mediators are elevated (e.g., fever and pain).
Inhibition of the COX-1 isoenzyme decreases production of
Helicobacter pylori
endogenous prostaglandins, particularly PGE1, PGE2, and PGI2.
Helicobacter pylori is a gram-negative microaerophilic rod Administration of NSAIDs parenterally (e.g., ketorolac) or rec-
that has a number of adaptive functions allowing it to live with- tally (e.g., indomethacin) is associated with an incidence of
in the acidic environment of the stomach. It is an S-shaped PUD that is similar to that with oral NSAIDs.
FIGURE 151. The

arachidonic acid
pathway.
Prostaglandins, through their effects on mucous cell secre- HP.9 Although endoscopy is the gold standard for detecting HP
tion, basal bicarbonate secretion, and mucosal growth, are infections, it may be associated with rare but severe complica-
important factors in gastric healing and protection. Inhibition tions and greater expense than non-endoscopic diagnostic
of prostaglandin production by NSAIDs compromises these methods. Endoscopy is therefore usually reserved for patients
important protective mechanisms. Finally, the antiplatelet greater than 50 years of age who have anemia, gastrointestinal
effects of NSAIDs may worsen bleeding complications associ- bleeding, or unexplained weight loss.
ated with PUD. Non-endoscopic testing methods include the urea breath
test, serologic testing, and the stool antigen assay. Compared
to endoscopic procedures, these tests are more comfortable,
COMPLICATIONS less expensive, and do not require a special procedure. The
urea breath test is usually the rst-line test to detect active
Hemorrhage is the most common complication of PUD and
may occur when an ulcer erodes the wall of a gastric or duo-
denal artery. Bleeding occurs in approximately 15% of PUD Presentation of Peptic Ulcer Disease
patients and is more frequently seen in patients greater than
60 years of age, particularly those who ingest NSAIDs. Up to
20% of patients who develop a PUD-related hemorrhage do
not have prior symptoms. Symptoms
Gastric outlet obstruction occurs in approximately 2% of Mild epigastric pain that may be described as burning,
patients with PUD and is usually caused by ulcer-related gnawing, or aching in character.
Abdominal pain may be described as burning or a feeling
inammation or scar formation near the peripyloric region.
of discomfort.
Signs and symptoms of outlet obstruction include early sati- Some patients report nocturnal pain.
ety after meals, nausea, vomiting, abdominal pain, and weight The severity of pain often uctuates.
loss. Ulcer healing with conventional acid-suppressive therapy The intensity of pain can vary widely (e.g., from dull to
is the primary treatment, but if this is unsuccessful then an sharp).
endoscopic procedure (e.g., balloon dilation) is required. Pain often occurs 1 to 3 hours after meals.
Patients may also complain of heartburn, belching, bloating,
nausea, or vomiting.
CLINICAL PRESENTATION AND DIAGNOSIS Signs
Weight loss may be associated with nausea and vomiting.
Diagnosis Complications such as bleeding, perforation, or obstruction
may occur.
Diagnostic tests for the presence of HP can be either endoscopic Alarm signs and symptoms include: bleeding, anemia,
or non-endoscopic. Endoscopic diagnosis requires the extrac- tarry stools or coffee-grounds emesis, and weight loss.
tion of gastric tissue samples that are subsequently tested for
Patient Encounter 1, Part 2: Physical Patient Encounter 2, Part 2: Physical

Examination, Laboratory Tests, and Examination, Laboratory Tests, and
Diagnostic Procedures Diagnostic Procedures
PE PE
VS: blood pressure 135/90 mm Hg, pulse 89 beats per VS: blood pressure 125/85 mm Hg, pulse 72 beats per
minute, respiratory rate 14/minutes, temperature 37.5C minute, respiratory rate 12/minutes, temperature 37.5C
Gen: NAD Gen: NAD
Skin: Normal turgor Skin: dry, intact
HEENT: PERRL HEENT: PERRL
CV: RRR; S1, S2 normal; no S3 or S4 CV: RRR, S1, S2
Lungs: CTA bilaterally Lungs: CTA B/L
ABD: Soft, non-tender, non-distended, (+) bowel sounds 4 ABD: Soft, non-tender, non-distended, (+) bowel sounds,
quadrants, 7/10 pain 5/10 pain on the epigastric region
Neuro: A&O 3, Cranial nerves intact, DTR 2+ Neuro: A&O 3, Cranial nerves intact, DTR 2+
Labs Labs
WBC 4.6 x 103/mm3, Hemoglobin 8.5 g/dL (5.3 mmol/L), WBC 9.9 x 103/mm3, Hemoglobin 12.1g/dL (7.5 mmol/L),
Hematocrit 24.7%, Platelets 327 x 103/mm3, aPTT Hematocrit 38.3%, Platelets 108 x 103/mm3, aPTT
32.5 seconds, PT 12.1 seconds, INR 1.02 27.9 seconds, PT 12.4 seconds, INR 1.09
Fecal occult blood: (+) EGD: One ulcer located on the antrum of the stomach
EGD: Multiple supercial ulcerations in the duodenum; measuring 3 cm in diameter; no bleeding or obstruction
largest ulcer measures 2 cm in diameter; no active bleeding noted
noted.
Given this information, what is your assessment of the
CLO test (urease test): (+) for H. pylori
patients condition?
What are your treatment goals?
Given this information, what is your assessment of the
What nonpharmacologic and pharmacologic treatment
patients condition?
alternatives are available for this patient?
What are your treatment goals?
What nonpharmacologic and pharmacologic alternatives
are available for this patient?
HP infection because it has a sensitivity and specicity greater TREATMENT

than 95% and a short turnaround time (2 days). Concomitant
acid-suppressive or antibiotic therapy may give false-negatives The treatment selected for PUD depends on the following fac-
with this test. tors: (1) the etiology of the ulcer; (2) whether the ulcer is new
Ofce-based serologic testing provides a quick assessment or recurrent; and (3) the presence of any ulcer-related compli-
(within 15 minutes) of an exposure to HP, but patients can cations. Figure 152 contains an algorithm for the evaluation
remain seropositive for up to 1 year after eradication, making and treatment of a patient with signs and symptoms suggestive
the clinical utility of this test limited. Stool antigen assays can of an H. pyloriassociated or NSAID-induced ulcer.
be useful for the initial diagnosis or to conrm HP eradica-
tion, and unlike the urea breath test, are less affected by con-
comitant medication use.9
Desired Outcomes
Radiologic and/or endoscopic procedures are usually The goals of PUD therapy are to: (1) resolve symptoms;
required to objectively document the presence of ulcers. (2) reduce acid secretion; (3) promote epithelial healing;
Barium studies have a high sensitivity and are considered (4) prevent ulcer-related complications; and (5) prevent
rst-line tests to radiographically document an ulcer. ulcer recurrence. For HP-related PUD, eradication of HP is
However, the cost and complexity of all of these tests has led to an additional outcome.
the promotion of an early empiric treatment strategy for
patients at low risk for PUD-related sequelae (e.g., malignancy).
An empiric treatment strategy is appropriate for patients less
than 50 years of age who have mild or intermittent epigastric Patients with PUD should avoid exposure to factors known
symptoms and no evidence of PUD-related systemic symp- to worsen the disease, exacerbate symptoms, or lead to ulcer
toms or complications. recurrence. Patients should be advised to reduce psychological
FIGURE 152. Approach

Ulcer-like signs and symptoms to the patient presenting
with ulcer-like symptoms.
GERD, gastroesophageal
Patient with no current or previous Patient with current or previous
reux disease; HP
NSAID use NSAID use Helicobacter pylori;
H2RA, histamine2-receptor
antagonist; NSAID, non-
Alarm signs and symptoms present steroidal anti-inammatory
HP history D/C NSAID drug; PPI, proton pump
(e.g., weight loss, bleeding, anemia)
Yes
inhibitor. (Adapted from
No Berardi RR, Welage LS.
Serologic Resolution of Persistence of Peptic ulcer disease. In:
Endoscopy
testing symptoms symptoms DiPiro JT, Talbert RL,
Negative Yee GC, et al, (eds.)
Pharmacotherapy: A
Treat with No further Treat with H2RA Pathophysiologic
H2RA or PPI Ulcer present Ulcer absent
treatment or PPI Approach. 6th ed. New
York: McGraw-Hill; 2005:
637, with permission.)
Consider other etiologies for
HP positive HP negative
prevention (e.g., GERD)
Positive
Treat with
PPI based HP Need to continue
On NSAIDs?
eradication NSAID therapy
regimens
Treat with PPI

D/C NSAID
followed by PPI
or misoprostol
as prophylaxis
Treat with
H2RA or PPI
stress and avoid cigarette smoking, alcohol consumption, as an alternative to HP eradication is discouraged because it is
foods or beverages that exacerbate ulcer symptoms, and associated with a higher incidence of ulcer recurrence and side
NSAID or aspirin use.10,11 effects. Reinfection rates are generally low after the initial course
The high success rates of medical therapies have reduced the of therapy as long as the patient has received a regimen with
number of surgical procedures performed and relegated surgery proven efcacy and is compliant with it. The HP regimen that
primarily to elective situations. For this reason, surgical interven- is chosen should have a per-protocol cure rate of greater than or
tions are generally reserved for complicated or refractory PUD. equal to 90% or a cure rate based on intention-to-treat analysis
Some surgical procedures include: (1) vagotomy and pyloro- of greater than or equal to 80%.9 In addition to proven efcacy,
plasty; (2) highly-selective vagotomy; or (3) vagotomy combined the optimal treatment regimen should cause minimal adverse
with antrectomy. Vagotomy is the central component of most events, have low risk for the development of bacterial resistance,
procedures because of its targeted effects on blocking further acid and be cost effective.9
secretion. These procedures are associated with a high success Helicobacter pylori treatment regimens are presented in
rate. Complications are rare but can include dumping syndrome, Table 153. Eradication therapy with a PPI-based three-drug
bile reux, diarrhea, malabsorption and gastric atony.12 regimen should be considered for all patients who test positive for
HP and have an active ulcer or a documented history of either an
Pharmacologic Therapy ulcer or ulcer-related complication. Different antibiotics should
be used if a second course of HP eradication therapy is required.
Treatment of Helicobacter pyloriAssociated Ulcers The rst-line regimen should contain a PPI plus clar-
The primary goal of HP therapy is to completely eradicate the ithromycin and either amoxicillin or metronidazole. The com-
organism using an effective antibiotic-containing regimen. bination of two antimicrobials and a PPI leads to cure rates
Reliance on conventional acid-suppressive drug therapy alone greater than 80% (by intention-to-treat basis) and reduces the
TABLE 153. Drug Regimens to Eradicate Helicobacter pyloria
Treatment Regimen Cure Ratesb

Two Drugs
Amoxicillin 1 g three times a day + omeprazole 20 mg twice a day Poor
Clarithromycin 500 mg three times a day + omeprazole 40 mg every day Poor
Clarithromycin 500 mg three times a day + RBC 400 mg twice a day Fair
Three Drugs
Clarithromycin 500 mg twice a day + metronidazole 500 mg twice a day + omeprazole 20 mg twice a day Goodexcellent
Clarithromycin 500 mg twice a day + amoxicillin 1 g twice a day + lansoprazole 30 mg twice a day Goodexcellent
Clarithromycin 500 mg twice a day + metronidazole 500 mg twice a day + RBC 400 mg twice a day Good
Amoxicillin 1 g twice a day + clarithromycin 500 mg twice a day + RBC 400 mg twice a day Good
Four Drugs
BSS 525 mg four times a day + metronidazole 250 mg four times a day + tetracycline 500 mg four times Goodexcellent
a day + H2RA (conventional ulcer-healing dose)c
BSS 525 mg four times a day + metronidazole 250 mg four times a day + amoxicillin 500 mg four times Good
a day + H2RA (conventional ulcer-healing doses)c
BSS 525 mg four times a day + metronidazole + amoxicillin + PPId Good
Rescue Therapye
BSS 525 mg four times a day + metronidazole 500 mg four times a day + tetracycline 500 mg four times Goodexcellent
a day + omeprazole 20 mg twice a dayd
Furazolidone 200 mg twice a day + amoxicillin 1 g twice a day + omeprazole 20 mg twice a dayf Good
Amoxicillin 1 g twice a day + rifabutin 300 mg every day + pantoprazole 40 mg twice a dayg Goodexcellent
a
These regimens based on efcacy for a 14-day treatment duration unless otherwise noted.
b
Cure rates based on intention-to-treat analysis from references 3, 12, 14, and 35, where: poor = less than 70% eradication, fair =
7080%, good = 8090%, and excellent = greater than 90%.
c
H2RA therapy should be continued for an additional 2 weeks.
d
Duration of therapy is 710 days.
e
Data based on refractory treatment data.
f
Given for 7 days.
g
Given for 10 days.
BSS, bismuth subsalicylate; H2RA, H2-receptor antagonist; PPI, proton pump inhibitor; RBC, ranitidine bismuth citrate (not available
in the United States).
risk of selecting out resistant organisms.13 Monotherapy with a with the initial regimen, or antimicrobial resistance. Factors
single antibiotic or antiulcer agent is not recommended due to associated with decreased compliance include use of a large
high failure rates. In the United States, two-drug regimens con- number of medications, a need for frequent drug administra-
sisting of a PPI and an antibiotic are also not recommended. tion or a long treatment duration, and the use of drugs that
The duration of therapy is controversial and varies by con- may cause intolerable side effects. Potential adverse drug
tinent. Europeans routinely treat patients for 7 days whereas events include taste disturbances (clarithromycin and
Americans usually rely on a 14-day regimen. While this seven metronidazole), nausea, vomiting, abdominal pain, and diar-
additional days of therapy improves the absolute cure rate by rhea. Superinfections with oral thrush or vaginal candidiasis
approximately 9%,14 longer courses decrease compliance and can occur.
increase drug cost. Preexisting antimicrobial resistance is an increasing cause of
Bismuth-based four-drug regimens have clinical cure rates treatment failure and is estimated to account for up to 70% of all
similar to three-drug, PPI-based regimens. Bismuth-based regi- treatment failures. Geography is the most important factor in HP
mens usually include tetracycline, metronidazole, and an antise- resistance. Metronidazole-resistant strains are more prevalent in
cretory agent (e.g., PPI or histamine2-receptor antagonist Asia (85%) than North America (30%).15 Primary resistance to
[H2RA]). Bismuth salts promote ulcer healing through antibac- amoxicillin and tetracycline remains low in both the United
terial and mucosal protective effects. Bismuth subsalicylate is the States and Europe. Clarithromycin resistance rates are estimated
only bismuth product available in the United States. While to be approximately 10% in the United States. Another con-
cheaper than most other regimens, drawbacks of bismuth-based founding factor when evaluating potential antibiotic resist-
regimens include the frequency of administration (four times a ance is that culture and sensitivity studies are not routinely
day), risk for salicylate toxicity in patients with renal impair- performed with HP infection.
ment, and propensity for bothersome side effects (e.g., stool and Initiation of a second HP treatment regimen after failure of the
tongue discoloration, constipation, nausea, and vomiting). initial treatment regimen is usually associated with a lower success
Patients may remain infected with HP after the initial rate. Reasons for failure are often the same as those reported
course of therapy because of reinfection, non-compliance with failure of the initial regimen: patient non-compliance and/or
antimicrobial resistance. In these situations, quadruple therapy is osteoarthritis, rheumatoid arthritis, or cardioprotection.
generally required, and metronidazole or clarithromycin should Misoprostol, H2RAs, PPIs, and COX-2 selective inhibitors
be replaced by another antibiotic if either one of these agents was have been evaluated in controlled trials to reduce the risk of
used in the initial regimen. If both clarithromycin and metro- NSAID-induced PUD. In patients at risk for NSAID-
nidazole were used as initial therapy, a regimen consisting of fura- induced ulcers, PPIs at standard doses reduce the risk of both
zolidone 100 mg four times a day with tetracycline, bismuth, and gastric and duodenal ulcers as effectively as misoprostol and are
a PPI can be used. Another second-line regimen consisting of a generally better tolerated.
PPI, amoxicillin 1 g twice daily and rifabutin 300 mg once daily for Although acute gastrointestinal bleeding is the most serious
10 days resulted in eradication rates greater than 80%.16,17 adverse outcome of NSAID therapy and is ultimately what cli-
nicians are trying to prevent with prophylactic therapy, few
studies have compared PUD prophylaxis strategies using this
Treatment of NSAID-Induced Ulcers
outcome measure. Acute gastrointestinal bleeding is not usual-
Treatment and dosing recommendations to heal peptic ulcers
ly evaluated in studies because of the low frequency with which
or provide maintenance therapy are shown in Table 154.
bleeding occurs in NSAID users, the small size of most pro-
Choice of regimen in a patient with PUD related to NSAID
phylaxis studies, and their short duration. Instead, studies usu-
use depends on whether NSAID use is to be continued.
ally rely on secondary outcome variables to evaluate efcacy
NSAIDs should be discontinued if possible and replaced with
such as the incidence of ulcers during screening endoscopy or
alternatives (such as acetaminophen) although this may not
the incidence of patient-reported ulcer symptoms. Correlation
be desirable or feasible in some patients. For patients discon-
between these secondary outcomes and PUD-related bleeding
tinuing NSAID therapy, PPIs, H2RAs, or sucralfate are all
events is poor and thus, clinicians must be cautious when
effective for ulcer healing. PPI therapy heals NSAID ulcers
extrapolating the results of these studies to patient care.
faster than H2RAs.16,17 For patients continuing NSAID thera-
py, PPIs are preferred over H2RAs or sucralfate.1821 If the deci-
Misoprostol
sion is made to continue NSAID therapy, adjunctive strategies
Misoprostol is a synthetic prostaglandin E1 analog that exoge-
may be required to promote ulcer healing and prevent future
nously replaces prostaglandin stores. The minimum effective
recurrences.
dose shown to inhibit acid secretion and promote mucosal
defense is 400 mcg/day. Misoprostol use is limited by a high fre-
Prevention of NSAID-Induced Ulcers quency of bothersome gastrointestinal effects such as abdom-
Prophylactic regimens against PUD are often required in inal pain, atulence, and diarrhea. In placebo-controlled
patients who require long-term NSAID or aspirin therapy for studies diarrhea occurred with twice the frequency in the
TABLE 154. Oral Drug Regimens to Heal Peptic Ulcers or Maintain Ulcer Healing
Duodenal Ulcer or Gastric Maintenance of DU or

Drug Ulcer Healing (mg/day) GU Healing (mg/day)
Mucosal Protectant
Sucralfate 1 g four times daily 1 g four times daily
2 g twice daily 12 g twice daily
H2-Receptor Antagonists
Cimetidine 300 mg four times daily 400800 mg daily
400 mg twice daily
800 mg at bedtime
Famotidine 20 mg twice daily 2040 mg daily
40 mg at bedtime
Nizatidine 150 mg twice daily 150300 mg daily
300 mg at bedtime
Ranitidine 150 mg twice daily 150300 mg daily
300 mg at bedtime
Esomeprazole 2040 mg daily 2040 mg daily
Lansoprazole 1530 mg daily 1530 mg daily
Omeprazole 2040 mg daily 2040 mg daily
Pantoprazole 40 mg daily 40 mg daily
Rabeprazole 20 mg daily 20 mg daily
DU, duodenal ulcer; GU, gastric ulcer.

misoprostol-treated groups and led to drug discontinuation COX-2 Selective Inhibitors

in a substantial number of patients. With the availability of NSAIDs with COX-2 selectivity, clini-
In two large multicenter, placebo-controlled trials, miso- cians postulated that these agents would avoid the need to add
prostol 200 mcg orally four times daily was effective in reduc- an additional prophylactic agent to therapy in patients with
ing the incidence of both GU and DU in patients taking PUD risk factors. However, selective COX-2 inhibitors have
NSAIDs.22,23 Misoprostol is superior to H2RAs in preventing not been shown to be any more effective than the combination of
NSAID-associated ulcers. One large randomized study found a PPI and a non-selective NSAID in reducing the incidence of
a signicantly lower incidence of GU in patients receiving ulcers, and questions remain regarding their long-term cardio-
misoprostol 200 mcg four times daily compared to those vascular safety.
receiving ranitidine 150 mg orally twice daily (1% versus 6%; Two large trials, the Vioxx Gastrointestinal Outcomes
p less than 0.01). However, the incidence of GI side effects such Research (VIGOR) study and the Celecoxib Long-term
as diarrhea was substantially higher in the misoprostol-treated Arthritis Safety Study (CLASS), compared selective COX-2
group.24 inhibitors and traditional, non-selective NSAID therapy in
terms of their ability to prevent clinical PUD (i.e., symptomatic
ulcers and ulcer complications). VIGOR (9-month median
follow-up) demonstrated that rofecoxib (50 mg daily) therapy
Refer to Chapter 14 on gastroesophageal reux disease for more
was signicantly more efcacious than naproxen.28 The CLASS
information on the H2RAs. When given in standard doses,
study (6-month median follow-up) found that high-dose cele-
H2RAs are not effective in preventing NSAID-related ulceration,
coxib (400 mg twice daily) was superior to non-selective
but they do reduce symptoms and are generally well tolerated.11
NSAID therapy (either ibuprofen 800 mg three times daily or
One randomized study demonstrated that high-dose therapy
diclofenac 75 mg twice daily).29
may be effective for preventing NSAID complications. When
A number of methodologic factors may account in part
famotidine 20 mg twice daily, famotidine 40 mg twice daily, and
for the lower incidence of clinical PUD observed with COX-2
placebo were compared in patients taking NSAIDs who required
therapy in these studies, including the short duration of clin-
GI prophylaxis, the incidence of GU was signicantly lower in
ical follow-up and the high doses of both celecoxib and rofe-
patients taking 40 mg twice daily than in those taking either
coxib used.30 An important difference between these two
20 mg twice daily or placebo.25 The incidence of duodenal
studies is that patients taking low-dose aspirin were excluded
ulceration was similar between both famotidine groups and
from VIGOR but not from CLASS. In CLASS, patients in the
was signicantly reduced with H2RA therapy. In summary,
celecoxib group who were taking low-dose aspirin had the
although standard-dose H2RA therapy reduces the risk of
same incidence of clinical PUD as those receiving a tradi-
NSAID-related duodenal ulcers, higher doses are needed to
tional NSAID therapy. This is an important issue, as many
reduce the risk of gastric ulcers.
patients with arthritis also have coronary artery disease and
are prescribed low-dose aspirin therapy because of its car-
Proton Pump Inhibitors dioprotective effects.31 Low-dose aspirin is associated with
Refer to Chapter 14 on gastroesophageal reux disease for more PUD bleeding itself, and its use with a COX-2 inhibitor
information on the PPIs. The PPI omeprazole is superior to appears to largely negate the gastrointestinal-sparing effects of
both ranitidine and misoprostol for preventing recurrence of these agents.
NSAID-associated PUD. In one study, omeprazole 20 mg daily Selective COX-2 inhibitors are not superior to PPIs in
was compared to misoprostol 200 mcg twice daily for NSAID- preventing NSAID-related PUD. One randomized, place-
associated PUD prevention. At 6 months, the omeprazole- bo-controlled trial that included 267 patients at high risk
treated group had signicantly fewer ulcers than those taking for ulceration (arthritic patients with a previously healed
misoprostol. Furthermore, more patients discontinued ulcer bleeding ulcer) compared celecoxib 200 mg twice daily to the
prophylaxis in the misoprostol group due to adverse events.26 combination of diclofenac 75 mg twice daily plus omeprazole
Another study randomized patients requiring NSAID pro- 20 mg daily.32 After 6 months, the risk for recurrent bleeding
phylaxis to either omeprazole 20 mg daily or ranitidine 150 mg was found to be similar between groups (celecoxib, 4.9% and
twice daily.19 At 6 months, more patients who received omepra- diclofenac/omeprazole, 6.4%); the authors concluded that
zole (72%) than ranitidine (59%) were in ulcer-free remission neither of these therapies can completely prevent recurrent
(p = 0.004). Omeprazole was also more efcacious in preventing ulcer complications.
GU recurrence than ranitidine (5.2% versus 16.3%; p less than Longer-term studies evaluating the cardiovascular risks
0.01). Adverse drug events were similar in the two groups. associated with the use of COX-2 inhibitors have found a
In patients who experience a PUD-related bleeding event higher incidence of cardiovascular mortality with the use of
while taking aspirin but who require continued aspirin therapy, these agents compared to traditional NSAIDs.29,33,34 This
the addition of a PPI reduces the incidence of recurrent GI prompted the withdrawal of both rofecoxib and valdecoxib
bleeding.27 from the market and the inclusion of a black box warning in
the celecoxib package insert.3436 Given the cardiovascular risk Obtain a baseline serum creatinine measurement. Calculate the
of the COX-2 inhibitors, it has been suggested that an older estimated creatinine clearance and adjust the dose of H2RAs
non-selective NSAID and a PPI can be used as an alternative and sucralfate according to package insert recommendations.
to COX-2 therapy in patients at high risk for NSAID-related Obtain a history of symptoms from the patient. Monitor for
PUD.5,37 improvements in pain symptoms (e.g., epigastric or abdom-
inal pain) daily.
Sucralfate Monitor the patient for the development of any alarm signs
Sucralfate is a negatively-charged, non-absorbable agent that and symptoms.
forms a complex by binding with positively-charged proteins Recommend a follow-up visit if signs and symptoms worsen
in exudates, forming a viscous, paste-like, adhesive substance. at any time or do not improve within the dened treatment
This forms a coating that protects the ulcerated area of the period.
gastric mucosa against gastric acid, pepsin, and bile salts. Assess for potential drug interactions whenever there is a
Limitations of sucralfate include the need for multiple daily change in the patients medications, particularly for patients
dosing, large tablet size, and interaction with a number of taking cimetidine, omeprazole, or sucralfate.
other medications. Adverse effects include constipation, nau- Educate the patient on the importance of adhering to the
sea, metallic taste, and the possibility for aluminum toxicity in HP-eradication regimen.
patients with renal failure. While sucralfate may be used for the Monitor the patient for complications related to antibiotic
treatment of an NSAID-related ulcer when NSAID therapy is therapy (e.g., diarrhea or oral thrush) during and after com-
being stopped, it is not recommended for use as prophylaxis pletion of HP eradication therapy.
against NSAID-induced ulcers. Recommend follow-up care if the patients signs and symptoms
do not improve after completion of HP-eradication therapy.
Conventional Treatment of Active Duodenal and Gastric
Ulcers and Long-Term Maintenance of Ulcer Healing
Conventional therapy prior to the advent of HP eradication Patient Care and Monitoring
therapy consisted of standard doses of sucralfate or an H2RA
for 6 to 8 weeks. A PPI provides equivalent efcacy with a treat-
ment duration of only 4 weeks. Long-term antiulcer therapy is General Recommendations: HP-Associated and NSAID-
ineffective for treating HP infections. Induced Ulcers
Low-dose maintenance therapy with a PPI or H2RA is only 1. Assess the severity of signs and symptoms. Identify the
presence of any alarm signs and symptoms.
indicated for patients who fail HP eradication, have HP-negative
ulcers, or develop severe complications related to ulcer disease. 2. Educate the patient on monitoring for alarm signs and
symptoms.
Drug regimens and doses are presented in Table 154.
3. Obtain a history of prescription medication, over-the-
counter medication, and dietary supplement use.
Treatment of Refractory Ulcers
4. Encourage lifestyle modications such as reducing tobacco
The presence of refractory ulcers [ulcers that persist beyond
use and ethanol ingestion and decreasing psychological
8 weeks (DU) or 12 weeks (GU)] requires thorough assess-
stress.
ment, including evaluation of medication compliance. The
5. Determine the appropriate duration of therapy for acid-
patient should be questioned regarding recent NSAID inges-
suppressive therapy.
tion. Tolerance has been reported with as few as 4 weeks of
H2RA therapy, and thus a change to PPI therapy should be 6. Dene the current impact of PUD on the patients quality
of life and the improvement in these outcomes sought
considered in this situation.38 Other assessments that may be
with drug therapy.
considered include an ulcer biopsy to exclude malignancy, HP
testing (if not done initially), a serum gastrin measurement to 7. Evaluate current drug therapy for potential adverse drug
reactions and drug interactions.
exclude ZES, and gastric acid studies. In one study, increasing
the starting dose of PPI therapy healed 90% of refractory Helicobacter pyloriAssociated Ulcers
ulcers after 8 weeks.39 1. Recommend an appropriate drug regimen that will eradi-
cate the organism.
2. Identify the patients drug allergies and avoid drug classes
OUTCOME EVALUATION a patient is allergic to.
3. Avoid regimens with tetracycline in children.
Obtain a baseline complete blood cell count (CBC).
Recheck the CBC if the patient exhibits alarm signs or (Continued)
symptoms.
PUD: peptic ulcer disease

4. Educate patients on specic adverse drug effects, par- SRMD: stress-related mucosal damage
ticularly with metronidazole (avoidance of alcohol) and VIGOR: Vioxx Gastrointestinal Outcomes Research (study)
bismuth (change in stool color). ZES: Zollinger-Ellison syndrome
5. Assess the potential for drug interactions, particularly in
patients taking regimens containing metronidazole, clar- Reference lists and self-assessment questions and answers are
ithromycin, and/or cimetidine. available at www.ChisholmPharmacotherapy.com.
6. Recommend different antibiotics if this treatment regimen
is a result of failure of a prior HP regimen.
7. Educate the patient on the importance of adherence to this chapter.
eradication therapy.
NSAID-Associated Ulcers
1. Assess for risk factors for NSAID ulcers and recommend KEY REFERENCES AND READINGS
an appropriate strategy to reduce ulcer risk.
2. Monitor for signs and symptoms of complications associ- Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and
ated with NSAID-related ulceration. omeprazole in reducing the risk of recurrent ulcer bleeding in
3. Recommend an appropriate treatment regimen to patients with arthritis. N Engl J Med 2002;347:21042410.
achieve the desired outcomes. Chan FKL, Leung WK. Peptic ulcer disease. Lancet 2002;360: 933941.
Howden CW, Hunt RH. Guidelines for the management of
4. Assess and counsel patients on potential adverse drug
Helicobacter pylori infection. Ad hoc committee on practice
events and drug interactions.
parameters of the American College of Gastroenterology. Am J
5. Inform patients who are receiving prophylactic therapy on Gastroenterol 1998;93:23302338.
the importance of its use, potential adverse drug events, Laheij RJ, Rossum LG, Janen JB, et al. Evaluation of treatment regi-
and the possible alarm symptoms associated with PUD. mens to cure Helicobacter pylori infection: a meta analysis.
Aliment Pharmacol Ther 1999;13:857864.
Megraud F, Lamouliatte H. The treatment of refractory Helicobacter
pylori infection. Aliment Pharmacol Ther 2003;17: 13331343.
ABBREVIATIONS Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces seri-
ous gastrointestinal complications in patients with rheumatoid
BAO: basal acid output arthritis receiving non-steroidal anti-inammatory drugs: a
cag-PAI: cag pathogenicity island randomized, double-blind, placebo-controlled trial. Ann Intern
CBC: complete blood cell count Med 1995;123:241249.
CLASS: Celecoxib Long-term Arthritis Safety Study Suerbaum S, Micchetti P. Helicobacter pylori infection. N Engl J Med
COX: cyclooxygenase 2002;347:11751186.
DU: duodenal ulcer Tannenbaum H, Bomardier C, David P, et al. An evidence-based
GU: gastric ulcer approach to prescribing non-steroidal antiinammatory drugs:
HP: Helicobacter pylori Third Canadian Consensus Conference. J Rheumatol 2006;33:
H2RA: histamine2-receptor antagonist 140157.
MALT: mucosa-associated lymphoid tissue Topol EJ. Arthritis medicines and cardiovascular events: house of
MAO: maximal acid output coxibs. JAMA 2005;293:366368.
NSAID: non-steroidal anti-inammatory drug Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of
PG: prostaglandin nonsteroidal anti-inammatory drugs. N Engl J Med 1999;340:
PPI: proton pump inhibitor 18881899.
16 INFLAMMATORY BOWEL DISEASE
Brian A. Hemstreet
LEARNING OBJECTIVES
UPON COMPLETION OF THE CHAPTER THE READER WILL BE ABLE TO:
1. Characterize the pathophysiologic mechanisms underlying inammatory bowel disease

(IBD).
2. Recognize the signs and symptoms of IBD, including major differences between ulcerative
colitis and Crohns disease.
3. Identify appropriate therapeutic outcomes for patients with IBD.
4. Describe pharmacologic treatment options for patients with acute or chronic symptoms of
ulcerative colitis and Crohns disease.
5. Create a patient-specic drug treatment plan based on symptoms, severity, and location of
ulcerative colitis or Crohns disease.
6. Recommend appropriate monitoring parameters and patient education for selected drug
regimens for treating symptoms of IBD.
KEY CONCEPTS Treatment of acute episodes of ulcerative colitis is dictated by

the severity and extent of disease, and rst-line therapy of mild
Inammatory bowel disease includes both ulcerative colitis to moderate disease involves oral or topical aminosalicylate
and Crohns disease and is associated with inammation of derivatives.
various areas of the gastrointestinal tract. Maintenance of remission of ulcerative colitis may be achieved
Differentiation of ulcerative colitis and Crohns disease is with oral or topical aminosalicylates. Immunosuppressants such
based on signs and symptoms as well as characteristic endo- as azathioprine or 6-mercaptopurine can be used for unrespon-
scopic ndings including the extent, pattern, and depth of sive patients or those who develop corticosteroid dependency.
inammation. Treatment of active mild to moderate Crohns disease involves
Patients may manifest extraintestinal symptoms of IBD, such as use of oral or topical aminosalicylate derivatives, whereas
arthritis, primary sclerosing cholangitis, erythema nodosum, moderate to severe disease may require systemic corticosteroid
and pyoderma gangrenosum, among others. therapy.
Major treatment goals for patients with IBD include alleviation Maintenance of remission of Crohns disease may be achieved
of signs and symptoms and suppression of inammation dur- with oral or topical aminosalicylate derivatives, immunosup-
ing acute episodes and maintenance of remission thereafter. pressants (such as azathioprine, 6-mercaptopurine, and metho-
When designing a drug regimen for treatment of IBD, several trexate), or iniximab.
factors should be considered, including the patients symp-
toms, medical history, current medication use, drug allergies, Inammatory bowel disease (IBD) encompasses both
and location and severity of disease. Crohns disease (CD) and ulcerative colitis (UC). Both disorders
Antidiarrheal medications that reduce GI motility, such as are associated with inammation of various regions within the
loperamide, diphenoxylate/atropine, or codeine should be gastrointestinal (GI) tract. Differences exist between UC and CD
avoided in patients with active IBD due to the risk of precipi- with regard to the regions of the GI tract that may be affected
tating acute colonic dilation (toxic megacolon). as well as in the distribution and depth of inammation. Some
281
patients with IBD may also have inammation involving organs the GI tract. Products derived from these bacteria may translo-
other than the GI tract, known as extraintestinal manifesta- cate across the mucosal layer of the GI tract and interact with
tions. Symptoms of IBD are associated with signicant morbid- various cells involved in immunologic recognition. The result is
ity, reduction in quality of life, and substantial costs to the health T-cell stimulation, excess production of proinammatory
care system. For purposes of this chapter, references made to IBD cytokines, and persistent inammation within the GI tract.
will include both UC and CD. Signicant differences between The intestinal mucosa of patients with CD has a prepon-
UC and CD will be discussed separately when applicable. derance of CD4+ type 1 helper T cells, while patients with UC
have more CD4+ lymphocytes with atypical type 2 helper T
cells.9 Likewise, drugs such as non-steroidal anti-inammatory
EPIDEMIOLOGY drugs (NSAIDs) that disrupt the integrity of the GI mucosa
may facilitate mucosal entry of intestinal antigens and lead to
Inammatory bowel disease is most common in westernized disease ares in patients with IBD.11
countries such as the United States. Ulcerative colitis affects up The role of antigens derived from dietary intake in the
to 500,000 people and Crohns disease affects up to 480,000 development of IBD is less well dened. There is some specu-
people in the United States.24 The age of initial presentation of lation that ingestion of large quantities of rened carbohy-
IBD is bimodal, with patients typically diagnosed between the drates or margarine leads to higher rates of CD. Use of oral
age ranges of 20 to 40 years or 60 to 80 years.5 The peak inci- contraceptives has been associated with increased development
dence of CD occurs in the second and third decades of life, with of IBD in some cohort studies, but a strong causal relationship
a smaller peak in the fth decade.2,5 Peak incidence of UC has not been proven.7
occurs between the ages of 15 and 25 years.6 Lastly, positive smoking status has been shown to have pro-
Men and women are approximately equally affected by IBD. tective effects in UC, leading to reductions in disease severity.
In general, whites are affected more often than blacks, and per- The opposite is true in CD, as smoking may lead to increases in
sons of Jewish descent also have higher reported incidences of symptoms or worsening of the disease.9
IBD. One of the greatest risk factors for development of IBD is a
positive family history of the disease. The incidence of IBD is 10
to 40 times greater in patients with a rst-degree relative who PATHOPHYSIOLOGY
has IBD compared to the general population.4,5,7 A positive fam-
ily history may be more of a contributing factor for development Ulcerative Colitis
of CD than UC.79 The inammatory response in UC is propagated by atypical
type 2 helper T cells that produce proinammatory cytokines
such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor
ETIOLOGY (TNF).7 As discussed previously, a genetic predisposition to
UC may partially explain the development of excessive colonic
The exact cause of IBD is not fully understood. Processes and rectal inammation. The nding of positive perinuclear
thought to be involved in its development include genetic pre- antineutrophil cytoplasmic antibodies (pANCA) in associa-
disposition, dysregulation of the inammatory response with- tion with the human leukocyte antigen (HLA)-DR2 allele in a
in the GI tract, or perhaps environmental or antigenic factors.3 large percentage of patients with UC supports this theory.4,12
The fact that a positive family history is a strong predictor of The role of an immune response to intestinal bacteria in the
IBD supports the theory that genetic predisposition may be development of UC may not be as strong a contributing factor
responsible in many cases. Many potential candidate genes as it is in CD. The potential role of environmental factors in the
have been identied. An example is a gene found on chro- development of UC implies that the immune response is
mosome 16 that encodes for nucleotide oligomerization directed against an unknown antigen. The ndings that devel-
domain 2 (NOD2). NOD2 is a cytoplasmic protein expressed in opment and severity of UC are reduced in patients who smoke,
macrophages, monocytes, and gut epithelial cells thought to be or in those with appendectomies, may support the theory that
involved in recognition and degradation of bacterial products these factors may somehow modify either the genetic compo-
by the gut wall. Presence of NOD2 mutations has been shown nent or phenotypic response to immunologic stimuli.11,13
to predispose patients to development of CD.9,10 Less is known NSAID use is also implicated in disease ares in patients
about genetic alterations that may predispose patients to UC, with UC. NSAIDs may affect production of both nuclear
but UC may share common genetic features with CD. factor and peroxisome proliferator activated receptors
An alteration in the inammatory response regulated by (e.g., PPAR-), both of which are involved in regulating the
intestinal epithelial cells may also contribute to development of intestinal responses.11
IBD. This may involve inappropriate processing of antigens pre- The inammatory process within the GI tract is limited to the
sented to the GI epithelial cells.3 The inammatory response in colon and rectum in patients with UC (Fig. 161). Most patients
IBD may actually be directed at bacteria that normally colonize with UC have involvement of the rectum (proctitis) or both the
CHAPTER 16 / INFLAMMATORY BOWEL DISEASE 283
Hepatic Flexure Splenic Flexure

Ulcerative Colitis Crohns Disease
Mucosa
Right sided disease
Left sided disease

Descending Colon
Transverse Colon
Ascending Colon
Submucosa
Terminal Ileum
Sigmoid Colon
Muscularis
Rectum
Serosa
Proctitis
Transmural disease
Proctosigmoiditis may result in penetration
or fistula formation
Involvement of entire colon and /or rectum = Pancolitis FIGURE 162. Depth of disease penetration in ulcerative coli-
tis and Crohns disease.
FIGURE 161. Major gastrointestinal landmarks and disease
distribution in inammatory bowel disease.
rectum and sigmoid colon (proctosigmoiditis). Inammation interferon- and TNF- may account for the excessive clinical
involving the majority of the colon is referred to as pancolitis. evidence of granulomatous disease in patients with CD.10
Left-sided disease, dened as inammation extending from the TNF- is also thought to induce production of nuclear factor
rectum to the splenic exure, occurs in 30% to 40% of patients.4 , which stimulates further production of TNF- and other
A small number of cases of UC involve mild inammation of the proinammatory cytokines.3,14
terminal ileum, referred to as backwash ileitis. The role of an immune response directed against endoge-
The pattern of inammation in UC is continuous and con- nous bacteria as the initiating factor is more evident in CD, as
uent throughout the affected areas of the GI tract. The evidenced by the apparent strong T-helper 1 activation against
inammation is also supercial and does not typically extend bacteria seen in animal models of this disease. Likewise, bac-
below the submucosal layer of the GI tract (Fig. 162). teria are often found deep in the intestinal mucosal layer of
Ulceration or erosion of the GI mucosa may be present and patients with CD. As mentioned previously, the nding of
varies with disease severity. The formation of crypt abscesses genetic mutations in NOD2 may result in excessive produc-
within the mucosal layers of the GI tract is characteristic of UC tion of IL-12 and inhibition of intestinal phagocytes to break
and may help to distinguish it from CD. Severe inammation down bacterial antigens.10
may also result in areas of hypertrophied GI mucosa, which Dysregulation of cytokines that normally downregulate
may manifest as pseudopolyps within the colon.12 The inam- inammatory responses, such as transforming growth factor-
matory response may progress in severity, leading to mucosal , may also be involved in the excessive inammatory response
friability and signicant GI bleeding. seen in CD. As in UC, patients with CD may have disease ares
due to ingestion of NSAIDs. The role of dietary antigens in the
development of CD compared to UC is also another potential
Crohns Disease
initiating factor. Excess ingestion of rened sugars or mar-
As with UC, the immune activation seen in CD involves the garine may be higher in patients who develop CD.7
release of many proinflammatory cytokines. Cytokines The distribution of inammation in CD differs from that
thought to play major roles in CD are derived from T-helper seen in UC, as any part of the entire GI tract may be affected
type 1 cells and include interferon-, TNF-, and IL-1, IL-6, in CD. The small intestine is the site most commonly involved.
and IL-12. TNF- is a major contributor to the inammatory Within the small intestine, the terminal ileum and cecum are
process seen in CD. Its physiologic effects include activa- almost always affected. Approximately 20% of patients have
tion of macrophages, procoagulant effects in the vascular isolated colonic involvement, whereas inammation proximal
endothelium, and increases in production of matrix metallo- to the small intestine is almost never seen without the pres-
proteinases in mucosal cells.9,15 Excessive production of both ence of small or large intestinal disease.12
In contrast to UC, the pattern of inammation in CD is

described as discontinuous. Areas of inammation are inter- Presentation of Inammatory Bowel
Disease
mixed with areas of normal GI mucosa, resulting in charac-
teristic skip lesions. Supercial aphthous ulcers may also
develop in the GI mucosa. These ulcers may coalesce into larger General
linear ulcers, resulting in ssure formation as they increase in Patients with CD or UC may present with similar symptoms.
depth, giving rise to the characteristic cobblestone pattern The onset may be insidious and subacute.
observed upon examination of the mucosa. Some patients present with extraintestinal manifestations
Furthermore, the inammation may be transmural, pene- before GI symptoms occur.
trating to the muscularis or serosal layers of the GI tract In approximately 10% of cases it may not be possible to
(Fig. 162). The propensity for transmural involvement may distinguish between UC and CD. These patients are
lead to serious complications of CD, such as strictures, stulae, described as having indeterminate colitis.
and abscesses.4,12 While rectal inammation is typically less
Symptoms
common in CD than UC, several types of perianal lesions may
Ulcerative colitis: Diarrhea (bloody, watery, or mucopu-
be observed in patients with CD. These include skin tags, rulent), rectal bleeding, abdominal pain/cramping,
hemorrhoids, ssures, anal ulcers, abscesses, and stulae.15 weight loss and malnutrition, tenesmus, constipation
(with proctitis)
Crohns disease: Diarrhea (less bloody than UC), rectal
CLINICAL PRESENTATION AND DIAGNOSIS bleeding (less than UC), abdominal pain/cramping,
weight loss and malnutrition (more common than UC),
Differentiation of ulcerative colitis and Crohns disease is fatigue/malaise
based on signs and symptoms as well as characteristic endoscopic
Signs
ndings, including the extent, pattern, and depth of inammation
Ulcerative colitis: Fever, tachycardia (with severe disease),
(see Presentation Box in second column).
dehydration, arthritis, hemorrhoids, anal ssures, perirec-
tal abscesses
Crohns disease: Fever, tachycardia (with severe disease),
Extraintestinal Manifestations and Complications dehydration, arthritis, abdominal mass and tenderness,
of IBD perianal ssure or stula
Patients may manifest signs and symptoms of disease in
Laboratory Tests
areas outside the GI tract. These extraintestinal manifestations
Ulcerative colitis: Leukocytosis, decreased
may occur in various body regions.5,8 Painful joint complica-
hematocrit/hemoglobin, elevated erythrocyte sedimenta-
tions associated with IBD include sacroiliitis and ankylosing tion rate (ESR), guaiac-positive stool, (+) perinuclear anti-
spondylitis. Ocular involvement with episcleritis, uveitis, or neutrophil cytoplasmic antibodies (pANCA; up to 70% of
iritis may manifest as blurred vision, eye pain, and photophobia. patients)
Associated skin ndings include pyoderma gangrenosum Crohns disease: Leukocytosis, decreased
(involving papules and vesicles that develop into painful hematocrit/hemoglobin, elevated ESR, guaiac-positive
ulcerations) and erythema nodosum (red nodules of varying stool, (+) antiSaccharomyces cerevisiae antibodies (up to
size typically found on the lower extremities). Nephrolithiasis 50% of patients), hypoalbuminemia with severe disease
may also develop at a higher rate in patients with IBD. Oxalate
stones are more common in CD, and uric acidcontaining
stones are more common in UC.
Liver and biliary manifestations of IBD include an with toxic megacolon typically manifest systemic signs of
increased incidence of gallstone formation in patients with severe inammation such as fever, tachycardia, and abdominal
CD and development of sclerosing cholangitis or cholangio- distention.3 Surgical intervention, including colonic resection,
carcinoma in patients with UC. Patients with UC are also at may be necessary to acutely manage toxic megacolon.
increased risk for development of colorectal cancer. Ongoing Formation of strictures, abscesses, stulae, and obstruc-
inammation due to active IBD may induce a hypercoagula- tions in patients with CD is possible. Patients with CD may
ble state, resulting in higher rates of both arterial and venous develop signicant weight loss or nutritional deciencies sec-
thromboembolism. Likewise, inammation and recurrent ondary to malabsorption of nutrients in the small intestine,
blood loss may result in the development of chronic anemia. or as a consequence of multiple small- or large-bowel resec-
Patients with IBD also have higher rates of osteopenia, osteo- tions. Common nutritional deciencies encountered in IBD
porosis, and fractures.16 include vitamin B12, fat-soluble vitamins, zinc, folate, and
A serious complication of UC is toxic megacolon, dened as iron. Malabsorption in children with CD may contribute to
dilation of the transverse colon of greater than 6 cm. Patients signicant reductions in growth and development.
Diagnosis
Patient Encounter 1, Part 1
Because patients often present with nonspecic GI symp-
toms, initial diagnostic evaluation includes methods to char-
acterize the disease and rule out other potential etiologies.
This may include stool cultures to examine for infectious A 25-year-old Caucasian woman presents to the university
causes of diarrhea. student clinic with complaints of intermittent crampy
Endoscopic approaches are typically used and may include abdominal pain and four to ve loose stools per day. She
colonoscopy, proctosigmoidoscopy, or possibly upper GI describes some visible mucus and blood in the stool and
endoscopy in patients with suspected CD. Endoscopy is useful states that these symptoms have been present for 6 to
for determining the disease distribution, pattern and depth of 8 weeks. She also has intermittent lower back pain, fatigue,
fever, and a 10-lb (4.5 kg) weight loss. The back pain started
inammation, and to obtain mucosal biopsy specimens.
about the same time as her gastrointestinal symptoms. She
Supplemental information from imaging procedures, such as denies any sick contacts and has not eaten any take-out
computed tomography (CT), abdominal x-ray, abdominal or restaurant food over the last 2 months. She takes non-
ultrasound, or intestinal barium studies may provide evidence prescription naproxen as needed for aches and pains. She
of complications such as obstruction, abscess, perforation, or has been using more naproxen recently because of the back
colonic dilation.3 pain. She also takes an oral contraceptive pill once daily.
After the diagnosis is made, the information derived from She consumes alcohol socially and currently smokes 1/2 to
diagnostic testing and the patients medical history and symp- 1 pack of cigarettes per day.
toms are used to gauge disease severity. The severity of active
UC is generally classied as mild, moderate, severe, or fulmi- What symptoms are suggestive of IBD in this patient?
nant.1 Mild UC typically involves up to four bloody or watery Are these symptoms more suggestive of UC or CD?
What factors may be contributing to her IBD symptoms?
stools per day without systemic signs of toxicity or elevation of
What additional information would you acquire prior to
ESR. Moderate disease is classied as more than four stools per recommending drug therapy?
day with evidence of systemic toxicity. Severe disease is consid-
ered more than six stools per day and evidence of anemia,
tachycardia, or an elevated ESR. Lastly, fulminant UC may
present as more than 10 stools per day with continuous bleed- may prevent major complications such as perforation and may
ing, signs of systemic toxicity, abdominal distention or tender- reduce the need for hospitalization or surgical intervention. Once
ness, colonic dilation, or a requirement for blood transfusion. control of active disease is obtained, treatment regimens are
A similar classication scheme is used to gauge the severity designed to achieve the following long-term goals: (1) main-
of active CD.2 Patients with mild to moderate CD are typically tenance of remission and prevention of disease relapse;
ambulatory and have no evidence of dehydration, systemic (2) improvement in the patients quality of life; (3) prevention
toxicity, loss of body weight, or abdominal tenderness, mass, of surgical intervention or hospitalization; (4) management of
or obstruction. Moderate to severe disease is considered in extraintestinal manifestations; (5) prevention of malnutrition;
patients who fail to respond to treatment for mild to moder- and (6) prevention of treatment-associated adverse effects.
ate disease, or those with fever, weight loss, abdominal pain or
tenderness, vomiting, intestinal obstruction, or signicant General Approach to Treatment
anemia. Severe to fulminant CD is classied as the presence of When designing a drug regimen for treatment of IBD, sev-
persistent symptoms or evidence of systemic toxicity despite eral factors should be considered, including the patients symp-
outpatient corticosteroid treatment, or presence of cachexia, toms, medical history, current medication use, drug allergies, and
rebound tenderness, intestinal obstruction, or abscess. location and severity of disease. A thorough patient history may
also help to identify a family history of IBD or potential exac-
erbating factors, such as tobacco or NSAID use.
TREATMENT
Desired Outcomes
No specic dietary restrictions are recommended for patients
Pharmacologic interventions for IBD are designed to target with IBD, but avoidance of high-residue foods in patients with
the underlying inammatory response. Treatment goals strictures may help to prevent obstruction. Nutritional strategies
involve both management of active disease and prevention of in patients with long-standing IBD may include use of vitamin
disease relapse. Major treatment goals include alleviation of and mineral supplementation. Administration of vitamin B12,
signs and symptoms and suppression of inammation during folic acid, fat-soluble vitamins, and iron may be needed to pre-
acute episodes and maintenance of remission thereafter. vent or treat deciencies. In severe cases, enteral or parenteral
Addressing active IBD in a timely and appropriate manner nutrition may be needed to achieve adequate caloric intake.
Patients with IBD, particularly those with CD, are also at Antidiarrheal medications that reduce GI motility, such as lop-
risk for bone loss. This may be a function of malabsorption or eramide, diphenoxylate/atropine, and codeine should be avoided
an effect of repeated courses of corticosteroids. Patients with in patients with active IBD due to the risk of precipitating acute
IBD should receive a baseline bone density measurement prior colonic dilation (toxic megacolon).8 Drugs with anticholinergic
to receiving corticosteroids. Vitamin D and calcium supple- properties, such as hyoscyamine and dicyclomine, are often
mentation should be used in all patients receiving long-term used to treat intestinal spasm and pain, but these drugs may
corticosteroids. Oral bisphosphonate therapy may also be also reduce GI motility and should generally be avoided in
considered in patients receiving prolonged courses of corti- active IBD. Once active disease is under control, antidiarrheal
costeroids or in those with osteopenia or osteoporosis. agents may be used with caution as adjunctive treatment.
Surgical intervention is a potential treatment option in Patients who have had multiple intestinal resections due to
patients with complications such as stulae or abscesses, or in CD may have diarrhea related to the inability to reabsorb bile
patients with medically refractory disease. Ulcerative colitis is salts. Cholestyramine has been demonstrated to improve diar-
curable with performance of a total colectomy. Patients with rheal symptoms in this population.8,15 NSAIDs should be
UC may opt to have a colectomy to reduce the chance of devel- avoided for pain management due to their ability to worsen
oping colorectal cancer. Patients with CD may have affected IBD symptoms. Narcotic analgesics should be used with cau-
areas of intestine resected. Unfortunately, CD may recur fol- tion, as they may signicantly reduce GI motility.
lowing surgical resection. Repeated surgeries may lead to sig-
nicant malabsorption of nutrients and drugs consistent with Aminosalicylates
development of short-bowel syndrome. The aminosalicylates are among the most commonly used drugs
for inducing and maintaining remission in patients with IBD
(Table 161). These drugs are designed to deliver 5-aminosal-
icylate (5-ASA, mesalamine) to areas of inammation within
Several pharmacologic classes are available for the treatment the GI tract. While the mechanism of mesalamine is not fully
and maintenance of IBD. Because there may be differences in understood, it appears to have favorable anti-inammatory
the underlying disease process, distribution, and severity effects. These effects may include reducing prostaglandin and
between CD and UC, response rates to drugs in the same phar- leukotriene production, inhibiting bacteria-induced chemo-
macologic class may differ between these two diseases. taxis, scavenging of free radicals, and inhibiting nuclear factor
Therefore, initial selection of an appropriate agent for patients .9 The delivery of mesalamine to the affected sites is accom-
with active IBD should be designed to deliver maximum ef- plished by either linking mesalamine to a carrier molecule or
cacy while minimizing toxicity. Response rates to individual altering the formulation to release drug in response to changes
classes of medications for both UC and CD will be discussed in intestinal pH. Topical suppositories and enemas are designed
within the specic treatment section for each disease. to deliver mesalamine directly to the distal colon and rectum.17,18
The prototypical aminosalicylate is sulfasalazine, which is
Symptomatic Interventions comprised of mesalamine linked by a diazo bond to the car-
Patients with active IBD often have severe abdominal pain and rier molecule sulfapyridine. This linkage prevents premature
diarrhea. Medications used to manage these types of symptoms absorption of mesalamine in the small intestine. Once sul-
may have adverse consequences in patients with active IBD. fasalazine is delivered to the colon, bacterial degradation of
TABLE 161. Aminosalicylates for Treatment of Inammatory Bowel Disease
Daily Dosage
Drug Trade Names Formulation Strengths Range Site of Action

Sulfasalazine Azuldine Immediate-release or 500 mg 26 g Colon
enteric-coated tablets
Azuldine Entabs
Sulfazine
Sulfazine EC
Mesalamine Rowasa Enema 4 g/60 mL 4g Distal left colon and
rectum
Asacol Delayed-release 400 mg 1.64.8 g Distal ileum and colon
resin tablet
Canasa Suppository 500 and 1000 mg 1g Rectum
Pentasa Microgranule controlled- 250 mg 24 g Small bowel
release capsule 500 mg 24 g Colon
Olsalazine Dipentum Capsule 250 mg 13 g Colon
Balsalazide Colazal Capsule 750 mg 26.75 g Colon
the diazo bond frees mesalamine from sulfapyridine. associated with signicant adverse effects, including cataracts,
Sulfapyridine is then absorbed and excreted renally, while skin atrophy, hypertension, hyperglycemia, adrenal suppression,
mesalamine acts locally within the GI tract. osteoporosis, and increased risk of infection, among others.19,22
Newer mesalamine products utilize non-sulfapyridine meth- Budesonide is a high-potency glucocorticoid used in CD that
ods for drug delivery. Olsalazine uses two mesalamine molecules has low systemic bioavailability when administered orally.23 The
linked together, while balsalazide uses the inert carrier molecule formulation releases budesonide in the terminal ileum for treat-
4-aminobenzoyl--alanine. Both drugs use a diazo bond simi- ment of disease involving the ileum or ascending colon. Due to its
lar to sulfasalazine. Other mesalamine formulations are pH- reduced bioavailability, budesonide may prevent some long-term
dependent formulations that release mesalamine at various adverse effects in patients who have steroid-dependent IBD.23,24
points throughout the GI tract.
Sulfasalazine is associated with various adverse effects, most Immunosuppressants
of which are thought to be due to the sulfapyridine compo- Agents targeting the excessive immune response or cytokines
nent. Common adverse effects that may be dose related involved in IBD are potential treatment options (Table 163).
include headache, dyspepsia, nausea, vomiting, and fatigue.19 Azathioprine and its active metabolite 6-mercaptopurine (6-MP)
Idiosyncratic effects include bone marrow suppression, reduc- are inhibitors of purine biosynthesis and reduce IBD-associated GI
tion in sperm counts in males, hepatitis, and pulmonitis. inammation. They are most useful for maintaining remission of
Hypersensitivity reactions may occur in patients allergic to IBD or reducing the need for long-term use of corticosteroids. Use
sulfonamide-containing medications. in active disease is limited by their slow onset of action, which
The use of non-sulfapyridinebased aminosalicylates has may be as long as 3 to 12 months. Adverse effects associated with
led to greater tolerability. Although the adverse effects are sim- azathioprine and 6-MP include hypersensitivity reactions result-
ilar to those of sulfasalazine, they occur at a much lower rate. ing in pancreatitis, fever, rash, hepatitis, and leukopenia.25,26
Olsalazine, in particular, is associated with a higher incidence Methotrexate is a folate antagonist used primarily for main-
of secretory diarrhea. These agents can also be used safely in taining remission of CD. It may be administered orally, subcu-
patients with a reported sulfonamide allergy. taneously, or intravenously and may result in a steroid-sparing
effect in patients with steroid-dependent disease.26,27 Long-term
Corticosteroids methotrexate use may result in serious adverse effects, includ-
Corticosteroids have potent anti-inammatory properties and ing hepatotoxicity, pulmonary brosis, and bone marrow sup-
are used in active IBD to rapidly suppress inammation. pression. Methotrexate is teratogenic and should not be used in
Corticosteroids have favorable effects in modulating several pregnant women or those who plan to become pregnant.
cell types involved in the inammatory process.20,21 They may Cyclosporine is a cyclic polypeptide immunosuppressant typi-
be administered systemically or delivered locally to the site of cally used to prevent organ rejection in transplant patients. Its use
action by altering the drug formulation (Table 162). Because is restricted to patients with fulminant or refractory symptoms
these drugs usually improve symptoms and disease severity in patients with active IBD. Signicant toxicities associated with
rapidly, they should be restricted to short-term management cyclosporine are nephrotoxicity, risk of infection, seizures,
of active disease. Long-term use of systemic corticosteroids is hypertension, and liver function test abnormalities.1,13,14
TABLE 162. Corticosteroids for Treatment of Inammatory

Bowel Disease
TABLE 163. Immunosuppressant and Biologic Agents for
Drug Trade Names Daily Dose Treatment of Inammatory Bowel Disease
Prednisone Generic 2060 mg orally Drug Trade Names Dose
Prednisolone Generic 2060 mg orally

Budesonide Entocort EC Induction: 9 mg orally Azathioprine Imuran , Azasan 1.52.5 mg/kg per day
Maintenance: 6 mg orally orally
Methylprednisolone Medrol (PO) 1560 mg orally or IV 6-Mercaptopurine Purinethol 1.52.5 mg/kg per day
Solu-Medrol orally
(IV) Methotrexate Rheumatrex, 1525 mg weekly
Hydrocortisone Solu-Cortef 300 mg IV in three Trexall (IM/SC/orally)
divided doses Cyclosporine Sandimmune 4 mg/kg per day IV
Cortenema 100 mg rectally at continuous infusion
bedtime Iniximab Remicade Induction: 5 mg/kg IV at
Cortifoam
90 mg rectally once or 0, 2, and 6 weeks;
twice daily 10 mg/kg per dose IV
Anucort 2550 mg rectally for non-responders
25 mg twice daily Maintenance: 5 mg/kg
Proctocort 2550 mg rectally IV every 8 weeks
30 mg twice daily
IM, intramuscular; IV, intravenous; SC, subcutaneous.
Biologic Agents
Iniximab is the only biologic agent routinely used for manag- Patient Encounter 1, Part 2: The
ing IBD. It is a murine-human IgG1 antibody directed against Medical History and Physical
TNF-.14 Reduction in TNF- activity in patients with IBD is Examination
associated with improvement in the underlying inammatory
PMH
process. Disadvantages of iniximab include need for intra-
Tonsillectomy at age 5, fractured right clavicle (sports related)
venous administration, signicant drug cost, and potential for
adverse effects. Adverse effects include infusion-related reactions FH
such as fever, chest pain, hypotension, and dyspnea.29 Iniximab Both parents alive; father has history of hypertension, type 2
DM, and dyslipidemia; mother has a history of colon cancer
has also been associated with reactivation of serious infections,
with subtotal colectomy; brother with history of indeterminate
particularly intracellular pathogens such as tuberculosis.19,30 For
colitis
this reason, iniximab should not be used in patients with cur-
rent infections, and patients should be screened for tuberculosis SH
prior to initiating therapy. Iniximab may also lead to the devel- College student, social alcohol use and 1/2 to 1 pack per
day tobacco use for 6 years
opment or exacerbation of heart failure; it should be avoided in
patients with advanced or decompensated heart failure.31 Meds
Naproxen 220 mg PO as needed, Lo-Ovral PO once daily
Other Agents ROS
Antibiotics have been studied based on the rationale that they may (+) Diarrhea, abdominal pain, fatigue, back pain, fever,
interrupt the inammatory response directed against endogenous weight loss
bacterial ora. Metronidazole and ciprooxacin have been the two
PE
most widely-studied agents.32 Metronidazole may benet some
VS: blood pressure 118/65 mm Hg, pulse 92 beats per minute,
patients with pouchitis (inammation of surgically-created respiratory rate 13/minutes, temperature 37.9C (100.2F)
intestinal pouches) and patients with CD who have had ileal CV: Tachycardia with normal rhythm, no murmurs, rubs,
resection or have perianal stulas. Ciprooxacin has shown or gallops
some efcacy in refractory active CD. Both drugs may cause HEENT: Dry mucous membranes
diarrhea, and long-term use of metronidazole is associated with Abd: Soft, non-distended, mild diffuse tenderness, (+) bowel
the development of peripheral neuropathy. sounds, () hepatosplenomegaly, () masses, heme (+) stool
Because smoking is associated with reduced symptoms of MS: Point tenderness over sacral area, () erythema, reduced
UC, nicotine has been studied as a potential treatment option. lower back ROM
Transdermal nicotine may result in some improvement in Labs
mild to moderate UC symptoms. Daily doses between 15 and Sodium 139 mEq/L (139 mmol/L), potassium 3.2 mEq/L
25 mg appear to be most effective, but the role of nicotine (3.2 mmol/L), chloride 100 mEq/L (100 mmol/L), bicarbonate
therapy is not well dened.1 27 mEq/L (27 mmol/L), blood urea nitrogen 12 mg/dL
Probiotics, such as Lactobacillus acidophilus or Bidobacter- (4.3 mmol/L urea), serum creatinine 1.0 mg/dL (88.4 mol/L),
ium, may offer possible benet, based on the rationale that albumin 4.2 g/dL (42 g/L), hemoglobin 11 g/dL (110 g/L
or 6.82 mmol/L), hematocrit 33%, white blood cell count
modication of the host ora may alter the inammatory
11.0 x 103/mm3 (11 109/L), platelets 300 103/mm3
response. Some evidence exists for improvement in disease
(300 109/L), ESR 120 mm/hour
symptoms, but further well-controlled trials are needed.26 Imaging: Abdominal x-ray: () obstruction, perforation, or
colonic dilation
Treatment of Ulcerative Colitis Colonoscopy: patchy cobblestone inammation in the
terminal ileum and ascending colon with evidence of
Drug and dosing guidelines based on disease severity and recent bleeding, () polyps or strictures, biopsy taken
location are presented in Table 164. Path: Evidence of disease extension to muscularis with non-
caseating granulomas
Mild to Moderate Active UC
Treatment of acute episodes of ulcerative colitis is dictated How is this additional information helpful in determining
by the severity and extent of disease, and rst-line therapy of disease type and severity?
mild to moderate disease involves oral or topical aminosalicylate What are your treatment goals for this patient?
derivatives. Topical suppositories and enemas are preferred for What factors should you consider in choosing appropriate
active distal UC (left-sided disease and proctitis), as they deliver therapy for this patient?
mesalamine directly to the site of inammation. Topical
mesalamine is superior to both topical corticosteroids and
oral aminosalicylates for inducing remission in active mild to
moderate UC.1,33,34 Enemas are appropriate for patients with
TABLE 164. Treatment Recommendations for Ulcerative Colitis
Disease Severity
and Location Active Disease Maintenance of Remission
Mild Disease
Proctitis Mesalamine suppository 1 g rectally daily May reduce suppository frequency to 1 g 3 times/week
Left-sided disease Mesalamine enema 1 g rectally daily, or May reduce enema frequency to 1 g every other day,
Mesalamine 2.44.8 g/day or sulfasalazine or Taper to mesalamine 1.62.4 g/day or
46 g/day orally sulfasalazine 24 g/day orally
Colitis Mesalamine 2.44.8 g/day or sulfasalazine Taper to mesalamine 1.62.4 g/day or sulfasalazine
46 g/day orally 24 g/day orally
Moderate Disease
Proctitis Mesalamine suppository 1 g rectally daily; May reduce suppository frequency to 1 g 3 times/week;
If no response to mesalamine: taper prednisone as soon as possible;
Prednisone 4060 mg/day orally Consider adding azathioprine or 6-MP 1.52.5 mg/kg
per day orally
Left-sided disease Mesalamine enema 1 g rectally at bedtime daily, May reduce enema frequency to 1 g 3 times/week if
or Mesalamine 2.44.8 g/day or sulfasalazine symptoms permit;
46 g/day orally May reduce dose of oral agents if symptoms permit;
Consider adding azathioprine or 6-MP 1.52.5
mg/kg per day orally
Colitis Mesalamine 2.44.8 g/day or sulfasalazine Taper mesalamine to 1.62.4 g/day or sulfasalazine
46 g/day orally; 24 g/day orally; If prednisone or iniximab were
If no response to mesalamine or sulfasalazine: required:
Prednisone 4060 mg/day orally; or Taper prednisone as soon as possible;
Iniximab 5 mg/kg IV at weeks 0, 2, and 6 Give iniximab 5 mg/kg IV every 8 weeks
Consider adding azathioprine or 6-MP 1.52.5 mg/kg
per day orally
Severe or Fulminant Hydrocortisone 300 mg IV daily (or equivalent) Change to oral corticosteroid and taper as soon as
Disease 7 days, or possible;
Iniximab 5 mg/kg IV at weeks 0, 2, and 6 Restart oral mesalamine or sulfasalazine
If no response to IV corticosteroids or iniximab: May continue iniximab at maintenance doses of
Cyclosporine 4 mg/kg per day IV 5 mg/kg every 8 weeks
IV, intravenous; 6-MP, 6-mercaptopurine.
left-sided disease, as the medication will reach the splenic exure. mesalamine products, sulfasalazine and olsalazine have a higher
Suppositories deliver mesalamine up to approximately 20 cm incidence of adverse effects.18 Induction of remission may
and are most appropriate for treating proctitis.6 require 4 to 8 weeks of therapy at appropriate treatment doses.
Topical mesalamine products provide a more rapid Oral corticosteroids may be used for patients who are
response than oral preparations. Improvement in symptoms unresponsive to sulfasalazine or mesalamine. Prednisone doses
may be seen in as little as 2 days, but 2 to 4 weeks of treatment of 40 to 60 mg per day (or equivalent) are recommended.1
may be necessary for maximal response. Response rates of up Azathioprine or 6-MP is used for patients unresponsive to
to 90% after 4 weeks of topical therapy have been reported, corticosteroids or those who become steroid-dependent. Over
compared to 45% to 62% response rates with oral therapy.6,18 a 12-month period, these agents have been shown to reduce
Oral and topical mesalamine preparations may be used together the relapse rate to 36% versus 59% seen with placebo.1
to provide maximal effect. Oral mesalamine may also be used Iniximab 5 mg/kg may also be used for patients who are
for patients who are unwilling to use topical preparations. unresponsive to conventional oral therapies and may reduce
Topical corticosteroids are typically reserved for patients who the need for colectomy after 3 months of treatment.35
do not respond to topical mesalamine. Patients should be prop-
erly educated regarding appropriate use of topical products. This Severe or Fulminant UC
includes proper administration and adequate retention of topical Patients with severe UC symptoms require hospitalization for
mesalamine products in order to maximize efcacy. management of their disease. If the patient is unresponsive to
For patients with more extensive disease extending proxi- oral or topical mesalamine and oral corticosteroids, then a
mal to the splenic exure, oral sulfasalazine or any of the newer course of intravenous corticosteroids should be initiated.1
oral mesalamine products is considered rst-line therapy.1 Hydrocortisone 300 mg/day given in three divided doses or
Doses should provide 4 to 6 g of sulfasalazine or 4.8 g of methylprednisolone 60 mg daily for 7 to 10 days are the pre-
mesalamine. While little differences in efcacy exist between ferred therapies.
Iniximab 5 mg/kg is also an option for severe UC. Oral sulfasalazine or mesalamine is effective in maintaining
Cyclosporine 2 to 4 mg/kg per day given as a continuous intra- remission in patients with more extensive disease.1,26 Lower
venous infusion should be reserved for patients unresponsive to daily doses (e.g., 2 to 4 g sulfasalazine or 1.6 to 2.4 g mesalamine)
7 to 10 days of intravenous corticosteroid therapy. may be used for disease maintenance. As with distal UC, oral
Patients with fulminant disease are treated similarly, corticosteroids are not effective for maintaining remission and
although iniximab is not indicated for this population. should be avoided due to the high incidence of adverse effects.
Patients with fulminant UC should be assessed for signs of
signicant systemic toxicity or colonic dilation, which may
Immunosuppressants such as azathioprine or
6-mercaptopurine can be used for unresponsive patients or those
require earlier surgical intervention.
who develop corticosteroid dependency. Remission may be main-
tained in up to 58% of patients after 5 years of treatment.1,25
Intermittent iniximab dosing (5 mg/kg IV every 8 weeks) may
Maintenance of Remission
be used to maintain disease remission and reduce the need for
Unfortunately, up to 50% of patients receiving oral therapies
corticosteroids in patients with moderate to severe UC.
and up to 70% of untreated patients relapse within 1 year
Colectomy is an option for patients with progressive disease
after achieving remission.26 For this reason, patients may
who cannot be maintained on drug therapy alone.
require maintenance drug therapy indenitely to preserve
remission.
Treatment of Crohns Disease
Maintenance of remission of ulcerative colitis may be
achieved with oral or topical aminosalicylates. Mesalamine sup- Drug and dosing guidelines based on disease severity and
positories 1 g daily may prevent relapse in up to 90% of location are presented in Table 165.
patients with proctitis.1 Mesalamine enemas are appropriate
for left-sided disease and may often be dosed three times Mild to Moderate Active CD
weekly. Oral mesalamine at lower doses (e.g., 1.6 g per day) Induction of remission of mild to moderate active CD is
may be combined with topical therapies to maintain remis- accomplished with oral aminosalicylates. Sulfasalazine 4 to 6 g
sion. Topical or oral corticosteroids are not effective for main- per day is most effective for patients with colonic involvement,
taining remission of distal UC and should be avoided. with response rates of 50%.2,5 Mesalamine products have
TABLE 165. Treatment Recommendations for Crohns Disease
Disease Location
and Severity Active Disease Maintenance of Remission
Mild Disease
Ileal or ileocolonic Mesalamine 2.44.8 g/day or sulfasalazine Taper mesalamine 1.62.4 g/day or sulfasalazine
46 g/day orally 24 g/day orally
Ileal +/ ascending colon Budesonide 9 mg daily orally for up to 8 weeks Taper budesonide to 6 mg daily for up to 3 months
Perianal Mesalamine 2.44.8 g/day or sulfasalazine Taper mesalamine to 1.62.4 g/day or sulfasalazine
46 g/day orally; 24 g/day orally
May add metronidazole 1020 mg/kg per day
or ciprooxacin 1 g daily
Moderate Disease Same treatment as for mild disease; Continue aminosalicylate at maintenance dose;
If inadequate response to aminosalicylate, consider; May continue iniximab at maintenance doses of
Iniximab 5 mg/kg IV at 0, 2, and 6 weeks, or 5 mg/kg every 8 weeks;
Prednisone 4060 mg/day orally, or Taper prednisone as soon as possible;
Budesonide 9 mg/day orally for up to 8 weeks; Taper budesonide to 6 mg daily for 3 months;
If stulizing disease, consider: Consider adding azathioprine or 6-MP 1.52.5 mg/kg
Iniximab 5 mg/kg IV at 0, 2, and 6 weeks per day orally or methotrexate 12.525 mg orally
or IM/SC once weekly
Severe or Fulminant Disease Hydrocortisone 300 mg IV daily (or equivalent) Taper corticosteroid as soon as possible;
7 days, or May continue iniximab 5 mg/kg IV every 8 weeks;
Iniximab (severe or stulizing disease) 5 mg/kg Consider adding azathioprine or 6-MP 1.52.5 mg/kg
IV at 0, 2, and 6 weeks; per day orally or methotrexate 12.525 mg orally
Consider cyclosporine 4 mg/kg per or IM/SC weekly
day for refractory disease
IM; intramuscular; IV, intravenous; 6-MP, 6-mercaptopurine; SC, subcutaneous

approximately 80% of patients at 8 weeks. Complete closure

Patient Encounter 2 of existing enterocutaneous stulae occurs in approximately
50% of patients. For patients with simple perianal stulae,
antibiotics and iniximab are appropriate treatment options.
Complex perianal stulae are those associated with multiple
A 57-year-old African-American man presents to the clinic
openings, abscess, stricture, or penetration into the vaginal wall.
for follow-up management of UC. He has had left-sided
disease for 3 years and has been maintained in remission These types of perianal stulae may require surgical interven-
on maximal doses of oral mesalamine and prednisone 35 mg tion but may also be amenable to treatment with antibiotics,
orally once daily. His provider has attempted several times iniximab, azathioprine, or 6-MP.2,15
to taper the prednisone dose, but the patient experiences a
reappearance of symptoms if the dose is lowered below this
level. Medical history is also signicant for hypertension and Severe to Fulminant Active CD
heart failure. He has no known drug allergies. Most patients with severe to fulminant CD require hospital-
ization for appropriate treatment. Patients should be assessed
What are the risks of long-term corticosteroid use in this for possible surgical intervention if abdominal distention,
patient? masses, abscess, or obstruction are present. Intravenous daily
What treatment options are available for reducing corti- doses of corticosteroids equivalent to prednisone 40 to 60 mg
costeroid dependency in this patient? are recommended as initial therapy to rapidly suppress severe
What other information is needed before recommending inammation.
a pharmacologic intervention?
If there are no contraindications, iniximab 5 mg/kg fol-
lowed by 5 mg/kg at weeks 2 and 6 may be used for severe
active CD. There is no evidence that iniximab is either safe or
effective for fulminant disease.
Adjunctive therapy with uid and electrolyte replacement
shown more variable results but may be used for patients with should be initiated. Nutritional support with enteral or par-
ileal, ileocolonic, or colonic CD.2,36 These drugs are typically enteral nutrition may be indicated for patients unable to eat for
better tolerated than sulfasalazine at full treatment doses. more than 5 to 7 days.2 Some evidence suggests that enteral
Induction of remission may require up to 16 weeks of treat- nutrition provides anti-inammatory effects in patients with
ment at full doses.36 active CD.40,41
Budesonide 9 mg orally once daily for up to 8 weeks may Limited evidence indicates that cyclosporine, or possibly
be used for mild to moderate active CD in patients with tacrolimus, may be effective as salvage therapy for patients
involvement of the terminal ileum or ascending colon, with who fail intravenous corticosteroid therapy.2 Surgical inter-
success expected in 50% to 60% of patients.23 Because the for- vention may ultimately be necessary for medically refractory
mulation releases budesonide in the terminal ileum, it is not disease.
effective in reaching sites distal to the ascending colon.23,36
Conventional oral corticosteroids such as prednisone and
methylprednisolone may be used for patients who are unre- Maintenance of Remission in CD
sponsive to aminosalicylates or budesonide. Patients with CD are at high risk for disease relapse after
Metronidazole or ciprooxacin can be used in patients who induction of remission. Within 2 years, up to 80% of patients
do not respond to oral aminosalicylates. Response rates of up to suffer a relapse; therefore, most patients should be evaluated
50% are reported, but the data are conicting and these agents for indenite maintenance therapy. Maintenance of remis-
should generally not be considered rst-line therapy.2,36 sion of CD may be achieved with oral or topical aminosalicy-
late derivatives, immunosuppressants (such as azathioprine,
6-mercaptopurine, and methotrexate), or iniximab.
Moderate to Severe Active CD In contrast to their use in UC, sulfasalazine and the newer
Patients with moderate to severe active CD may be treated aminosalicylates are marginally effective in preventing CD
with oral corticosteroids, such as prednisone 40 to 60 mg daily.2 relapse in patients with medically-induced remission, with
Budesonide 9 mg orally once daily may be used for moderate success rates of only 10% to 20% at 1 year.26 Nevertheless,
active CD involving the terminal ileum or ascending colon. aminosalicylates are routinely used to maintain remission of
Iniximab is an effective alternative to corticosteroid therapy CD. Some evidence does exist that the aminosalicylates may
for patients with moderate to severe CD, including patients prevent or delay disease recurrence in patients with surgically-
with stulizing or perianal disease.15,3739 The recommended induced remisson.2,26
regimen for induction of remission is iniximab 5 mg/kg at Several other treatment options exist for maintaining
weeks 0, 2, and 6; it is effective in inducing remission in remission that may also reduce the need for corticosteroids.
Iniximab has been shown to maintain remission in 46% of Children and Adolescents
patients compared to 23% of those treated with placebo over CD occurs in approximately 4.56 per 100,000 pediatric
a 54-week period.39 The dose used to maintain remission is patients, and UC occurs in about 2.14 cases per 100,000.43 A
5 mg/kg IV given every 8 weeks. The dose may be increased to major issue in children with IBD is the risk of growth failure
10 mg/kg if patients lose response over time. secondary to inadequate nutritional intake. Failure to thrive
Azathioprine and 6-MP in oral doses up to 2.5 mg/kg per may be an initial presentation of IBD in this population.
day have been shown to maintain remission in 45% of Aggressive nutritional interventions may be required to
patients for up to 5 years.2,25,26 These drugs may be used to facilitate adequate caloric intake. Chronic corticosteroid ther-
prevent disease recurrence after surgically-induced remission. apy may also be associated with reductions in growth.
Methotrexate in doses ranging from 12.5 to 25 mg per week Pediatric patients are also at higher risk for IBD-associated
given orally, intramuscularly, or subcutaneously has resulted bone demineralization, which is accelerated by the use of sys-
in remission rates of up to 52% at 3 years.26,27 temic corticosteroids.
Corticosteroids, while effective for rapidly inducing The aminosalicylates, azathioprine, 6-MP, and iniximab
remission, are not effective for maintenance therapy and are are all viable options for treatment and maintenance of IBD
associated with signicant adverse effects with long-term in pediatric patients. Use of immunosuppressive therapy or
use. Therefore, systemic or topical corticosteroids should not iniximab may help reduce overall corticosteroid exposure.
be used for maintaining remission in patients with IBD.
Unfortunately up to 50% of patients treated acutely with
Pregnant Women
corticosteroids become dependent on them to prevent
Inducing and maintaining remission of IBD prior to concep-
symptoms.2
tion is the optimal approach in women planning to become
In place of conventional corticosteroids, budesonide
pregnant. Active IBD may result in prematurity and low birth
6 mg orally once daily may be used for up to 3 months after
weight. Thus, pregnant women with IBD should be moni-
remission induction for mild to moderate CD. Remission
tored closely, particularly during the third trimester.44
rates decline signicantly after this period.23,24 The lower
Patients do not need to discontinue drug therapy for IBD
systemic bioavailability of budesonide results in a lower
once they become pregnant, but certain adjustments may be
incidence of adverse effects than seen with conventional
required.44,45 The aminosalicylates are considered safe to use in
corticosteroids.
pregnancy, but sulfasalazine is associated with folate malab-
sorption. Because pregnancy results in a higher folate require-
Treatment of IBD in Special Populations ment, pregnant patients treated with sulfasalazine should be
supplemented with folic acid 1 mg orally twice daily.44 As with
Elderly Patients non-pregnant patients, corticosteroids may be used for treat-
Approximately 8% to 20% of patients with UC and 7% to ment of active disease but not for maintenance of remission.
26% of patients with CD are elderly at initial diagnosis.42 In Generally, corticosteroids confer no additional risk on the
general, IBD presents similarly in elderly patients compared to mother or fetus and are generally well tolerated. Both azathio-
younger individuals. Elderly patients may have more comor- prine and 6-MP have been used successfully in pregnant
bid diseases, some of which may make the diagnosis of IBD patients and do not appear to be associated with an increased
more difcult. Such conditions include ischemic colitis, diver- risk, despite carrying a Food and Drug Administration (FDA)
ticular disease, and microscopic colitis. Increased age is also pregnancy category D rating. Cyclosporine has been used suc-
associated with a higher incidence of adenomatous polyps, cessfully for severe disease in pregnant patients and appears to
but the onset of IBD at an advanced age does not appear to be relatively safe; however, it should be reserved for fulminant
increase the risk of developing colorectal cancer. Elderly disease unresponsive to conventional medical therapy.
patients may also use more medications, particularly NSAIDs, Iniximab is FDA category B and also appears to carry
which may induce or exacerbate colitis. minimal risk in pregnant patients. Little is known about
Treatment of elderly patients with IBD is similar to that excretion of iniximab in breast milk, so benet versus risk
for younger patients, but special consideration should be should be considered if it is used during nursing.
given to some of the medications used. Corticosteroids may Methotrexate is a known abortifacient and carries an FDA
worsen diabetes, hypertension, heart failure, or osteoporosis. category X pregnancy rating. Thus, it is contraindicated during
Iniximab should be used cautiously in patients with heart pregnancy. Metronidazole carries a theoretical risk of muta-
failure and should be avoided in New York Heart Association genicity in humans, but short courses are safe during preg-
Class III or IV disease. Lastly, elderly patients requiring major nancy. Prolonged use of metronidazole should be avoided in
surgical interventions may be at higher risk for surgical com- pregnant patients due to lack of safety data supporting its
plications or may not meet eligibility criteria for surgery use.45 First-trimester use of the antidiarrheal diphenoxylate
because of comorbid conditions, age-related organ dysfunc- has been associated with fetal malformations and should be
tion, or reduced functional status. avoided.
OUTCOME EVALUATION These tests should be monitored closely (every 2 to 4 weeks) at

the start of therapy and then approximately every 3 months
Monitor for improvement of symptoms in patients with during maintenance therapy.
active IBD, such as reduction in the number of daily stools, With azathioprine and 6-MP, monitor for hypersensitivity
abdominal pain, fever, and heart rate. reactions, including severe skin rashes and pancreatitis.
For patients in remission, assure that proper maintenance Educate the patient regarding signs and symptoms of pan-
doses of medications are used and educate the patient to seek creatitis (nausea, vomiting, and abdominal pain).
medical attention if symptoms recur or worsen. Prior to initiating methotrexate therapy, obtain complete
Evaluate patients receiving systemic corticosteroid therapy blood count, serum creatinine, liver function tests, chest x-ray,
for improvement in symptoms and opportunities to taper and pregnancy test (if female). Monitor blood counts weekly
or discontinue steroid therapy. For patients using more than for 1 month, then monthly thereafter.
5 mg daily of prednisone for more than 2 months or for Prior to initiating iniximab, obtain a tuberculin skin test to
steroid-dependent patients consider the following: rule out latent tuberculosis. Assure that patients do not have
Central bone mineral density testing to evaluate the need a clinically signicant systemic infection or New York Heart
for preventive or therapeutic bisphosphonate therapy; Association Class III or IV heart failure.
Periodic monitoring of blood glucose, lipids, and blood In patients receiving iniximab, monitor for infusion-related
pressure; reactions such as hypotension, dyspnea, fever, chills, or chest
Evaluation for evidence of cushingoid features or signs or pain when administering intravenous doses.
symptoms of infection. In patients with stulae, monitor at every iniximab dosing
When considering treatment with azathioprine or 6-MP, interval for evidence of stula closure and overall reduction
obtain baseline complete blood counts and liver function tests. in the number of stulae.
Patient Care and Monitoring duration. Decide when the patient should receive follow-up
care.
7. Outline parameters to evaluate the efcacy and toxicity
of the drug regimen you are recommending. Determine
1. Evaluate the patients symptoms to determine if they are whether the patient will need preventive drug therapy or
consistent with UC or CD. Determine whether the patient diagnostic testing to prevent or screen for potential drug-
has evidence of extraintestinal manifestations or GI complica- related toxicities.
tions related to IBD. Identify any psychosocial problems 8. Educate the patient on proper use of drug therapy,
related to the presence of IBD. including when to expect symptom improvement after
2. If the patient is presenting with an exacerbation of initiation of treatment and which signs or symptoms to
preexisting IBD, determine if the symptoms are report that might be related to adverse drug effects.
similar in type and severity to the patients previous 9. Provide patient education on the proper use of aminosal-
episodes. icylate medications and assess regularly for adherence.
3. Assess the patients medical history for pertinent drug Include the following:
allergies, tobacco use, and current prescription and non- Proper use of suppositories and enemas
prescription drug therapies. Determine if any of the med- The appropriate number of tablets or capsules to take
ications could exacerbate IBD. If applicable, inquire per day
about adherence or recent changes to the patients cur- Appropriate dose titration, particularly with oral
rent IBD drug regimen. sulfasalazine
4. Use available diagnostic laboratory, endoscopic, and The time frame the patient can expect improvement
imaging data to gauge the extent and severity of the based on drug dose and disease severity
patients disease. Signs or symptoms of potential adverse effects
5. Construct a drug treatment plan based on the disease 10. Once remission is achieved, evaluate the patients drug
severity and location. Identify potential contraindications regimen to determine if dose reductions or changes in
or nancial barriers to drug therapy. Inquire if the patient frequency of administration are required. Reinforce the
has an aversion to or inability to properly use certain need for adherence to drug therapy in order to maximize
drug formulations that you may wish to recommend, effectiveness.
such as topical (rectal) products. 11. Educate patients about their disease state. Refer the patient
6. Assess whether the patient will require maintenance therapy to available support groups or IBD organizational resources
after remission induction. If so, identify the treatment if they are having difculty in coping with their disease.
ABBREVIATIONS KEY REFERENCES AND SUGGESTED READINGS
5-ASA: 5-aminosalicylate American Gastroenterological Association technical review on peri-

CD: Crohns disease anal Crohns Disease. Gastroenterology 2003;125:15081530.
CT: computed tomography Feagan BG. Maintenance therapy for inammatory bowel disease.
ESR: erythrocyte sedimentation rate Am J Gastroenterol 2003;98(12 Suppl):S6S17.
FDA: Food and Drug Administration Hanauer SB, Sandborn W. Management of Crohns disease in adults.
GI: gastrointestinal Am J Gastroenterol 2001;96:635643.
HLA: human leukocyte antigen Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in
IBD: inammatory bowel disease adults (update): American College of Gastroenterology, Practice
IL: interleukin Parameters Committee. Am J Gastroenterol 2004;99:13711385.
IM: intramuscular Navarro F, Hanauer SB. Treatment of inammatory bowel disease:
IV: intravenous Safety and tolerability issues. Am J Gastroenterol 2003;
6-MP: 6-mercaptopurine 98(12 Suppl):S18S23.
NOD2: nucleotide oligomerization domain 2 Regueiro MD. Diagnosis and treatment of ulcerative proctitis. J Clin
NSAID: non-steroidal anti-inammatory drug Gastroenterol 2004;38:733740.
pANCA: perinuclear antineutrophil cytoplasmic antibodies Sandborn WJ. Evidence based treatment algorithm for mild to moder-
PO: orally ate Crohns disease. Am J Gastroenterol 2003;98(12 Suppl):S1S5.
PPAR-: peroxisome proliferator activated receptor- Sandborn WJ, Targan SR. Biologic therapy of inammatory bowel
PR: per rectum disease. Gastroenterology 2002;122:15921608.
SC: subcutaneous Steinlauf AF, Present DH. Medical management of the pregnant
TNF-: tumor necrosis factor- patient with inammatory bowel disease. Gastroenterol Clin
UC: ulcerative colitis North Am 2004;33:361385.
Viscido A, Aratari A, Maccioni F, et al. Inammatory bowel diseases:
Reference lists and self-assessment questions and answers are Clinical update of practical guidelines. Nucl Med Commun
available at www.ChisholmPharmacotherapy.com. 2005;26:649655.

this chapter.
17 NAUSEA AND VOMITING
Sheila Wilhelm
LEARNING OBJECTIVES
1. Identify several causes of nausea and vomiting.

2. Describe the pathophysiologic mechanisms of nausea and vomiting.
3. Describe the three stages of nausea and vomiting.
4. Distinguish between simple and complex nausea and vomiting.
5. Identify the goals of treating nausea and vomiting.
6. Recommend a treatment regimen for a patient with nausea and vomiting associated with
cancer chemotherapy, surgery, pregnancy, or motion sickness.
7. Outline a monitoring plan to evaluate the treatment outcomes for nausea and vomiting.
KEY CONCEPTS nausea and vomiting require pharmacologic and non-

pharmacologic measures tailored to individual patients and
Nausea and vomiting are symptoms that can be due to a num- situations.
ber of different causes.
To treat nausea and vomiting most effectively, it is important ETIOLOGY AND EPIDEMIOLOGY
to rst identify the underlying cause of the symptoms.
Nonpharmacologic approaches to treating nausea and vomiting Nausea and vomiting are symptoms that can be due to a
include dietary, physical, and psychological changes. number of different causes. Various disorders of the gastroin-
For prophylaxis of acute chemotherapy-induced nausea and testinal, cardiac, neurologic, and endocrine systems can lead to
vomiting, the combination of a 5-HT3 antagonist and a corti- nausea and vomiting (Table 171).14 Cancer chemotherapy
costeroid is recommended for patients receiving highly eme- agents are rated according to their emetogenic potential, and
togenic cisplatin or noncisplatin-based chemotherapy. antiemetic therapy is prescribed based on these ratings. Due to
Droperidol or a 5-HT3 receptor antagonist should be admin- potentially severe nausea and vomiting, some patients are
istered at the end of surgery to patients at high risk for devel- unable to complete their chemotherapy treatment regimen.
oping postoperative nausea and vomiting. Radiation therapy can induce nausea and vomiting, especially
Nausea and vomiting of pregnancy affects the majority of when it is used to treat abdominal malignancies.5
pregnant women; the teratogenic potential of the therapy is Oral contraceptives, hormone therapy, oral hypoglycemic
the primary therapeutic consideration. agents, anticonvulsants, and opiates are other common thera-
Because the vestibular system is replete with muscarinic-type pies that can cause nausea and vomiting.1 Some medications,
cholinergic and histaminic (H1) receptors, anticholinergics such as digoxin and theophylline, cause nausea and vomiting
and antihistamines are the most commonly used pharmaco- in a dose-related fashion. Nausea and vomiting may indicate
logic agents to prevent and treat motion sickness. higher-than-desired drug concentrations. Ethanol and other
toxins also cause nausea and vomiting.
Nausea and vomiting are due to complex interactions of the Postoperative nausea and vomiting (PONV) occurs in 30%
gastrointestinal system, the vestibular system, and various of surgical patients overall, and in up to 70% of high-risk
portions of the brain. Nausea and vomiting have a variety of patients.6,7 This can be due to severing or disturbing the vagus
causes that can be simple or complex. Preventing and treating nerve leading to gastric motility abnormalities. Additional risk
295
TABLE 171. Causes of Nausea and Vomiting
Gastrointestinal or Cardiac Therapy-Induced

Intraperitoneal Cardiopulmonary disease Cancer chemotherapy
Obstructing disorders Cardiomyopathy Antibiotics
Pyloric obstruction Myocardial infarction Cardiac anti-arrhythmics
Small bowel obstruction Congestive heart failure Digoxin
Colonic obstruction Neurologic Oral hypoglycemics
Achalasia Vestibular disease Oral contraceptives
Superior mesenteric artery Motion sickness Theophylline
syndrome Labyrinthitis Opiates
Enteric infections Head trauma Anticonvulsants
Inammatory bowel diseases Migraine headache Radiation therapy
Pancreatitis Increased intracranial pressure Ethanol
Appendicitis Intracranial hemorrhage Toxins
Cholecystitis Meningitis Operative procedures
Biliary colic Hydrocephalus Endocrine/Metabolic
Gastroparesis Psychogenic causes Pregnancy (morning
Postvagotomy syndrome Psychogenic vomiting sickness and hyper-emesis
Intestinal pseudo-obstruction Depression gravidarum)
Functional dyspepsia Psychiatric illness Renal disease (uremia)
Gastroesophageal reux Self-induced Diabetes (ketoacidosis)
Peptic ulcer disease Anticipatory Thyroid and parathyroid
Hepatitis Rumination disease
Peritonitis Other Causes Adrenal insufciency
Gastric malignancy Bulimia and anorexia nervosa Electrolyte abnormalities
Liver failure Cyclic vomiting syndrome (hyponatremia, hypercalcemia)
FIGURE 171. Physiologic pathways that result in nausea and vomiting. 5-HT3, serotonin type 3 receptor; D2,
dopamine type 2 receptor; GI, gastrointestinal; H1, histamine type 1 receptor, NK1, neurokinin-1. (Adapted
from American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic
management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation
therapy or undergoing surgery. Am J Health Syst Pharm 1999;56:729764, with permission.)
CHAPTER 17 / NAUSEA AND VOMITING 297
factors for PONV include female gender, history of motion Motion sickness is caused by stimulation of the vestibu-
sickness or PONV, non-smoking status, and use of opioids in lar system. This area contains many histaminic (H1) and
the postoperative period.8 The choice of anesthetic agents and muscarinic cholinergic receptors. The higher brain (i.e.,
the duration of surgery may also contribute to PONV.6 cerebral cortex) is affected by sensory input such as sights,
Pregnancy-associated nausea and vomiting is common, smells, or emotions that can lead to vomiting. This area is
affecting 70% to 85% of pregnant women, especially early in involved in anticipatory nausea and vomiting associated
pregnancy.9 Approximately one-half of pregnant women expe- with chemotherapy.
rience nausea and vomiting of pregnancy (NVP), one-quarter Nausea and vomiting can be classied as either simple or
experience nausea alone, and one-quarter are not affected.9 In complex.4 Simple nausea and vomiting occurs occasionally
0.5% to 2% of pregnancies, this can lead to hyperemesis gravi- and is either self-limiting or relieved by minimal therapy. It
darum, a potentially life-threatening condition of prolonged does not have detrimental effects on hydration status, elec-
nausea, vomiting, and consequently, malnutrition.9 trolyte balance, or weight because it is short-lived. Alter-
natively, complex nausea and vomiting requires more aggressive
PATHOPHYSIOLOGY therapy because electrolyte imbalances, dehydration, and
weight loss may occur. Unlike simple nausea and vomiting,
Nausea and vomiting consist of three stages: (1) nausea, complex nausea and vomiting can be caused by exposure to
(2) retching, and (3) vomiting. Nausea is the subjective feeling of noxious agents.
a need to vomit.1 It is often accompanied by autonomic symp-
toms such as pallor, tachycardia, diaphoresis, and salivation.
Retching, which follows nausea, consists of diaphragm, abdomi- CLINICAL PRESENTATION AND DIAGNOSIS
nal wall, and chest wall contractions and spasmodic breathing
against a closed glottis.1 Retching can occur without vomiting,
but this stage produces the pressure gradient needed for vom- Clinical Presentation of Nausea and
iting, although no gastric contents are expelled. Vomiting, or Vomiting
emesis, is a reexive, rapid, and forceful oral expulsion of
upper gastrointestinal contents due to powerful and sustained
Symptoms
contractions in the abdominal and thoracic musculature.1 Patients with nausea often complain of autonomic symp-
Vomiting, like nausea, can be accompanied by autonomic toms such as diaphoresis, general disinterest in surround-
symptoms. ings, pallor or faintness, and salivation.
Regurgitation, unlike vomiting, is a passive process with-
out involvement of the abdominal wall and diaphragm wherein Signs
With complex and prolonged nausea and vomiting,
gastric or esophageal contents move into the mouth.1 In patients
patients may show signs of malnourishment, weight loss,
with gastroesophageal reux disease (GERD), one hallmark
and dehydration (dry mucous membranes, skin tenting,
symptom is acid regurgitation. tachycardia, and lack of axillary sweat).
Various areas in the brain and the gastrointestinal (GI) tract
are stimulated when the body is exposed to noxious stimuli Laboratory Tests
(e.g., toxins), gastrointestinal irritants (e.g., infectious agents), Dehydration, electrolyte imbalances, and acid-base dis-
or chemotherapy. These areas include the chemoreceptor trig- turbances may be evident in complex and prolonged
nausea and vomiting.
ger zone (CTZ) in the area postrema of the fourth ventricle of
Elevated blood urea nitrogen (BUN) and serum creatinine
the brain, the vestibular system, visceral afferents from the GI
(SCr) concentrations, especially with a BUN to SCr ratio
tract, and the cerebral cortex.2,3 These in turn stimulate regions of 20:1 or greater, suggest dehydration.
of the reticular areas of the medulla within the brain stem. This Calculated fractional excreted sodium (FeNa) less than
area is the central vomiting center, the area of the brain stem 1% in patients with compromised baseline renal func-
that coordinates the impulses sent to the salivation center, res- tion, and less than 0.2% in patients with normal base-
piratory center, and the pharyngeal, GI, and abdominal mus- line renal function indicates dehydration and reduced
cles that lead to vomiting (Fig. 171).10 renal perfusion.
The CTZ, located outside the bloodbrain barrier (BBB), Low serum chloride and elevated serum bicarbonate levels
is exposed to cerebrospinal uid and blood.2,3 Therefore it is indicate metabolic alkalosis.
easily stimulated by uremia, acidosis, and the circulation of Arterial blood gases with a normal or elevated pH
indicates metabolic alkalosis that may or may not be
toxins such as chemotherapeutic agents. The CTZ has many
compensated.
serotonin type 3 (5-HT3), neurokinin-1 (NK1), and dopamine
Hypokalemia may occur from gastrointestinal potassium
(D2) receptors.2 Visceral vagal nerve bers are rich in 5-HT3 losses and intracellular potassium shifts to compensate
receptors. They respond to gastrointestinal distention, mucosal for alkalosis.
irritation, and infection.
TREATMENT procedures when applied prior to exposure to emetic stimuli

such as anesthetic agents.13 In contrast, the bands were not
Desired Outcomes effective for preventing nausea and vomiting due to motion
sickness in one study.14
The primary goal of treatment is to relieve the symptoms of Hypnosis may be effective for severe NVP.11 Psychotherapy
nausea and vomiting, which should increase the patients is another non-invasive treatment approach that is safe during
quality of life. Drug therapy for nausea and vomiting should pregnancy or in situations in which adverse treatment effects
be safe, effective, and economical. and drug interactions are a concern. One small study suggested
that patients with hyperemesis gravidarum may benet from
General Approach to Treatment the combination of psychotherapy and antiemetics.
To treat nausea and vomiting most effectively, it is impor-
tant to rst identify the underlying cause of the symptoms. Pharmacologic Therapy
Treating the cause (if possible) will in turn eliminate the nau- Table 172 contains the names, usual adult dosages, and com-
sea and vomiting. mon adverse effects of the pharmacologic treatments for nau-
Profuse or prolonged vomiting can lead to complications of sea and vomiting.1,4,10
dehydration and metabolic abnormalities. Patients must have
adequate hydration and electrolyte replacement orally (if toler-
Antacids and Antisecretory Agents
ated) or intravenously to prevent and correct these problems.
Antacids act locally in the stomach by neutralizing gastric acid
Some pharmacologic treatments work locally in the GI tract
and can be used to relieve nausea and vomiting related to gas-
(e.g., antacids and prokinetic agents), whereas others work in the
tric acid or heartburn.4 Common antacids include magnesium
central nervous system (e.g., antihistamines and antiemetics).1
hydroxide, aluminum hydroxide, and calcium carbonate.
Antacids are generally safe when used infrequently but can
Nonpharmacologic Therapy cause diarrhea or constipation, which is product dependent
A variety of effective pharmacologic treatments exist for nau- (see Chapter 14 on gastroesophageal reux disease for more
sea and vomiting, but they all have unwanted adverse treat- detailed information on antacids). Because these agents are
ment effects. For this reason, nonpharmacologic treatment available over the counter (OTC), they are often used as rst-
options may be considered in selected patients. line therapy.
Nonpharmacologic options are desirable for treating NVP The histamine2-receptor antagonists or H2RAs (cimetidine,
due to concern for teratogenic effects with drug therapies. famotidine, nizatidine, and ranitidine) and proton pump
When treating PONV, the nonpharmacologic approach is inhibitors (omeprazole, esomeprazole, lansoprazole, pantopra-
appealing to minimize additive CNS depression with antiemet- zole, and rabeprazole) reduce the amount of acid secreted into
ics and anesthetic agents. Nonpharmacologic approaches to the stomach by gastric parietal cells. These agents are also help-
treating nausea and vomiting include dietary, physical, and psy- ful for nausea and vomiting related to gastric acid secretion.
chological changes.
Dietary approaches are the cornerstone of treatment for Anticholinergics (Scopolamine)
NVP.11 They are included in treatment guidelines even though The anticholinergic agent scopolamine blocks muscarinic recep-
there is little evidence to support their effectiveness.9 tors in the vestibular system, thereby halting signaling to the cen-
Recommendations include eating frequent, small meals; tral nervous system (CNS). It is effective for preventing and
avoiding spicy or fatty foods; eating high-protein snacks; and treating motion sickness and perhaps for preventing PONV as
eating bland or dry foods the rst thing in the morning.9,11 In well.15,16 Scopolamine is available as an adhesive transdermal
addition to dietary changes, there is some evidence that patch that is effective for up to 72 hours after application. This
women taking a multivitamin at the time of conception are less may be benecial for patients unable to tolerate oral medications
likely to seek medical attention for NVP.9 or those requiring continuous prevention of motion sickness
Acupressure and acupuncture have been investigated based (e.g., passengers on cruise ships). Scopolamine is associated with
on the theory that certain points on the body control specic adverse anticholinergic effects such as sedation, visual distur-
bodily functions.11 The P6 (Neiguan) point on the inside of the bances, dry mouth, and dizziness.
wrist has been used historically by acupuncturists to treat nau-
sea and vomiting. While this approach seems safe and cost Antihistamines
effective, efcacy data in the treatment of NVP are conicting. Antihistamines are commonly used to prevent and treat nau-
The majority of studies showed a benet to this approach, but sea and vomiting due to motion sickness, vertigo, or migraine
the studies had methodologic aws.9,11,12 headache.1,17 Their efcacy is presumably due to the high
Acupressure has also been investigated as a preventative tool concentration of histamine (H1) and muscarinic cholinergic
for PONV and motion sickness.13,14 Acupressure wrist bands receptors within the vestibular system. Similarly to scopo-
may be effective in preventing PONV after short surgical lamine, antihistamines such as diphenhydramine and
TABLE 172. Antiemetic Agents: Adult Doses and Adverse Effects
Drug Adult Dosing Adverse Effectsa

Antacids
Magnesium hydroxide, aluminum 1530 mL every 24 hours as needed Diarrhea, constipation
hydroxide, calcium carbonate,
others
Cimetidine (Tagamet HB) 200 mg twice daily as needed Most common: Headache, diarrhea
Famotidine (Pepcid AC) 10 mg twice daily as needed Less common: Constipation
Nizatidine (Axid AR) 75 mg twice daily as needed Rare: Anemia, elevated hepatic transaminases
Ranitidine (Zantac 75) 75 mg twice daily as needed
Esomeprazole (Nexium) 20 mg once daily as needed Most common: Headache
Lansoprazole (Prevacid) 15 mg once daily as needed Less common: Diarrhea, abdominal pain, nausea, vomiting
Omeprazole (Prilosec) 20 mg once daily as needed Rare: Elevated hepatic transaminases, hyperglycemia
Pantoprazole (Protonix) 40 mg once daily as needed
Rabeprazole (Aciphex) 20 mg once daily as needed
Anticholinergics
Scopolamine (Transderm Scop) 0.5 mg every 72 hours as needed Most common: Dry mouth, drowsiness, impaired eye
accommodation
Rare: Disorientation, memory disturbances, dizziness,
hallucinations
Antihistamines
Cyclizine (Marezine) 50 mg every 46 hours as needed Most common: Sedation, dry mouth, constipation
Dimenhydrinate (Dramamine) 50100 mg every 46 hours as needed Less common: Confusion, blurred vision, urinary retention
Diphenhydramine (Benadryl) 10150 mg every 46 hours as needed
Hydoxyzine (Atarax, Vistaril) 25100 mg every 6 hours as needed
Meclizine (Bonine, Antivert) 2550 mg every 24 hours as needed
Phenothiazines
Chlorpromazine (Thorazine) 1025 mg every 46 hours as needed Most common: Sedation, lethargy, skin sensitization
Chlorpromazine suppository 50100 mg every 68 hours as needed Less common: Cardiovascular effects,
Prochlorperazine (Compazine) 510 mg 34 times daily as needed extrapyramidal effects, cholestatic jaundice,
Prochlorperazine suppository 25 mg twice daily as needed hyperprolactinemia
Promethazine (Phenergan) 12.525 mg every 46 hours as needed Rare: Neuroleptic malignant syndrome, hematologic
Thiethylperazine (Torecan) 10 mg 3 times daily abnormalities
Butyrophenones
Droperidol (Inapsine) 2.55 mg every 46 hours as needed Most common: Sedation, hypotension, tachycardia
Haloperidol (Haldol) 15 mg every 12 hours as needed Less common: Extrapyramidal effects, dizziness, increase
in blood pressure, chills, hallucinations
Benzamides
Domperidone (Motilium)b 1020 mg 3 times daily as needed Most common: Sedation, restlessness, diarrhea
Metoclopramide (Reglan) PONV: 1020 mg 10 minutes prior (metoclopramide), agitation, central
to anesthesia; nervous system depression
CINV: 12 mg/kg every 2 hours 2, Less common: Extrapyramidal effects (more frequent
then every 3 hours 3; Delayed with higher doses), hypotension, neuroleptic
CINV: 0.5 mg/kg or 20 mg every syndrome, supraventricular tachycardia (with
6 hours as needed, days 24 intravenous administration)
Trimethobenzamide (Tigan) 200250 mg 3 to 4 times daily as needed
Corticosteroids
Dexamethasone (Decadron) 10 mg prior to chemotherapy, repeat Most common: Gastrointestinal upset, anxiety, insomnia
with 48 mg every 6 hours for Less common: Hyperglycemia, facial ushing,euphoria,
a total of 4 doses perineal itching or burning (with dexamethasone,
Methylprednisolone (Solu-Medrol) 125500 mg every 6 hours for total probably secondary to vehicle and rate of injection)
of 4 doses
Cannabinoids
Dronabinol (Marinol) 57.5 mg/m2 every 24 hours as needed Most common: Drowsiness, euphoria, somnolence,
Nabilone (Cesamet) 12 mg 23 times daily as needed vasodilation, vision difculties, abnormal thinking,
dysphoria
Less common: Diarrhea, ushing, tremor, myalgia
(Continued )
TABLE 17-2. Antiemetic Agents: Adult Doses and Adverse Effects (Continued)
Drug Adult Dosing Adverse Effectsa

Benzodiazepines
Lorazepam (Ativan) 0.52 mg prior to chemotherapy Most common: Sedation, amnesia
Rare: Respiratory depression, ataxia, blurred vision,
hallucinations, paradoxical reactions (weeping,
emotional reactions)
Serotonin Antagonists
Dolasetron (Anzemet) 1.8 mg/kg intravenously 30 minutes prior Most common: Headache, asymptomatic prolongation of
to chemotherapy electrocardiographic interval
or Less common: Constipation, asthenia, somnolence, diarrhea,
100 mg orally within 1 hour before fever, tremor or twitching, ataxia, lightheadedness,
chemotherapy dizziness, nervousness, thirst, muscle pain, warm or
ushing sensation on intravenous administration
Rare: Transient elevations in hepatic transaminases
Granisetron (Kytril) 10 mcg/kg intravenously prior to
chemotherapy
or
1 mg orally up to 1 hour prior to
chemotherapy and 1 mg 12 hours after
the rst dose, or 2 mg up to 1 hour
prior to chemotherapy
Ondansetron (Zofran) 32 mg intravenously prior to chemotherapy
as a single dose, or 0.15 mg/kg prior to
chemotherapy, repeat at 4 and 8 hours
or
8 mg orally 30 minutes prior to chemotherapy,
repeat at 4 and 8 hours and every 12 hours
for 12 days after chemotherapy
completion
Palonosetron (Aloxi) 0.25 mg intravenously 30 minutes prior to
chemotherapy
Neurokinin-1 Antagonist
Aprepitant (Emend) 125 mg on day 1, 1 hour prior to Most common: Fatigue, hiccups
chemotherapy; 80 mg on days 2 and 3 Less common: Dizziness, headache, insomnia
Rare: Transient elevations in hepatic transaminases
a
Most common, greater than 10%, less common, 110%, rare, less than 1%. Based on FDA-approved labeling and generalized to the drug class.
b
Not available in the United States.
CINV, chemotherapy-induced nausea and vomiting; PONV, postoperative nausea and vomiting.
meclizine cause undesired effects including drowsiness and act primarily via a central antidopaminergic mechanism in
blurred vision. Cetirizine and fexofenadine, two second- the CTZ.1 Common phenothiazines that have long been used
generation antihistamines without CNS depressant proper- for treating nausea and vomiting include promethazine,
ties, were found to be ineffective for treating motion sickness, prochlorperazine, chlorpromazine, and thiethylperazine. They
perhaps because they lack CNS effects.17 are available as oral solids and liquids, rectal suppositories, and
Some antihistamines such as diphenhydramine, dimenhy- parenteral formulations. This permits effective use of phe-
drinate, and meclizine are available without a prescription, nothiazines in a variety of settings including treatment of
making self-treatment convenient for patients. Antihistamines severe motion sickness or vertigo, gastritis or gastroenteritis,
are available in a variety of dosage forms, including oral cap- NVP, PONV, or CINV.5,6,9,1820
sules, tablets and liquids. Liquid formulations are convenient Phenothiazines may cause sedation, orthostatic hypotension,
for children or adults who are unable to swallow solid dosage and extrapyramidal symptoms (EPS) such as dystonia (invol-
forms. untary muscle contractions), tardive dyskinesia (irreversible and
permanent involuntary movements), and akathisia (motor rest-
Dopamine Antagonists lessness or anxiety).1,21,22 Chronic phenothiazine use has been
Stimulation of dopamine (D2) receptors in the CTZ leads to associated with EPS, but single doses have also caused these
nausea and vomiting (Fig. 171). Phenothiazine antiemetics effects.23
Akathisia is disturbing for patients and can be disruptive Corticosteroids

to patient care. Giving diphenhydramine with prochlor- Corticosteroids, especially dexamethasone and methylpred-
perazine may reduce the incidence of akathisia, but the nisolone, are used alone or in combination with other antiemet-
combination increases the risk of sedation.24 Slowing the ics for preventing and treating CINV or radiation-induced
intravenous infusion rate of prochlorperazine does not nausea and vomiting.5,10 They are administered either orally or
decrease akathisia.22,23 intravenously. Their efcacy is thought to be due to release of
Droperidol, a butyrophenone derivative, is another cen- 5-HT, reduction in the permeability of the BBB, and reduction
trally-acting anti-dopaminergic agent effective for preventing of inammation.32 Common adverse effects with short-term
PONV and treating opioid-induced nausea and vomiting.1,6 It use include gastrointestinal upset, anxiety, insomnia, and
is also used for treating CINV for patients who are intolerant hyperglycemia.10 Because treatment for CINV is generally of
to serotonin receptor antagonists and corticosteroids.5 short duration, long-term adverse effects (e.g., reduction in
Adverse effects of droperidol include sedation, agitation, bone mineral density, corticosteroid-related diabetes, and
and restlessness. In addition, droperidol carries a United States cataracts) are not usually seen.
Food and Drug Administration (FDA) black box warning
regarding the potential for QT interval prolongation and car- Cannabinoids
diac arrhythmias that may result in torsades de pointes and Cannabinoids have antiemetic activity when used alone or in
sudden cardiac death.25 Droperidol should not be used in combination with other antiemetics.5 Dronabinol and
patients with a prolonged QT interval or in those who are at nabilone are commercially available oral formulations used
risk for developing a prolonged QT interval (e.g., heart failure, for preventing and treating refractory CINV.5,10 Dronabinol is
electrolyte abnormalities, or concurrently taking other med- also used to treat anorexia and weight loss associated with
ications that may prolong the QT interval).25 A 12-lead elec- human immunodeciency virus (HIV) infection.
trocardiogram (ECG) is recommended prior to treatment Cannabinoids are thought to exert their antiemetic effect cen-
with droperidol. trally, although the exact mechanism of action is unknown.1,10
The substituted benzamides metoclopramide and dom- Sedation, euphoria, hypotension, ataxia, dizziness, and vision
peridone (not available in the United States) act as dopamine difculties can occur with cannabinoids.
(D2) antagonists both centrally in the CTZ and peripherally in
the GI tract.1,26 They also display cholinergic activity, which Benzodiazepines
increases lower esophageal sphincter tone and promotes Benzodiazepines, especially lorazepam, are used to prevent
gastric motility. Metoclopramide at high doses has anti- and treat CINV.5,10 Lorazepam is thought to prevent input
serotonergic properties as well. Because metoclopramide and from the cerebral cortex and limbic system from reaching the
domperidone have both antiemetic and prokinetic effects, central vomiting center in the brain stem.10 Sedation and
both are used for a variety of disorders including PONV, amnesia are common side effects. Respiratory depression can
CINV, NVP, gastroparesis, GERD, and migraine occur with high doses or when other central depressants such
headaches.1,5,6,9,2729 Metoclopramide is available in injectable, as alcohol are combined with benzodiazepines.
oral solid, and oral liquid dosage forms, allowing for its use in
both hospitalized and ambulatory patients. Other substituted Serotonin Antagonists
benzamides include trimethobenzamide and benzquinamide. Chemotherapeutic agents cause release of 5-hydroxytryptamine
Metoclopramide crosses the BBB and has centrally-mediated (5-HT, serotonin) from enterochromafn cells in the intestinal
adverse effects. Young children and the elderly are especially sus- mucosa.32 This increase in 5-HT concentrations leads to stimu-
ceptible to these effects, which include somnolence, reduced lation of the visceral vagal nerve bers and CTZ, thereby trig-
mental acuity, anxiety, depression, and EPS (akathisia, dysto- gering nausea and vomiting. Both the CTZ and the vagal viscer-
nia, and tardive dyskinesia).30 The overall incidence of adverse al nerve bers are rich in 5-HT3 receptors.2 Selective 5-HT3
effects is estimated to be 10% to 20%.1 receptor antagonists (ondansetron, granisetron, dolasetron, and
Domperidone minimally crosses the BBB; it acts in the palonosetron) are available to prevent and treat nausea and
CTZ which lies outside of the BBB. As such, domperidone is vomiting due to stimulation of these receptors, especially for
less likely to cause the centrally-mediated adverse effects seen prevention and treatment of CINV.5,10,32 They are also used to
with metoclopramide and has an estimated overall incidence treat PONV.6 These agents are well tolerated; the most common
of 5% to 10%.1,30 However, domperidone has been associated adverse effects are headache, somnolence, diarrhea, and consti-
with prolonged QT intervals, cardiac arrhythmias, and sud- pation.10 Asymptomatic electrocardiograph changes have also
den death.31 It should not be used for patients with underly- been reported.
ing long QT interval or for those on other medications that
prolong the QT interval. Both metoclopramide and domperi- Neurokinin-1 Receptor Antagonists
done can cause hyperprolactinemia, galactorrhea, and Aprepitant is the rst NK1 receptor antagonist antiemetic drug.33
gynecomastia. NK1 receptors are present in the CTZ and GI tract and are involved
in the nausea and vomiting response, especially CINV.10,32

Aprepitant is effective for preventing acute and delayed CINV Patient Encounter 1
when used with a 5-HT3 antagonist and a corticosteroid.33,34
Chemotherapy-Induced Nausea and Vomiting A 28-year-old healthy woman seeks your advice. She is
about to leave on a 7-day Caribbean cruise and is con-
CINV is classied as: (1) acute (occurring within 24 hours cerned about motion sickness. She recently experi-
after receiving chemotherapy); (2) delayed (occurring more enced nausea and one episode of vomiting while on a
than 24 hours after receiving chemotherapy); or (3) anticipa- sailboat on Lake Michigan for an afternoon. She is not
tory (occurring prior to chemotherapy in patients who expe- allergic to any medications. She does not smoke and
rienced acute or delayed nausea and vomiting with previous only occasionally drinks alcohol. She takes an oral
courses).10 Risk factors for CINV include poor emetic control contraceptive (ethinyl estradiol and norgestimate) and
with prior chemotherapy, female gender, low chronic alcohol occasional ibuprofen for headaches.
intake, and younger age.5 Chemotherapeutic agents are classi- What nonpharmacologic and pharmacologic options are
ed according to their emetogenic potential (Table 173), available for this woman?
which aids in predicting CINV.35 Risk factors that are useful How would you instruct her to use the recommended
in predicting anticipatory nausea and vomiting include modalities?
poor prior control of CINV and a history of motion sick- What adverse effects would you discuss with her?
ness or NVP.5,10
TABLE 173. Emetogenicity of Chemotherapeutic Agents
Lowest Emetogenic Potential Moderate Emetogenic Potential

Androgens Aldesleukin
Bleomycin Cyclophosphamide (IV, less than or equal to 750 mg/m2)
Busulfan (oral less than 4 mg/kg per day) Dactinomycin (less than or equal to 1.5 mg/m2)
Capecitabine (oral) Doxorubicin HCl (2060 mg/m2)
Chlorambucil (oral) Epirubicin HCl (less than or equal to 90 mg/m2)
Cladribine Idarubicin
Corticosteroids Ifosfamide
Doxorubicin (liposomal) Methotrexate (2501000 mg/m2)
Fludarabine Mitoxantrone (less than or equal to 15 mg/m2)
Hydroxyurea High Emetogenic Potential
Interferon Carboplatin
Melphalan (oral) Carmustine (less than 250 mg/m2)
Mercaptopurine Cisplatin (50 mg/m2)
Methotrexate (less than or equal to 50 mg/m2) Cyclophosphamide (greater than 750 mg/m2
Thioguanine (oral) to less than or equal to 1500 mg/m2)
Tretinoin Cytarabine (greater than or equal to 1g/m2)
Vinblastine Dactinomycin (greater than 1.5 mg/m2)
Vincristine Doxorubicin HCl (greater than 60 mg/m2)
Vinorelbine Irinotecan
Low Emetogenic Potential Melphalan (IV)
Asparaginase Methotrexate (greater than 1 g/m2)
Cytarabine (less than 1 g/m2) Mitoxantrone (greater than 15 mg/m2)
Docetaxel Oxaliplatin
Doxorubicin HCl (less than 20 mg/m2) Highest Emetogenic Potential
Etoposide Carmustine (greater than 250 mg/m2)
Fluorouracil (less than 1 g/m2) Cisplatin (greater than 50 mg/m2)
Gemcitabine Cyclophosphamide (greater than 1500 mg/m2)
Methotrexate (greater than 50 mg/m2; less than 250 mg/m2) Dacarbazine (greater than or equal to 500 mg/m2)
Mitomycin Lomustine (greater than 60 mg/m2)
Paclitaxel Mechlorethamine
Teniposide Pentostatin
Thiotepa Streptozocin
Topotecan
Data from DiPiro CV, Taylor AT. Nausea and vomiting. In: DiPiro JT, Talbert RL, Yee GC, et al., (eds.) Pharmacotherapy: A
Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 665676, and Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal
for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997; 15:103109.
For prophylaxis of acute CINV, the combination of a 5-HT3 occurs, benzodiazepines and behavioral therapy such as relax-
antagonist and corticosteroid is recommended for patients receiving ation techniques are the suggested approaches.1,5
highly emetogenic cisplatin or noncisplatin-based chemotherapy.5,10
Patients receiving moderately emetogenic chemotherapy should Postoperative Nausea and Vomiting
receive a corticosteroid such as dexamethasone or methylpred- PONV is a common complication of surgery and can lead to
nisolone alone, whereas patients receiving chemotherapy delayed discharge and unanticipated hospitalization.6 The over-
unlikely to cause CINV should not require prophylaxis.5,10 all incidence of PONV for all surgeries and patient populations
Antiemetics can be administered either intravenously or orally is 25% to 30%, but PONV can occur in 70% to 80% of high-
in this situation, depending on patient characteristics such as risk patients.6,26 Risk factors for PONV include patient factors
ability to take oral medications, dosage form availability, and cost (female gender, non-smoking status, and history of PONV or
considerations.5,10 The intravenous and oral routes are equally motion sickness), anesthetic factors (use of volatile anesthetics,
effective. When used at equipotent doses, the 5-HT3 antagonists nitrous oxide, or intraoperative or postoperative opioids), and
have similar efcacy in preventing acute CINV, despite pharma- surgical factors (duration and type of surgery).6,8,26
cokinetic and receptor binding afnity differences.5,10,36 The rst step in preventing PONV is reducing baseline risk
Patients undergoing chemotherapy should have antiemet- factors when appropriate.6 Regional anesthesia rather than
ics available to treat breakthrough nausea and vomiting even general anesthesia should be used. Opioids should be replaced
if prophylactic antiemetics were given.10 A variety of
antiemetics may be used, including lorazepam, dexametha-
sone, methylprednisolone, prochlorperazine, promethazine,
metoclopramide, and dronabinol. The 5-HT3 antagonists are Patient Encounter 2
effective for treating breakthrough nausea and vomiting, but
they have not been shown to be superior to more traditional
and less expensive antiemetics.
A 57-year-old woman is scheduled for an abdominal hys-
Delayed nausea and vomiting is more difcult to prevent and terectomy due to uterine broids. She is very anxious about
treat. It occurs most often with cisplatin- and cyclophosphamide- her surgery.
based regimens, especially if delayed nausea and vomiting
PMH
occurred with previous courses of chemotherapy.10 Patients at Uterine broids
greatest risk are those who previously had poorly-controlled Hypertension 6 years
acute CINV.5 Patients receiving highly emetogenic chemotherapy Hypercholesterolemia 6 years
should receive a corticosteroid plus metoclopramide or a 5-HT3 FH
antagonist to prevent delayed nausea and vomiting.5,10 Father died of lung cancer; mother is still alive with a history
Intermediate or low emetogenic chemotherapy regimens do not of hypertension and cerebrovascular accident
require prophylactic regimens for delayed nausea and vomiting. SH
The NK1 receptor antagonist aprepitant has shown promise Works as a high school teacher; drinks one glass of wine
for preventing delayed nausea and vomiting.33,34,37,38 When with dinner three times per week; does not use tobacco
aprepitant was added to a standard antiemetic regimen for Med
patients receiving cisplatin-based highly emetogenic chemo- Hydrochlorothiazide 25 mg PO once daily
therapy, complete response rates (no emesis and no rescue Lisinopril 20 mg PO once daily
therapy) were signicantly improved for both acute and Simvastatin 40 mg PO once daily at bedtime
delayed nausea and vomiting.34,37 Aprepitant may also benet Aspirin 81 mg PO once daily
patients receiving moderately emetogenic chemotherapy, but Acetaminophen as needed for headache or body aches
more data are needed.33,39 Labs
The 5-HT3 antagonist palonosetron is the rst 5-HT3 Within normal limits
antagonist to be approved for prevention of both acute and ECG: Normal sinus rhythm
delayed CINV.40 Compared to the other 5-HT3 antagonists, Anesthesia for the surgery will be thiopental 4.5 mg/kg,
palonosetron has a longer serum half-life (40 hours compared atracurium 0.5 mg/kg, and fentanyl 0.05 mg followed by
to 4 to 9 hours) and a higher receptor binding afnity, which tracheal intubation, 70% nitrous oxide, and 0.5% to 2%
may contribute to its efcacy in preventing delayed CINV.41 isourane in oxygen.
The best strategy for preventing anticipatory nausea and What risk factors for PONV does this patient have?
vomiting is to prevent acute and delayed CINV by using the Identify your treatment goals for this patient.
most effective antiemetic regimens recommended based on What nonpharmacologic and pharmacologic measures
the emetogenic potential of the chemotherapy and patient can be taken to prevent PONV?
factors. CINV should be aggressively prevented with the rst Discuss any contraindications or adverse effects associated
cycle of therapy rather than waiting to assess patient response with your recommended treatments.
to less effective regimens. If anticipatory nausea and vomiting
with other analgesics such as non-steroidal anti-inammatory

drugs. Nitrous oxide and volatile inhaled anesthetics should Patient Encounter 1, Part 2
be avoided.
Droperidol or a 5-HT3 receptor antagonist should be admin-
istered at the end of surgery to patients at high risk for developing Four months later, the patient returns to your practice. She
postoperative nausea and vomiting.1,6,7,26,42 Dexamethasone is is 8 weeks pregnant and complains of nausea and occa-
also effective when given as a single dose prior to induction of sional vomiting. She is only taking prenatal vitamins. She
anesthesia.6,42,43 Anticholinergics and antihistamines are also does not smoke or drink alcohol. She was told at her last
effective for preventing PONV.6 prenatal visit that she was appropriately gaining weight. She
asks for your advice about preventing and treating nausea
Combinations of antiemetics may be the most effective
and vomiting.
method of preventing PONV for high-risk patients.7,42
Droperidol plus a 5-HT3 antagonist or dexamethasone plus a What general considerations about treating nausea and
5-HT3 antagonist are effective combinations.43,44 Three-drug vomiting of pregnancy will you discuss with this patient?
combinations such as dexamethasone, droperidol, and a 5-HT3 What nonpharmacologic and pharmacologic treatment
antagonist have not been formally studied but may be a rea- options are available for her?
sonable approach.42
Nausea and Vomiting of Pregnancy Because the vestibular system is replete with muscarinic-
type cholinergic and histaminic (H1) receptors, anticholinergics
Nausea and vomiting of pregnancy affect the majority of preg- and antihistamines are the most commonly used pharmacologic
nant women; the teratogenic potential of the therapy is the primary
agents to prevent and treat motion sickness. Oral medications
therapeutic consideration.9 Risks and benets of any therapy must
should be taken prior to motion exposure to allow time for ade-
be weighed by the health care professional and the patient.
quate absorption. Once nausea and vomiting due to motion
Nonpharmacologic therapy such as dietary, physical, and
sickness occur, oral medication absorption may be unreliable,
behavioral approaches should be considered rst. Pyridoxine
making the therapies ineffective. Scopolamine, the anticholin-
(vitamin B6) 10 to 25 mg three to four times daily alone or in
ergic medication used for motion sickness, is available as a
combination with an antihistamine such as doxylamine is
transdermal patch delivery system, which may be helpful for
often used for NVP.9,11,12 This combination was previously
patients who cannot tolerate oral medications or who require
marketed as Bendectin or Debendox but was withdrawn due
treatment for a prolonged period. Drowsiness and reduced
to concerns over possible teratogenic effects, although the lit-
mental acuity are the most bothersome side effects of antihist-
erature did not support this claim.11,12 Pyridoxine is well tol-
amines and anticholinergics. Visual disturbances, dry mouth,
erated, but doxylamine and other antihistamines commonly
and urinary retention can also occur.
cause drowsiness. For more severe NVP, promethazine, meto-
clopramide, and trimethobenzamide may be effective and
OUTCOME EVALUATION
have not been associated with teratogenic effects.9
In rare instances (0.5% to 2% of pregnancies), NVP pro-
The symptoms of simple nausea and vomiting are self-limited
gresses to hyperemesis gravidarum.9 Treatment may require
or can be relieved with minimal treatment. Monitor patients for
the use of enteral or parenteral nutrition if weight loss is pres-
adequate oral intake and alleviation of nausea and vomiting.
ent. A corticosteroid such as methylprednisolone may be con-
Patients with complex nausea and vomiting may have mal-
sidered. Methylprednisolone is associated with oral clefts in
nourishment, dehydration, and electrolyte abnormalities.
the fetus when used during the rst trimester; therefore, cor-
Monitor patients for adequate oral intake. If the patient
ticosteroids should be reserved as a last resort and should be
has weight loss, assess whether enteral or parenteral nutri-
avoided during the rst 10 weeks of gestation.9,11
tion is needed.
Assess for dry mucous membranes, skin tenting, tachycar-
Motion Sickness and Vestibular Disturbances
dia, and lack of axillary sweat to determine if dehydration
Nausea and vomiting can be caused by disturbances of the is present.
vestibular system in the inner ear.18 Vestibular disturbances Obtain blood urea nitrogen (BUN), serum creatinine
can result from infection, traumatic injury, neoplasm, and (SCr), calculated fractional excretion of sodium (FeNa),
motion. Patients may experience dizziness and vertigo in serum electrolytes, and arterial blood gases.
addition to nausea and vomiting. If a patient is susceptible to Ask patients to rate the severity of nausea.
motion sickness, some general preventive measures include Monitor the number and volume of vomiting episodes.
minimizing exposure to movement, restricting visual activity, Ask patients about adverse effects to the antiemetics used.
ensuring adequate ventilation, reducing the magnitude of Use this information to assess efcacy and tailor the patients
movement, and taking part in distracting activities.45 antiemetic regimen.
ABBREVIATIONS
BBB: bloodbrain barrier
BUN: blood urea nitrogen
CINV: chemotherapy-induced nausea and vomiting
1. Identify the underlying cause of the nausea and vomiting CNS: central nervous system
and eliminate it if possible. Counsel the patient to avoid CTZ: chemoreceptor trigger zone
known triggers. D2: dopamine type 2 receptor
2. Assess the patient to determine whether the nausea and ECG: electrocardiogram
vomiting is simple or complex and whether patient- EPS: extrapyramidal symptom
directed therapy is appropriate. FDA: United States Food and Drug Administration
FeNa: fractional excretion of sodium
3. Obtain a thorough patient history including the prescrip- GERD: gastroesophageal reux disease
tion, non-prescription, and herbal medications being GI: gastrointestinal
used. Identify any substances that may be causing or H1: histamine type 1 receptor
worsening nausea and vomiting. Determine which treat- HIV: human immunodeciency virus
ments for nausea and vomiting have been used in the H2RA: histamine2-receptor antagonist
past and their degree of efcacy. 5-HT3: 5-hydroxytryptamine (serotonin) type 3 receptors
4. Develop a treatment plan with the patient and other NK1: neurokinin type 1 receptors
health care professionals if appropriate. Choose thera- NVP: nausea and vomiting of pregnancy
peutic options based on the underlying cause of nausea OTC: over the counter
and vomiting, duration and severity of symptoms, comor- PONV: postoperative nausea and vomiting
bid conditions, medication allergies, presence of con- SCr: serum creatinine
traindications, risk of drug-drug interactions, and treat-
ment adverse-effect proles. Reference lists and self-assessment questions and answers are
5. Use the oral route of administration if the patient has mild
nausea with minimal or no vomiting. Seek an alternative Log into the website: www.pharmacotherapyprinciples.com
route (e.g., transdermal, rectal suppository, or parenteral)
if the patient is unable to retain oral medications due to
vomiting.
this chapter.
6. Educate the patient about nonpharmacologic measures

such as stimulus avoidance, dietary changes, acupressure KEY REFERENCES AND READINGS
or acupuncture, and psychotherapy.
American College of Obstetricians and Gynecologists. ACOG prac-
7. To assess efcacy, ask the patient whether he or she is tice bulletin: nausea and vomiting of pregnancy. Obstet Gynecol
still experiencing nausea or vomiting while using the 2004;103:803814.
therapy. Assess whether treatment failure is due to American Society of Health-System Pharmacists. ASHP therapeutic
inappropriate medication use or the need for addi- guidelines on the pharmacologic management of nausea and
tional or different treatments and proceed vomiting in adult and pediatric patients receiving chemotherapy
accordingly. or radiation therapy or undergoing surgery. Am J Health-Syst
8. Assess for adverse effects by asking the patient what he Pharm 1999;56:729764.
or she has experienced. Also, patient observation or Bles W, Bos JE, Kruit H. Motion sickness. Curr Opin Neurol 2000;13:
examination is useful for diagnosing adverse effects 1925.
such as EPS. Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for managing
postoperative nausea and vomiting. Anesth Analg 2003;97:6271.
9. Provide patient education regarding causes of nausea
Gralla RJ, Osoba D, Kris MG, et al. Recommendations for the use of
and vomiting, avoidance of triggers, potential complica-
antiemetics: evidence based clinical practice guidelines. J Clin
tions, therapeutic options, medication adverse effects,
Oncol 1999;17:29712994.
and when to seek medical attention.
Quigley EM, Hasler WL, Parkman HP. AGA technical review on
nausea and vomiting. Gastroenterology 2001;120:263286.
18 CONSTIPATION, DIARRHEA,
AND IRRITABLE BOWEL SYNDROME
Beverly C. Mims and Clarence E. Curry, Jr.
LEARNING OBJECTIVES
1. Identify the causes of constipation.

2. Compare the features of chronic constipation with those of constipation-predominant
irritable bowel syndrome (IBS).
3. Recommend lifestyle modications and therapeutic interventions for the treatment of
constipation.
4. Distinguish between acute and chronic diarrhea.
5. Compare and contrast diarrhea caused by different infectious agents.
6. Explain how medication use can lead to diarrhea.
7. Discuss nonpharmacologic strategies for treating diarrhea.
8. Identify the signs and symptoms of IBS.
9. Contrast diarrhea-predominant IBS and constipation-predominant IBS.
10. Discuss the goals of IBS treatment.
11. Evaluate the effectiveness of principal pharmaceutical therapies for IBS.
KEY CONCEPTS The principal goal of IBS treatment is to reduce or control

symptoms.
Constipation has been dened in many ways and it is impor-
tant to know what is meant when the term is used.
Chronic constipation exists when symptoms last for at least CONSTIPATION
3 months.
Lifestyle modications should be employed prior to the use of Constipation has been dened in many ways, and it is
laxatives in most instances of constipation. important to know what is meant when the term is used.
Oral laxatives are the primary pharmacologic intervention for Constipation, when not associated with symptoms of irritable
relief of constipation. bowel syndrome (IBS), can be dened as a heterogeneous dis-
When diarrhea is severe and oral intake is limited, dehydra- order characterized by disorganized passage of feces resulting
tion can occur, particularly in the elderly and infants. in infrequent stools, difcult passage of stools or both.1 It may
The primary treatment of acute diarrhea includes uid and be described as difculty passing stool with too much effort,
electrolyte replacement, dietary modications, and drug unproductive urges, too small amount of stool, too hard con-
therapy. sistency of stool, painful elimination of stool, or a feeling of
IBS is generally described as a functional disorder rather than incomplete evacuation. The existence of some or all of these
a distinct disease entity. symptoms suggests the presence of constipation when the fre-
IBS symptoms typically cluster around two main types: quency of elimination of feces is limited to twice weekly or less
diarrhea-predominant IBS and constipation-predominant IBS. or when more than 3 days have passed without elimination of
Diagnosis of IBS is made by symptom-based criteria and the stool. Chronic constipation exists when symptoms last for at
exclusion of organic disease. least 3 months.
307
EPIDEMIOLOGY AND ETIOLOGY Constipation affects about 50% of pregnant women.

Progesterone levels may be responsible in part for slowing
Constipation is a common complaint of patients seeking digestion. Reabsorption mechanisms may affect colon water
medical attention, and about one-third of patients with con- during pregnancy leading to harder stools and more difcult
stipation seek medical treatment. Constipation occurs in bowel movements. Intake of iron supplements may also con-
approximately 20% of the population.2 Approximately 2.5 tribute to constipation during pregnancy.
million physician visits and 90,000 hospitalizations per year in
the United States are due to constipation3,4 Many medications CLINICAL PRESENTATION AND DIAGNOSIS
and some disease states are associated with constipation.
Constipation is associated with high socioeconomic costs and Diagnosis
has considerable quality-of-life ramications.5
Elderly patients, non-Caucasians, women, and those of lower A complete history should be obtained so that the patients
educational and socioeconomic levels are more likely to report symptoms can be evaluated and the diagnosis of constipation
being constipated. Constipation in children can occur because conrmed. The diagnosis of constipation is suggested by
of a change in the usual diet or uid intake, a deviation from fewer than three bowel movements per week, consistency of
usual toileting routines such as during vacations, or avoidance of hard lumpy stool, excessive straining, prolonged defecation
bowel movements because of pain associated with having a time, or need to support the perineum or digitally manipulate
stool. Children who are diagnosed with severe constipation at a the anorectum.
young age are likely to continue to suffer through puberty. Dietary habits should be evaluated and attention paid to psy-
chosocial issues. A complete family history should be obtained,
PATHOPHYSIOLOGY
Constipation can be due to primary and secondary causes Clinical Presentation of Constipation
(Table 181). Primary or idiopathic constipation is typied by
normal-transit constipation, slow-transit constipation, and
dyssynergic defecation. In the normal-transit type, colonic Symptoms
motility is unchanged and patients tend to experience hard Functional constipation (constipation occurring in the
stools despite normal movements. In the slow-transit type, absence of a demonstrated pathologic condition) involves the
motility is decreased leading to infrequent harder, drier stools. presence of at least two of the following symptoms: straining,
In dyssynergic defecation (also known as pelvic oor dysfunc- lumpy or hard stools, sensation of incomplete evacuation,
tion), patients have lost the ability to relax the anal sphincter sensation of anorectal obstruction or blockage, need for man-
while coordinating muscle contractions of the pelvic oor. ual maneuvers to facilitate defecation and/or, infrequent
Some causes of secondary constipation are listed in Table 181. (fewer than three) bowel movements per week.
Other complaints may include painful or difcult defeca-
tion, bloating, and absence of loose stools.
TABLE 181. Causes of Constipation
Alarm (or red ag) symptoms include worsening of con-
Primary Causes stipation, blood in the stools, weight loss, fever, anorexia,
Normal-transit constipation (includes idiopathic or functional nausea, and vomiting.
disorders) The patient should seek medical attention when symp-
Slow-transit constipation (includes motility disorders) toms are severe, last longer than 3 weeks, are disabling,
Defecatory or rectal evacuation disorders (e.g., Hirschsprungs when alarm symptoms occur, or whenever a signicant
disease, pelvic oor dyssynergia) change in usual bowel habits occurs.
Secondary Causes (selected)
Laboratory Tests (to identify secondary causes)
Endocrine/metabolic conditions (diabetes mellitus,
hypothyroidism, hypercalcemia) Thyroid function tests; abnormal thyroid hormone levels
Gastrointestinal conditions (irritable bowel syndrome, may suggest hypo- or hyperthyroidism, either of which
diverticulitis, hemorrhoids) may be associated with constipation.
Neurogenic conditions (brain trauma, spinal cord injury, Serum calcium; either increased or decreased serum cal-
cerebrovascular accident, Parkinsons disease) cium levels may be associated with constipation.
Psychogenic (postponing the urge to defecate, psychiatric Glucose; increased blood glucose may indicate diabetes
conditions) mellitus, which may be associated with constipation.
Medications (analgesics, anticholinergerics, calcium channel Serum electrolytes; dehydration may be associated with
blockers, clonidine, diuretics, phenothiazines, tricyclic constipation.
antidepressants, iron supplements, calcium- and aluminum-
Urinalysis may also indicate dehydration, if present.
containing antacids)
Miscellaneous (immobility, poor diet, laxative abuse, hormonal Complete blood count; anemia may be due to cancer or
disturbances) another systemic disorder accompanied by constipation.
CHAPTER 18 / CONSTIPATION, DIARRHEA, AND IRRITABLE BOWEL SYNDROME 309
particularly as it relates to inammatory bowel disease and Pharmacologic Therapy

colon cancer. A full record of prescription and over-the-
counter medications is mandatory to identify drug-related
Oral laxatives are the primary pharmacologic interven-
tion for relief of constipation (Table 182). There are several
causes of constipation.
different drug classes, as described below.
In most cases, there is no underlying cause of constipation,
and the physical examination and rectal examination are nor-
Bulk-Forming Laxatives
mal. Sigmoidoscopy, barium enema, or colonoscopy alone or
These agents are either naturally derived (psyllium) or syn-
in combination are required in patients who have weight loss,
thetic (methylcellulose). They act by swelling in intestinal
rectal bleeding, or anemia with constipation. These examina-
uid, forming a gel that aids in fecal elimination and pro-
tions can be used to exclude the presence of cancer or stric-
moting peristalsis. They may cause atulence (which is less
tures, especially in patients over the age of 50 years.
common with methylcellulose) and abdominal cramping.
Sigmoidoscopy alone is appropriate in patients without alarm
Bulk-forming laxatives must be taken with sufcient water to
symptoms and those younger than 50 years of age. However, all
avoid becoming lodged in the esophagus and producing an
adults older than 50 years of age who present with new-onset
obstruction. Bulk-forming laxatives must be taken with suf-
constipation should undergo colonoscopy to rule out malig-
cient water to avoid becoming lodged in the esophagus and
nancy. When bleeding is present, a double-contrast barium
producing obstruction or worsening constipation.
enema may be ordered.
Osmotic Laxatives
These products cause water to enter the lumen of the colon.
TREATMENT Lactulose and sorbitol are osmolar, non-absorbable sugars.
Magnesium containing products increase secretion of electrolytes
Desired Outcomes
In patients with constipation, the principal goals are to: (1) TABLE 182. Dosage Recommendations for Selected Laxatives
and Cathartics
identify and treat secondary causes, (2) relieve symptoms, and
(3) restore normal bowel function. Agent Recommended Adult Dose
Agents That Cause Softening of Feces in 13 Days
Nonpharmacologic Therapy Bulk-forming agents
Methylcellulose 46 g/day
Lifestyle modications should be employed prior to the use Polycarbophil 46 g/day
of laxatives in most instances of constipation. Constipation usu- Psyllium Varies with product
Emollients
ally responds to dietary ber supplementation, hydration, and Docusate sodium 50360 mg/day
exercise. Increasing ber intake to 20 to 35 grams/day may help Docusate calcium 50360 mg/day
overcome constipation. Foods high in ber include beans, Docusate potassium 100300 mg/day
whole grains, bran cereals, fresh fruits, and vegetables such as Lactulose 1530 mL orally
asparagus, brussels sprouts, cabbage, and carrots. Persons with Sorbitol 3050 g/day orally
Mineral oil 1530 mL orally
constipation should avoid excessively processed low-ber
Agents That Result in Soft or Semiuid Stool in 612 Hours
foods such as luncheon meats, hot dogs, certain cheeses, and Bisacodyl (oral) 515 mg orally
ice cream. Phenolphthalein 30270 mg orally
Adequate uid intake is also important; the recommended Cascara sagrada Dose varies with
intake for people who do not require uid restriction is 6 to 8 formulation
eight-ounce glasses of water daily. Senna Dose varies with
formulation
Walking and other aerobic exercises help to tone the mus- Magnesium sulfate (low dose) Less than 10 g orally
cles of the lower abdominal area, which promotes propulsion
Agents That Cause Watery Evacuation in 16 Hours
in the bowel. Constipation is a frequent complaint of seden- Magnesium citrate 18 g in 300 mL water
tary persons. Magnesium hydroxide 2.44.8 g orally
Each day most persons experience a strong peristaltic wave Magnesium sulfate (high dose) 1030 g orally
known as the gastrocolic reex. A bowel movement usually Sodium phosphates Varies with salt used
follows. When the urge to have a bowel movement occurs, it Bisacodyl (suppository) 10 mg rectally
Polyethylene glycol-electrolyte 4L
should not be ignored. Some people put off having a stool for preparations
various reasons, which may lead to more difculty in passing
stool. Time should be planned daily to attempt having a stool. From Spruill WJ, Wade WE. Diarrhea, constipation and irritable bowel
syndrome. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy:
A busy lifestyle should not be allowed to interfere with normal A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill, Inc;
bowel function. 677692, with permission.
and water into gut lumen. Products containing magnesium Lubiprostone is contraindicated in patients with a history
or sodium phosphate derivatives (saline laxatives) are most of mechanical gastrointestinal obstruction. Safety has not
useful for acute bowel evacuation. A principal concern with been established in pregnant women; animal studies indicated
these agents is that improper use can cause dehydration and the potential to cause fetal loss. Women who could become
electrolyte disturbances. Osmotic agents may cause atulence, pregnant should have a negative pregnancy test result prior to
abdominal cramping, and bloating. Magnesium may accumu- beginning therapy with lubiprostone.
late inpatients with renal dysfunction. Gastrointestinal adverse events reported with lubiprostone
Polyethylene glycol (PEG, MiraLax) is an osmotic laxative include nausea, diarrhea, abdominal distention, abdominal
available only by prescription. It is useful in patients who are pain, atulence, vomiting, loose stools, and dyspepsia. Nausea
experiencing acute constipation and who have had inadequate is a prominent adverse effect and may be minimized when
response to more traditional agents. Principal adverse effects lubiprostone is taken with food.
include upset stomach, bloating, cramping, and gas. The recommended dose of lubiprostone is 24 mcg orally
twice daily with food. Early studies evaluated lubiprostone use
Lubricants for no longer than 4 weeks. Patients should be assessed peri-
Lubricant laxatives work by coating the stool, which allows it odically for the need to continue therapy.
to be expelled more easily. The oily lm covering the stool also
keeps the stool from losing its water to intestinal reabsorption Treatment Recommendations
processes. Mineral oil (liquid petrolatum) is a non-prescription Slow-transit constipation can be treated with chronic admin-
heavy oil that should be used with caution, if at all, since it istration of osmotic laxatives. Tegaserod maleate 6 mg orally
may be aspirated into the lungs and cause lipoid pneumonia. twice daily is an acceptable treatment. Senna, bisacodyl, and
This is of particular concern in the young or the elderly. other stimulants should be used only when the others fail to
deliver the desired effect.
Stimulant Laxatives Laxatives may provide appropriate relief when constipation
Diphenylmethane derivatives (e.g., bisacodyl) and anth- occurs during the postpartum period, when not breastfeeding
raquinones (e.g., senna) have a selective action on the nerve and in immobile patients. Patients who are not constipated but
plexus of intestinal smooth muscle leading to enhanced who need to avoid straining (e.g., patients with hemorrhoids,
motility. The onset of effect is rapid but the effects can be hernia, or myocardial infarction) may benet from stool
harsh (cramping), depending on the dose taken. Castor oil is softeners or mild laxatives.
another member of this class that is used less frequently. Laxatives should not be given to children younger than
6 years of age unless prescribed by a physician. Because
Emollients children may not be able to describe their symptoms well,
Also known as surfactants and stool softeners, emollients (e.g., they should be evaluated by a physician before being given a
salts of docusate) act by increasing the surface wetting action laxative. Treating secondary causes may resolve the constipation
on the stool leading to a softening effect. They reduce friction without the use of laxatives. As in adults, children benet from
and make the stool easier to pass. These agents are not recom- a healthy balanced diet, adequate uid, and regular exercise.
mended for treating constipation of long duration. Because many elderly persons experience constipation, laxa-
tive use is sometimes viewed as a normal part of daily life.
Tegaserod Maleate However, mineral oil can be a special hazard in bedridden elderly
Tegaserod maleate (Zelnorm) is a partial serotonin (5-HT4) persons because it can lead to pneumonia through inhalation of
receptor agonist that causes an increase in peristaltic activity oil droplets into the lungs. Lactulose may be a better choice in
and intestinal secretion and moderation of visceral sensitivity. this situation. Regular use of any laxative that affects uid and
It increases the frequency of bowel movements and reduces electrolytes may result in signicant unwanted adverse effects.
abdominal discomfort, bloating, and straining. It is indicated Bulk-forming laxatives are commonly used during preg-
for the treatment of patients younger than 65 years of age who nancy. Stool softeners (Category C) should not be used during
experience chronic idiopathic constipation. The most common pregnancy. To avoid constipation pregnant women should be
adverse effects include headache, abdominal pain, diarrhea, and advised to eat regular meals that are balanced among fruit,
nausea. vegetables and whole grains; maintain adequate water intake;
and get appropriate exercise.
Lubiprostone Patients with the following conditions should use laxa-
Lubiprostone (Amitiza), a bicyclic acid oral agent, is approved tives only under the supervision of a health care provider:
for treatment of chronic idiopathic constipation in adults. It (1) colostomy; (2) diabetes mellitus (some laxatives contain
has not been studied in children. Lubiprostone acts locally on large amounts of sugars such as dextrose, galactose, and/or
intestinal chloride channels and increases intestinal uid secre- sucrose; (3) heart disease (some products contain sodium;
tion, resulting in increased intestinal motility and thereby (4) kidney disease; and (5) swallowing difculty (bulk-formers
increasing the passage of stool.6 may produce esophageal obstruction).
OUTCOME EVALUATION DIARRHEA
Ask the patient about the absence or improvement in symp- Diarrhea is not a disease in itself but rather a symptom of some
toms to determine whether laxative therapy is effective. underlying problem. It is a condition marked by increased stool
Patients should have an increase in stool frequency to more frequency (usually greater than 3 times daily), stool weight,
than three well-formed stools per week. Patients should liquidity, and decreased consistency of stools compared to a
report the absence of prolonged defecation time or the patients usual pattern. Acute diarrhea is defined as diar-
absence of the need for excessive straining. rhea lasting for 14 days or less. Diarrhea lasting more than
When acute overuse or chronic misuse of saline or stimulant 30 days is called chronic diarrhea. Illness of 15 to 30 days is
laxatives is suspected, it may be necessary to check for elec- referred to as persistent diarrhea.7
trolyte disturbances (e.g., hypokalemia, hypernatremia,
hyperphosphatemia, or hypocalcemia). EPIDEMIOLOGY AND ETIOLOGY
Some laxatives (e.g., bulk-forming agents) contain signi-
cant amounts of sodium or sugar and may be unsuitable for Most cases of diarrhea in adults are mild and resolve quickly.
salt-restricted or diabetic patients. When low-sodium or Infants and children (especially under 3 years of age) are
sugar-free products are not used, monitor serum concentra- highly susceptible to the dehydrating effect of diarrhea, and its
tions of sodium and glucose as needed with chronic use. occurrence in this age group should be taken seriously.
Saline laxatives containing magnesium, potassium, or phos-
phates should be used cautiously in persons with reduced Acute Diarrhea
kidney function. Monitor appropriate serum electrolyte con-
There are many possible causes of acute diarrhea, but infection is
centrations in patients with unstable renal function evi-
the most common cause. Infectious diarrhea occurs because of
denced by changing serum creatinine or creatinine clearance.
food and water contamination via the fecal-oral route. Viruses
All laxatives are contraindicated in patients with abdominal are the cause in a large proportion of cases. Likely viral suspects
pain, nausea, vomiting, symptoms of appendicitis or undiag- include Rotavirus, Norwalk, and adenovirus. Patients usually
nosed abdominal pain. Patients should consult their physi- exhibit sudden low-grade fever, vomiting, and watery stools.
cians if sudden changes in bowel habits persist for more than Bacteria are likely precipitants in many other cases includ-
fourteen days or if use of a laxative for seven days results in ing Escherichia coli, Salmonella species, Shigella species, Vibrio
no effect. cholerae, and Clostridium difcile. The term dysentery has
often been used to describe some of these bacterial infec-
tions when associated with serious occurrences of bloody
diarrhea. Additionally, acute diarrheal conditions can be
prompted by parasitesprotozoa such as Entamoeba histolytica,
Patient Care and Monitoring for Microsporidium, Giardia lamblia, and Cryptosporidium parvum.
Constipation Most of these infectious agents can be causes of travelers
diarrhea, a common malady aficting travelers worldwide. It
usually occurs during or just after travel subsequent to the
1. Assess the patients symptoms to determine if patient-
ingestion of fecally-contaminated food or water. It has an
directed therapy is appropriate or whether the patient
should be evaluated by a physician. Determine type and abrupt onset but usually subsides within 2 to 3 days.
frequency of symptoms.
2. Review available diagnostic data to determine the cause
Patient Encounter 1
or type of constipation.
3. Obtain a thorough history of prescription, non-prescription,
and dietary supplement use. Determine what treatments
have been helpful in the past. Is the patient taking any A 70-year-old man complains of small, hard stools for the
medications that may contribute to constipation? past 2 weeks. He also states that his bowel movements are
4. Remember that no single therapy has proven effective for less frequent than normal and that he has not had constipa-
all patients who present with constipation. tion previously. He has a history of hypertension, angina pec-
5. Develop a plan to assess the effectiveness of laxative use toris, and osteoarthritis and began a new medication 3 weeks
in cases of chronic constipation. ago. He asks for your recommendation of a laxative.
6. Evaluate the patient for the presence of adverse drug What are the possible causes of his constipation?
reactions, drug allergies, and drug interactions. What are the special considerations in this older man?
7. Provide patient education about constipation, lifestyle What nonpharmacologic and pharmacologic therapies
modications, and drug therapy. would be appropriate for his condition?
TABLE 183. Selected Drugs and Substances That May Cause mechanisms, which include osmotic, secretory, inammatory,
Acute Diarrhea and altered motility.
Osmotic diarrhea results from the intake of unabsorbable
Drugs
Antibiotics Hydralazine Metformin Sorbitol
but water-soluble solutes in the intestinal lumen leading to
Colchicine Laxatives Misoprostol Theophylline water retention. Common causes include lactose intolerance
Digitalis Mannitol Quinidine and ingestion of magnesium-containing antacids.
Dietary Supplements Secretory diarrhea results in an increase in the net move-
St. Johns wort Echinacea Ginseng Aloe vera ment (secretion) of ions into the intestinal lumen leading to
Poisons an increase in intraluminal uid. Medications, hormones, and
Arsenic Cadmium Mercury toxins may be responsible for secretory activity.
Inammatory (or exudative) diarrhea results from changes
to the intestinal mucosa that damage absorption processes
Noninfectious causes of acute diarrhea include drugs and and lead to an increase in proteins and other products in the
toxins (Table 183), laxative abuse, food intolerance, irritable intestinal lumen with uid retention. The presence of blood or
bowel syndrome (IBS), inammatory bowel disease, ischemic fecal leukocytes in the stool is indicative of an inammatory
bowel disease, lactase deciency, Whipples disease, pernicious process. The diarrhea of inammatory bowel disease (e.g.,
anemia, diabetes mellitus, malabsorption, fecal impaction, ulcerative colitis) is inammatory in nature.
diverticulosis, and celiac sprue. Increased motility results in decreased contact between
Lactose intolerance is responsible for many cases of acute ingested food and drink and the intestinal mucosa, leading to
diarrhea, especially in patients of African descent, Asians, and reduced reabsorption and increased uid in the stool. Diarrhea
Native Americans. Foods should be considered as possible resulting from altered motility is often established after other
causes, especially fat substitutes, dairy products, and products mechanisms have been excluded. IBS-related diarrhea is due to
containing non-absorbable carbohydrates. altered motility.
The diarrhea of IBS is sudden and perhaps watery but likely Although diarrhea can often be attributed to a specic mech-
loose, usually accompanied by urgency, bloating, and abdomi- anism, some patients develop diarrhea due to overlapping mech-
nal pain occurring upon arising in the morning or immedi- anisms. For example, malabsorption syndromes and travelers
ately following a meal. Inammatory bowel disease is typically diarrhea are associated with both secretory and osmotic diarrhea.
associated with the sudden onset of bloody diarrhea accom- Drug-induced diarrhea can occur by several mechanisms.
panied by urgency, crampy abdominal pain, and fever. First, water can be drawn into the intestinal lumen osmotically.
Patients who experience bowel ischemia may develop bloody Second, the intestinal bacterial ecosystem can be upset leading
diarrhea, particularly if they progress to shock. to the emergence of invasive pathologic organisms triggering
secretory and inammatory processes. Saline laxatives are an
example of the rst mechanism and many antibiotics act by the
Chronic Diarrhea second. A third way is through altered motility as may occur
Chronic diarrhea lasts for longer than 4 weeks. Most cases result with tegaserod maleate. Other drugs such as procainamide or
from functional or inammatory bowel disorders, endocrine colchicine produce diarrhea through undetermined mecha-
disorders, malabsorption syndromes and drugs (including nisms. Discontinuation of the offending drug may be the only
laxative abuse). In chronic diarrhea, daily watery stools may not measure needed to ameliorate the diarrhea.
occur. Diarrhea may be either intermittent or persistent.

PATHOPHYSIOLOGY
Diagnosis
During normal processes, approximately 9 liters of uid traverse Patients with diarrhea should be questioned about the onset
the gastrointestinal tract daily. Of this amount, 2 liters represent of symptoms, recent travel, diet, source of water, and medica-
gastric juice, 1 liter is saliva, 1 liter is bile, 2 liters are pancreatic tion use. Other important considerations include duration
juice, 1 liter is intestinal secretions, and 2 liters are ingested. Of and severity of the diarrhea along with an accounting of the
these 9 L of uid presented to the intestine, only about 150 to presence of associated abdominal pain or vomiting, blood in the
200 mL remain in the stool after reabsorptive processes occur. stool, stool consistency, stool appearance, stool frequency, and
Any event that leads to a signicant increase in the amount weight loss. Although most cases of diarrhea are self-limited,
of uid retained in the stool may result in diarrhea. Large- infants, children, elderly persons, and immunocompromised
stool diarrhea often signies small intestinal involvement, patients are at risk for increased morbidity.
whereas small-stool diarrhea usually originates in the colon. Findings on physical examination can assist in determining
Diarrhea may be classied according to pathophysiologic hydration status and disease severity. The presence of blood in
TREATMENT
Clinical Presentation of Acute
Diarrhea Most healthy adults with diarrhea do not develop dehydration
or other complications and can be treated symptomatically by
Signs and Symptoms
self medication. When diarrhea is severe and oral intake is
Patients with acute diarrhea have the abrupt onset of limited, dehydration can occur, particularly in the elderly and
loose, watery, or semi-formed stools. infants. Other complications of diarrhea resulting from uid
Abdominal cramps and tenderness, rectal urgency, nau- loss include electrolyte disturbances, metabolic acidosis, and
sea, bloating, and fever may be present. cardiovascular collapse.
The disorder is generally self-limited, lasting 3 to 4 days Children are more susceptible to dehydration (particularly
even without treatment. when vomiting occurs) and may require medical attention early
Patients with acute infectious diarrhea from invasive organ- in their course, especially if younger than the 3 years of age.
isms also have bloody stools and severe abdominal pain. Physician intervention is also necessary for elderly patients
Laboratory Tests in Acute Diarrhea who are sensitive to uid loss and electrolyte changes due to
Stool cultures can help identify infectious causes. concurrent chronic illness.
Cultures are subject to time delay. New methodology Patients should undergo medical evaluation in the following
using real-time polymerase chain reaction (PCR) shortens circumstances: (1) moderate to severe abdominal tenderness,
the reporting time. distention, or cramping; (2) bloody stools; (3) evidence of dehy-
Stool may also be analyzed for mucus, fat, osmolality, dration (e.g., thirst, dry mouth, fatigue, dark-colored urine,
fecal leukocytes, and pH. The presence of mucus suggests
infrequent urination, reduced urine, dry skin, rapid pulse, rapid
colonic involvement. Fat in the stool may be due to a
malabsorption disorder. Fecal leukocytes can be found in
breathing, muscle cramps, muscle weakness, sunken eyes, or
inammatory diarrheas including infections caused by light-headedness); (4) high fever (greater than or equal to 101F
invasive bacteria (e.g., E. coli, Shigella, and Campylobacter or 38C); (5) evidence of weight loss greater than 5% of total
species). Stool pH (normally greater than 6) is decreased body weight; and (6) diarrhea that lasts greater than 48 hours.
by bacterial fermentation processes.
Stool volume and electrolytes can be assessed in large- Desired Outcomes
volume watery stools to determine whether the diarrhea
The goals of treatment for diarrhea are to relieve symptoms,
is osmotic or secretory.
CBC and blood chemistries may be helpful in patients
maintain hydration, treat the underlying cause(s), and main-
whose symptoms persist. The presence of anemia, leuko- tain nutrition. The primary treatment of acute diarrhea
cytosis, or neutropenia may provide further clues to the includes uid and electrolyte replacement, dietary modications,
underlying cause. and drug therapy.
Signs and Symptoms of Chronic Diarrhea
In patients with chronic diarrhea, symptoms may be
severe or mild. Weight loss can be demonstrated, and
weakness may be present. Fluid and Electrolytes
Dehydration may be manifested by decreased urination, Fluid replacement is not a treatment to relieve diarrhea but
dark-colored urine, dry mucous membranes, increased rather an attempt to restore uid balance. In many parts of the
thirst, and tachycardia. world where diarrheal states are frequent and severe, uid
Laboratory Tests in Chronic Diarrhea replacement is accomplished using oral rehydration solution
All of the tests described for acute diarrhea would be used (ORS), a measured mixture of water, salts, and glucose. The
to establish a diagnosis of chronic diarrhea because the dif- World Health Organizationrecognized solution consists of
ferential diagnosis is more complicated. The data obtained 75 mEq/L sodium, 75 mmol/L glucose, 65 mEq/L chloride,
can help categorize the diarrhea as watery, inammatory, 20 mEq/L potassium, and 10 mEq/L citrate, having a total
or fatty, narrowing the focus on a primary disorder. osmolarity of 245 mOsm/L. A simple solution can be pre-
Colonoscopy allows visualization and biopsy of the colon pared from 1 L water mixed with 8 teaspoonfuls of sugar and
and is preferred if blood has been found in the stool or if 1 teaspoonful of table salt. Some commercial products include
the patient has AIDS. Pedialyte, Rehydralyte, and Ceralyte. Patients with diarrhea
who are not dehydrated may replace uid by drinking at soft
the stool suggests an invasive organism, an inammatory drinks such as ginger ale, tea, fruit juice, broth, or soup.
process, or perhaps a neoplasm. Large-volume stools suggest a Caution is advised in using sports drinks for dehydration, as
small-intestinal disorder, whereas small-volume stools suggest they may not provide an appropriate amount of electrolytes.
a colon or rectal disorder. Patients with prolonged or severe Severe diarrhea may require the use of parenteral solutions
symptoms may require colonoscopic evaluation to identify such as lactated Ringers or normal saline solution to replace
the underlying cause. large and life-threatening uid losses.8
Dietary Modications while avoiding complications (Table 184). Most infectious

Once an acute diarrheal situation ensues, patients typically diarrheas are self-limited or curable with anti-infective
eat less as they become focused on the diarrhea. Both chil- agents.
dren and adults should attempt to maintain nutritional
intake. Food provides not only nutrients but also uid vol-
Adsorbents and Bulk Agents
ume that helps replace what is lost. However, food-related
Attapulgite adsorbs excess uid in the stool with few adverse
uid may not be enough to compensate for diarrheal losses.
effects. Calcium polycarbophil is a hydrophilic polyacrylic
Some foods may be inappropriate if they irritate the gas-
resin that also works as an adsorbent, binding about 60 times
trointestinal tract or if they are implicated as the cause of the
its weight in water and leading to the formation of a gel that
diarrhea. Patients with chronic diarrhea may nd that
enhances stool formation. Neither attapulgite nor polycar-
increasing bulk in the diet may help (e.g., rice, bananas,
bophil is systemically absorbed. Both products are effective in
whole-wheat, and bran).
reducing uid in the stool but can also adsorb nutrients and
other medications. Their administration should be separated
from other oral medications by 2 to 3 hours. Psyllium and
The goal of drug therapy is to control symptoms, enabling methylcellulose products may also be used to reduce uid in
the patient to continue with as normal a routine as possible the stool and relieve chronic diarrhea.
TABLE 184. Pharmacotherapy for Diarrhea
Drug Usual Dose Type of Diarrhea

Attapulgite Adults: 12001500 mg after Acute and chronic
each loose stool
Maximum 9000 mg in 24 hours
Children ages 612: 750 mg after
each loose stool
Maximum 4500 mg in 24 hours Chronic
Calcium polycarbophil Adults: 1000 mg 4 times daily
or after each loose stool, not
to exceed 12 tablets per day
Children ages 612: 500 mg 3
times daily
Children ages 36: 500 mg twice daily
Loperamide Adults: 4 mg initially, then 2 mg Acute and chronic
after each subsequent loose
stool; maximum 16 mg in
24 hours
Childrens maximum doses:
Ages 25: 3 mg
Ages 68: 4 mg
Ages 812: 6 mg
Diphenoxylate/atropine Adults: Two tablets (5 mg) initially, Acute and chronic
then one tablet every 34 hours,
not to exceed 20 mg in 24 hours
Children 212 years old: Oral solution
(avoid tablets) 0.3 to 0.4 mg/kg
per day in divided doses
Do not administer to children less
than 2 years of age
Bismuth subsalicylate Adults: 30 mL (regular strength) Travelers and nonspecic
or 2 tablets, repeated every acute diarrhea
3060 minutes as needed
Maximum 8 doses daily
Children: Consumers should speak
with a physician before giving to
children under 12 years of age
Antiperistaltic (Antimotility) Agents

Antiperistaltic drugs prolong intestinal transit time, thereby Patient Encounter 2
reducing the amount of uid lost in the stool. The two drugs
in this category are loperamide HCl (available over the
counter as Imodium A-D and generically) and diphenoxylate
KW, a 31-year-old day care teacher, complains of nausea,
HCl with atropine sulfate (available by prescription as
vomiting, abdominal cramps, and frequent watery stools for
Lomotil and generically). The atropine is included only as an the past 2 days. She also indicates that her heart has been
abuse deterrent; when taken in large doses, the unpleasant anti- racing and her mouth has been very dry. Although she
cholinergic effects of atropine negate the euphoric effect of looks ill, she does not have a fever.
diphenoxylate. Both loperamide and diphenoxylate are effec-
tive in relieving symptoms of acute non-infectious diarrhea What is the likelihood that her diarrhea is due to an inva-
and are safe for most patients experiencing chronic diarrhea. sive microorganism?
These products should be discontinued in patients whose Which of her symptoms suggest the presence of
diarrhea worsens despite therapy. dehydration?
Discuss potential treatment measures for this woman.
Antisecretory Agents
Bismuth subsalicylate is thought to have antisecretory and
antimicrobial effects and is used to treat acute diarrhea. Anti-Infectives
Although it passes largely unchanged through the gastroin- Empiric antibiotic therapy is an appropriate approach to trav-
testinal tract, the salicylate portion is absorbed in the stomach elers diarrhea. Eradication of the causal microbe depends on
and small intestine. For this reason, bismuth subsalicylate the etiologic agent and its antibiotic sensitivity. Most cases of
should not be given to people who are allergic to salicylates, travelers diarrhea and other community-acquired infections
including aspirin. Caution should be exercised with regard to result from enterotoxigenic (ETEC) or enteropathogenic
the total dose administered in patients who concurrently take (EPEC) Escherichia coli. Routine stool cultures do not identify
salicylates for other reasons to avoid the possibility of sali- these strains; primary empiric antibiotic choices include uoro-
cylism. Patients taking bismuth subsalicylate should be quinolones such as ciprooxacin or levooxacin. Azithromycin
informed that their stool will turn black. may be a feasible option when uoroquinolone resistance is
Octreotide is an antisecretory agent that has been used for encountered.
severe secretory diarrhea associated with cancer chemother- Although most cases of infectious diarrhea resolve with
apy, HIV, diabetes, gastric resection, and gastrointestinal therapy, routine antibiotic use may contribute to antimicro-
tumors. It is administered as a subcutaneous or intravenous bial resistance. Empiric treatment should be considered for
bolus injection in an initial dose of 500 mcg three times daily other acute infectious diarrhea including those caused by
to assess the patients tolerance to gastrointestinal adverse nonhospital acquired invasive organisms such as Shiga
effects. Biweekly serum levels of insulin-like growth factor-1 toxinproducing Escherichia coli (STEC) O157, Campylobacter,
(IGF-1 or somatomedin C) can be used as a guide to dose Salmonella, and Shigella organisms producing moderate to
titration. Possible adverse effects include nausea, bloating, severe fever, tenesmus, and bloody stools.9
pain at the injection site, and gallstones (with prolonged
therapy).
OUTCOME EVALUATION
Probiotics
Probiotics are dietary supplements containing bacteria that Monitor the patient with diarrhea from the point of rst
may promote health by enhancing the normal microora of contact until symptoms resolve, keeping in mind that most
the gastrointestinal tract while resisting colonization by episodes are self-limiting.
potential pathogens. Probiotics can stimulate the immune Question the patient to determine whether symptom resolu-
response and suppress the inammatory response. Yogurt can tion occurs within 48 to 72 hours in acute diarrhea.
provide relief from diarrhea due to lactose intolerance. It sup- Monitor for the maintenance of hydration, particularly when
ports digestion of lactose because the bacteria used to make symptoms continue for more than 48 hours. Look for increas-
yogurt produce lactase and digest the lactose before it reaches ing thirst, decreased urination, dark-colored urine, dry mucous
the colon. The Lactobacillus acidophilus in yogurt, cottage membranes, and rapid heartbeat as suggestive of dehydration,
cheese, and acidophilus milk improves digestion of lactose especially when nausea and vomiting have been present.
and may prevent or relieve diarrhea related to lactose de- Monitor for symptom control in patients with chronic
ciency and milk intake. Although lactase is not a probiotic, diarrhea.
lactase tablets may also be used to prevent diarrhea in suscep- When antibiotics are used, monitor for completion of the
tible patients. course of therapy.
medical attention. The associated costs to society are signi-

Patient Care and Monitoring for cant, and the recurrent nature of IBS contributes to these costs
Diarrhea through missed workdays, inattention on the job, and high
consumption of health services.10
1. Assess the patients symptoms to determine if patient- In the United States, IBS affects women about twice as
directed therapy is appropriate or whether the patient often as men. However, this may reect a womans tendency to
should be evaluated by a physician. Determine the type seek medical care more often than a man may. Irritable bowel
of symptoms, severity, frequency, and exacerbating fac- syndrome can occur at any age, but presentation is most
tors. Remember to inquire about recent foreign travel. common between the ages of 20 and 50 years. Onset beyond
2. Determine if the patient is dehydrated. 60 years of age is rare. However, prevalence for older adults is
3. Determine whether the patient has a history of disease the same as for young persons. Prevalence is similar in
that might be associated with diarrhea. Caucasians and African-Americans but may be lower in peo-
4. Obtain a thorough current history of prescription, nonpre- ple of Hispanic origin. A genetic link is unproven, but IBS
scription, and dietary supplement use. Remember to review seems more common in certain families.
the current therapy as a potential cause of diarrhea.
There is strong association between emotional distress and
5. Determine if any diarrhea treatments have been attempted,
IBS. Psychosocial trauma (e.g., a history of abuse, recent death of
including home remedies.
a close relative or friend, or divorce) is more likely to be found in
6. Medical referral is advised if the patient is pregnant,
patients presenting with IBS than in the general population. An
breast-feeding, younger than 3 or older than 70 years of
age, or suffers from multiple medical conditions. increased prevalence of psychiatric disorders such as anxiety,
7. If home care is recommended, provide clear instructions depression, personality disorders, and somatization (psycholo-
about how to proceed if symptoms do not improve or gical distress expressed as physical symptoms) occurs among
new symptoms emerge. adult patients with IBS. Alcohol consumption and smoking have
8. Discuss the importance of maintaining nutrition by modify- not been shown to be risk factors for developing IBS.11
ing the diet to include low-residue meals (low-ber meals). Some people show rst evidence of IBS after contracting
9. Educate the patient about: (1) the causes of acute and gastroenteritis, which has led to speculation about whether an
chronic diarrhea; (2) the possible complications of diar- infection makes the gastrointestinal tract susceptible to func-
rhea; (3) the goals of treatment for diarrhea; (4) the tional problems. Women with IBS may have symptoms trig-
antidiarrheal medication used to manage acute or chronic gered by menstrual periods.
diarrhea; and (5) if appropriate, the circumstances when
antibiotics are used to treat diarrhea.
PATHOPHYSIOLOGY
IRRITABLE BOWEL SYNDROME Enteric nerves control intestinal smooth muscle action and
are connected to the brain by the autonomic nervous system.
Irritable bowel syndrome (IBS) is a disorder of the gastrointesti- IBS is thought to result from dysregulation of this brain-gut
nal tract that interferes with the normal functions of the colon. axis. The enteric nervous system is composed of two gan-
At various points in the past, IBS has been referred to as mucous glionated plexuses that control gut innervation: the submu-
colitis, spastic colon, irritable colon, or nervous stomach. IBS cous plexus (Meissners plexus) and the myenteric plexus
is generally described as a functional disorder rather than a disease (Auerbachs plexus). The enteric nervous system and the cen-
per se. A functional disorder involves symptoms that cannot be tral nervous system (CNS) are interconnected and interde-
attributed to a specic injury, infection, or other physical problem. pendent. A number of neurochemicals mediate their function,
A functional disorder occurs because of altered physiologic including serotonin (5-hydroxytryptamine or 5-HT), acetyl-
processes rather than structural or biochemical defects and may choline, substance P, and nitric oxide, among others.
be subject to nervous system inuence. IBS is associated with Two 5-HT receptor sub-types, 5-HT3 and 5-HT4, are
frequent uctuation in symptoms, loss of productivity, and involved in gut motility, visceral sensitivity, and gut secretion.
decreased quality of life. Although IBS has been referred to as The 5-HT3 receptors slow colonic transit and increase uid
functional bowel disease, true functional bowel disease may absorption, whereas 5-HT4 receptor stimulation results in
be more indicative of widespread gastrointestinal involvement accelerated colonic transit.
including (but not limited to) the colon. Although no single pathologic defect has been found to
account for the pattern of exacerbations and remissions seen
EPIDEMIOLOGY AND ETIOLOGY in IBS, CNS abnormalities, dysmotility, visceral hypersensitiv-
ity, and a number of other factors have been implicated.12
IBS is one of the most common disorders seen in primary care The passage of uids into and out of the colon is regulated
and the most common reason for referral to gastroenterolo- by epithelial cells. In IBS, the colonic lining (epithelium)
gists. Although between 15% and 20% of Americans suffer appears to work properly. However, increased movement of the
from IBS, only about one-quarter of those affected seek contents in the colon can overwhelm its absorptive capacity.
Disturbed intestinal motility appears to be a central feature of obtaining a careful and thorough history to identify symp-
IBS, which leads to altered stool consistency. Studies suggest toms characteristic of the disorder. It is equally important to
that the colon of IBS sufferers is abnormally sensitive to nor- distinguish between IBS and conditions having similar symp-
mal stimuli.13 This enhanced visceral sensitivity manifests as toms. Patients should be questioned about the character of
pain, especially related to gut distention. their stools. This should include questions about frequency,
IBS activity may be affected by the immune system. Some IBS consistency, color, and size. Moreover, because of the func-
patients have been found to have antibodies, which may indicate tional nature of IBS, a patient may present with symptoms of
food hypersensitivity that might be involved in symptom pro- upper gastrointestinal problems such as gastroesophageal
duction.14 Specically, sensitivity has been demonstrated to reux disease (GERD) or with excessive atulence. Patients
common foods such as wheat, beef, pork, soy, and eggs. should also be questioned about diet to determine whether
symptoms seem to occur in relationship to meals or speci-
cally after consumption of certain dietary products.
Barium enema, sigmoidoscopy, or colonoscopy may be indi-
cated in the presence of red ag symptoms (fever, weight loss,
Diagnosis
bleeding, and anemia, which may be accompanied by persistent
The diagnosis of IBS is made by symptom-based criteria severe pain), which often point to a potentially serious non-IBS
and the exclusion of organic disease. IBS is diagnosed by problem. A barium enema may identify polyps, diverticulosis,
Clinical Presentation of Irritable Bowel Signs

Syndrome The physical examination is often normal in IBS.
The patient may appear to be anxious.
Palpation of the abdomen may reveal left lower quadrant
Symptoms tenderness, which may indicate a tender sigmoid colon.
Patients report a history of abdominal pain or discomfort that Abdominal distention may be present in some cases.
is relieved with defecation. Symptom onset is associated with The following red ag or alarm features are not associated
change in frequency or appearance of stool. Some persons with IBS and may indicate inammatory bowel disease,
experience hard, dry stools whereas others experience loose cancer, or other disorders: fever, weight loss, bleeding,
or watery stools. Some stools may be small and pellet-like in and anemia, which may be accompanied by persistent
appearance while others may be narrow and pencil-like. severe pain.
Symptoms can typically be categorized as either
diarrhea-predominant IBS (IBS-D) or constipation-predominant Laboratory Tests
IBS (IBS-C). Patients with IBS-D usually report more than In most cases, laboratory testing reveals no abnormalities
three loose or watery stools daily. Those with IBS-C usually in IBS, but certain tests can be used to identify other causes
have fewer than three bowel movements per week; stools are for the patients symptoms.
typically hard and lumpy and accompanied by straining. Complete blood cell count (CBC) may identify anemia,
While many patients t into one of these categories, some which may suggest blood loss and an organic source for GI
patients report alternating episodes of diarrhea and constipation. symptoms.
Other common symptoms include: (1) feelings of incom- Serum electrolytes and chemistries may indicate metabolic
plete evacuation; (2) abdominal fullness; (3) bloating; causes of symptoms.
(4) atulence; (5) passage of clear or white mucus with a Thyroid-stimulating hormone (TSH) should be ordered
stool; and (6) occasional fecal incontinence. when thyroid dysfunction is suspected. Hypothyroidism
Periods of normal stools and bowel function are punctu- may be responsible for constipation and related
ated by episodes of sudden symptoms. symptoms.
Symptoms are often exacerbated by stress. Stool testing for ova and parasites may identify Clostridium
Left lower quadrant abdominal pain is often brought on or difcile and amoeba as possible causes of diarrhea rather
made worse by eating. Passage of stool or atus may pro- than IBS.
vide some relief. Fecal leukocytes can be found in inammatory diarrhea,
IBS-C can often be distinguished from chronic constipation pri- especially when due to invasive microorganisms.
marily by the presence of abdominal pain and discomfort. A positive stool guaiac test indicating blood in the gastroin-
Although pain and discomfort may be present in some patients testinal tract does not support a diagnosis of IBS.
with chronic constipation, it is an expected feature of IBS. An elevated erythrocyte sedimentation rate (ESR) is consis-
Patients with IBS may experience comorbidities outside the tent with a systemic inammatory process such as inam-
gastrointestinal tract such as bromyalgia, sleep distur- matory bowel disease rather than IBS.
bances, headaches, dyspareunia, and temporomandibular Testing for lactose deciency can conrm the presence of
joint syndrome. lactose intolerance, which may explain the symptoms.
impairment; and (3) the presence of psychological compo-

Patient Encounter 3, Part 1 nents. A standard treatment regimen is not possible because
of the heterogeneous nature of the IBS patient population.
Patients suffering from IBS can benet from clinician sup-
port and reassurance, since specic pathology is unlikely to
A 38-year-old woman presents complaining of headache,
be found.
abdominal pain, bloating, occasional nausea, and excessive
belching. These symptoms have occurred with increasing
frequency over the past 2 to 3 weeks. The abdominal pain is Nonpharmacologic Therapy
crampy in character and located in the left lower abdominal
area. She has also had alternating episodes of diarrhea and Diet and Other Lifestyle Modications
constipation and the presence of white threadlike material in
Dietary modication is a standard therapeutic modality. Food
her stool during some of the past 3 weeks.
hypersensitivities and adverse effects are thought to occur widely
Which of the patients symptoms are characteristics of IBS? in IBS patients, especially those with diarrhea-predominant
How well does this woman t the typical epidemiologic type. Elimination diets are the most commonly used strategy,
prole of patients with IBS? usually focusing on milk and dairy products, fructose and sor-
bitol, wheat, and beef. Flatulence may be controlled by reduc-
ing gas-causing foods such as beans, celery, onions, prunes,
tumors, or other abnormalities that might be responsible for bananas, carrots, and raisins. Response to elimination diets
the symptoms. In addition, exaggerated haustral contractions varies widely but they may be useful in individual patients.
may be noted with barium enema. Such contractions impede Care must be taken to avoid creating nutritional decits while
stool movement and contribute to constipation. attempting to eliminate an offending food.
Flexible sigmoidoscopy can be performed to identify
obstruction in the rectum and lower colon, whereas Psychological Treatments
colonoscopy can evaluate the entire colon for organic disease. Psychotherapy focused on reducing the inuence of the CNS
The diagnostic basis for IBS has long been centered on the on the gut has been studied. Cognitive behavioral therapy
presence of symptoms, rst dened by the Manning criteria: (CBT), dynamic psychotherapy, relaxation therapy, and hyp-
(1) abdominal pain relieved by defecation with either (a) looser notherapy have been reported to be effective in some patients.
stools with pain onset, or (b) frequent stools with pain onset; However, CBT and relaxation therapy do not appear to be bet-
(2) abdominal distention; (3) mucus in the stool; and (4) sen- ter than standard approaches.18 Biofeedback may provide
sation of incomplete evacuation.15,16 These practical criteria relief in cases of severe constipation, but definitive evidence
have been used widely. is lacking.16 Psychotherapy interventions provide relief
The Rome II criteria (preceded by Rome I) are the most cur- from pain and diarrhea but not constipation.19
rent diagnostic criteria for establishing the presence of IBS.
They presume the absence of a structural or biochemical expla-
nation for the symptoms. These rather stringent criteria can be
applied clinically, but not as easily as the older Manning criteria.17
Botanicals
The Rome II criteria dene IBS as occurring when symptoms of
Peppermint oil is widely advocated; it acts as an antispas-
abdominal discomfort or pain exist at least 12 weeks (which
modic agent due to its ability to relax gastrointestinal smooth
need not be consecutive) in the preceding 12 months that have
muscle. However, it also relaxes the lower esophageal sphinc-
two of the three following features: (1) relieved with defecation;
ter, which could allow reux of gastric contents into the
(2) onset associated with a change in the frequency of stool;
esophagus. The usual dose is 1 to 2 enteric-coated capsules
and/or (3) onset associated with a change in the form of stool.
containing 0.2 mL of peppermint oil two to three times daily.
IBS is unlikely if symptom onset occurs in old age, the disorder
Matricaria recutita, known as German chamomile, is also
has a steady but aggressive course, or the patient experiences
purported to have antispasmodic properties. It is taken most
frequent awakening because of symptoms.
often as a tea up to four times a day. Benzodiazepine, alcohol,
and warfarin users should be cautioned against taking this
product because it can cause drowsiness, and it contains
TREATMENT coumarin derivatives.20

Antispasmodics
The principal goal of IBS treatment is to reduce or control Antispasmodic agents such as dicyclomine or hyoscyamine
symptoms. The treatment strategy is based on: (1) the prevail- have been among the most frequently used medications for
ing symptoms and their severity; (2) the degree of functional treating abdominal pain in patients with IBS (Table 185).
TABLE 185. Common Pharmacologic Treatments for Irritable the signicant effect of serotonin in the gut. SSRIs principally
Bowel Syndrome act on 5-HT1 or 5-HT2 receptors, but they can also have some
effect on gut-predominant 5-HT3 and 5-HT4 receptors, per-
Generic (Brand) Name Dose
haps reducing visceral hypersensitivity. They may be bene-
Antispasmodics cial for patients with IBS-C or when the patient presents with
Dicyclomine (Bentyl) 1020 mg every 46 hours
IBS complicated by a mood disorder.19 SSRIs should be
as needed
Hyoscyamine (Levsin) 0.1250.25 mg orally or reserved for use when TCAs are not effective because evidence
sublingually every supporting their use solely in IBS is lacking.
4 hours as needed
Propantheline bromide 15 mg three times a day Bulk-Forming Agents
(Pro-Banthine) (before meals) and 30 mg
at bedtime
Bulk-forming agents may improve stool passage in constipation-
Clidinium bromide plus 510 mg three to four predominant patients but are unlikely to have a favorable effect
chlordiazepoxide HCl times a day on pain or global IBS symptoms.21 Psyllium may increase at-
(Librax) ulence, which may worsen discomfort in some patients.
Hyoscyamine, scopolamine, 12 tablets three to four Methylcellulose products are less likely to increase gas pro-
atropine, phenobarbital times daily
(Donnatal)
duction. Although ber-based supplements are more likely to
be useful in constipation-predominant IBS, these products
Tricyclic Antidepressants In Diarrhea-Predominant
IBS: may be dose-adjusted in diarrhea to increase stool consis-
Amitriptyline 50150 mg daily tency. Other laxative products might be used in constipation-
Doxepin 10150 mg daily predominant IBS, but most are less desirable than bulking
Selective Serotonin Reuptake In Constipation-Predominant agents due to the potential for unwanted effects.
Inhibitors IBS:
Paroxetine (others can be used) 1040 mg daily
Anti-Motility Agents
Bulk-Forming Laxatives Loperamide stimulates enteric nervous system receptors,
Psyllium (Metamucil) 2.54 g daily
Methylcellulose (Citrucel) 46 g daily
inhibiting peristalsis and uid secretion. It improves stool
consistency and reduces the number of stools.21 Consequently,
Antimotility Agents
Loperamide (Imodium A-D) 4 mg; then 2 mg after it is most useful in patients who have diarrhea as a prominent
each loose stool; daily symptom. However, it can occasionally aggravate abdomi-
maximum 16 mg nal pain.
5-HT3 Receptor Antagonist
Alosetron (Lotronex) 1 mg daily Alosetron
5-HT4 Receptor Agonist Stimulation of 5-HT3 receptors triggers hypersensitivity and
Tegaserod maleate (Zelnorm) 6 mg twice daily hyperactivity of the large intestine. Alosetron (Lotronex) is a
5-HT, serotonin. selective 5-HT3 antagonist that blocks these receptors and is
used to treat women with severe diarrhea-predominant IBS.
Eligible patients should have frequent and severe abdominal
Side effects include blurred vision, constipation, urinary pain, frequent bowel urgency or incontinence, and restricted
retention, and (rarely) psychosis. Although their effectiveness daily activities. Alosetron has been shown to improve overall
remains unconrmed, these drugs may deserve a trial in symptoms and quality of life. Alosetron can cause constipa-
patients with intermittent postprandial pain.16 tion in some patients.
Because alosetron has been associated with ischemic coli-
Antidepressants tis, it may be prescribed only under strict guidelines, includ-
Tricyclic antidepressants (TCAs) such as amitriptyline and ing signing of a consent form by both patient and physician.
doxepin have been used with some success in the treatment of Patients selected for therapy should exhibit chronic IBS symp-
IBS-related pain (Table 185). They modulate pain princi- toms and have failed to respond to conventional therapy.
pally through their effect on neurotransmitter reuptake, espe-
cially norepinephrine and serotonin. Their helpfulness in Tegaserod Maleate
functional gastrointestinal disorders seems independent of Tegaserod maleate (Zelnorm) stimulates 5-HT4 receptors in
mood-altering effects normally associated with these agents. the GI tract, thereby increasing intestinal secretion, peristalsis,
Low-dose TCAs (e.g., amitriptyline, desipramine, or doxepin and small bowel transit. It also reduces sensitivity related to
10 to 25 mg daily) may help patients with IBS who predomi- abdominal distention. It has been shown to be more effective
nantly experience diarrhea or pain. than placebo in improving global IBS symptoms and altered
The selective serotonin reuptake inhibitors (SSRIs) parox- bowel habits in constipation-predominant IBS.21 Diarrhea is a
etine, uoxetine, and sertraline are potentially useful due to possible adverse effect.
Monitor for adequate relief of symptoms. Patients whose

Patient Encounter 3, Part 2 pain does not respond to drug therapy may have a psycho-
logical comorbid condition and may require psychiatric
intervention.
Specically, monitor for relief of pain if present initially. Monitor
Upon further questioning, the patient states that she had
patients with symptoms of constipation or diarrhea for fre-
similar symptoms near the end of graduate school 6 years
ago. The symptoms gradually subsided after graduation, so quency, appearance, and size of stools in relationship to their
she did not seek medical attention. She is an accountant normal characteristics. As stools normalize, associated symp-
and recently received a promotion at work. As a result, she toms such as bloating and abdominal distention should resolve.
has taken on considerably more responsibility. For patients taking bulk-forming agents, monitor for relief of
PMH
constipation. Hard stools should become softer within 72 hours.
Anxiety; muscle contractions; headaches Monitor antidepressant therapy for relief of lower abdominal
pain.
FH
Assess 5-HT4 receptor agonists (tegaserod) for relief of crampy
Mother has migraine headaches
abdominal pain and bloating.
SH Evaluate 5-HT3 receptor antagonists (alosetron) for relief of
Non-smoker; drinks a glass of wine occasionally abdominal pain and fecal incontinence.
Meds Antispasmodics may provide limited relief of crampy abdom-
Naproxen 220 mg every 12 hours as needed for headaches inal pain.
and menstrual pain Antimotility agents should be expected to reduce stool fre-
Loperamide 2 mg as needed for diarrhea quency and control diarrhea.
Allergies Monitor complete blood cell count, serum electrolytes and
No known drug allergies chemistries, stool guaiac, and erythrocyte sedimentation rate
Physical Exam yearly for changes that might signal an overlapping organic
Gen: Alert and oriented, well developed and well nour- problem.
ished, anxious black woman Refer any patient presenting with red ag signs for medical
VS: blood pressure 137/88 mm Hg, pulse 80 beats per evaluation.
minute, respiratory rate 21/minutes, temperature 98.7F
(37.1C), Ht 57, Wt 74 kg
Integ: Hair and nails unremarkable; scalp dry and aky; Patient Care and Monitoring
skin otherwise unremarkable
HEENT: PERRLA, EOMI
Chest: Clear to A & P bilaterally
CV: RRR, normal S1 and S2; no S3 or S4 1. Assess symptoms to determine if patient-directed therapy
Abd: (+) BS, mildly tender LLQ is appropriate or whether physician evaluation is needed.
Rectal: No palpable masses; no hemorrhoids; stool negative 2. Determine the type, severity, and frequency of symptoms
for occult blood and possible exacerbating factors.
What information is consistent with the diagnosis of IBS? 3. Listen attentively to the patients complaints and reassure
Outline an appropriate therapeutic plan for this patient. the patient to allay fears about invasive disease.
4. Obtain a thorough current history of prescription, non-
prescription, and dietary supplement use.
Ischemic colitis has been observed in some patients taking 5. Determine if any IBS treatments have been attempted
tegaserod. The drug should be discontinued promptly if rectal and how effective they have been.
bleeding, bloody diarrhea, or worsening abdominal pain occurs. 6. Determine whether the patient has received educational
In March of 2007, the FDA announced that tegaserod intervention about IBS, health promotion, and symptom
maleate would be voluntarily withdrawn from the market prevention measures.
because of information indicating an increased risk of serious 7. Provide patient education about IBS symptoms, lifestyle
cardiovascular events (myocardial infarction, unstable angina, modications, and drug therapy for IBS:
and stroke). Explain how to use medications relative to symptom
intensity.
If taking alosetron, determine compliance with special
OUTCOME EVALUATION use requirements.
Describe potential adverse effects.
Because symptoms vary in intensity and among patients, a List drugs that may interact with the therapy.
specic drug therapy may not lead to equivalent symptom Discuss what to do if red ag symptoms occur.
abatement in different patients.
ABBREVIATIONS Brandt L, Schoenfeld P, Prather C, et al. American College of

Gastroenterology Functional Gastrointestinal Disorders Task
CBC: complete blood cell count Force. An evidence based approach to the management of chronic
CBT: cognitive behavioral therapy constipation in North America. Am J Gastroenterol 2005;100:
CNS: central nervous system S1S21.
EPEC: enteropathogenic Escherichia coli Cremonini F, Talley NJ. Irritable bowel syndrome: epidemiology,
ESR: erythrocyte sedimentation rate natural history, health care seeking and emerging risk factors.
ETEC: enterotoxigenic Escherichia coli Gastroenterol Clin North Am 2005;34:189204.
GERD: gastroesophageal reux disease Gore JI, Surawicz C. Severe acute diarrhea. Gastroenterol Clin North
GI: gastrointestinal Am 2003;32:12491267.
5-HT4: serotonin Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the
IBS: irritable bowel syndrome management of infectious diarrhea. Clin Infect Dis 2001;32:
IBS-C: constipation-predominant irritable bowel syndrome 331351.
IBS-D: diarrhea-predominant irritable bowel syndrome King CK, Glass R, Bresee JS, et al. Managing acute gastroenteritis
IGF-1: insulin-like growth factor-1 among children: Oral rehydration, maintenance, and nutri-
ORS: oral rehydration solution tional therapy. MMWR Morb Mortal Wkly Rep 2003;
PCR: polymerase chain reaction 52(RR16):116.
PEG: polyethylene glycol Locke GR, Pemberton JH, Phillips SF. American Gastroenterological
SSRI: selective serotonin reuptake inhibitor Association medical position statement on constipation.
STEC: Shiga toxinproducing Escherichia coli Gastroenterology 2000;119:17661778.
TCA: tricyclic antidepressant Mertz HR. Drug therapy: irritable bowel syndrome. N Engl J Med
TSH: thyroid-stimulating hormone 2003;349:21362146.
Muller-Lissner SA, Kamm MA, Scarpignato C, Wald A. Myths and
Reference lists and self-assessment questions and answers are misconceptions about chronic constipation. Am J Gastroenterol
available at www.ChisholmPharmacotherapy.com. 2005;100:232242.
Schoenfeld P. Efcacy of current drug therapies in irritable bowel
Log into the website: www.pharmacotherapyprinciples.com syndrome: What works and does not work. Gastroenterol Clin
for information on obtaining continuing education credit for North Am 2005;34:319335.
this chapter.
Boyce PM, Talley NJ, Balaam B, et al. A randomized controlled trial of

cognitive behavior therapy, relaxation training, and routine clini-
cal care for the irritable bowel syndrome. Am J Gastroenterol
2003;98:22092218.
19 PORTAL HYPERTENSION AND CIRRHOSIS
Laurajo Ryan
LEARNING OBJECTIVES
1. Describe the epidemiology and social impact of portal hypertension and cirrhosis.
2. Explain the pathophysiology of cirrhosis and portal hypertension.
3. Outline the progression of liver damage from excessive alcohol intake.
4. Identify the signs and symptoms of liver disease in a given patient.
5. Clarify the consequences associated with decreased hepatic function.
6. List the treatment goals for a patient with portal hypertension and its complications.
7. Evaluate patient history and physical exam ndings and recommend a specic regimen
including both pharmacologic and nonpharmacologic therapy.
KEY CONCEPTS Lactulose is the foundation of pharmacologic therapy to prevent

and treat hepatic encephalopathy because its unique mechanism
Portal hypertension is the precipitating factor for the compli- binds ammonia in the gut and facilitates its excretion.
cations of cirrhotic liver diseaseascites, spontaneous bacterial
peritonitis (SBP), variceal bleeding, and hepatic encephalopa- Cirrhosis is the progressive replacement of normal hepatic
thy. Lowering portal pressure can reduce the complications of cells by brous scar tissue. This scarring is accompanied by the
cirrhosis and decrease morbidity and mortality. loss of viable hepatocytes, which are the functional cells of the
Chronic excessive ingestion of ethanol causes progressive liver liver. Progressive cirrhosis is irreversible and leads to portal
damage because both ethanol and its metabolic products are hypertension that is in turn responsible for many of the compli-
direct hepatotoxins. cations of advanced liver disease. These consequences include (but
Cirrhosis is irreversible; treatments are directed at limiting are not limited to) spontaneous bacterial peritonitis (SBP),
disease progression and minimizing complications. hepatic encephalopathy, and variceal bleeding.1
Non-selective -blockers are rst-line treatment for prevent-
ing variceal bleeding; they vasoconstrict the splanchnic bed
through multiple mechanisms. EPIDEMIOLOGY AND ETIOLOGY
The goals of treating ascites are to minimize acute discomfort,
re-equilibrate ascitic uid, and prevent SBP. Treatment should Cirrhosis is the result of long-term insult to the liver, so dam-
modify the underlying disease pathology; without directed age is typically not evident clinically until the fourth decade of
therapy, uid will rapidly reaccumulate. life. Chronic liver disease and cirrhosis combined were the
Cirrhosis is a high aldosterone state; spironolactone is a direct 12th leading cause of death in the United States in 2002. In
aldosterone antagonist and a primary treatment for ascites. patients between the ages of 25 and 64, damage from excessive
During acute variceal hemorrhage, crucial desired outcomes alcohol use accounted for over one-half of the deaths.2
include controlling bleeding, preventing rebleeding, and Alcoholic liver disease and viral hepatitis are the most com-
avoiding acute complications such as SBP. mon causes of cirrhosis in the United States and worldwide.
Long-term antibiotic prophylaxis for SBP decreases mortality Variations occur, but cirrhosis typically develops after 10 or
in patients with a history of SBP and low-protein ascites more years of daily ingestion of 80 g of ethyl alcohol; this is an
[ascitic uid albumin less than 1 g/dL (less than 10 g/L)]. average of 6 to 8 drinks per day (a drink is equivalent to 1 ounce
323
of hard liquor, 4 ounces of wine, or a 12-ounce beer).3 With

Inferior vena cava
equivalent alcohol intake, women tend to develop cirrhosis Hepatic vein
more quickly than men do. Differences in alcohol metabolism
Left
may account for this gender disparity; women metabolize less Liver gastric vein
alcohol in the gastrointestinal (GI) tract, allowing delivery of
higher levels of ethanol to the liver.4 Genetic factors also play a Stomach
role in development of alcoholic liver disease; some persons will
progress to cirrhosis with much less cumulative alcohol use
than is typical in a cirrhotic patient (either fewer drinks per day,
or faster disease development) while others do not develop the
disease with even more excessive intake. Portal
Infection with one or more strains of viral hepatitis often vein
causes acute inammation of the liver, while chronic infection Splenic vein
with hepatitis B or C can lead to cirrhosis. Hepatitis B and C Inferior vena cava Spleen
are common in intravenous drug users and can also be trans- Left renal vein
Right renal vein
mitted through sexual contact, but many cases of hepatitis C
are idiopathic.5,6 Hepatitis C is a more common cause of cir-
rhosis than hepatitis B in the United States while hepatitis B is Inferior
more common in the rest of the world.7 See Chapter 21 on Superior
mesenteric vein
viral hepatitis for a complete discussion of infectious hepatitis. mesenteric vein
Approximately 30% of patients with cirrhosis experience
variceal bleeding at some point. Variceal bleeding carries a
remarkably high mortality rate; up to 55% of patients with
advanced disease die from their rst bleeding episode.
Mortality from variceal bleeding correlates with disease sever-
ity; risk factors for bleeding varices include poor liver function, FIGURE 191. The portal venous system. (From Timm EJ,
large varices, and red signs (wales) on endoscopic examina- Stragand JJ. Portal hypertension and cirrhosis. In: DiPiro JT,
tion.8 In patients who survive the rst incident of bleeding, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A
more than two-thirds experience a repeat episode. Pathophysiologic Approach. 6th ed. New York: McGraw-Hill;
Development of ascites in cirrhotic patients is a particu- 2005: 694, with permission.)
larly ominous marker; mortality 1 year after initial develop-
ment of ascites is approximately 50%.9
In addition to the high mortality rate, cirrhosis carries an the blood delivered to the liver. The hepatic artery provides the
enormous social burden from hospitalizations, lost wages, and remaining 25% of the blood supply in the form of oxygenated
decreased productivity, not to mention the emotional strain blood from the abdominal aorta. Normal portal vein pressure is
of the disease on both patients and families. between 5 and 10 mm Hg; this level maintains blood ow to the
Once cirrhosis is diagnosed, disease progression is relentless, liver at approximately 1 L/minute. Portal hypertension occurs
regardless of the initial insult to the liver. Determining the specic when portal vein pressure exceeds 10 to 12 mm Hg.10,11
cause of cirrhosis requires examination of both physical presenta- Portal hypertension is a consequence of increased resistance
tion and past medical history. An accurate social history is partic- to blood ow through the portal vein. Increased resistance is usu-
ularly important because few factors in the physical and laboratory ally due to restructuring of intrahepatic tissue (sinusoidal dam-
examination aid in determining disease etiology. Understanding age) but may also be caused by presinusoidal damage such as
the cause of a patients cirrhosis is imperative because it can affect portal vein occlusion from trauma, malignancy, or thrombosis. A
therapeutic options and treatment decisions. third (and the least common) mechanism is outow obstruction
of the hepatic vein. This latter damage is posthepatic, and normal
liver structure is maintained. This chapter will focus on portal
hypertension caused by intrahepatic damage from cirrhosis.
PATHOPHYSIOLOGY
Sinusoidal damage from cirrhosis is the most common
cause of portal hypertension. The sinusoids are porous vessels
Portal Hypertension and Cirrhosis
within the liver that surround radiating rows of hepatocytes,
The portal vein is the primary vessel leading into the liver; it the basic functional cells of the liver (Fig. 192). Progressive
receives deoxygenated venous blood ow from the small intes- destruction of hepatocytes and an increase in broblasts and
tine, stomach, pancreas, and spleen (Fig. 191). The inow connective tissue surrounding the hepatocytes culminate in
from these organ systems accounts for approximately 75% of cirrhosis. Fibrosis and regenerative nodules of scar tissue
CHAPTER 19 / PORTAL HYPERTENSION AND CIRRHOSIS 325
Hepatic cell
Hepatocytes
Liver
Lymph vessel lobule
3 Terminal
1 2 hepatic
Sinusoid venule
Portal vein Portal vein

Bile duct
Hepatic artery Hepatic artery
Bile duct
Terminal hepatic venule
FIGURE 192. Relationship of sinusoids to hepatocytes and the venous system. (From Timm EJ, Stragand JJ. Portal hypertension and
cirrhosis. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill;
modify the basic architecture of the liver, disrupting blood feminization in male patients. Another deleterious effect of
flow and liver function. Reduced hepatic blood ow alters changes in sex hormone metabolism is the development of
normal metabolic breakdown processes and decreases protein spider angiomata (nevi). Spider angiomata are vascular
synthesis within the liver. lesions found mainly on the trunk. The lesion has a central
The sinusoids transport both portal and arterial blood to the arteriole (body) surrounded by radiating legs. When
hepatocytes. The systemic blood delivered to the liver contains blanched, the lesions ll from the center body outward toward
nutrients, drugs, and ingested toxins. The liver processes the the legs. Spider angiomata are not specic to cirrhosis, but the
nutrients (carbohydrates, proteins, lipids, vitamins, and min- number and size do correlate with disease severity and their
erals) for either immediate use or for storage, while the drugs presence relates to risk of variceal hemorrhage.12
and toxins are metabolized through a variety of processes Increased intrahepatic resistance to portal ow increases
known as rst-pass metabolism. The liver also processes meta- pressure on the entire splanchnic bed; an enlarged spleen
bolic waste products for excretion. In cirrhosis, bilirubin (from (splenomegaly) is a common nding in cirrhotic patient and
the enzymatic breakdown of heme) can accumulate; this causes can result in thrombocytopenia due to splenic sequestration
jaundice (yellowing of the skin), scleral icterus (yellowing of the of the platelets. Portal hypertension mediates systemic and
sclera), and tea-colored urine (urinary bilirubin excretion). splanchnic arterial vasodilation through production of nitric
Changes in steroidal hormone production, conversion, and oxide and other vasodilators in an attempt to counteract the
handling are also prominent features of cirrhosis. These changes increased pressure gradient. Nitric oxide causes a fall in systemic
can result in decreased libido, gynecomastia (development arterial pressure; unfortunately, this activates both the renin-
of breast tissue in men), testicular atrophy, and features of angiotensin-aldosterone and sympathetic nervous systems and
increases antidiuretic hormone (vasopressin) production.13 hepatic lymph nodes allows uid to seep into the peritoneal cav-
The activation of these systems is an attempt to maintain arte- ity, further contributing to ascitic uid formation.
rial blood pressure through increases in renal sodium and As previously discussed, increased portal pressure triggers
water retention. Increased systemic and portal pressure put the release of nitric oxide to directly vasodilate the splanchnic
increased pressure on the vascular system. The umbilical vein, arterial bed and decrease portal pressure. Unfortunately, nitric
which is usually eradicated in infancy, may become patent and oxide also dilates the systemic arterial system, causing a
increase blood ow to the abdominal veins. The prominent decrease in blood pressure and a decrease in renal perfusion by
veins are called caput medusae because they resemble the lowering the effective intravascular volume. The kidney reacts
head of the mythical Gorgon Medusa. by activating the renin-angiotensin-aldosterone system, which
The aim of pharmacologic treatment in portal hyperten- increases plasma renin activity, aldosterone production, and
sion is to decrease portal pressure and reduce the effects of sodium retention. This increase in intravascular volume fur-
sympathetic activation. thers the imbalance of intravascular oncotic pressure, allowing
even more uid to escape to the extravascular spaces.
Ascites Vasodilation and decreased arterial pressure are also
Ascites is the accumulation of uid in the peritoneal space and detected centrally. The sympathetic nervous system is acti-
is often one of the rst signs of decompensated liver disease. vated to increase blood pressure, which in turn increases por-
Ascites is the most common complication of cirrhosis and tal pressure. Unchecked, these combined effects enable the
portends a dire prognosis.14 cycle of portal pressure and ascites to continue, setting up a
The pathophysiologic mechanisms of portal hypertension self-perpetuating loop of ascites formation.
and of cirrhosis itself are entwined with the mechanisms of Most patients with large ascites also retain sodium avidly
ascites (Fig. 193). Cirrhotic changes and the subsequent and may become hyponatremic if there is a decrease in free
decrease in synthetic function lead to a decrease in production of water excretion. Untreated, this can lead to a decrease in renal
albumin (hypoalbuminemia). Albumin is the major intravas- function and the hepatorenal syndrome.4,13
cular protein involved in maintaining oncotic pressure in the vas-
cular system; low serum albumin levels and increased capillary Varices
permeability allow uid to leak from the vascular space into body
The splanchnic system drains venous blood from the GI tract
tissues. This can result in peripheral edema, ascites, and uid in
to the liver. In portal hypertension there is increased resistance
the pulmonary system. The obstruction of hepatic sinusoids and
to drainage from the originating organ so collateral vessels
(varices) develop in the esophagus, stomach, and rectum to
compensate for the increased blood volume. Varices divert
CIRRHOSIS
blood meant for hepatic circulation back to the systemic cir-
culation; this has the unintended deleterious effect of decreas-
Albumin Intrahepatic
vascular
NO ing clearance of medications and potential toxins through loss
resistance of rst-pass metabolism. Varices are weak supercial vessels,
and any additional increase in pressure can cause these vessels
Plasma oncotic Arteriolar
pressure
Portal venous
vasodilation
to rupture and bleed.15
pressure
Hepatic
lymph Splanchnic
pooling Central Spontaneous Bacterial Peritonitis
ASCITES sympathetic
outflow Spontaneous bacterial peritonitis (SBP) is an acute bacterial
Effective infection of peritoneal uid in the absence of intra-abdominal
Na+ retention intravascular
volume
infection or intestinal perforation. Estimates of the prevalence
of SBP in patients with ascites range from 10% to 30%.16
Enteric gram-negative aerobes are the most common bacteria
Renal
perfusion isolated from ascitic uid; usually Escherichia coli or Klebsiella
Aldosterone (Intrarenal
redistribution
pneumoniae. One proposed cause is translocation of intestinal
of blood flow)
bacteria seeding the ascitic uid.17 Bacterial translocation
Plasma renin correlates with the delay in intestinal transit time and increased
activity
intestinal wall permeability observed in cirrhotic patients.
FIGURE 193. Factors involved in the development of ascites. Another possible mechanism is the hematogenous spread of
NO, nitric oxide. (From Chung RT, Podolsky DK. Cirrhosis and bacteria into the peritoneal space.18 Streptococcus pneumoniae is
its complications. In: Kasper DL, Braunwald E, Fauci AS, et al, the most common gram-positive pathogen associated with
(eds.) Harrisons Principles of Internal Medicine. 16th ed. New
York: McGraw-Hill, 2005: 18581869, with permission.)
SBP.19 Once a bacterial pathogen has been identied, the anti-
biotic spectrum can be narrowed; SBP is rarely polymicrobial.
Hepatic Encephalopathy maintenance of blood homeostasis. With advanced disease the

liver is unable to synthesize these proteins, resulting in extended
Decreased cognition, confusion, and changes in behavior
clotting times (e.g., prothrombin time) and bleeding irregulari-
combined with physical signs such as asterixis (characteristic
ties.21 An additional coagulation abnormality seen in advanced
apping of hands upon extension of arms with wrist exion)
liver disease is thrombocytopenia. This is a result of decreased
indicate hepatic encephalopathy (HE). To objectively stage the
platelet production and splenic sequestration of platelets.
degree of impairment, the patient should be assessed in ve
Macrocytic anemia may also occur because of decreased intake,
distinct categories:
metabolism, and storage of folate and vitamin B12.
1. Level of consciousness
2. Cognition (attention, memory, and disorientation) Alcoholic Liver Disease
3. Behavior (e.g., mood, anger, and paranoia)
4. Motor function (e.g., coordination, reexes, and asterixis) Progression of alcoholic liver disease moves through several
5. Response to psychometric tests distinct phases from development of fatty liver to the devel-
opment of alcoholic hepatitis and cirrhosis. Fatty liver and
These changes may be acute, and therefore possibly alcoholic hepatitis may be reversible with cessation of alcohol
reversible, or they may be of a more chronic, insidious nature intake, but cirrhosis itself is irreversible. Although the scarring
from which patients rarely recover. of cirrhosis is permanent, maintaining abstinence from alco-
Numerous factors, many of them poorly understood, are hol can still decrease complications and slow development to
involved in the development of HE. In severe hepatic disease, end-stage liver disease.22 Continuing to imbibe speeds the
systemic circulation bypasses the liver, so many of the sub- advancement of liver dysfunction and its complications.
stances normally metabolized by the liver remain in the sys- Metabolism of ethanol begins even prior to absorption,
temic circulation and accumulate to toxic levels. In excess, when alcohol dehydrogenase (ADH) within the gastric mucosa
these metabolic by-products, especially nitrogenous waste, oxidizes a portion of the alcohol to acetaldehyde. The remain-
cause alterations in central nervous system functioning.20 ing alcohol is rapidly absorbed from the GI tract, and since it
Ammonia (NH3) is just one of the toxins implicated in HE. is highly lipid-soluble, it enters the body tissues quite easily.
It is a metabolic by-product of protein catabolism and is also ADH metabolizes ethanol in body tissues, primarily the liver,
generated by bacteria in the GI tract. In a normally functioning producing hypoxic damage.23 High levels of ethanol saturate the
liver, hepatocytes take up ammonia and degrade it to form urea, ADH enzyme system; when the ADH system is overwhelmed,
which is then renally excreted. In patients with cirrhosis, the the microsomal ethanol oxidizing system must take over the
conversion of ammonia to urea is retarded and ammonia accu- detoxication process. The microsomal ethanol oxidizing sys-
mulates, resulting in encephalopathy. This decrease in urea for- tem is an inducible cytochrome P-450 (CYP)450 enzyme sys-
mation is manifest on laboratory assessment as decreased blood tem; it participates in phase 1 metabolism and also produces
urea nitrogen (BUN), but BUN levels do not correlate with acetaldehyde as its end product.24,25 Acetaldehyde exerts direct
degree of HE. Patients with HE commonly have elevated serum toxic effects on the liver by damaging hepatocytes, inducing
ammonia concentrations, but the levels do not correlate well brosis, and by directly coupling to proteins, interfering with
with the degree of central nervous system impairment.20 their intended actions. Metabolism of large amounts of ethanol
False neurotransmitters resulting from increased levels of shifts hepatic metabolic processes away from oxidation and
aromatic amino acids, high levels of -aminobutyric acid, and toward reduction. This shift produces a change in metabolism
endogenous benzodiazepines have also been implicated in accounting for the fatty liver, hypertriglyceridemia, and
HE. These substances bind to both the -aminobutyric acid acidemia observed in alcoholic liver disease.
and benzodiazepine receptors and act as agonists at the active
receptor sites.20 Less Common Causes of Cirrhosis
Patients with previously stable cirrhosis who develop acute
encephalopathy often have an identiable precipitating event Genetics and metabolic risk factors mediate other less common
that can account for the increased production and/or decreased causes of cirrhosis. These diseases vary widely in prevalence,
elimination of these toxins. Infections, variceal hemorrhage, disease progression, and treatment options.
renal insufciency, electrolyte abnormalities, and increased Primary biliary cirrhosis is characterized by progressive
dietary protein have all been associated with acute develop- inammatory destruction of the bile ducts. Immune-mediated
ment of HE. inammation of intrahepatic bile ducts results in remodeling
and scarring, causing retention of bile within the liver and sub-
sequent hepatocellular damage and cirrhosis. The number of
Bleeding Diathesis and Synthetic Failure
patients affected with primary biliary cirrhosis is difcult to esti-
Coagulopathies signal end-stage liver disease. The liver manu- mate because many people are asymptomatic and incidental
factures coagulation factors essential for blood clotting and diagnosis during routine health care visits is common.
Clinical Presentation of Cirrhosis and Decreases in clotting factors may manifest as abnormal
Complications of Portal Hypertension bruising and bleeding.
Dupuytrens contracture is a contraction of the palmar fas-
cia that usually affects the fourth and fth digits.27 It is not
General specic to cirrhosis and can be seen in repetitive use
Most signs and symptoms that bring patients to the attention injuries.
of medical personnel are specic to the complication the
patient is experiencing and vary with severity and sudden- Laboratory Abnormalities
ness of onset. Hepatocellular damage manifests as elevated serum
aminotransferases [alanine aminotransferase (ALT) and
Symptoms aspartate aminotransferase (AST)]. The degree of
Patients with cirrhosis may exhibit nonspecic symptoms transaminase elevation does not correlate with the
such as fatigue and weakness but may be asymptomatic remaining functional metabolic capacity of the liver. An
until acute complications develop. AST level two-fold higher than ALT is indicative of
Nonspecic symptoms include anorexia, fatigue, easy alcoholic liver damage.
bruising and bleeding from minor injuries, decreased Elevated alkaline phosphatase is nonspecic and may correlate
libido, and pruritus (particularly with biliary involvement). with liver or bone disease; it tends to be elevated in biliary tract
Patients with ascites may complain of abdominal pain, disease.
nausea, increasing tightness and fullness in the abdomen, -Glutamyl transferase (GGT) is specic to the bile ducts,
shortness of breath and early satiety. and in conjunction with an elevated alkaline phosphatase,
Hemorrhage associated with variceal bleeding may be asso- suggests hepatic disease. Extremely elevated GGT levels
ciated with nausea, vomiting, and hematemesis. Patients further indicate obstructive biliary disease. GGT is also ele-
may also present with pallor, fatigue, and weakness from vated in those who drink three or more alcoholic drinks
blood loss. daily.
In patients with bleeding varices, digestion of swallowed Increased total, direct, and indirect bilirubin concentrations
blood represents a high protein load; this causes nausea indicate defects in transport, conjugation, or excretion of
and can precipitate symptoms of HE. bilirubin.
In patients with HE, neurologic changes can be overwhelming Lactate dehydrogenase (LDH) is a nonspecic marker of hepa-
or so subtle that they are not clinically apparent except during tocyte damage; disproportionate elevation of LDH indicates
a targeted clinical evaluation. ischemic injury.
Patients with HE may complain of disruption of sleep patterns Thrombocytopenia may occur because of decreased
and day-to-night inversion; patients have delayed to-bed and platelet production and splenic platelet sequestration.
wake times, which may progress to complete inversion of the Anemia (decreased hemoglobin and hematocrit) occurs as
normal diurnal cycle. a result of variceal bleeding, decreased erythrocyte produc-
If SBP occurs, symptoms of infection may include fever, tion, and hypersplenism.
chills, and abdominal pain. Elevated prothrombin time (PT) and International
Normalized Ratio (INR) are coagulation derangements that
Signs indicate loss of synthetic capacity in the liver and correlate
Nonspecic signs on physical exam include jaundice, tea- with functional loss of hepatocytes.
colored urine, bruising, hepatomegaly, splenomegaly, spider Decreased serum albumin and total protein occur in
angiomata, caput medusae, palmar erythema, gynecomastia, chronic liver damage due to loss of synthetic capacity
and testicular atrophy. within the liver.
Ascites can be detected by increased abdominal girth The serum albumin-to-ascites gradient is greater than or equal
accompanied by shifting dullness and a uid wave. to 1.1 g/dL (11 g/L) in association with portal hypertension.
Signs of variceal bleeding depend on the degree of blood Increased blood ammonia concentration is characteristic of
loss and abruptness of onset. Rapid and massive blood loss hepatic encephalopathy, but levels do not correlate well
is more likely to result in hemodynamic instability than is with the degree of impairment.
slow, steady bleeding. Signs of acute bleeding may include Signs and symptoms of SBP in a patient with cirrhosis and
pallor, hypotension, tachycardia, mental status changes, ascites should prompt a diagnostic paracentesis (Fig. 194).
and hematemesis. In SBP, there is decreased total serum protein, elevated
Markers of hepatic encephalopathy include decreased cog- white blood cell count (with left shift), and the ascitic uid
nition, confusion, changes in behavior, and asterixis. contains at least 0.250 103/mm3 (0.250 109/L) neu-
Patients with SBP may present with fever, abdominal pain, trophils. Bacterial culture of ascitic uid may be positive,
and changes in mental status. but lack of growth does not exclude the diagnosis.
FIGURE 194. Treatment algorithm for

Active bleeding active gastrointestinal bleeding resulting
from portal hypertension. (From Schianotd,
Bodenheimer HC. Complications of
After documented upper Chronic Liver Disease. In: Friedman SL,
gastrointestinal bleeding
McQuaid KR, Grendell JH (eds.)
Current Diagnosis & Treatment in
Stabilize the patient Gastroenterology. 2nd ed. New York:
hemodynamically McGraw-Hill, 2003, with permission)
Stop active bleeding

with pharmacotherapy
(vasopression or octreotide)
Bleeding ceases Continued bleeding
Effective Emergent sclerotherapy or

variceal band ligation
Prevent recurrent bleeding
Continued bleeding
Blockers in conjunction
with endoscopic Balloon tamponade
sclerotherapy/band ligation
Effective
Effective Ineffective Continued bleeding
Transjugular intrahepatic TIPS or surgical

Effective
portal-systemic shunt (TIPS) portal-systemic shunt
Ineffective Continued bleeding
Surgical shunt or Surgical shunt or

liver transplantation liver transplantation
Non-alcoholic fatty liver disease begins with asymptomatic A third autosomal recessive genetic disease is 1-antitrypsin
fatty liver but may progress to cirrhosis. This is a disease of deciency. Abnormalities in the 1-antitrypsin protein impair
exclusion; elimination of any possible viral, genetic, or envi- secretion from the liver. 1-Antitrypsin deciency causes cir-
ronmental causes must be made prior to making this diagnosis. rhosis in children as well as adults; adults usually have concomi-
Non-alcoholic fatty liver disease is related to numerous meta- tant pulmonary disease such as chronic obstructive pulmonary
bolic abnormalities. Risk factors include diabetes mellitus, disease.
dyslipidemia, obesity, and other conditions associated with
increased hepatic fat.26
Hereditary hemochromatosis is an autosomal recessive dis-
ease of increased intestinal iron absorption and deposition in
hepatic, cardiac, and pancreatic tissue. Hepatic iron overload
Diagnosis of Cirrhosis
results in the development of brosis, hepatic scarring, cir-
rhosis, and hepatocellular carcinoma. Hemochromatosis can In some cases, cirrhosis is diagnosed incidentally before the
also be caused by repeated blood transfusions, but this mech- patient develops symptoms or acute complications. Other
anism rarely leads to cirrhosis. patients may have decompensated cirrhosis at initial presenta-
Wilsons disease is another autosomal recessive disease lead- tion; they may present with variceal bleeding, ascites, SBP, or
ing to cirrhosis. Protein abnormalities result in excessive copper HE. Patients may also have some of the laboratory abnormali-
deposition in body tissues. The faulty protein is responsible for ties and/or signs and symptoms listed above that are associated
facilitating copper excretion in the bile, so copper accumulates with cirrhosis.28
in hepatic tissue. High copper levels within hepatocytes are Ultrasound examination is used routinely to evaluate cir-
toxic, and brosis and cirrhosis may develop in untreated rhosis; a small, nodular liver with increased echogenicity is
patients. Those with Wilsons disease usually present with symp- consistent with cirrhosis. Liver biopsy is the only way to diag-
toms of liver or neurologic disease while still in their teens. nose cirrhosis denitively, but it is often deferred in lieu of a
TABLE 191. Child-Pugh and MELD Classications for portal hypertension. The differential diagnoses for SAAG val-
Determining Severity of Liver Damage ues less than 1.1 g/dL (less than 11 g/L) include peritoneal car-
cinoma, peritoneal infection (tuberculosis, fungal, or
Child-Pugh
Classicationa
cytomegalovirus), and nephrotic syndrome. Serum albumin
Variable 1 Point 2 Points 3 Points measurements should be made at the same time ascitic uid is
obtained for an accurate comparison.22
Bilirubin (mg/dL) Less than 2 23 Greater than 3
(mol/L) Less than 34 3451 Greater than 51
Albumin (g/dL) Greater than 3.5 2.83.5 Less than 2.8
(g/L) Greater than 35 2835 Less than 28 TREATMENT OF CIRRHOSIS, PORTAL
Prothrombin time 13 46 Greater than 6 HYPERTENSION, AND COMPLICATIONS
(seconds
prolonged)
Ascites None Slight Moderate
Desired Outcomes
Encephalopathy None Stages 12 Stages 34 Recognizing and treating the cause of cirrhosis is paramount.
MELD Classication Cirrhosis is irreversible; treatments are directed at limiting
The formula for the MELD score is 3.8 loge [bilirubin (mg/dL)] +
disease progression and minimizing complications. The imme-
11.2 loge (INR) + 9.6 loge [creatinine (mg/dL)] + 6.4
(etiology: 0 if cholestatic or alcoholic, 1 otherwise). diate treatment goals are to stabilize acute complications such
as variceal bleeding and prevent spontaneous bacterial peri-
a
Class A: 16 total points; B: 79 points; C: 1015 points. tonitis. Once life-threatening conditions have stabilized, the
INR, International Normalized Ratio; MELD, Model for End-Stage Liver
Disease. focus shifts to preventing complications and preventing further
liver damage. Complication prevention involves both primary
presumptive diagnosis since it is an invasive procedure. The and secondary prophylaxis. To determine appropriate prophy-
decision to perform a biopsy is based on the expected clinical lactic therapy, a careful analysis of patient characteristics and
utility of the biopsy results. If the results could change the disease history is mandatory. The sections that follow concen-
course of treatment, it may be advisable to perform a biopsy. trate on treatment and prevention of cirrhotic complications.
The Child-Pugh and Model for End-Stage Liver Disease
(MELD) classication systems (Table 191) are used to clas- Nonpharmacologic Therapy
sify disease severity and evaluate the need for transplantation.
Patients with ascites or known varices must be assumed to Lifestyle modications can limit disease complications and
have portal hypertension and are treated as such, even if slow further liver damage. Avoidance of additional hepatic
direct measurements of portal pressure have not been insult is critical for successful cirrhosis treatment. The only
made.29 proven treatment for alcoholic liver disease is the immediate
cessation of alcohol consumption. Patients who have cirrhosis
Diagnosis of Ascites from etiologies other than alcoholic liver disease should also
abstain from alcohol consumption to prevent further liver
In obese patients or those with only small amounts of uid damage.
accumulation, ultrasound evaluation may be necessary to All patients with ascites require counseling on dietary
detect ascites with certainty. sodium restriction. Salt intake should be limited to less than
Analysis of ascitic uid obtained during paracentesis pro- 800 mg sodium (2 g sodium chloride) per day. More stringent
vides diagnostic clues to the etiology of the ascites. Diagnostic restriction may cause faster mobilization of ascitic uid, but
evaluation should include cell count with differential, albumin, adherence to such strict limits is very difcult. Patients usually
total protein, Gram stain, and bacterial cultures. In patients respond well to sodium restriction accompanied by diuretic
without an established diagnosis of liver disease, the serum- therapy.14,22,31,32 The goal of therapy is to achieve urinary
ascites albumin gradient (SAAG) is sensitive in determining if sodium excretion of at least 78 mEq (78 mmol) per day.22 While
the ascites is caused by portal hypertension.22 SAAG compares a 24-hour urine collection provides this information, a spot
the serum albumin concentration to the ascitic uid albumin urine sodium/ potassium ratio greater than 1.0 provides the
concentration: same information and is much less cumbersome to perform.
Medication use must be monitored carefully for potential
Albserum Albascites = SAAG hepatotoxicity. Hepatically metabolized medications have the
potential to accumulate in patients with liver disease. Little
A value of greater than or equal to 1.1 g/dL (greater than or guidance is available on drug dosing in hepatic impairment
equal to 11 g/L) identies portal hypertension as the cause of because these patients are often excluded from drug trials.
the ascites with 97% accuracy.22,30 In portal hypertension Daily acetaminophen use should not exceed 2 g. Dietary sup-
the ascitic uid is low in albumin; this balances the oncotic plements have not been well studied in hepatic impairment
pressure gradient with the hydrostatic pressure gradient of and cannot be recommended.
be a useful adjuvant to pharmacologic therapy, but long-term

Patient Encounter 1, Part 1 protein restriction in cirrhotic patients is not recommended.
These patients are already in a nutritionally decient state, and
prolonged protein restriction will exacerbate the problem.20
Vaccination against hepatitis A and B is recommended in
ES is a 44-year-old man who presents to the emergency
patients with underlying cirrhosis to prevent additional liver
department with complaints of abdominal pain.
damage from an acute viral infection.35 Pneumococcal and
Chief complaint inuenza vaccination may also be appropriate and can reduce
My belly feels tight
hospitalizations due to inuenza or pneumonia.
HPI Endoscopic band ligation and sclerotherapy are both means
Increasing feelings of fullness and abdominal tightness that to stop acutely bleeding varices. Endoscopic band ligation is the
have become noticeable over the past 2 weeks, accompanied application of a stricture around the varix, whereas sclerotherapy
by nausea without vomiting and decreased food intake
involves injecting the varix with substances designed to decrease
PMH blood ow to the area and prevent rebleeding. Endoscopic band
Hypertension 15 years, acute pancreatitis 2 episodes ligation has replaced sclerotherapy as the preferred endoscopic
PSH treatment and is effective in stopping acute variceal bleeding in
No surgeries up to 90% of patients.36 It is the standard of care for secondary
SH prophylaxis of repeat bleeding in patients with a history of either
Married, currently separated; denies tobacco and illicit drug esophageal or gastric variceal bleeding. Endoscopic band ligation
use; typically drinks a 12-pack of beer daily and several shots is best used in conjunction with pharmacologic treatment.3739
of tequila; use has recently increased due to depression over Balloon tamponade involves the application of direct pressure
marital separation to the area of bleeding with an inatable balloon attached to a
FH nasogastric tube. It is an option for patients in whom drug
Father died at age 45 from coronary disease, mother alive therapy and band ligation fail to stop variceal bleeding. Balloon
at age 62 with type 2 diabetes mellitus, hypertension, tamponade is used only when other methods have failed.
hyperlipidemia, and gastroesophageal reux disease Once the direct pressure of the balloon is removed, rebleeding
Outpatient Meds often occurs, so balloon tamponade is only a temporary measure
Chlorthalidone 25 mg daily prior to more denitive treatment such as shunting.11
ROS Shunts are long-term solutions to decrease elevated portal
(+) Anorexia and nausea; denies vomiting, constipation, or pressure. They divert blood ow either through or around the
diarrhea; patient endorses moderate shortness of breath and diseased liver, depending on the location and type of shunt
dyspnea on exertion employed. Transjugular intrahepatic portosystemic shunts
PE (TIPS) create a communication pathway between the intrahep-
VS: Blood pressure 125/75 mm Hg, pulse 84 beats per atic portal vein and the hepatic vein. TIPS procedures have an
minute, temperature 37.3C (99.1F), respiratory rate advantage over surgically-inserted shunts because they are
18/minutes, oxygen saturation 98% on room air placed through the vascular system rather than through an inva-
CV: RRR, no murmurs, rubs, or gallops sive surgical procedure, but they still carry a risk of bleeding and
Chest: CTA bilaterally, no crackles or wheezes infection. TIPS placement is also associated with an increased
Abd: Tense, distended abdomen that is tender to palpation, incidence of hepatic encephalopathy.40 This results from
decreased bowel sounds, (+) hepatosplenomegaly decreased detoxication of nitrogenous waste products because
Exts: 2+ pedal pulses, 2+ pitting edema
the shunt allows blood to evade metabolic processing.
What are this patients risk factors for liver disease?
Identify features of his presentation that are consistent
with cirrhosis. Drug therapy for portal hypertension and cirrhosis can allevi-
ate symptoms and prevent complications but it cannot reverse
cirrhosis. Drug therapy is available to treat the complications
In patients with variceal bleeding, nasogastric suction of ascites, varices, spontaneous bacterial peritonitis, hepatic
reduces the risk of aspirating stomach contents. Aspiration encephalopathy, and coagulation abnormalities.
pneumonia is a major cause of death in patients with variceal
bleeding. Nasogastric suction is also helpful in decreasing Portal Hypertension
vomiting during acute episodes of variceal bleeding.33,34 Blood Non-selective b-blockers such as propranolol and nadolol
within the gastrointestinal tract is very nauseating; removal of are rst-line treatments to reduce portal hypertension. This
the blood can decrease vomiting. effect reduces bleeding and decreases mortality in patients
In acute hepatic encephalopathy, temporary protein with known varices. Use of -blockers to prevent variceal for-
restriction to decrease the rate of ammonia production can mation is controversial.
Only non-selective -blockers reduce bleeding complica- -blockers either alone or in combination may be intolerable
tions in patients with known varices. Blockade of 1 receptors for many patients with cirrhosis.
reduces cardiac output and splanchnic blood ow. 2-
Adrenergic blockade prevents 2-receptormediated splanch- Ascites
nic vasodilation while allowing unopposed -adrenergic The goals of treating ascites are to minimize acute discom-
effects; this enhances vasoconstriction of both the systemic fort, re-equilibrate ascitic uid, and prevent SBP. Treatment
and splanchnic vascular beds. The combination of 1 and 2 should modify the underlying disease pathology; without directed
effects makes the non-selective -blockers preferable to car- therapy, uid will rapidly re-accumulate.
dioselective agents in treating portal hypertension.1,36,41 In the case of tense ascites, relief of acute discomfort may be
Because -blockers decrease blood pressure and heart rate, accomplished by therapeutic paracentesis. Often the removal of
they should be started at low doses to increase tolerability. just 1 to 2 L of ascitic uid provides relief of pain and fullness.
Propranolol is hepatically metabolized, and its half-life and When removing 5 L or more of uid at once, volume resuscita-
pharmacologic effects are prolonged in portal hypertension. A tion with 8 to 10 g of albumin given intravenously should be
reasonable starting dose of propranolol is 10 mg two to three provided for each liter of uid removed. If less than 5 L of uid
times daily. is removed in a hemodynamically stable patient, albumin is not
Doses should be titrated as tolerated with the goal of warranted.22
decreasing heart rate by 25% or to approximately 55 to
60 beats/minute.11,36 Heart rate is not an accurate marker for Diuretics
portal pressure reduction, but it is the accepted surrogate Diuretics are often required in addition to the sodium restric-
marker for effectiveness because there are no other acceptable tion described previously. Spironolactone and furosemide form
alternatives. the basis of pharmacologic therapy for ascites. Spironolactone is an
Nitrates have been suggested in patients who do not achieve aldosterone antagonist and counteracts the effects of activation of
therapeutic goals (heart rate reduction) with -blocker therapy the renin-angiotensin-aldosterone system. In hepatic disease not
alone. Trials to evaluate the effects of nitrates (e.g., isosorbide only is aldosterone production increased, but its half-life is pro-
mononitrate) on portal pressure, both alone and in combination longed because it is hepatically metabolized. Spironolactone acts
with -blockers, show enhanced reduction of portal pressure; to conserve the potassium that would be otherwise excreted
however, there is an increase in mortality when nitrates are used because of elevated aldosterone levels.
alone. Adverse effects are signicantly higher in patients treated Spironolactone is usually used in combination with a loop
with the combination of non-selective -blockers and nitrates diuretic (e.g., furosemide) for more potent diuresis. A ratio of
as opposed to -blocker monotherapy.42,43 Unfortunately, 40 mg furosemide (the most commonly used loop diuretic) to
In the emergency department, a chest x-ray was normal. The following laboratory test results were
obtained:
Sodium 128 mEq/L (mmol/L) Platelets 178 103/mm3 ( 109/L)

Potassium 3.1 mEq/L (mmol/L) Albumin 2.7 g/dL (27 g/L)
Chloride 106 mEq/L (mmol/L) Total bilirubin 2.3 mg/dL (39.3 mol/L)
Bicarbonate 24 mEq/L (mmol/L) Alk phos 177 IU/L (2.95 Kat/L)
BUN 27 mg/dL (9.64 mmol/L) AST 443 IU/L (7.38 Kat/L)
Scr 1.1 mg/dL (97.2 mol/L) ALT 206 IU/L (3.43 Kat/L)
Glucose 145 mg/dL (8.05 mmol/L) INR 1.6
Hemoglobin 12.5 g/dL (7.75 mmol/L) GGT 185 IU/L (3.1 Kat/L)
Hematocrit 38% (0.38) LDH 203 IU/L (3.38 Kat/L)
WBC count 7.4 103/mm3 ( 109/L) PT 29 seconds
Which of these values are consistent with the diagnosis of cirrhosis?

Does the current presentation imply the underlying cause of the disease?
Are the laboratory results suggestive of complications related to cirrhosis?
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; INR,
international normalized ratio; LDH, lactate dehydrogenase; PT, prothrombin time.
which limits its usefulness. The recommended octreotide dose

Patient Encounter, Part 3 is a 50- to 100-mcg intravenous (IV) loading dose followed by
a continuous IV infusion of 25 to 50 mcg/hour. Therapy
should continue for at least 24 to 72 hours after bleeding has
stopped. Some clinicians continue octreotide for a full 5 days
ES is found to have ascites. Therapeutic paracentesis is
ordered to relieve shortness of breath and abdominal pain; since this is the time frame during which the risk of rebleeding
4 L of ascitic uid is removed. is highest. Octreotide combined with endoscopic therapy results
in decreased rebleeding rates and transfusion needs when com-
What are the goals for treating ascites in this patient? pared to endoscopic treatment alone.36
What lifestyle modications should the patient make that
may decrease his risk of hospitalization and death from Spontaneous Bacterial Peritonitis
cirrhosis? Initiation of prophylactic antibiotics is recommended during
What pharmacologic options are available to treat ascites acute variceal bleeding; this is typically done with an oral uo-
in this patient? roquinolone (e.g., ciprooxacin 500 mg twice daily 7 days) or
an IV third-generation cephalosporin. Prophylactic antibiotic
therapy reduces in-hospital infections and mortality in patients
hospitalized for variceal bleeding.44
each 100 mg spironolactone usually maintains serum potas- If the presence of SBP is suspected, empiric antibiotic
sium concentrations within the normal range. Therapy is therapy with a broad-spectrum anti-infective agent should
commonly initiated with oral spironolactone 100 mg and be initiated until cultures and susceptibilities are available
furosemide 40 mg per day. (Fig. 195).45,46 In the setting of presumed infection, delaying
Doses should be titrated at intervals no more frequent than
every 2 to 3 days. Because spironolactone is used for its anti-
aldosterone effects, much higher doses (up to 400 mg/day) are Patient Encounter, Part 4
used than those used when treating hypertension. If intolerable
side effects such as gynecomastia occur with spironolactone,
other potassium-sparing diuretics may be used, but clinical ES is brought to the emergency department by ambulance
trials have not shown equivalent efcacy.22 2 months after the initial presentation.
The target in treating ascites is to effect a uid loss of approx-
Chief complaint
imately 0.5 L per day.22 Because ascites equilibrates with vascular Ive been vomiting black stuff and Im really tired
uid at a much slower rate than does peripheral edema, aggres-
HPI
sive diuresis is associated with intravascular volume depletion
Hematemesis for the past 2 days, worsening today and
and should be avoided unless patients have concomitant peri- accompanied by profound weakness; patient is continuing
pheral edema. Patients with peripheral edema in addition to to drink alcohol at the same rate
ascites may require increasing furosemide doses until euvolemia
Outpatient Meds
is achieved; intravenous diuretics are often necessary.22 Diuretic Spironolactone 100 mg daily
therapy in cirrhosis is typically lifelong.
Furosemide 40 mg daily
ROS
Varices (+) Nausea, coffee-grounds emesis, and melena; denies con-
Unfortunately, active variceal bleeding is common; it accounts stipation or diarrhea; (+) bilateral lower extremity edema
for between 10% and 30% of all cases of upper GI hemor- PE
rhage. During acute variceal hemorrhage, crucial desired VS: Blood pressure 98/60 mm Hg, pulse 122 beats per
outcomes include controlling bleeding, preventing rebleeding, minute, temperature 37.1C (98.8F), respiratory rate
and avoiding acute complications such as SBP; mortality from 21/minutes, oxygen saturation 91% on room air
rst bleeding episode is up to 55%, and patients must by treated CV: Tachycardia, no murmurs, rubs, or gallops
aggressively. A treatment algorithm for acute variceal bleeding Chest: CTA bilaterally
is depicted in Fig. 193. Abd: Mildly distended, tender to deep palpation, decreased
bowel sounds, (+) hepatosplenomegaly and fecal occult
blood test
Octreotide Exts: Decreased pedal pulses, 3+ pitting edema
Octreotide is a synthetic analogue of somatostatin; it selec-
tively causes vasoconstriction of the splanchnic bed, decreasing What are the immediate treatment goals for ES?
portal venous pressure with few serious side effects. Vaso- Does this presentation warrant prophylaxis to prevent
pressin has been used, but since it causes non-selective vaso- further disease complications?
constriction, it carries the risk of systemic consequences,
identied, antibiotic coverage can be narrowed to an agent

Initial Evaluation: Identify Precipitants and Correct if Possible
that is highly active against that organism.
Diagnostic paracentesis: Cell count SBP has been associated with development of signicant
Culture and Gram stain renal failure. Treatment with intravenous albumin can mit-
Albumin (serum albumin)*
igate these effects when dosed at 1.5 g/kg of body weight
initially, followed by 1 g/kg of body weight on day three of
therapy.47
Large volume paracentesis If Gram stain positive
(albumin)
Initial control
or PMN greater than
250/L: Presumptive
Patients who have previously experienced spontaneous
diagnosis of SBP bacterial peritonitis and have low-protein ascites (ascitic uid
maintenance albumin less than 1 g/dL [less than 10 g/L]) are candidates for
long-term prophylactic therapy. Recommended regimens
Begin antibiotic include either a single trimethoprim-sulfamethoxazole double-
Na restriction (less than (e.g., cefotaxime 2 g strength tablet 5 days per week (Monday through Friday) or
2 g/day) (fluid restriction IV q 812 hours
if Na less than 120 meq/L) for 510 days) ciprooxacin 750 mg once weekly.19,46 Any patient who has
experienced an episode of variceal bleeding should also receive
Inadequate
(Change coverage
prophylactic antibiotics.
Spironolactone 100 mg/day
according to culture
furosemide 40 mg/day
result)
(escalate up to 400 mg/day Encephalopathy
and 160 mg/day)
Inadequate
Lactulose
Monitor serum and
urine electrolytes,
Lactulose is the foundation of pharmacologic therapy to pre-
BUN, creatinine vent and treat hepatic encephalopathy. It is a non-digestible syn-
Consider: TIPS thetic disaccharide laxative that is hydrolyzed in the gut to an
Peritoneovenous shunt
Add furosemide Liver transplantation
osmotically-active compound that draws water into the colon and
or hydrochlorothiazide stimulates defecation. Lactulose also lowers colonic pH, which
favors the conversion of ammonia (NH3) to ammonium (NH4+).48
FIGURE 195. Approach to the patient with ascites and spon- Ammonium is ionic and cannot cross back into systemic circula-
taneous bacterial peritonitis (SBP). tion; it is eliminated in the feces. Lactulose is usually initiated at 15
*
If PMN greater than 250/L but culture is negative (culture-
to 30 mL two to three times per day and titrated to a therapeutic
negative neutrocytic ascites) begin empiric antibiotics and
retap after 48 hours. If culture is positive but PMN less than goal of two to four soft bowel movements daily.20,49,50
250/L, treat as if PMN greater than 250/L (presumed SBP). If
polymicrobial infection exists, exclude SBP.
BUN, blood urea nitrogen; IV, intravenous; Na, sodium; PMN
polymorphonuclear leukocyte; TIPS, transjugular intrahepatic
portosystemic shunt. (From Chung RT, Podolsky DK. Cirrhosis
and its complications. In: Kasper DL, Braunwald E, Fauci AS,
et al, (eds.) Harrisons Principles of Internal Medicine. 16th ed.
New York: McGraw-Hill, 2005: 18581869, with permission.)
During the hospital stay, ES had endoscopic band ligation to
treat esophageal and gastric varices. Propranolol 20 mg three
times a day was initiated; IV furosemide 60 mg twice daily
resolved the pedal edema. Prescriptions for spironolactone
200 mg daily and furosemide 40 mg twice daily were pro-
treatment while awaiting laboratory conrmation is inappro- vided at discharge. Three weeks later, ES is brought to clinic by
priate and may result in death. The initial antibiotic should be his daughter who states that he is confused and doesnt seem
an intravenous third-generation cephalosporin (e.g., cefotaxime like himself. She is unsure if he has been taking his medica-
2 g every 48 hours, ceftriaxone 2 g every 24 hours), an intra- tion but says he continues to drink and has been eating poorly.
venous extended-spectrum penicillin (e.g., piperacillin
What are the presenting signs and symptoms of hepatic
tazobactam 3.375 g every 6 hours or 4.5 g every 8 hours), or encephalopathy?
an oral uoroquinolone (e.g., levooxacin 500 mg every day), What factors could contribute to hepatic encephalopathy
since these agents cover the most common gram-negative and in this patient?
gram-positive agents. Third-generation cephalosporins are What is the prognosis for this patient who has developed
usually recommended as rst-line therapy; uoroquinolones ascites, variceal bleeding, and hepatic encephalopathy
are used if resistant (extended-spectrum -lactamase positive) within 3 months?
organisms are suspected. Once an infectious agent has been
Flumazenil
Evidence for the false transmitter theory as the cause of Patient Care and Monitoring
encephalopathy is demonstrated by the fact that administration
of umazenil (a benzodiazepine antagonist) has resulted in func-
tional improvement. Unfortunately, long-term benet has not
1. Obtain a complete history of alcohol intake and hepato-
been shown, and since umazenil can only be administered par-
toxic drug use, including over-the-counter products and
enterally, it is not an appropriate choice for long-term therapy. dietary supplements.
2. At each encounter, ask the patient specic questions
Coagulation Abnormalities about adherence to prescribed therapy, dietary restric-
Vitamin K is an essential factor in the production of coagula- tions and cessation of alcohol intake.
tion proteins within the liver. Elevated clotting times from 3. At each visit, evaluate the pharmacotherapy regimen for
decreased protein synthesis are indistinguishable from those appropriate drug choice and dose, non-prescription drug
produced by low vitamin K levels caused by malnutrition or use, adverse effects, and use of potentially hepatotoxic
poor intestinal absorption. Vitamin K (phytonadione) 10 mg medications.
subcutaneously daily for 3 days can help to establish whether 4. Question the patient about adverse effects, since hepati-
the prolonged bleeding time results from loss of synthetic cally metabolized medications may accumulate and
function in the liver or vitamin K deciency. cause adverse effects.
5. Consider antibiotic prophylaxis for SBP in patients with a
history of variceal bleeding or prior SBP.
OUTCOME EVALUATION 6. Conduct a review of systems and physical examination at
each visit to determine if the patient has had progression
Re-evaluate the pharmacotherapy regimen at each visit to of complications.
assess effectiveness, adverse events, and need for drug titration. 7. Ask specic questions about bleeding, bruising, and
Assess the effectiveness of -blocker therapy by measuring fatigue. There is a direct link between loss of synthetic
heart rate. Heart rate reduction of 25% from baseline or to 55 function and disease progression.
to 60 beats/minute is desirable. Ask the patient specic, 8. Refer the patient to substance abuse counseling for edu-
directed questions regarding adverse effects of -blockers; cation about alcohol cessation if appropriate.
inquire about symptoms of orthostatic hypotension (e.g., 9. Provide education regarding dietary sodium restrictions
lightheadedness, dizziness, or fainting). at each visit; consider a referral to a dietician if
Evaluate effectiveness of diuretic therapy with regard to appropriate.
ascitic uid accumulation and development of peripheral
edema. Ask the patient directed questions about abdominal
girth, fullness, tenderness, and pain. Weigh the patient at each ABBREVIATIONS
visit, and ask the patient to keep a weight diary. Assess for
peripheral edema at each visit. ADH: alcohol dehydrogenase
Measure spot urine sodium/potassium ratio to assess adher- ALT: alanine aminotransferase
AST: aspartate aminotransferase
ence to dietary sodium restrictions.
Assess dietary sodium intake by patient food recall or by spot
CYP: cytochrome P-450 isoenzyme
urine sodium/potassium ratio for appropriate sodium excretion. GGT: -glutamyl transpeptidase
Obtain complete blood count and PT/INR to assess for ane- GI: gastrointestinal
mia, thrombocytopenia, or coagulopathy. Ask about increases HE: hepatic encephalopathy
in bruising, bleeding, or development of hematemesis, hema- INR: International Normalized Ratio
tochezia, or melena to assess for bleeding. IV: intravenous
Review biopsy reports and laboratory data. Transaminases LDH: lactate dehydrogenase
and blood ammonia levels do not correlate well with disease MELD: Model for End-Stage Liver Disease
progression, but increased coagulation times are markers of NG: nasogastric
loss of synthetic function. NH3: ammonia
NH4+: ammonium
Evaluate for signs and symptoms of hepatic encephalopathy.
PT: prothrombin time
Mental status changes may be subtle; questioning family
SAAG: serum-ascites albumin gradient
members or caregivers about confusion or personality changes SBP: spontaneous bacterial peritonitis
may reveal mild hepatic encephalopathy even if the patient is TIPS: transjugular intrahepatic portosystemic shunt
unaware of the decits.
In patients taking lactulose therapy, titrate the dose to two to Reference lists and self-assessment questions and answers are
four soft bowel movements daily. available at www.ChisholmPharmacotherapy.com.
Log into the website: www.pharmacotherapyprinciples.com Lubel JS, Angus PW. Modern management of portal hypertension.
for information on obtaining continuing education credit for Int Med J 2005;35:4549.
this chapter. Martin PY, Gines P, Schrier RW. Nitric oxide as a mediator of hemo-
dynamic abnormalities of sodium and water retention in cir-
rhosis. N Engl J Med 1998;339:533541.
Rimola A, Garcia-Tsao G, Navasa M, et al. Diagnosis, treatment
KEY REFERENCES AND READINGS and prophylaxis of spontaneous bacterial peritonitis: a con-
sensus document. J Hepatol 2000;32:142145.
Blei AT, Cordoba J, and the Practice Parameters Committee of the Runyon BA. American Association for the Study of Liver Diseases
American College of Gastroenterology. Hepatic encephalopathy (AASLD) Practice Guideline: Management of adult patients
practice guidelines. Am J Gastroenterol 2001;96:19681976. with ascites due to cirrhosis. Hepatology 2004;39:841856.
Gines P, Cardena A, Arroyo V, Rodes J. Management of cirrhosis and Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage.
ascites. N Engl J Med 2004;350:16461654. N Engl J Med 2001;345:669681.
20 PANCREATITIS
Joseph J. Kishel
LEARNING OBJECTIVES
1. Describe the pathophysiology of acute and chronic pancreatitis.

2. Differentiate the signs and symptoms of acute from chronic pancreatitis.
3. Discuss the clinical implications of pancreatic uid collections, pancreatic abscess, and
pancreatic necrosis in acute pancreatitis.
4. Formulate care plans for managing acute pancreatitis.
5. Identify pharmacologic and nonpharmacologic means of preventing repeat episodes of
chronic pancreatitis.
6. Choose appropriate pancreatic enzyme supplementation for patients with chronic
pancreatitis.
KEY CONCEPTS juice that contains various digestive enzymes. These enzymes are
produced and stored as inactive proenzymes within zymogen
The most common causes of acute and chronic pancreatitis in granules to prevent autolysis and digestion of the pancreas. The
adults are ethanol abuse and biliary stones. zymogen granules are also responsible for enzyme transport to
Pancreatic necrosis occurs within the rst 2 weeks of acute the pancreatic duct. Amylase and lipase are released from the
pancreatitis and develops in 10% to 30% of patients with zymogen granules in the active form whereas the proteolytic
acute pancreatitis. enzymes are activated in the duodenum by enterokinase.
Primary therapy for acute pancreatitis is supportive, with uid Enterokinase triggers the conversion of trypsinogen to the
repletion, discontinuation of oral intake, and analgesia. active protease, trypsin. Trypsin then activates the other proen-
Medications aimed at decreasing pancreatic enzyme release zymes to their active enzymes.
(e.g., somatostatin), nasogastric suction, and anticholinergic The pancreatic juice is released through the ampulla of
medications have all failed to show benet in the treatment of Vater into the duodenum to aid in the digestive process as well
acute pancreatitis. as buffer acidic uid released from the stomach (Fig. 201).
Treatment of chronic pancreatitis is aimed at removing the The pancreas contains a trypsin inhibitor to prevent autolysis.
cause (ethanol abuse or biliary stones), providing analgesia,
supplementing with pancreatic enzyme preparations, and
ACUTE PANCREATITIS
implementing dietary restrictions.
Long-term sequelae of chronic pancreatitis include dietary
malabsorption, impaired glucose tolerance, cholangitis, and
potential addiction to opioid analgesics. In the Western hemisphere, acute pancreatitis is caused
mainly by ethanol use/abuse and gallstones. Other common
The pancreas is a gland in the abdomen lying in the curvature causes of acute pancreatitis include hypertriglyceridemia,
of the stomach as it empties into the duodenum. The pancreas endoscopic retrograde cholangiopancreatography (ERCP),
functions primarily as an exocrine gland, although it also has and autodigestion due to early activation of pancreatic
endocrine function. The exocrine cells of the pancreas are called enzymes. Numerous medications have also been implicated as
acinar cells. They produce an alkaline uid known as pancreatic causes of acute pancreatitis (Table 201).
337
Autolysis of the pancreas can occur when zymogens are

Right hepatic duct Left hepatic duct
activated in the pancreas before being released into the duo-
Cystic duct
denum. Acute pancreatitis can result from the initial injury to
Common hepatic duct
the zymogen-producing cells, which is followed by neutrophil
Common bile duct invasion of the pancreas, and that ends in further activation of
Gallbladder
enzymes within the pancreas. This cascade of events can be
destructive to the pancreas and harmful to the patient.
Acute pancreatitis can progress to several distinct conse-
Pancreas quences. Pancreatic uid collections and pancreatic abscesses
can form during the course of acute pancreatitis. Pancreatic
necrosis can occur when pancreatic enzymes damage the pan-
Accessory
pancreatic duct
creatic tissue or when pancreatic abscesses become secondarily
Main pancreatic duct
infected. This infection is usually due to bacteria that are nor-
mally found in the gastrointestinal tract, including Escherichia
Duodenum
Ampulla of Vater coli, Enterobacteriaceae, Staphylococcus aureus, viridans group
streptococci, and anaerobes.
FIGURE 201. Anatomic structure of the pancreas and biliary
tract. (From Berardi RR, Montgomery PA. Pancreatitis. In:
DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Clinical Presentation and Diagnosis
Pathophysiologic Approach. 6th ed. New York: McGraw-Hill;
2005: 722, with permission.) Patients at greatest risk for mortality from acute pancreatitis
are those who have multi-organ failure (e.g., hypotension, res-
piratory failure, or renal failure), pancreatic necrosis, obesity,
Pathophysiology volume depletion, greater than 70 years of age, and an elevated
Ethanol abuse may cause precipitation of pancreatic enzymes APACHE II score.3,4 The Acute Physiology, Age, and Chronic
in the ducts of the pancreas leading to chronic inammation Health Evaluation (APACHE) II score is a rating scale of disease
and damage. Ethanol itself may be directly toxic to the pan- severity in critically ill patients.
creatic cells. Gallstones may obstruct the ampulla of Vater A patient with acute pancreatitis may develop many severe
causing pancreatic enzymes or bile to move in a retrograde local and systemic complications. Local complications involve
fashion into the pancreas.1 uid collection, necrosis, or abscess in the pancreas. A pancreatic
uid collection (or pancreatic pseudocyst) is a collection of tis-
sue, pancreatic enzymes, and blood that forms weeks after acute
TABLE 201. Selected Medications Associated with Acute
pancreatitis. Many pancreatic pseudocysts resolve spontaneously,
Pancreatitis
but some require surgical drainage.5 Rupture of a pancreatic
Denite Association Probable Association pseudocyst with associated erosion and hemorrhage of major
5-Aminosalicylic acid Ampicillin
abdominal blood vessels can have a mortality approaching 60%;
Asparaginase Angiotensin-converting enzyme thus, continued monitoring of a pseudocyst is prudent.6
Azathioprine inhibitors Pancreatic necrosis is a diffuse inammation of the pan-
Didanosine Bumetamide creas with infectious etiology. Pancreatic necrosis occurs
Estrogens Calcium within the rst 2 weeks of acute pancreatitis and develops in
Furosemide Chlorthalidone
Mercaptopurine Cimetidine
10% to 30% of patients with acute pancreatitis. The necrotic
Methyldopa Cisplatin pancreas can become secondarily infected with enteric gram-
Metronidazole Clozapine negative bacteria (such as E. coli), and disseminated infection
Pentamidine Corticosteroids may result from pancreatic necrosis.7,8
Sulfonamides Cytarabine Pancreatic abscess is a collection of pus that forms in the pan-
Sulindac Ethacrynic acid
Tetracycline Ifosfamide
creas 4 to 6 weeks after acute pancreatitis. Pancreatic abscess is
Thiazides Interferon alfa-2b usually less life-threatening than pancreatic necrosis or pancreatic
Valproic acid/salts Losartan pseudocyst and can be managed with percutaneous drainage.5
Meglumine antimoniate Systemic complications can affect virtually any organ system
Piroxicam but tend to target the pulmonary and cardiovascular systems
Procainamide
Salicylates
and the kidneys. Multi-organ failure is a poor prognostic indi-
Sodium stibogluconate cator. Acute respiratory distress syndrome (ARDS) is a life-
Zalcitabine threatening syndrome of acute lung injury with resulting
hypoxia. ARDS may be due to the systemic release of pancreatic
(From Berardi RR, Montgomery PA. Pancreatitis. In: DiPiro JT, Talbert RL,
Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. enzymes causing destruction of pulmonary surfactant, which
6th ed. New York: McGraw-Hill; 2005:723, with permission.) is required for proper lung function.9 Circulating pancreatic
CHAPTER 20 / PANCREATITIS 339
enzymes can cause cardiovascular shock. Acute renal failure

Clinical Presentation of Acute may result from hypovolemia and hyperkalemia.10
Pancreatitis
Diagnosis
Symptoms Diagnosis of acute pancreatitis is based on the patients history
Abdominal pain radiating to the back is the most com-
and presenting signs and symptoms. Evaluation of laboratory
mon presenting symptom. Pain can be due to intestinal
results, specically the serum amylase and lipase, aids in diag-
immobility or chemical peritonitis induced by pancreatic
enzymes. nosis. Serum amylase is elevated early in the disease process
Other common symptoms include nausea, vomiting, and but may return to normal within 12 hours.10 Serum lipase will
abdominal pain. remain elevated for days after the acute event and may lend
itself more to the diagnosis depending on when the patient
Signs presents for evaluation.11
Tachycardia, hypotension, fever, and abdominal disten- The patients history will identify risk factors for acute pan-
tion may be present.
creatitis, such as age greater than 70 years or history of alcohol
There may be a positive Cullens sign (bluish discol-
abuse. Finally, computed tomography (CT) scan or ultrasound of
oration of the periumbilical skin indicating blood in the
peritoneum). the abdomen can help to identify pancreatic uid collections.12
After 2 to 3 days of acute hemorrhagic pancreatitis,
there may be a positive Turners sign [local areas of Treatment
discoloration (bruising) and induration of the skin near
the umbilicus due to extravasation of blood]. Desired Outcomes
The goals of treatment for acute pancreatitis include: (1) reso-
Laboratory Tests
lution of nausea, vomiting, abdominal pain, and fever; (2) abil-
The serum amylase can be elevated three times the upper
ity to tolerate oral intake; (3) normalization of serum amylase,
limit of normal within the rst 12 hours of the onset of
acute pancreatitis. The degree of elevation does not pre- lipase, and white blood cell count; and (4) resolution of abscess,
dict the severity of disease. pseudocyst, or uid collection as measured by CT scan.
As acute pancreatitis progresses, the serum lipase can
also become elevated.2 Nonpharmacologic Therapy
Other possible laboratory abnormalities include elevated Many medications can precipitate an attack of acute pancre-
white blood cell count, hyperglycemia, hypocalcemia, atitis. If a medication is determined to be the cause of acute
hyperbilirubinemia, elevated serum lactate dehydroge- pancreatitis, it should be discontinued and alternative therapy
nase (LDH), and hypertriglyceridemia. considered.13,14
Therapy of acute pancreatitis is primarily supportive unless
a specic etiology is identied (Fig. 202). Supportive therapy
involves uid repletion, discontinuation of oral intake, and anal-
gesia. Patients with acute pancreatitis are administered intra-
venous uids to maintain hydration and blood pressure. Fluids
may be given in the form of crystalloids (e.g., 0.9% sodium
chloride for infusion) or colloids (e.g., dextran or albumin for
Presentation of Acute Pancreatitis infusion).15 Sodium chloride 0.9% for infusion (normal
A 55-year-old man with a history of ethanol abuse is admitted saline) at a rate of 50 to 100 mL/hour is reasonable for patients
to the emergency department complaining of sharp persistent with mild to moderate uid depletion. However, as much as
pain in the right upper quadrant of the abdomen. The pain 200 mL/hour may be required for patients with severe uid
was milder 2 days ago but has progressed to the severe pain losses.16 Electrolytes such as potassium and magnesium may
he has now. He was nauseated at home and has vomited be added to the infusions if necessary. Hyperglycemia can be
twice in the emergency department; he is also febrile. The managed with insulin-containing intravenous infusions.
patient is overweight, a smoker, and has a history of dyslipi-
It is common practice to discontinue oral feedings during an
demia including hypertriglyceridemia.
attack of acute pancreatitis. In theory, discontinuation of oral
What information about the patient presentation is con- intake will decrease the secretory functions of the pancreas and
sistent with acute pancreatitis? minimize further complications from the disease. Some patients
What risk factors does the patient have for acute can be fed with minimal oral intake. Tube feeding delivered via
pancreatitis? a nasojejunal tube will feed the patient beyond the ampulla of
What additional laboratory tests would you Vater, minimizing stimulation of the pancreas.15,16 If oral intake
recommend? is discontinued for a protracted period, total parenteral nutri-
tion must be used to maintain adequate nutrition.17,18
FIGURE 202. Algorithm for evaluation and

Acute pancreatitis treatment of acute pancreatitis. ERCP, endo-
scopic retrograde cholangiopancreatography.
(From Berardi RR, Montgomery PA. Pancreatitis.
Mild disease Severe disease In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.)
Favorable prognosis Unfavorable prognosis Pharmacotherapy: A Pathophysiologic
No systemic complications Systemic complications
Approach. 6th ed. New York: McGraw-Hill;
Supportive care
Analgesics Interstitial Necrotizing
Nutrition Intensive care required Intensive care required
Fluid resuscitation Fluid resuscitation
Treat systemic complication Treat systemic complication
ERCP for gallstones? ERCP for gallstones?
Parenteral/enteral nutrition? Parenteral/enteral nutrition?
Consider antibiotics
Improvement No improvement
Continue treatment Rule out infected

pancreatic necrosis
If infected, surgical debridement

If sterile, continue treatment
If pancreatic necrosis has been identied, surgical debridement Antibiotics

is necessary because mortality approaches 100% without drainage Empiric antibiotics are not necessary if the patient has mild
or surgical intervention. Percutaneous drainage is an option for disease or a non-infectious etiology of acute pancreatitis.
managing pancreatic necrosis but is best used only in unstable Antibiotics have not been shown to prevent the formation of
patients as a bridge to surgery. Repeated surgery may be required pancreatic abscess or necrosis when given early in the course
in patients with a protracted or progressing disease state.5,19 of acute pancreatitis.
Antibiotics are appropriate for pancreatic necrosis, which
Pharmacologic Therapy can be infected initially or be susceptible to a secondary
infection.21 Selected intravenous antibiotic regimens are shown
Analgesics in Table 202. If necrosis is conrmed, antibiotics are insuf-
Meperidine has historically been the most popular analgesic cient as sole therapy; surgical debridement is necessary for cure.
in acute pancreatitis since it is purported to cause less spasm Broad-spectrum antibiotics with activity against enteric
and resulting pain in the sphincter of Oddi than other opioids. gram-negative bacilli are appropriate. Imipenem/cilastatin
However, the clinical importance of this phenomenon is reduces sepsis resulting from necrotizing pancreatitis and
unclear.15,20 As a result, patients with acute pancreatitis should provides antibacterial coverage for the organisms likely to be
be given the most effective analgesic. Morphine and fentanyl are causing pancreatic necrosis.22
reasonable alternatives to meperidine and may be more desir- It is often difcult to narrow the spectrum of activity of
able due to other adverse effects associated with meperidine. the antibiotic choice since the infections are usually poly-
Refer to Chapter 30 on pain management for guidance in microbial. As such, patients may receive long courses of
selecting an analgesic dose. broad-spectrum antibiotics such as imipenem/cilastatin and
TABLE 202. Intravenous Antimicrobial Regimens for Pancreatic Necrosis
Drug Usual Dosea Notes

Imipenem/cilastatin 500 mg every 6 hours ~5% incidence of seizure; nausea
is also a concern
Piperacillin/tazobactam 3.375 g every 6 hours Avoid if allergic to penicillin
Cefepime + metronidazole 2 g every 12 hours + 500 mg every 6 hours Will not cover enterococci
Aztreonam + vancomycin + 1 g every 8 hours + 15 mg/kg Option for penicillin-allergic patients
metronidazole every 12 hours + 500 mg every 6 hours
a
Doses must be adjusted for the degree of renal impairment.
Patient Encounter 1, Part 2: Medical Patient Encounter 1, Part 3: Treatment

History, Physical Exam, and Diagnostic and Monitoring for Acute Pancreatitis
Tests in Acute Pancreatitis
The patient has been transferred from the CT scanner to the
PHM surgical intensive care unit for mechanical ventilation, blood
Dyslipidemia, diagnosed years ago; obesity pressure support, and surgical evaluation. A diagnosis of acute
FH pancreatitis with pancreatic necrosis is made.
Fathers whereabouts unknown; mother deceased at age 78
from heart failure; two half brothers, alive and well Formulate a care plan for this patient.
What are some possible causes of respiratory failure and
SH
hypotension in this patient? Are these ndings poor prog-
Consumes 6 to 9 alcoholic beverages per evening; smokes 1
nostic indicators?
pack cigarettes per day
What is the recommended treatment for pancreatic necrosis?
Meds What empiric antibiotic regimen would be a reasonable
No prescription medications; does not see a physician regularly choice in this patient? Provide a drug, dose, route, and
frequency.
Maalox 15 mL PO 4 times daily as needed for heartburn,
Suppose a surgeon requested piperacillin/tazobactam
stomach upset
3.375 g IV every 6 hours for this patient. Would this be a
Loperamide 2 mg PO as needed diarrhea reasonable choice? Why or why not?
Guaifenesin 200 mg PO 4 times daily as needed for cough
Ranitidine 75 mg PO once daily (when patient remembers
to take it) administering somatostatin or atropine, reducing gastric acidity
ROS and decreasing pancreatic secretion with histamine2-receptor
Positive for sharp right upper quadrant abdominal pain radi- antagonists, inhibition of pancreatic enzymes using protease
ating to the back, nausea, vomiting, recent unintentional inhibitors such as aprotinin, and immunomodulation.11,2426
weight loss (although patient is still obese) and chronic Nasogastric suction has only been effective in patients with ileus
cough; negative for chest pain or shortness of breath or persistent vomiting.27
PE
Wt: 120 kg, Ht: 510, blood pressure 100/66 mm Hg, Outcome Evaluation
pulse 120 beats per minute, respiratory rate 18/minutes,
Given the severity of acute pancreatitis, patients are moni-
temperature 38.5C
tored closely in the intensive care setting. Patients with mild
CV: Regular rate and rhythm, no murmurs
Abd: Distended, (+) rebound tenderness, (+) bowel sounds, disease can be managed more conservatively with observation
marked hepatosplenomegaly and supportive care. Critically ill patients may require surgery
and aggressive life support measures.16,28
Labs
Amylase 200 units/L (3.3 Kat/L), lipase 1000 units/L
Abdominal CT: Pending CHRONIC PANCREATITIS
Given this additional information, what is your assessment Epidemiology and Etiology
of the patients condition?
Why is the amylase low and the lipase high? The incidence of chronic pancreatitis is approximately 1 in
What pharmacologic and nonpharmacologic goals are 10,000 people. The most common cause of chronic pancreatitis
available for this patient? in adults in Western countries is ethanol abuse. The most common
cause in children is cystic brosis, due to preexisting pancreatic
insufciency inherent in the disease. Gallstones can occur at the
may develop superinfections due to more resistant bacteria or
same time as chronic pancreatitis but are not often implicated as
bacteria not susceptible to imipenem/cilastatin. Antifungal
the cause. Unlike acute pancreatitis, chronic pancreatitis has an
agents such as uconazole may be considered if peritonitis or
unknown etiology in a signicant number of cases (30%).29,30
gastrointestinal perforation develops due to the presence of
fungi such Candida albicans in the gastrointestinal tract.23
Pathophysiology
Ineffective Therapies Chronic pancreatitis is an inammatory process that occurs over
Several pharmacologic therapies have been proven to be a long period of time. The inammation damages the enzyme-
ineffective in reducing morbidity or mortality from the disease. producing cells in the pancreas and can also disrupt or destroy
Ineffective therapies include: reducing pancreatic secretion by the endocrine function of the pancreas by causing diffuse
scarring and brosis.29 Ethanol abuse may cause precipitation of Diagnosis

pancreatic enzymes in the ducts of the pancreas leading to
Differentiating an episode of acute pancreatitis from chronic
chronic inammation and damage. Ethanol may also be directly
pancreatitis may be difcult because the clinical presentations
toxic to pancreatic cells.31 Counterintuitively, the amount of
can be similar. The diagnosis of chronic pancreatitis is made
ethanol consumed does not correlate with the incidence or pro-
by looking for the effects of chronic pancreatic inammation
gression of chronic pancreatitis. A patient who binge drinks by
and scarring on the pancreas and the patient as a whole.
consuming large amounts of ethanol over short periods of time
Computed tomography or ERCP will allow visualization of
is as likely to develop chronic pancreatitis as someone who chron-
chronic calcied lesions in the pancreas when present.37
ically consumes socially acceptable amounts of alcohol. Patients
who die from the rst diagnosed episode of chronic pancreatitis
may have had undiagnosed chronic pancreatitis for some time.32 Treatment
As patients lose exocrine function of the pancreas, they
have decreased ability to absorb lipids and protein ingested Desired Outcomes
with normal dietary intake. Weight loss from nutritional mal- The goals of pharmacotherapy for chronic pancreatitis are:
absorption is a common symptom of chronic pancreatitis not (1) prevention and resolution of chronic abdominal pain;
often seen in acute pancreatitis. Fatty- or protein-containing and (2) correction of dietary malabsorption with exogenous
stools are also common; carbohydrate absorption is usually pancreatic enzymes.
unaffected. Even though patients with chronic pancreatitis
have decreased ability to absorb lipid from the gastrointestinal Nonpharmacologic Therapy
tract, there does not appear to be an increased incidence of Lifestyle modications are an important part of the therapy
fat-soluble vitamin deciency in these patients.34 for chronic pancreatitis. Avoidance of ethanol and fatty
meals can decrease the pain of chronic pancreatitis.
Clinical Presentation and Diagnosis Many surgical procedures have been employed to reduce
the inammation or remove the strictures that cause pain in
chronic pancreatitis. However, most procedures have not been
Clinical Presentation of Chronic
Pancreatitis proven effective in clinical trials and carry a high risk of mor-
bidity and mortality.39
General Pharmacologic Therapy

The presentation of chronic pancreatitis can be similar to
that of acute pancreatitis. Analgesics
Symptoms Pain management is an important component of therapy and
Pain is the most common chief complaint. Pain can be is similar to that of acute pancreatitis. Non-opioid analgesics
dull or sharp, and it may be localized to the area around are preferred, but the severe and persistent nature of the pain
the stomach or can radiate to the back. The pain is not often requires opioid therapy. Patients can require chronic
relieved by antacids and can be provoked by ethanol doses of opioid analgesics, with a resulting risk of addiction.
ingestion or a fatty meal.33 Pain can also be managed by removing the stimulus of exacer-
Weight loss can result from chronic fat and protein
bation if identied.31,38
malabsorption.
Signs Pancreatic Enzymes
Patients often present with chronic fat-containing diarrhea The goal of pancreatic enzyme supplementation is to deliver
due to dietary lipid malabsorption. exogenous enzyme to the duodenum without causing further
Gastrointestinal bleeding can result from erosion of intes-
gastrointestinal side effects from the medication, risking non-
tinal blood vessels by pancreatic enzymes or as a result
of thrombosis.
compliance due to the large number of dosage units required,
Chronic obstruction of the common bile duct by the or causing undue medication expense.40
inamed pancreas can cause icterus, cholangitis, and Supplementation with pancreatic enzymes may reduce the
biliary cirrhosis.36 pain and fatty diarrhea associated with chronic pancreatitis
(Table 203). Best results are achieved in patients who have
Laboratory Tests
Glucose intolerance may occur because of chronic
mild non-alcoholic pancreatic disease. Common pancreatic
destruction of the endocrine function of the pancreas.35 enzyme supplements contain lipase, amylase, and protease in
Serum amylase and lipase levels are not usually elevated varying proportions. Thus, the dose can be tailored to the
in chronic pancreatitis. patients requirement for exogenous enzyme supplementation
The serum bilirubin or alkaline phosphatase may be ele- and response to therapy.
vated due to inammation near the common bile duct. Nonenteric-coated pancreatic enzyme supplements
require high doses to compensate for loss of enzyme due to
TABLE 203. Frequently Used Pancreatic Enzyme Preparations

Patient Encounter 2
Dosage Enzyme Content (Units)a
Product Form Lipase Amylase Protease
Creon-10 ECMS 10,000 33,200 37,500
Creon-20 ECMS 20,000 66,400 75,000 Chronic Pancreatitis
Ku-Zyme HP C 8000 30,000 30,000 The same patient described in the rst encounter is now
Lipram-CR10 ECMS 10,000 33,200 37,500 57 years old. He presents to the clinic with right upper
Lipram-PN16 ECMS 16,000 48,000 48,000 quadrant pain radiating to his back. He is also jaundiced
Lipram-CR20 ECMS 20,000 66,400 75,000 and nauseated.
Lipram-PN20 ECMS 20,000 56,000 44,000
Lipram-UL12 ECMS 12,000 39,000 39,000 PMH
Lipram-PN10 ECMS 10,000 30,000 30,000 Dyslipidemia, with preponderance of hypertriglyceridemia
Lipram-UL18 ECMS 18,000 58,500 58,500 Hypertension
Lipram-UL20 ECMS 20,000 65,000 65,000 Weight loss, initially intentional through diet and exercise,
Pancrease ECMS 4500 20,000 25,000 but now unintentionally excessive
Pancrease MT-4 ECMT 4000 12,000 12,000 Type 2 diabetes, requiring insulin
Pancrease MT-10 ECMT 10,000 30,000 30,000
Gastroesophageal reux disease
Pancrease MT-16 ECMT 16,000 48,000 48,000
Pancrease MT-20 ECMT 20,000 56,000 44,000 SH
Ultrase MT 12 ECMT 12,000 39,000 39,000 Consumes 1 to 2 alcoholic beverages per evening; quit
Ultrase MT 18 ECMT 18,000 58,500 58,500 smoking 2 years ago
Ultrase MT 20 ECMT 20,000 65,000 65,000
Viokaseb P 16,800 70,000 70,000 Meds
Viokase 8 UCT 8000 30,000 30,000 Atorvastatin 40 mg PO once daily
Viokase 16 UCT 16,000 60,000 60,000 Hydrochlorothiazide 25 mg PO once daily
a
Amlodipine 5 mg PO once daily
All listed products contain pancrelipase. Pancrelipase contains not less Lantus insulin 30 units per day
than 24 USP units of lipase activity, not less than 100 USP units of amylase
activity, and not less than 100 USP units of protease activity per milligram. Multivitamin 1 tablet daily
b
Units of 0.7 g of powder. Pantoprazole 40 mg PO once daily
C, powder encased in a cellulose capsule; ECMS, enteric-coated Maalox 15 mL PO 4 times daily as needed for
microspheres encased in a cellulose or gelatin capsule; ECMT, enteric- heartburn/stomach upset
coated microtablets encased in a cellulose capsule; UCT, uncoated
tablet; P, powder.
Acetaminophen 325 mg PO every 6 hours as needed for
(From Berardi RR, Montgomery PA. Pancreatitis. In: DiPiro JT, Talbert RL, pain/headache
Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. ROS
6th ed. New York: McGraw-Hill; 2005: 733, with permission.)
Positive for sharp right upper quadrant abdominal pain radi-
ating to the back, nausea, and recent unintentional weight
loss; negative for chest pain or shortness of breath, fatty
diarrhea present for months.
destruction by the low pH of the stomach. This effect can be PE
minimized by administering a histamine2-receptor antagonist Wt: 70 kg Ht 510, blood pressure 130/86 mm Hg, pulse
or proton pump inhibitor. Nonenteric-coated pancreatic 80 beats per minute, respiratory rate 16/minute, temperature
enzyme supplements may have an advantage in minimizing 37.0C (98.6F)
pain early in the disease state through regulation of proteases CV: Regular rate and rhythm, no murmurs noted
in the duodenum. Abd: Distended, (+) rebound tenderness, (+) bowel sounds,
Nonenteric-coated pancreatic enzyme supplements can marked hepatosplenomegaly
be used for initial therapy. The relative dose of amylase, lipase, Labs
and protease may be increased until control of pain and fatty Amylase 100 units/L (1.67 Kat/L), lipase 100 units/L
diarrhea is achieved or the patient experiences intolerable CT scan: Diffuse pancreatic scarring and calcications
side effects. If pain and diarrhea control are achieved, the
patient can be transitioned to an enteric-coated supplement Formulate a care plan for this patient.
Why are the serum amylase and lipase normal?
to maximize compliance. A reasonable example starting regi-
What lifestyle modications can this patient make to min-
men is Viokase-8, six tablets with each meal and at bedtime, imize impact from his disease state?
given with famotidine 20 mg at bedtime. Is this patient taking any medication(s) that could exacer-
Most pancreatic enzyme supplements are enteric coated to bate pancreatitis? If so, what alternatives can you offer?
release enzymes in the alkaline environment of the intestine; What medications may help alleviate the fatty diarrhea
this minimizes enzyme destruction in the stomach. Enteric- the patient is experiencing?
coated pancreatic enzyme supplements require fewer daily How would you monitor the effectiveness of your recom-
dosage units, but delivery of the drug to the site of action and mendations?
effectiveness may be delayed by gastric emptying time.41
Pancreatic enzyme supplements should be taken immediately ABBREVIATIONS

prior to meals to aid in the digestion and absorption of food.
Alternately, patients can supplement their diet with medium APACHE: Acute Physiology, Age, and Chronic Health Evaluation
chain triglycerides (MCTs) or ingest foods rich in MCTs since ARDS: acute respiratory distress syndrome
they do not require pancreatic enzymes for absorption. An CT: computed tomography
appropriate regimen incorporates the successful doses of each ERCP: endoscopic retrograde cholangiopancreatography
enzyme (amylase, lipase, and protease) from the starting LDH: lactate dehydrogenase
MCT: medium chain triglycerides
nonenteric-coated regimen. As with the previous example, a
RUQ: right upper quadrant
patient stabilized on Viokase-8, six tablets with each meal, can be
transitioned to Pancrease MT-16 three tablets with meals. The Reference lists and self-assessment questions and answers are
famotidine can then be discontinued. available at www.ChisholmPharmacotherapy.com.
Outcome Evaluation Log into the website: www.pharmacotherapyprinciples.com

Monitor for adequate pain control and the need for escala- this chapter.
tion or de-escalation of analgesia.
If pain relief is achieved by avoiding ethanol or fatty meals,
encourage continuation of these practices. KEY REFERENCES AND READINGS
When dietary malabsorption exists, monitor patients for
weight gain or loss, activity level, and ability to perform activ- Banks PA. Epidemiology, natural history, and predictors of disease
ities of daily living. outcome in acute and chronic pancreatitis. Gastrointest Endosc
Ask patients to monitor the frequency and consistency of 2002;56(6 Suppl):S226S230.
stool output as an indicator of malabsorption. Bornman PC, Marks IN, Girdwood AW, et al. Pathogenesis of pain
Educate patients that compliance with and proper use of in chronic pancreatitis: ongoing enigma. World J Surg 2003;27:
dietary pancreatic enzyme supplementation is key to improved 11751182.
outcomes.31,33,38 Clancy TE, Benoit EP, Ashley SW. Current management of acute pan-
creatitis. J Gastrointest Surg 2005;9:440452.
Kramer KM, Levy H. Prophylactic antibiotics for severe acute pancre-
Patient Care and Monitoring atitis: the beginning of an era. Pharmacotherapy 1999;19:592602.
Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus
enteral nutrition in patients with acute pancreatitis. BMJ 2004;
328(7453):1407.
1. Determine whether ethanol is a contributing causative Mayerle J, Simon P, Lerch MM. Medical treatment of acute pancreatitis.
factor. If so, reinforce counseling on the need for abstinence Gastroenterol Clin North Am 2004;33:855869.
and provide appropriate resources to maintain abstinence Nathens AB, Curtis JR, Beale RJ, et al. Management of the critically ill
(e.g., professional counseling, alcoholics anonymous). patient with severe acute pancreatitis. Crit Care Med 2004;32:
2. Obtain a thorough history of prescription, non-prescription, 25242536.
and dietary supplement use to identify products that may
exacerbate chronic pancreatitis.
3. Refer the patient for nutritional counseling if there is
decreased caloric intake and weight loss. Compare
actual body weight to ideal body weight.
4. Make a plan for analgesia, in conjunction with a pain
management service if possible, to control and prevent
pain. Recommend an analgesic with ease of dosing and
minimal side effects, realizing that patients with chronic
pancreatitis may require large doses of opioids.
5. Optimize pancreatic enzyme supplementation, starting
rst with a nonenteric-coated enzyme supplement and
an H2RA. When pain and diarrhea are stabilized, consider
switching to an enteric-coated enzyme supplement for
ease of dosing.
6. Develop a plan for reassessing pancreatic enzyme sup-
plementation and analgesia on an outpatient basis.
7. Assess improvement in quality of life measures such as phy-
sical, psychological, and social functioning and well-being.
21 VIRAL HEPATITIS
Juliana Chan
LEARNING OBJECTIVES
1. Differentiate the ve types of viral hepatitides by their epidemiology, etiology,

pathophysiology, clinical presentation and natural history.
2. Identify modes of transmission and risk factors among the major types of viral hepatitis.
3. Evaluate hepatic serologies to diagnose the type of hepatitis infection a patient acquired.
4. Create treatment goals for a patient with viral hepatitis.
5. Recommend an appropriate pharmacotherapeutic agent for prevention of viral hepatitis.
6. Develop a pharmaceutical care plan for the treatment of viral hepatitis.
7. Formulate a monitoring plan to assess the untoward effects of agents used to treat viral hepatitis.
KEY CONCEPTS present as either acute or chronic illnesses, which are prima-
rily differentiated based on disease duration. Acute hepatitis
Prevention and treatment of viral hepatitis may prevent progres- may be associated with all ve types of hepatitis and rarely
sion to chronic hepatitis, cirrhosis, and end-stage liver disease. exceeds 6 months in duration.
There is no specic pharmacologic treatment for acute viral Chronic hepatitis (disease lasting longer than 6 months) is
hepatitis A, B, C, D, or E; only supportive care is available. usually associated with hepatitis B, C, and D. Chronic viral
Good personal hygiene and proper disposal of sanitary waste are hepatitis may lead to the development of cirrhosis, which may
required to prevent the fecal-oral transmission of the hepatitis A induce end-stage liver disease (ESLD). Complications of
virus. ESLD include ascites, edema, jaundice, hepatic encephalopa-
Individuals may minimize their risk of acquiring both hepatitis B thy, infections, and bleeding esophageal varices. Therefore,
and C infection by avoiding contaminated blood products and prevention and treatment of viral hepatitis may prevent
not indulging in high-risk behavior such as intravenous drug use. ESLD.
Persons at high risk of acquiring the hepatitis B virus should be Viral hepatitis can occur at any age and is the most com-
vaccinated with the hepatitis B vaccine at months 0, 1, and 6. mon cause of liver disease in the world. The true prevalence
A vaccine that combines both inactivated hepatitis A and recom- and incidence may be underreported because most patients
binant hepatitis B (Twinrix) is approved for immunizing indi- are asymptomatic. The epidemiology, etiology, and pathogen-
viduals greater than 18 years of age with indications for both esis vary depending on the type of hepatitis and will be con-
hepatitis A and B vaccines. sidered separately below.
The drug of choice for chronic hepatitis B depends on the
patients past medical history, aminotransferase level, HBV
DNA level, and most importantly, HBeAg status.
HEPATITIS A
Hepatitis D infection is possible only if the patient also has the
hepatitis B virus present; therefore, hepatitis B vaccination can
indirectly prevent hepatitis D infection.
Hepatitis A affects 1.4 million people yearly worldwide.1 The
There are ve types of viral hepatitis: hepatitis A (HAV), B prevalence is highest in underdeveloped countries including
(HBV), C (HCV), D (HDV), and E (HEV). These types may Africa, parts of South America, the Middle East, and Southeast
345
Asia. In contrast, developed parts of the world including humans, with hepatic cells as the primary site for viral repli-
Australia, parts of western and northern Europe, Japan, and cation. As part of the viral degradation process, the HAV is
the United States have a lower prevalence. This is primarily due released into the biliary system causing elevated concentra-
to vaccination programs, but outbreaks still can happen as evi- tions of the virus in the feces.5
denced by an outbreak in Pennsylvania in 2003.2,3
Thirty-one percent of the American population has been
HEPATITIS B
infected with the HAV.1 Overall, Mexican Americans are at
greatest risk for HAV infection, and African Americans are
more likely to be infected than Caucasians.
The hepatitis A virus is primarily detected in contaminated Hepatitis B is a blood-borne infection affecting more than
feces and infects people via the fecal-oral route. Outbreaks occur 2 billion people in the world. Approximately 350 million people
primarily in areas of poor sanitation.1,4 Individuals at greatest have chronic infection, which may lead to cirrhosis and compli-
risk of acquiring HAV are listed in Table 211. Approximately cations of ESLD. Deaths related to hepatitis B range from
50% of the reported cases have no identiable risk factors.1 500,000 to 750,000 yearly.6 Despite having an effective vaccine
To date, there are no documented cases of chronic hepati- against HBV, more than 300,000 newly-diagnosed infections
tis A.1 Death associated with HAV is rare and is mostly associ- emerge each year. The prevalence of chronic hepatitis B is geo-
ated with fulminant hepatitis, with which approximately 100 graphically dependent; the rate is about 1% in North America
people die annually.1 and Western Europe compared to 10% to 15% in developing
areas such as Southeast Asia.7
The highest concentration of the HBV is found in blood
Pathophysiology
and serous uids. Therefore, the primary mode of hepatitis B
Hepatitis A is a non-enveloped single-stranded ribonucleic transmission is either by blood or body uids through peri-
acid (RNA) virus classied as the Hepatovirus genus under natal, sexual, or percutaneous exposure.8 Infants born of
the Picornaviridae family.1 The only host for the HAV is mothers who are infected with HBV that is actively replicating
have a 90% risk of developing chronic hepatitis B. If an infant
TABLE 211. Risk Factors for Acquiring Viral Hepatitis
residing in an endemic area is not infected at birth, the risk of
acquiring chronic hepatitis B is still 30% to 60% within the
Hepatitis A rst 5 years of life from horizontal transmission.9,10 Individuals
International travelers to endemic areas (e.g., Africa, Asia, and at greatest risk of acquiring HBV are listed in Table 211.
parts of South America) Approximately 33% of the reported hepatitis B cases have no
Sexual contact with infected persons (e.g., men having sex with identiable risk factors.8
other men)
Shellsh infected with HAV (e.g., raw oysters)
Day care centers or household contacts with people infected Pathophysiology
with HAV
Health care workers Hepatitis B (also known as the Dane particle) belongs to the
Intravenous drug users using unsterilized needles Hepadnaviridae family that was rst discovered by associating
Workers involved with non-human primates individuals who developed hepatitis from blood transfusions.11
Food service handlers The HBV is unique in that it is a partially double-stranded
Patients with clotting factor disorders deoxyribonucleic acid (DNA) virus with a phospholipid layer
Individuals residing in health care institutions
Hepatitis B and Hepatitis D containing hepatitis B surface antigen (HBsAg) that surrounds
Men having sex with other men the nucleocapsid. The nucleocapsid contains the core protein
Individuals with multiple heterosexual partners that produces hepatitis B core antigen (HBcAg), which is unde-
Intravenous drug users using unsterilized needles tectable in the serum. The exact mechanism of hepatocellular
Recipients of blood products injury from hepatitis B is still being investigated but it is
Household contacts with acute hepatitis B with open cuts
Health care providers in contact with contaminated needles thought that a cytotoxic immune reaction occurs when HBcAg
Patients undergoing dialysis is expressed on the surface of the hepatic cells. Fortunately, anti-
Hepatitis C bodies against hepatitis B core antigen (anti-HBc) are measur-
Recipients of blood products able in the blood, where anti-HBc to immunoglobulin M (IgM)
Health care providers in contact with infected needles indicates active infection and anti-HBc to IgG relates to either
Individuals having multiple sexual partners
Perinatal transmission (less than 5%) chronic infection or possible immunity against HBV.
Unprofessional body piercing and tattooing Viral replication occurs when hepatitis B envelope anti-
Hepatitis E gen (HBeAg) is present and circulating in the blood. HBV
International travelers to endemic areas (e.g., parts of Asia, DNA is utilized to measure viral infectivity and assess and
Africa, and Mexico) quantify viral replication. Once the hepatitis B infection
Ingesting foods and drinks contaminated with bodily waste
resolves, antibodies against hepatitis B envelope (anti-HBe) and
CHAPTER 21 / VIRAL HEPATITIS 347
antibodies against hepatitis B surface antigen (anti-HBs) true mechanism of hepatic injury is still in question, but it is
develop, and HBV DNA levels become undetectable. However, theorized that structural and nonstructural (NS) peptides
if these antibodies do not develop, then the likelihood of devel- may be responsible for RNA viral replication, specically the
oping chronic hepatitis B increases. This is primarily dependent NS5 peptide. Currently, there are six genotypes (numbered 1
on the hosts immune system at the time the infection was to 6) and more than 90 subtypes (genotype 1a, 1b, 2a, 3b, etc.)
attained. If an individual is immunocompetent, the disease that are unique to hepatitis C.
resolves spontaneously in most cases with no further sequelae. Antibodies against HCV (anti-HCV) in the blood indicate
In an immunocompromised person, the infection is less likely infection with the HCV. If the infection persists for more than
to be eradicated.11 6 months and viral replication is conrmed by HCV RNA lev-
els, then the person has chronic hepatitis C. Chronic disease
Natural History of Hepatitis B may be due to an ineffective host immune system against the
Approximately 90% of adults infected with HBV develop HCV. Cytotoxic T lymphocytes are ineffective in eradicating the
anti-HBs resulting in lifelong immunity. About 2% develop HCV, thus allowing persistent damage to hepatic cells.
acute infections leading to fulminant hepatitis, which has a Therefore, immunocompromised individuals are less likely to
60% to 90% mortality rate.7 Fifteen percent of individuals eliminate HCV.12
who do not develop anti-HBs develop chronic hepatitis B. Of
Natural History of Hepatitis C
this population, the chance of developing chronic disease is
less than 20% if the infection was acquired during adulthood. Only 10% to 15% of patients have acute hepatitis C that resolves
The risk of developing chronic hepatitis B increases to greater without any further sequelae.10 In more than 85% of cases, hepati-
than 40% if the infection occurred perinatally.7 It may take 20 tis C develops into a chronic disease. Approximately 70% of
to 40 years from the time cirrhosis is conrmed before signs chronic HCV cases progress to mild, moderate, or severe hepati-
and symptoms associated with ESLD develop. tis. While the natural history of the progression to cirrhosis is not
clear, it is estimated that 10% to 20% of cases may take up to 20 to
HEPATITIS C 40 years from the time of exposure to advance from brosis to cir-
rhosis.10 Fifteen to twenty percent of patients infected with HCV
Epidemiology and Etiology develop complications associated with cirrhosis. Once cirrhosis is
conrmed, the rate of developing hepatocellular carcinoma
More than 170 million people are infected with hepatitis C increases to 1% to 4% per year.10 The estimated death rate from
worldwide, and more than 4 million have the disease in the HCV infection is 1.8 deaths per 100,000 persons per year.12,15
United States.12,13 The prevalence is higher among non-
Hispanic blacks (3.2%) than non-Hispanic whites (1.5%), and
men are more likely to be infected than women.14 Additionally, HEPATITIS D
genotypes are geographically specic. For example, genotype 1
is commonly found in patients in the United States whereas Epidemiology and Etiology
genotype 4 is common in the Middle East.12 Approximately Hepatitis D affects approximately 15 million people world-
75% of those infected with HCV in the United States have wide. The highest prevalence is in southern Italy, parts of
genotype 1, and about 14% and 5% have genotypes 2 and 3, Russia, and Romania; prevalence is moderate in northern
respectively. Genotype does not dictate disease severity or clin- Italy, Spain, Turkey, and Egypt.16 Southeast Asia and China
ical outcomes but is used to determine the duration of therapy have the lowest prevalence of HDV despite having the highest
and the likelihood of therapeutic response. prevalence of HBV infections.
Prior to routine screening of blood products in the early There are three major HDV genotypes that are geographi-
1990s, the primary route of transmission of the HCV was cally specic. Genotype 1a primarily affects those residing in
blood transfusions, when the risk was 0.02% per unit trans- the United States, and genotype 1b affects the Asian population.
fused. Since then, the risk has decreased signicantly (0.001% Both 1a and 1b are equally represented in the Mediterranean
per unit transfused).13 Today, intravenous drug users utilizing Basin. Individuals residing in Japan and Taiwan are mostly diag-
contaminated paraphernalia are responsible for most HCV nosed with genotype 2. Patients in South America (specically
transmission. Other populations at risk for acquiring HCV Colombia, Venezuela, and Peru) are mostly infected with
are listed in Table 211. Approximately 10% of the individuals genotype 3.16
infected with HCV have no identiable risk factors. The most likely modes of transmitting the HDV are similar
to those of HBV, including intravenous drug users using
Pathophysiology unsterilized needles and recipients of contaminated blood
Hepatitis C, rst known as non-A, non-B hepatitis, is a blood- products. Sexual and perinatal transmission are rare for
borne infection that is a single-stranded RNA virus belonging HDV.16 Individuals at greatest risk of acquiring HDV are sim-
to the Flaviviridae family and the Hepacivirus genus.12 The ilar to those seen in HBV (Table 211).
Pathophysiology
Clinical Presentation of Viral Hepatitis
Hepatitis D (originally referred to as delta hepatitis) belongs
to the genus Deltavirus of the Deltaviridae family.16 The HDV
virion is a defective single-stranded circular RNA virus that
requires the presence of HBV for HDV viral replication. This Symptoms
is because the hepatitis D virus antigen (HDVAg) is coated by Most patients infected with any type of viral hepatitis
the hepatitis B surface antigen (HBsAg). have no symptoms.
Those who have symptoms may experience any of the
The exact mechanism of hepatic damage induced by HDV
following: ulike symptoms, fevers, fatigue/malaise,
is still being investigated, but it is known that replication of
anorexia, nausea, vomiting, diarrhea, dark urine, pale-
HDV cannot occur without HBV being present causing either appearing stools, pruritus, and abdominal pain.
co-infection (both hepatitis B and D infection occurring
simultaneously) or superinfection (acquiring HDV after hav- Signs
Jaundice may be evident in the whites of the eyes (scleral
ing long-standing disease with HBV).17
icterus) or skin.
An enlarged liver (hepatomegaly) and spleen
(splenomegaly) may be present.
HEPATITIS E In fulminant hepatitis with hepatic encephalopathy,
patients may have asterixis and coma.
In rare instances, extrahepatic symptoms may develop:
Epidemiology and Etiology arthritis, postcervical lymphadenopathy, palmar erythema,
Hepatitis E is associated with more than 50% of the acute hep- cryoglobulinemia, and vasculitis.
atitis cases in endemic areas (Afghanistan, Bangladesh, Burma,
China, India, Indonesia, Kazakhstan, Kyrgyzstan, Malaysia,
Mongolia, Nepal, Pakistan, Tajikistan, Turkmenistan, Uzbekistan, Hepatitis A
Mexico, the Middle East, Northern Africa, and sub-Saharan The diagnosis of hepatitis A is made by detecting immuno-
Africa). The virus is primarily transmitted by the fecal-oral route. globulin antibody to the capsid proteins of the HAV. The pres-
Transmission of HEV is more prominent in underdeveloped ence of IgM anti-HAV in the serum indicates an acute infection.
countries where sanitation is poor. IgM appears approximately 3 weeks after exposure and
The mortality rate in pregnant women with acute infections becomes undetectable within 6 months. In contrast, IgG anti-
may reach 25%. Rarely does HEV cause endemics in industri- HAV appears in the serum at approximately the same time IgM
alized countries, where the prevalence rate is 1% to 5%.18,19 anti-HAV develops but indicates protection and lifelong immu-
nity against hepatitis A.1
Pathophysiology
Hepatitis B
Hepatitis E is a non-enveloped single-stranded messenger Hepatitis B is diagnosed when HBsAg is detectable in the
RNA virus of unclassied genus.18 The HEV is similar to HAV serum. The nucleocapsid of the HBsAg contains the core pro-
in that the virus is harvested in contaminated feces, thus tein that produces HBcAg, which is undetectable in the serum.
infecting people via the fecal-oral route. High HEV levels in The presence of antibodies against anti-HBc to IgM indicates
the bile often prompt viral shedding in the feces. The severity active infection, and anti-HBc to IgG relates to either chronic
of hepatic damage is dependent on the HEV strain: Mex 14, infection or possible immunity against HBV.
Sar 55, or the US 2 strain.19 No cases of chronic hepatitis E Viral replication occurs when HBeAg is present. Measurement
have yet been documented. of HBV DNA is used to determine viral infectivity and assess and
quantify viral replication. Once the hepatitis B infection resolves,
anti-HBe and anti-HBs develop, and HBV DNA levels
becomes undetectable.
Hepatitis C
Diagnosis of Viral Hepatitis
Hepatitis C is diagnosed by testing for anti-HCV in the serum.
Diagnosing viral hepatitis may be difcult because most The disease is conrmed by the presence of HCV RNA. HCV
infected individuals are asymptomatic. Because symptoms RNA levels quantify viral replication and are used to deter-
cannot identify the specic type of hepatitis, laboratory serolo- mine if antiviral treatment for HCV is effective.
gies must be obtained (Table 212). In addition, liver function
tests may be obtained to assess the extent of cholestatic and Hepatitis D
hepatocellular injury. However, the denitive test to determine Hepatitis D infection requires the presence of HBV for HDV
the amount of damage and inammation of hepatic cells is a viral replication. Measuring HDV RNA levels in the serum by
liver biopsy. polymerase chain reaction (PCR) conrms the presence of
TABLE 212. Interpretation of Viral Hepatitis Serology Panels
Type Laboratory Test Result Interpretation of Panel

Hepatitis A IgM anti-HAV Negative Susceptible to infection
IgG anti-HAV Negative
IgM anti-HAV Positive Acutely infected
IgG anti-HAV Positive Immune due to either natural infection
or HAV vaccine
Hepatitis Ba HBsAg Negative Susceptible to infection
anti-HBc Negative
anti-HBs Negative
HBsAg Negative Immune due to natural infection
anti-HBc Positive
anti-HBs Positive
HBsAg Negative Immune due to hepatitis B vaccination
anti-HBc Negative
anti-HBs Positive
HBsAg Positive Acutely infected
anti-HBc Positive
IgM anti-HBc Positive
anti-HBs Negative
HBsAg Positive Chronically infected
anti-HBc Positive
IgM anti-HBc Negative
anti-HBs Negative
HBsAg Negative Four interpretations possibleb
anti-HBc Positive
anti-HBs Negative
Hepatitis C anti-HCV Negative Susceptible to infection
anti-HCV Positive Acutely or chronically infected
Hepatitis Dc IgM anti-HDV Positive Acute HBV-HDV coinfection
HDVAg Positive
HBsAg Positive
HBeAg Positive
anti-HBc Positive
Hepatitis E IgM anti-HEV Negative Susceptible to infection
IgG anti-HEV Negative
IgM anti-HEV Positive Acutely infected
IgG anti-HEV Positive Immune due to natural infection
a
Centers for Disease Control and Prevention. Hepatology. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/b/
Bserology.htm. Accessed February 19, 2006.
b
(1) May be recovering from acute HBV infection; (2) May be distantly immune and test is not sensitive enough to detect
very low level of anti-HBs in serum; (3) May be susceptible with a false-positive anti-HBc; (4) May be undetectable level
of HBsAg present in the serum and the person is actually a carrier.
c
Hepatitis D should be suspected in those who have HBsAg positivity. Hepatitis D may present as either coinfection where
both HDV and HBV serologies appear simultaneously whereas for superinfection, HBV has been present for some time,
and later HDV develops.
anti-HAV, hepatitis A antibody; anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; HBsAg,
hepatitis B surface antigen; anti-HCV, hepatitis C antibody; anti-HDV, hepatitis D antibody; anti-HEV, hepatitis E antibody;
HAV, hepatitis A virus; HBV, hepatitis B virus; HDV, hepatitis D virus; HDVAg, hepatitis D antigen; IgG, immunoglobulin
G; IgM, immunoglobulin M.
HDV and is the most accurate diagnostic test. The presence of PREVENTION AND TREATMENT OF VIRAL
IgM antibodies to HDV Ag (IgM anti-HD) indicates active dis- HEPATITIS
ease, and IgG anti-HD also becomes detectable if the infection
does not resolve spontaneously. Unlike the antibodies devel- Desired Outcomes
oped against HAV, HDV antibodies do not confer immunity.
General outcomes for treating hepatitis are to: (1) prevent the
Hepatitis E spread of the disease; (2) prevent and treat symptoms; (3) sup-
The diagnosis of hepatitis E is based on the presence of anti- press viral replication; (4) normalize hepatic aminotrans-
HEV antibodies. A test for hepatitis E RNA levels is not yet ferases; (5) improve histology on liver biopsy; and (6) decrease
available for commercial use but is used in clinical trials. morbidity and mortality by preventing cirrhosis, hepatocellu-
lar carcinoma, and ESLD.
For hepatitis B, additional treatment goals include: (1) sero-
Patient Encounter, Part 1 conversion or loss of HBsAg; (2) seroconversion or loss of
HBeAg; and (3) achieving undetectable HBV DNA levels.
Additional goals for chronic hepatitis C include: (1) achieving
undetectable HCV RNA; and (2) obtaining a sustained viro-
A 41-year-old Caucasian man is required by his employer
logic response.
to obtain a physical exam. He has no medical complaints
but does report some stress from an impending divorce and
from needing to take care of his ve young children.
PMH
General Approach
Non-contributory Managing viral hepatitis involves both prevention and treat-
PSH ment. Prevention of hepatitis A and B (and indirectly for hep-
Appendectomy in 1987 at the age of 27 that required blood atitis D) can be achieved with immune globulin or vaccines.
transfusions There is no specic pharmacologic treatment for acute viral
FH hepatitis A, B, C, D, or E; only supportive care is available.
Mother and father alive and well Individuals with mild to moderate symptoms rarely require
hospitalization. Occasionally, hospitalization is required in
SH
Smoked cigarettes 1 pack per day 15 years but quit
individuals experiencing signicant nausea, vomiting, diar-
5 years ago; used illicit drugs once in the past; drinks daily rhea, and encephalopathy. Liver transplantation may be
for the past 30 years; has 1 tattoo on the left arm done required in rare instances if fulminant hepatitis develops.
unprofessionally; works as a mail carrier Patients with viral hepatitis B, C, and D may develop
chronic disease leading to ESLD. Treatment is only available for
Meds
None chronic liver disease associated with HBV, HCV, and HDV.20,21
ROS
Complains only of irritability and mild depression; no nausea,
vomiting, diarrhea, abdominal pain, or anorexia; never had an Hepatitis A Prevention
episode of jaundice, pale stools, or tea-colored urine Good personal hygiene and proper disposal of sanitary
PE waste are required to prevent the fecal-oral transmission of the
VS: blood pressure 128/80 mm Hg, pulse 80 beats per HAV.1,4 This includes frequent handwashing with soap and
minute, respiratory rate 20/minutes, temperature 37.0C water after using the bathroom and prior to eating meals.
(98.6F), Wt 81 kg (178 lbs), Ht 59 (175 cm) Drinking bottled water and avoiding fruits, vegetables, and
Abd: Soft, non-tender, normal liver span; no hepato- raw shellsh harvested from sewage-contaminated water in
splenomegaly, no ascites.
areas where HAV is most endemic will also minimize the risk
Labs of becoming infected with hepatitis A.
All within normal limits except for aspartate aminotrans- Individuals at high risk of acquiring hepatitis A (see
ferase 69 IU/L (1.15 Kat/L) and alanine aminotransferase Table 211) should receive either serum immune globulin
92 IU/L (1.53 Kat/L); anti-HCV (+), genotype 2; HCV RNA or the hepatitis A vaccine, depending on their personal cir-
91,230 IU/mL
cumstances, as described below.1,5
Liver biopsy: Mild inammation and minimal brosis (grade 1,
stage 1 disease) that is consistent with chronic hepatitis C
Immune Globulin
What information is suggestive of viral hepatitis?
Immune globulin (IG) is a solution containing antibodies from
What risk factors does he have for viral hepatitis?
What additional information do you need before creating
sterilized pooled human plasma that provides passive immu-
a treatment plan for this patient? nization against various infectious diseases, including hepatitis
A.5 Immune globulin is available for either intravenous (IVIG)
or intramuscular (IGIM) administration, but only IGIM is The risk of infection may be decreased by 90% if IGIM is
used for prevention of hepatitis A. IGIM does not confer life- given within 2 weeks of being exposed to the hepatitis A virus.
long immunity, but it is effective in providing pre-exposure IGIM may still be benecial if it is given more than 2 weeks
and postexposure prophylaxis against HAV.5 after exposure to a known case of HAV, as it may decrease the
Adverse effects of IGIM are rare. There have been reports of severity of hepatic damage.1,5
anaphylaxis in individuals who have immunoglobulin A de-
ciency after receiving repeated IG administration. Therefore, Hepatitis A Vaccine
these patients should not receive IGIM. IGIM is not con- Persons at risk of acquiring the HAV should receive the hepa-
traindicated in pregnant or lactating women or infants requir- titis A vaccine when appropriate.
ing hepatitis A immunization. The thimerosal-free preparation There is no benet in administering the vaccine after a per-
should be used in infants.1 son has been exposed to the HAV. Two inactivated hepatitis A
IGIM should be injected into a deltoid or gluteal muscle. It vaccines, Havrix and VAQTA, are available in the United States
does not affect the immune response of inactivated vaccines, and are effective in providing active immunization. The major
oral polio virus, or yellow fever vaccine. The administration of difference between the two vaccines is that HAVRIX con-
live vaccines [e.g., measles, mumps, rubella (MMR) vaccine] tains 2-phenoxyethanol as a preservative whereas VAQTA is
concomitantly with IGIM may decrease the immune response preservative-free.1 Either vaccine is effective in providing
signicantly; thus, MMR and varicella vaccine should be active pre-exposure prophylaxis when given in two injections
delayed for at least 3 and 5 months, respectively, after IGIM 6 months apart (referred to as months 0 and 6). The two vac-
has been administered. Additionally, IGIM should not be cines are considered interchangeable, and doses are dependent
given within 2 weeks of the MMR administration or within on age (Table 213).
3 weeks of the varicella vaccine to maximize the efcacy of the Efcacy is dened by measuring antibody response. For
immunization.1 HAVRIX, levels greater than 20 mIU/mL measured with the
modied enzyme immunoassay, and for VAQTA, levels greater
Pre-exposure Prophylaxis than 10 mIU/mL measured with the modied radioimmuno-
Pre-exposure prophylaxis with IGIM is indicated for individ- assay are considered protective. After the rst dose of vaccine has
uals at high risk of acquiring the HAV who cannot receive the been administered, 94% to 100% of adults and 97% to 100% of
hepatitis A vaccine (e.g., because of allergy to the components children and adolescents develop protective antibody concentra-
alum or 2-phenoxyethanol). Additionally, travelers who plan tions against the HAV. All recipients over the 2 years of age receiv-
to depart for endemic areas within 2 weeks and have not yet ing the second dose at month 6 have 100% antibody coverage,
received the hepatitis A vaccine should receive IGIM because therefore, postvaccination measurement of antibody response is
active vaccine immunity takes several weeks to develop. not required.1
The dose of the IGIM determines the duration of coverage. The hepatitis A vaccine may provide effective immunity
A dose of 0.02 mL/kg confers immunity against hepatitis A for for 8 years in adults and children. Additionally, kinetic models
less than 3 months and doses of 0.06 mL/kg provide immu- have theorized that immunity with the vaccine may be
nity up to 5 months. If protection against HAV is required longer than 20 years, but this has not been conrmed in clin-
beyond 5 months, then readministration of IGIM may be ical trials.1
indicated.1,5 The most common adverse effects in adults include injec-
tion site reactions (e.g., tenderness, pain, and warmth),
Postexposure Prophylaxis headaches within 5 days after vaccination, and fatigue. Local
Individuals in contact with people infected with acute HAV, reactions may be minimized by using an appropriate needle
including household and sexual partners, staff and children length based on the persons age and size and by administering
from day care facilities, and food handlers of restaurant estab- the injection intramuscularly in the deltoid muscle. Children
lishments may be candidates for postexposure prophylaxis. may also have feeding disturbances. Hepatitis A vaccine given
TABLE 213. Recommended Intramuscular Doses of Hepatitis A Vaccines
Recipient Age No. of Schedule

Product (Years) Dose Volume (mL) Doses (Months)
VAQTA 118 25 units 0.5 2 0, 618
Greater than or equal to 19 50 units 1 2 0, 6
Havrix 118 720 EL units 0.5 2 0, 612
Greater than or equal to 19 1440 EL units 1 2 0, 612
EL units, enzyme-linked immunosorbent assay units.

From Chan J. Viral hepatitis. Pharmacotherapy Self-Assessment Program. 5th ed. Kansas City: MO, American College
of Clinical Pharmacy, 2005:1, 4, with permission.
during pregnancy has not been evaluated in clinical trials. protection against acquiring the HBV when the immunization is
Since both brands of vaccine are made from inactivated HAV, given at months 0, 1, and 6. The two non-dialysis formulations
the risk of developing fetal complications should be minimal. of the hepatitis B vaccines are considered interchangeable, but
the same brand should be used for the entire three-dose series.
Hepatitis B Prevention Additionally, the doses depend on the persons age (Table 214).
Individuals may minimize their risk of acquiring the hepa- The difference between the two vaccines is that Engerix-B con-
titis B infection by avoiding contaminated blood products or tains trace amounts of thimerosal that is not used as a preser-
indulging in high-risk behavior such as intravenous drug use. In vative but is produced during the manufacturing process;
addition, those who are at high risk of acquiring the HBV Recombivax HB is completely free of thimerosal.
(Table 211) should be vaccinated with the hepatitis B vaccine.8 For optimal response, the hepatitis B vaccine should be
In some cases, postexposure prophylaxis with hepatitis B administered intramuscularly only (into the anterolateral
immune globulin (HBIG) may be recommended to prevent the thigh region in neonates and infants; the deltoid region in
development of acute infection and complications associated adults) and not intravenously or intradermally. The vaccine
with HBV. should not be given in the gluteal region, as it may result in
lower rates of immunity. In rare cases, the vaccine may be given
Hepatitis B Immune Globulin subcutaneously in individuals at risk for hemorrhage (e.g.,
Hepatitis B immune globulin (HBIG) is a sterile solution con- hemophiliacs); however, this route of administration should be
taining antibodies prepared from pooled human plasma that used with caution, as subcutaneous nodules have developed
has a high concentration of anti-HBs (antibodies to hepatitis when other similar vaccines have been used.8
B surface antigen). HBIG provides passive immunization for The efcacy of the hepatitis B vaccine is established when
postexposure prophylaxis against the HBV. Similar to IGIM, antibody concentrations are greater than 10 mIU/mL. After
HBIG should only be administered intramuscularly. completing the vaccination series given at months 0, 1, and 6,
The most common side effects of HBIG include erythema 96% of recipients obtain adequate antibody levels; for this rea-
at the injection site, headaches, myalgia, fatigue, urticaria, son, postvaccination testing is not usually recommended.
nausea, and vomiting. Serious adverse effects are rare and may However, protective antibody levels may be decreased in
include liver function test abnormalities, arthralgias, and ana- immunocompromised patients (e.g., human immunodeciency
phylactic reactions. HBIG should be used with caution in virus (HIV)-positive, hemodialysis, or immunosuppressive
individuals who have experienced hypersensitivity reactions therapy); postvaccine testing may be warranted 1 to 6 months
to immune globulin or those who have immunoglobulin A after completing the vaccination series in these patients.8 The
deciency. Similar to IGIM, concomitant administration of duration of immunity and whether a booster dose of the hepa-
HBIG and live vaccines should be avoided because the efcacy titis B vaccine is required are still being investigated.
of the immunization may decrease signicantly.8 The most frequent adverse effects are local reactions at the
injection site (pain, tenderness, erythema, swelling, and pruri-
Hepatitis B Vaccine tus), fevers (greater than 37.5C or 99.5F), headaches, dizziness,
The two hepatitis B vaccines available in the United States are and irritability. Anaphylaxis and hypersensitivity reactions have
Recombivax HB and Engerix-B. These vaccines are produced been reported rarely and occur within a few hours after vaccine
with recombinant DNA technology by inserting the gene for administration. In rare instances, a serum sicknesslike apparent
HBsAg into the plasmid that is synthesized by Saccharomyces hypersensitivity syndrome (arthralgia, urticaria, ecchymoses,
cerevisiae cells. Both vaccines are effective in providing erythema multiforme, and erythema nodosum) has been
TABLE 214. Recommended Intramuscular Dosing Regimens for Hepatitis B Vaccines
Patient Dose No. of Schedule

Product Categories (mcg) Volume (mL) Doses (months)
Recombivax HB 019 years of age 5 0.5 3 0, 1, 6
1115 years of agea 10 1 2 1, 46
Greater than or equal to 20 years of age 10 1 3 0, 1, 6
Hemodialysis 40 1 3 0, 1, 6
Engerix-B 019 years of age 10 0.5 3 0, 1, 6
Greater than or equal to 20 years of age 20 1 3 0, 1, 6
Hemodialysis 40b 2 4 0, 1, 2, 6
a
Adolescents 11 through 15 years of age may receive either the 5 mcg, 3-dose pediatric formulation or a 10 mcg, 2-dose regimen
using the adult formulation.
b
Two 20 mcg in one or two injections.
From Chan J. Viral hepatitis. Pharmacotherapy Self-Assessment Program. 5th ed. Kansas City: MO, American College of Clinical
Pharmacy, 2005:1, 8, with permission.
reported days to weeks postvaccination. Hepatitis B vaccine within 24 hours of birth.8 If the mother is HBsAg negative,
given during pregnancy has not been evaluated in clinical trials. the newborn should be given only the hepatitis B vaccine
However, if the mother is at risk of acquiring the hepatitis B (Table 216).
virus, then vaccination should be considered.
Hepatitis A and B Combination Vaccine Chronic Hepatitis B Treatment

A vaccine that combines both inactivated hepatitis A and Persons with conrmed chronic hepatitis B should be eval-
recombinant hepatitis B (Twinrix) is approved for immunizing uated for treatment, which may include interferon, pegylated
individuals greater than 18 years of age with indications for both interferon, lamivudine, adefovir dipivoxil, or entecavir. The
hepatitis A and B vaccines.22 A 1 mL dose of Twinrix contains drug of choice for chronic hepatitis B depends on the patients
the antigenic components of not less than 720 ELISA units of past medical history, aminotransferase level, HBV DNA level,
Havrix and 20 mcg of recombinant HBsAg protein of and most importantly, HBeAg status.
Engerix-B and should be administered at months 0, 1, and 6. Patients who are hepatitis B carriers (dened as having a
2-Phenoxyethanol is used as a preservative, and trace amounts positive HBsAg, normal alanine aminotransferase (ALT) levels,
of thimerosal are present due to the manufacturing process. and negative HBeAg) should not be treated because hepatitis B
Antibody seroconversion for hepatitis A and B was greater antiviral agents rarely result in HBeAg seroconversion, and
than 98% in adult volunteers tested 1 month after a three-dose long-term treatment leads to drug resistance. Patients with ele-
vaccine series. The side-effect prole of Twinrix is similar to vated ALT and HBV DNA levels (regardless of the presence or
giving each vaccine separately.23 absence of HBeAg) require treatment to delay progression to
cirrhosis and prevent the development of ESLD. The treatment
Postexposure Prophylaxis response for a patient who is positive for HBeAg is different
HBIG and hepatitis B vaccine are indicated after exposure to the from that of a patient who is negative for HBeAg because
HBV to prevent chronic hepatitis B disease. The dose and obtaining seroconversion is less likely to occur.
immunization regimen depend on how the individual acquired
the virus.8 Adults acutely exposed to blood containing HBsAg
from an accidental needlestick, sexual contacts, or intravenous Interferon and Peyglated Interferon
drug use should be immunized based on the source of exposure Interferon alfa is an antiviral agent that is effective in sup-
and the vaccination status of the exposed person (Table 215). A pressing hepatitis B viral replication. Interferon alfa-2b and
single dose of HBIG of 0.06 mL/kg is 75% effective in prevent- pegylated interferon alfa-2a are the only interferon therapies
ing chronic hepatitis B infections if administered within 14 days approved for the treatment of chronic hepatitis B.
of exposure. Interferon therapy has an advantage over other antiretrovi-
Postexposure prophylaxis for perinatal exposure depends ral treatment in that it is effective in suppressing, and in some
upon the mothers HBsAg status.24 Mothers who are HBsAg- cases ceasing, viral replication without inducing resistance.
positive should have their newborns immunized with both the Approximately one-third of HBsAg-positive patients become
hepatitis B vaccine and HBIG 0.5 mL. This regimen is 85% effec- seronegative after 4 to 6 months of treatment.25 The HBeAg sero-
tive in preventing the hepatitis B carrier status if administered conversion rate is 18% greater than those who are not treated.25
TABLE 215. Recommendations for Prophylaxis after Exposure to Hepatitis B Virus
Treatment to Administer if Serology Test of Source Person Is:

Exposed Persons
Vaccination Status HBsAg Positive HBsAg Negative Unknown or Unavailable for Testing
Unvaccinated HBIG 1 and initiate Initiate HB vaccine series Initiate HB vaccine series
HB vaccine series
Previously vaccinated:
Known responder No treatment No treatment No treatment
Known non-responder HBIG 1 and initiate No treatment If known high-risk source, treat as
HB revaccination or HBIG 2 if source were HBsAg-positive
Antibody response Test exposed person for anti-HBs: No treatment Test exposed person for anti-HBs:
unknown (1) if adequate, no treatment; (1) if adequate, no treatment; (2) if
(2) if inadequate, HBIG 1 and inadequate, vaccine booster and
vaccine booster recheck titer in 12 months
HB, hepatitis B; anti-HBs, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBIG, hepatitis B immune globulin.
From Chan J. Viral hepatitis. Pharmacotherapy Self-Assessment Program. 5th ed. Kansas City: MO, American College of Clinical Pharmacy, 2005:1, 9,
with permission.
TABLE 216. Recommendations for Hepatitis B Prophylaxis to Prevent Perinatal

Transmission
Mothers HBsAg Status:

Treatment Positive Negative Unknown
a
HBIG Given within 12 hours None If positive, give within
of birth 7 days; if negative,
give none
AND
Hepatitis B vaccineb
Dose 1 Within 12 hours of birth Based on infants Within 12 hours of
weightc birth
Dose 2 At month 12 At month 12 At month 12
Dose 3 At month 6 At month 618 At month 6
a
0.5 mL intramuscularly.
b
See Table 214 for appropriate hepatitis B vaccine dose.
c
Full-term infants who are medically stable and weigh greater than or equal to 2000 grams born to
HBsAg-negative mothers should receive the hepatitis B vaccine before hospital discharge. Preterm infants
weighing less than 2000 grams born to HBsAg-negative mothers should receive the rst dose of hepatitis
B vaccine 1 month after birth or at hospital discharge.
From Centers for Disease Control and Prevention. A Comprehensive Immunization Strategy to Eliminate
Transmission of Hepatitis B Virus Infection in the United States. Recommendations of the Advisory
Committee on Immunization Practices (ACIP) Part 1: Immunization of Infants, Children, and Adolescents.
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5416a1.htm?s_cid=rr5416a1_e.
Accessed February 16, 2006.
Additionally, the durability (likelihood of developing and The subcutaneous dose of interferon alfa-2b (Intron A) in
sustaining HBeAg seroconversion) is greater than 80% after patients who are HBsAg-positive is either 5 million units daily
treatment has been discontinued. If interferon treatment (better tolerated) or 10 million units three times weekly. The
duration is extended to 12 to 24 weeks, HBsAg loss is observed dose for HBsAg-negative patients is 5 to 6 million units three
in about 10% of patients. times weekly. The approved dose for pegylated interferon alfa-2a
Pegylated interferon is interferon that is attached to a poly- (Pegasys) for chronic hepatitis B is 180 mcg subcutaneously
ethylene glycol molecule that increases the half-life of the drug, once weekly. Interferon doses may need to be adjusted in
thus allowing once-weekly dosing versus thrice-weekly admin- patients with renal impairment.
istration required for the unmodied formulation. Pegylated Even though the advantages of interferon therapy include a
interferon is well tolerated and is superior in efcacy to unmod- nite duration of treatment, lack of resistance, and possible
ied interferon for the treatment of chronic hepatitis B.26 HBsAg loss or seroconversion (development of anti-HBs), there
Patients with chronic hepatitis B who are HBeAg-negative are several signicant disadvantages. These include the need
may achieve undetectable HBV DNA levels and normalize for subcutaneous injections, and more importantly, the pro-
ALT levels during treatment with any of the antiviral thera- nounced adverse-effect prole that may require treatment dis-
pies; however, once treatment has ceased, these endpoints continuation. The most common complaints include injection
return to pretreatment values.27 Patients treated with unmod- site reactions and ulike symptoms of fevers, chills, joint pain, and
ied interferon have an end-of-treatment response (dened as muscle aches. Systemic adverse effects include anorexia, nausea,
undetectable HBV DNA and normal ALT levels) ranging from diarrhea, fatigue, headache, insomnia, irritability, depression,
60% to 70%; however, the rate of sustaining virologic alopecia, and dermatitis. Hematologic abnormalities are com-
response once therapy has been discontinued is approximately mon including neutropenia, anemia, and thrombocytopenia,
20%.20 Patients with HBeAg-negative chronic hepatitis B which require either a dose reduction or treatment discontinua-
should be treated with more than 12 months of therapy.28 tion.28,29 Uncommon side effects include cardiac arrhythmias, dia-
When the duration of interferon therapy is prolonged beyond betes, thyroid disorders, amenorrhea, and vision disturbances.
12 months, undetectable HBV DNA may be sustained, as well
as increasing the chance of losing HBsAg. Lamivudine
Factors associated with a higher likelihood of response to Lamivudine (Epivir-HBV) is an oral synthetic cytosine nucleoside
interferon therapy are baseline HBV DNA levels less than analogue having antiviral effects against HIV and hepatitis
200 pg/mL and ALT concentrations greater than 5 times the B virus. In patients with chronic hepatitis B, lamivudine is
upper limit of normal.29 effective in suppressing hepatitis B viral replication, normalizing
ALT levels, and improving liver histology.30,31 Patients with Patients infected with HBeAg-negative chronic hepatitis B
HBeAg-positive chronic hepatitis B may have a similar or a have a signicant response while on adefovir dipivoxil, but the
superior response in achieving these endpoints when com- response is not sustained after treatment discontinuation.
pared to interferon. A signicant loss of serum HBV DNA level Serum ALT levels normalized in 72% of patients treated for
was observed in 44% of subjects receiving lamivudine com- 48 weeks compared to 29% who received placebo. Additionally,
pared to 16% receiving placebo. Normalization of ALT levels 51% had undetectable HBV DNA levels with adefovir dipivoxil,
and improvement in histology occurred in approximately 50% whereas none achieved this in the placebo arm.20,27,32
of patients with HBeAg-positive hepatitis B. HBeAg loss, 18% Resistance rates to adefovir dipivoxil are lower than with
at the end of 52 weeks of treatment, is quite similar between lamivudine, potentially allowing for prolonged treatment
interferon and lamivudine. However, prolonged lamivudine duration. At present, the longest trial with adefovir dipivoxil is
therapy may be needed to sustain seroconversion, as durability 5 years with a resistance rate of 29%,35 compared to 5 years of
of response is only 50% to 80%.32 Extending the duration of lamivudine therapy with a resistance rate of 70%.
treatment is not without consequences, as lamivudine resist- The dose of adefovir dipivoxil is 10 mg once daily. The most
ance has been reported at 14% after 1 year of treatment and common side effects include asthenia, abdominal pain, diar-
increases to 70% at 5 years.29 rhea, dyspepsia, headaches, nausea, and atulence. Lactic aci-
Compared to those treated with placebo, 60% to 70% of dosis, pancreatitis, and hepatomegaly have been reported
patients with HBeAg-negative hepatitis B treated with lamivu- rarely. Unlike lamivudine, adefovir dipivoxil is associated with
dine for 52 weeks have undetectable HBV DNA levels and nor- dose-related nephrotoxicity, which was most commonly seen
malization of ALT levels. However, the rate of relapse is 80% to in HIV patients receiving doses larger than 60 mg. Therefore,
90% once the treatment has been discontinued.20 Lamivudine the dose of adefovir dipivoxil must be adjusted in patients with
therapy beyond 12 months may be considered to sustain renal insufciency (CrCl less than 50 mL/minute).
response, but biochemical and virologic breakthrough com-
monly occurs due to the development of drug resistance.29 Entecavir
The dose of lamivudine is 100 mg orally once daily for Entecavir (Baraclude) is a guanosine nucleoside analogue that
treatment of chronic hepatitis B. The dose must be adjusted in inhibits HBV DNA polymerase, thereby inhibiting DNA repli-
patients with renal dysfunction [creatinine clearance (CrCl) cation. Unlike the other two oral antiretroviral agents, ente-
less than 50 mL/minute]. cavir has no activity against HIV and is only effective against
Adverse effects are minimal and include fatigue, diarrhea, HBeAg-positive, HBeAg-negative, and lamivudine-resistant
nausea, vomiting, and headaches. In rare cases, pancreatitis, chronic hepatitis B. In treatment-nave patients with either
hepatomegaly, and potentially fatal lactic acidosis have been HBeAg-positive or HBeAg-negative HBV, doses of 0.5 mg once
reported. ALT levels should be monitored carefully, especially daily for 52 weeks are comparable to lamivudine 100 mg daily
when lamivudine has been discontinued, as an elevation may in histologic improvement, viral load reduction, and normal-
indicate a are in disease activity that may lead to liver failure. ization of ALT levels.
The advantages of lamivudine over interferon are oral Patients who develop resistance to lamivudine have signi-
administration and low drug cost with minimal adverse effects. cant improvement in histology while receiving entecavir, but
The major disadvantage is the prolonged treatment duration higher doses (1 mg daily) are required. Additionally, 19% of
required to achieve and sustain HBeAg and HBsAg seroconver- lamivudine-resistant patients had undetectable HBV DNA lev-
sion. Even so, this approach increases the drug resistance rate els compared to 1% of those who continued treatment with
signicantly with each additional year of treatment. lamivudine.36 At present, no resistance has been associated with
entecavir in patients treated for 1 year, but the data beyond 1 year
Adefovir Dipivoxil of therapy are unknown. Entecavir resistance has only been
Adefovir dipivoxil (Hepsera) is a prodrug of adefovir, an seen in patients who already had lamivudine resistance.37
adenosine nucleotide analog that inhibits DNA polymerase. It The side-effect prole for entecavir is similar to lamivudine
is effective against HIV and HBV, specically lamivudine- and adefovir dipivoxil and comparable to placebo. Patients
resistant HBV. Treatment with adefovir dipivoxil 10 mg daily treated with entecavir should be monitored for signs and symp-
is comparable to lamivudine in normalizing aminotransferase toms associated with lactic acidosis and severe hepatomegaly
levels and improving histologic activity.33,34 Undetectable with steatosis, because some cases have been fatal. Dosage
HBV DNA levels were observed in 21% of patients treated for adjustments are required in patients with renal dysfunction.
48 weeks and in 56% of patients when the treatment duration
was extended to 144 weeks.33 Unlike lamivudine, extending
Hepatitis C Prevention
the duration of adefovir dipivoxil therapy resulted in a rela-
tively low resistance rate, approximately 11% after 3 years. The The risk factors for hepatitis C and hepatitis B are quite simi-
percentage of seroconversion and loss of HBeAg are compara- lar; thus, the risk of acquiring the HCV is minimized by avoid-
ble to patients who received lamivudine.20 ing contaminated blood products and high-risk behaviors
such as sharing needles among intravenous drug users. No vac- Management of the Adverse Effects of Interferon,
cines are available for preventing hepatitis C. However, indi- Pegylated Interferon, and Ribavirin
viduals at high risk (Table 211) should be tested for the hepa- The type and incidence of adverse effects associated with
titis C virus because the disease presents asymptomatically. unmodied interferon and pegylated interferon are compara-
ble. Approximately 10% to 30% of patients receiving inter-
Chronic Hepatitis C Treatment feron and/or ribavirin require a dosage reduction or treatment
discontinuation to minimize side effects. Patients should be
Individuals with conrmed chronic hepatitis C should be screened for uncommon adverse effects and laboratory abnor-
evaluated for treatment with pegylated interferon with or malities prior to starting interferon and ribavirin because
without ribavirin. treatment may exacerbate or worsen some medical conditions.
Most patients treated with either interferon or pegylated
Interferon or Peyglated Interferon plus Ribavirin interferon experience ulike symptoms (fevers, chills, rigors,
Interferon alfa-2a (Roferon A), interferon alfa-2b (Intron-A), and myalgias). These symptoms may be mild to moderate in
and interferon alfacon-1 (Infergen) are approved for chronic severity and usually occur with the rst injection and dimin-
hepatitis C. However, they are not prescribed alone because ish as the treatment continues. The ulike symptoms may be
only 12% to 16% of patients achieve a sustained virologic minimized by premedication with acetaminophen or a non-
response (SVR). Adding ribavirin, a synthetic guanosine ana- steroidal anti-inammatory drug.
logue that inhibits viral polymerase, increases the SVR rate to Psychiatric adverse effects occur frequently and may include
35% to 45%. irritability, depression, and rarely, suicidal ideation. Individuals
Pegylated interferon alfa-2a (Pegasys) and pegylated inter- with a history of uncontrolled psychiatric disorders must weigh
feron alfa-2b (PEG-Intron) are also effective FDA-approved the risk versus benet of treatment, as interferon may exacerbate
treatments for hepatitis C.38,39 These pegylated interferons are or worsen the psychiatric condition. Patients who develop mild
similar to those used to treat hepatitis B, where the interferon to moderate symptoms may require antidepressants or anxio-
is attached to a polyethylene glycol molecule that extends the lytics. Those with severe symptoms including suicidal ideation
interferons half-life allowing for once-weekly administration. should have the treatment discontinued immediately.43
Pegylated interferon therapy alone for 48 weeks achieves a 25% There are several hematologic abnormalities associated with
to 40% SVR, which is similar to the unmodied interferon plus either interferon or pegylated interferon plus ribavirin therapy.
ribavirin regimen. Therefore, the combination of pegylated Up to 35% of patients treated for hepatitis require either a
interferon and ribavirin would be expected to have SVR rates dosage reduction or drug discontinuation due to either throm-
of 45% to 55% when used for treatment of hepatitis C.38,39 bocytopenia, neutropenia, or anemia.43 With either formulation
Patient variables associated with a higher virologic response of interferon, a decrease in platelet count of about 25% to 30%
include low baseline HCV RNA levels, female gender, acquiring usually occurs within 6 to 8 weeks after initiation of treatment.
the infection at a later age, lower body weight, and a minimal Decreasing the dose or discontinuing interferon therapy is rarely
brosis score on liver biopsy.40 However, the most important required because of signicant thrombocytopenia [(dened as a
pretreatment factor is the patients genotype. Individuals with platelet count less than 50,000 cells/mm3 less than 50 109/L)].
genotype 2 or 3 achieve an SVR of 75% to 85% compared to However, caution is required in patients with cirrhosis because
40% to 50% for patients with genotype 1.38,39 they may already have low platelet counts prior to starting treat-
Genotype also determines the duration of therapy. ment. At present there are no adjunctive therapies for interferon-
Those with nongenotype 1 are treated for 24 weeks and induced thrombocytopenia. Interferon should either be reduced
genotype 1 patients are treated for 48 weeks. Additionally, or discontinued if the platelet counts signicantly decline or
for genotype 1 patients the dose of ribavirin is weight based symptoms of bruising and bleeding are present.
(less than 75 kg or 165 lbs = 1,000 mg daily; greater than or equal Neutropenia associated with interferon or pegylated inter-
to 75 kg or 165 lbs = 1200 mg daily), whereas nongenotype 1 feron therapy is dened as an absolute neutrophil count (ANC)
patients receive 800 mg daily regardless of weight.41 of less than 1000 cells/mm3; in rare cases, an ANC less than 500
Adherence to therapy is another important factor in increas- cells/mm3 may be observed. The neutropenia is more common
ing and maintaining SVR. Patients who were adherent with and in some cases more severe with pegylated interferon than
interferon and ribavirin therapy (taking more than 80% of with unmodied interferon. Neutropenia usually occurs within
doses for more than 80% of the treatment duration) had an the rst 2 weeks after initiating either formulation of interferon,
SVR of 52% whereas those who were not compliant had an with the WBC count stabilizing by week four or six. The neu-
SVR of 44%.42 tropenia is reversible upon discontinuing therapy. Granulocyte
At present, pegylated interferon plus ribavirin is the regi- colony-stimulating factor has been used as an adjunctive therapy
men of choice for the treatment of hepatitis C.41 Interferon, for interferon-induced neutropenia in hepatitis patients.44
pegylated interferon, and ribavirin have signicant adverse Ribavirin causes a dose-related hemolytic anemia. Once treat-
effects, as discussed below. ment has been initiated, the hemoglobin concentration may
decrease by 2.9 to 3.7 g/dL (29 to 37 g/L or 1.8 to 2.3 mmol/L) At present, only acute cases of hepatitis E have been docu-
within 4 weeks. In addition, interferon may slightly suppress mented. There are no vaccines available to prevent hepatitis E;
bone marrow erythroprogenitor cells. Therefore, a mixed however, a recombinant hepatitis E vaccine is undergoing
anemia (hemolytic anemia and bone marrow suppression Phase II/III study to determine its efcacy in preventing hep-
occurring simultaneously) develops when both interferon and atitis E infections.49 Supportive care is the only treatment
ribavirin are used. This is a reversible process with the hemo- available for acute hepatitis E infection.19
globin level returning to baseline within 7 to 8 weeks after
either drug has been discontinued.
About 10% to 25% of patients treated with interferon and rib- OUTCOME EVALUATION
avirin require dosage reductions when hemoglobin levels decrease
or they develop intolerable symptoms such as shortness of breath Monitoring for efcacy in patients treated for chronic hepa-
or severe fatigue. If warranted, erythropoietin may be used as titis B or C includes evaluating aminotransferase levels and
adjunctive therapy for ribavirin-induced hemolytic anemia.45 viral loads.
All women of childbearing age and men who are able to father
a child should use two forms of contraception during ribavirin Hepatitis B
therapy and 6 months after treatment because ribavirin has been In patients with either HBeAg-positive or HBeAg-negative
documented to cause teratogenic and embryocidal effects. hepatitis B, monitor hepatitis B serologies and HBV DNA
levels every 3 months to determine treatment response
Hepatitis D Prevention and Treatment regardless of the therapy given.28,32
At month 3, if the viral count is still positive or fails to decrease
Hepatitis D infection is possible only if the patient also has at least 1 log, the patient is deemed a treatment failure.
the hepatitis B virus present; therefore, hepatitis B vaccination Reevaluate the patient for a different hepatitis B antiviral agent.
can indirectly prevent hepatitis D infection. Patients are considered responders if at least a 1-log drop in
While there are no FDA-approved treatments for hepatitis viral count and normalization of ALT levels occur. Continue
D, interferon has been shown to be effective.4648 Various doses treatment.
have been evaluated, with the most effective treatment being Patients are considered to have relapsed if the viral load
9 million units three times weekly.47 Seventy-one percent of increases during treatment. The beginnings of drug resist-
patients who were treated with this regimen for 48 weeks had ance may also be evidenced by increasing ALT and HBV
normalized ALT levels.47 Adverse effects and monitoring DNA levels during treatment.
parameters for interferon therapy are similar to treatment for
hepatitis C. In some situations, patients infected with hepati- Hepatitis C
tis D who develop hepatic decompensation and ESLD may The National Institutes of Health Consensus Development
need to undergo liver transplantation. Conferences in 1997 and 2002 dened several therapeutic
endpoints in the management of hepatitis C:40
Hepatitis E Prevention and Treatment Virologic response is dened as having an undetectable
viral load or HCV RNA level.
Hepatitis E is similar to hepatitis A in that the mode of trans-
Biochemical response is dened as normalization of
mission is via the fecal-oral route. Therefore, the most effective
aminotransferase levels, specically ALT concentrations.
ways to prevent acquiring the virus are good personal hygiene
Histologic response is dened as improving inammation
and proper disposal of sanitary waste. Frequent handwashing
and brosis as noted by pretreatment and posttreatment
and avoiding contaminated foods and vegetables decrease the
biopsy scores.
risk of infection.
Measure these outcomes at the end of treatment to deter-
mine the end-of-treatment response and at 24 weeks after
treatment has been discontinued to determine SVR.
Patient Encounter, Part 2 In patients with genotype 1 HCV, check the HCV RNA level at
week 12 of therapy to determine the effectiveness of treatment.41
Discontinue treatment if the HCV RNA has not decreased by
Creating a Care Plan at least 2 logs or become undetectable.
Based on the information presented, create a care plan for this Continue treatment for at least another 36 weeks (48 weeks
patients hepatitis. Your plan should include: (1) a statement total) if the HCV RNA level becomes negative or decreases
of the drug-related needs and/or problems; (2) the goals of by at least 2 logs.
therapy; (3) a patient-specic detailed therapeutic plan; and At the end of the 48-week treatment, obtain an HCV RNA
(4) a follow-up plan to determine whether the goals have been level to determine end-of-treatment response and repeat at
achieved and to identify potential adverse effects of therapy. 6 months post-therapy to determine SVR.
In patients infected with nongenotype 1 HCV disease, check ABBREVIATIONS

the HCV RNA level at the end of treatment (24 weeks). If
HCV RNA is undetectable, continue treatment for another ALT: alanine aminotransferase
24 weeks. Repeat the HCV RNA 24 weeks after completion ANC: absolute neutrophil count
of therapy to determine SVR.41 anti-HAV: hepatitis A virus antibody
Monitor patients carefully during treatment with interferon anti-HBc: hepatitis B core antibody
or pegylated interferon with or without ribavirin. anti-HBe: hepatitis B envelope antibody
anti-HBs: hepatitis B surface antibody
Monitor the WBC count, ANC, platelets, and hemoglobin
anti-HCV: hepatitis C antibody
levels either weekly or biweekly during the rst month of
anti-HDV: hepatitis D antibody
therapy and monthly thereafter if stable. anti-HEV: hepatitis E antibody
Monitor serum creatinine because patients with renal AST: aspartate aminotransferase
insufciency (CrCl less than 50 mL/minute) may have CrCl: creatinine clearance
reduced ribavirin elimination resulting in increased drug DNA: deoxyribonucleic acid
accumulation and toxicity (e.g., hemolytic anemia). ESLD: end-stage liver disease
HAV: hepatitis A virus
HBcAg: hepatitis B core antigen
Patient Care and Monitoring HBeAg: hepatitis B envelope antigen
HBIG: hepatitis B immunoglobulin
HBsAg: hepatitis B surface antigen
HBV: hepatitis B virus
1. Evaluate the patient for risk factors for acquiring viral HBV DNA: hepatitis B deoxyribonucleic acid
hepatitis (Table 211). HCV: hepatitis C virus
2. Educate patients to avoid hepatotoxic agents (e.g., some HCV RNA: hepatitis C virus ribonucleic acid
dietary supplements). HDV: hepatitis D virus
HDVAg: hepatitis D antigen
3. Educate patients to avoid consuming any alcohol if
HDV RNA: hepatitis D virus ribonucleic acid
viral hepatitis has been diagnosed.
HEV: hepatitis E virus
4. Determine if the patient has been vaccinated against HIV: human immunodeciency virus
hepatitis A and B. If not, then vaccinate accordingly IgG: immunoglobulin G
(Tables 213 and 214). IgG anti-HD: IgG antibodies to hepatitis D virus antigen
5. Obtain a thorough past medical history focusing on IgM: immunoglobulin M
psychiatric disorders, cardiac disorders, endocrine dis- IgM anti-HD: IgM antibodies to hepatitis D virus antigen
ease, and renal insufciency. IG: immune globulin
6. Review the liver biopsy report (if available) to deter- IGIM: immune globulin for intramuscular administration
mine the severity of liver damage and need for chronic IGIV: immune globulin for intravenous administration
hepatitis B or C treatment. MMR: measles, mumps, rubella vaccine
PCR: polymerase chain reaction
7. Assess for adverse effects in patients with hepatitis C RNA: ribonucleic acid
treated with interferon or pegylated interferon with or SVR: sustained virologic response
without ribavirin.
8. Encourage medication compliance with viral hepatitis Reference lists and self-assessment questions and answers are
treatments to increase sustaining virologic response. available at www.ChisholmPharmacotherapy.com.
9. Encourage patients to drink at least 8 glasses of water to
prevent dehydration while on hepatitis C medications. Log into the website: www.pharmacotherapyprinciples.com
10. Educate all women of childbearing age and men who for information on obtaining continuing education credit for
are able to father a child to use two forms of contracep- this chapter.
tion during and 6 months after ribavirin therapy.
11. Provide patient education:
How to prevent viral hepatitis transmission KEY REFERENCES AND READINGS
Who should be vaccinated against hepatitis A and B
The importance of taking all medications at scheduled Centers for Disease Control and Prevention. Prevention of hepatitis
times A thorough active or passive immunization: recommendations
Adverse effects of interferon, pegylated interferon, of the Advisory Committee on Immunization Practices (ACIP).
and ribavirin therapy MMWR Recomm Rep 2006;55(RR-07):130.
How to self-administer interferon and pegylated inter- Centers for Disease Control and Prevention. A Comprehensive
feron injections Immunization Strategy to Eliminate Transmission of Hepatitis
The importance of appropriate disposal of used needles B Virus Infection in the United States. Recommendations of
the Advisory Committee on Immunization Practices (ACIP).
Part 1: Immunization of Infants, Children and Adolescents. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for
MMWR Recomm Rep 2005;54(RR-16):139. the management of chronic hepatitis B virus infection in the
Centers for Disease Control and Prevention. Recommendations for United States an update. Clin Gastroenterol Hepatol 2006;4:
prevention and control of hepatitis C virus (HCV) infection 936962.
and HCV-related chronic disease. MMWR Recomm Rep 1998; Lok ASF, McMahon BJ. Practice Guidelines Committee, American
47(RR-19):139. Association for the Study of Liver Diseases (AASLD). Chronic
Farci P, Roskams T, Chessa L, et al. Long-term benet of interferon hepatitis B: Update of recommendations. Hepatology 2004;39:
alpha therapy of chronic hepatitis D: regression of advanced 857861.
hepatic brosis. Gastroenterology 2004;126:17401749. Lok AS. The maze of treatments for hepatitis B. N Engl J Med 2005;
Hepatitis Delta. Department of Communicable Disease Surveillance 352:27432746.
and Response. World Health Organization. http:// www. who.int/ Dienstag JL, McHutchison JG. American Gastroenterological
csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf. Association technical review on the management of hepatitis C.
Accessed August 29, 2005. Gastroenterology 2006;130:231264.
Hepatitis E. Department of Communicable Disease Surveillance and
Response. World Health Organization. http://www. who. int/csr/
disease/hepatitis/HepatitisE_whocdscsredc2001_12.pdf.
Accessed August 29, 2005.
Section 4. Renal Disorders
22 ACUTE RENAL FAILURE

Mary K. Stamatakis
LEARNING OBJECTIVES
1. Assess a patients kidney function based on clinical presentation, laboratory results, and
urinary indices.
2. Identify pharmacotherapeutic outcomes and endpoints of therapy in a patient with acute
renal failure.
3. Apply knowledge of the pathophysiology of acute renal failure to the development of a
treatment plan.
4. Design a diuretic regimen that considers the pharmacokinetic and pharmacodynamic
characteristics of the drug.
5. Select pharmacotherapy to treat complications associated with acute renal failure.
6. Develop strategies to minimize the occurrence of acute renal failure.
7. Monitor and evaluate the safety and efcacy of the therapeutic plan.
KEY CONCEPTS denes ARF as a 50% increase in baseline serum creatinine

concentration, a 25% decrease in GFR, or a urine output of less
Equations to estimate creatinine clearance that incorporate a than 0.5 mL/kg per hour for at least 6 hours.1 It should be noted
single creatinine concentration (e.g., Cockcroft-Gault) may that no single serum creatinine value is a threshold for ARF.
underestimate or overestimate kidney function depending on
whether acute renal failure is worsening or resolving.
There is no evidence that supports drug therapy in hastening EPIDEMIOLOGY
the recovery period, decreasing length of hospitalization, or
improving survival in acute renal failure. Between 5% and 25% of all hospitalized patients develop
Loop diuretics are the diuretics of choice for the management ARF.2 A greater prevalence of ARF is found in critically ill
of volume overload in acute renal failure. patients.3 Despite improvements in the medical care of indi-
Renal dose dopamine is not recommended in the prevention viduals with ARF, mortality generally exceeds 50%.4
or treatment of acute renal failure.
Identifying patients at high risk for development of acute PATHOPHYSIOLOGY
renal failure and implementing preventive methods to
decrease its occurrence or severity is critical. There are typically three categories of ARF: prerenal, intrinsic,
and postrenal ARF. The pathophysiologic mechanisms differ
Acute renal failure (ARF) is a potentially life-threatening clin- for each of the categories.
ical syndrome that occurs primarily in hospitalized patients
and frequently complicates the course of the critically ill. It is
characterized by a rapid decrease in glomerular ltration rate Prerenal Acute Renal Failure
(GFR) and the resultant accumulation of nitrogenous waste Prerenal ARF is characterized by reduced blood delivery to
products (e.g., creatinine and urea nitrogen), with or without the kidney. A common cause is intravascular volume deple-
a decrease in urine output. A recent consensus statement tion due to conditions such as hemorrhage, dehydration, or
361
362 SECTION 4 / RENAL DISORDERS
gastrointestinal uid losses. Prompt correction of volume Postrenal Acute Renal Failure
depletion can restore renal function to normal because no
Postrenal ARF is due to obstruction of urinary outflow.
structural damage to the kidney has occurred. Conditions of
Causes include benign prostatic hypertrophy, pelvic
reduced cardiac output (e.g., congestive heart failure or
tumors, and precipitation of renal calculi.7 Rapid resolu-
myocardial infarction) and hypotension can also reduce
tion of postrenal ARF without structural damage to the
renal blood ow, resulting in decreased glomerular perfu-
kidney can occur if the underlying obstruction is cor-
sion and prerenal ARF. With a mild to moderate decrease in
rected. Postrenal ARF accounts for less than 10% of cases
renal blood ow, intraglomerular pressure is maintained by
of ARF.6
dilation of afferent arterioles (arteries supplying blood to
the glomerulus), constriction of efferent arterioles (arteries
removing blood from the glomerulus), and redistribution
of renal blood ow to the oxygen-sensitive renal medulla.5
Functional ARF occurs when these adaptive mechanisms ASSESSMENT OF RENAL FUNCTION
are compromised and is often caused by drugs. Non-
steroidal anti-inflammatory drugs (NSAIDs) impair The most common measure of overall kidney function is
prostaglandin-mediated dilation of afferent arterioles. GFR. It is dened as the volume of plasma ltered across the
Angiotensin-converting enzyme (ACE) inhibitors and glomerulus per unit time and correlates well with the ltra-
angiotensin receptor blockers (ARBs) inhibit angiotensin tion, secretion, reabsorption, endocrine, and metabolic func-
IImediated efferent arteriole vasoconstriction. Cyclosporine tions of the kidney. In addition to aiding in the diagnosis and
and tacrolimus, especially in high doses, are potent renal assessment of the severity of ARF, an accurate estimate of
vasoconstrictors. All of these agents can reduce intra- GFR can assist in proper dosing of drugs that undergo renal
glomerular pressure, with a resultant decrease in GFR. elimination. In an individual with normal kidney function,
Prompt discontinuation of the offending drug can often GFR ranges from approximately 90 to 120 mL/minute. Because
return renal function to normal. Other causes of prerenal ARF GFR is difcult to measure directly, it is routinely estimated
are renovascular obstruction (e.g., renal artery stenosis), by determining the renal clearance of a substance that is l-
hyperviscosity syndromes (e.g., multiple myeloma), or sys- tered at the glomerulus and which does not undergo signi-
temic vasoconstriction (e.g., hepatorenal syndrome). Prerenal cant tubular reabsorption or secretion. Creatinine is an
ARF occurs in approximately 10% to 25% of patients diag- endogenous substance that is a normal by-product of muscle
nosed with ARF.6 metabolism. Ninety percent of creatinine is eliminated by
glomerular ltration; tubular secretion is responsible for the
remaining 10%.
Direct measurement of creatinine clearance (CrCl) requires
Intrinsic Acute Renal Failure
collection of urine over an extended time interval (usually
Intrinsic renal failure, also referred to as intrarenal ARF, is 24 hours) with measurement of urine volume, urine creati-
caused by diseases that can affect the integrity of the tubules, nine concentration, and serum creatinine concentration
glomerulus, interstitium, or blood vessels. Damage is within (Table 221). Because kidney function can uctuate signi-
the kidney; changes in kidney structure can be seen on cantly during ARF, this method may underestimate or over-
microscopy.7 Acute tubular necrosis (ATN) represents a estimate kidney function depending on whether ARF is
pathophysiologic condition that results from toxic (amino- worsening or resolving.
glycosides, contrast agents, or amphotericin B) or ischemic Numerous equations have been developed for a quick
insult to the kidney. ATN results in necrosis of the proximal bedside estimate of creatinine clearance or GFR. They incor-
tubule epithelium and basement membrane, decreased porate patient-specic variables such as serum creatinine
glomerular capillary permeability, and backleak of glomeru- concentration, body weight, age, gender, albumin, and blood
lar ltrate into the venous circulation.8 Maintenance of ATN urea nitrogen (BUN) concentration. Two of the most widely
is mediated by intrarenal vasoconstriction.8 The most com- used equations are the Cockcroft-Gault equation and the
mon cause of intrinsic renal failure is ATN and it accounts for Modication of Diet in Renal Disease (MDRD) equation
approximately 50% of all cases of ARF.6 Glomerular, intersti- (Table 221).9,10 They are generally considered acceptable
tial, and blood vessel diseases may also lead to intrinsic ARF, in individuals whose renal function is relatively constant.
but occur with a much lower incidence. Examples include Because only a single serum creatinine concentration is fac-
glomerulonephritis, systemic lupus erythematosus, intersti- tored into these equations, the calculated creatinine clearance
tial nephritis, and vasculitis. In addition, prerenal ARF can or GFR may underestimate or overestimate kidney function
progress to intrinsic ARF if the underlying condition is not depending on whether acute renal failure is worsening or
promptly corrected.7 resolving.
CHAPTER 22 / ACUTE RENAL FAILURE 363
TABLE 221. Equations for Estimation of Creatinine Clearance (CrCl)
Urine Collection Method

CrCl (mL/minute) = (Ucr)(V) Ucr = urine creatinine concentration, mg/dL
(Scr)(T) V = volume of urine, mL
Scr = serum creatinine concentration, mg/dL
T = time of urine collection, minute
(Note: time equals 1440 minutes for a 24-hour collection)
Cockcroft-Gault Equation for Adults9
(140 age) BW Age, in years
CrCl (mL/minute) = (0.85 if women)
(Scr) 72 BW = actual body weight (kg)a
Scr = serum creatinine concentration, mg/dL
MDRD10
4-Variable Method
GFR = 186 [Scr]1.154 [age]0.203 [0.742 if female] [1.212 if African-American]
6-Variable Method
GFR = 170 [Scr]0.999 [age]0.176 [0.762 if female] [1.180 if African-American] [BUN]0.170 [albumin]0.318
Jelliffe Equation for Changing Renal Function11

Males
ESS = IBW [29.3 0.203 (age)] ESS = steady-state creatinine excretion
ESScorr = ESS[1.035 0.0337 (Scr2)] t = time in days between measurement of Scr1 and Scr2
E = ESScorr [4 IBW (Scr2 Scr1]/t IBW = ideal body weight, kg
CrCl (mL/minute/1.73 m2) = E/14.4 (Scr) age = years
Females ESScorr = corrected steady-state creatinine excretion
ESS = IBW [25.1 0.175 (age)] Scr1 = rst serum creatinine concentration
ESScorr = ESS [1.035 0.0337 (Scr)] Scr2 = second serum creatinine concentration
E = ESScorr [4 IBW (Scr2 Scr1]/t E = creatinine excretion
CrCl (mL/minute/1.73 m2) = E/14.4(Scr)
MDRD, per the Modication of Diet in Renal Disease study.

a
Often substituted with ideal body weight, or adjusted body weight when body weight is signicantly greater than ideal body weight.
Several equations have been developed to assess unstable may still represent severe ARF but may be associated with better
kidney function. The Jelliffe equation (Table 221) estimates patient outcomes.12
creatinine clearance by considering the change in serum crea-
tinine over a specied time period.11 While it is more mathe-
matically difcult to calculate, it better estimates creatinine
clearance in patients with rapidly changing kidney function
compared to an equation that only includes a single creatinine
concentration. A 73-year-old man with a history of diabetes mellitus,
Estimating creatinine clearance is only one part of evaluat- chronic kidney disease, gout, osteoarthritis, and hypertension
ing a patients overall kidney function. Other factors, such as is hospitalized with possible urosepsis. He recently com-
symptomatology, laboratory test results, urinary indices, and pleted a 10-day course of antibiotics and was ready for dis-
results of diagnostic procedures will aid in the diagnosis and charge when his morning labs showed an increase in BUN
assessment of the severity of disease. By monitoring serum and serum creatinine concentration. Upon examination, he
creatinine concentrations on a routine basis, it can be esti- was found to have 2+ pitting edema, weight gain, nausea,
elevated blood pressure, and rales on chest auscultation.
mated whether kidney function is improving or worsening.
Kidney function can also be evaluated based on urine output. What sign and symptoms does the patient have that may
Oliguria and anuria are dened as urine outputs of less than indicate ARF?
400 mL and 50 mL over 24 hours, respectively. Patients with What risk factors does he have for the development of ARF?
reduced urine output often have an increased mortality and What additional information do you need to fully assess
may represent a more severe form of ARF. Non-oliguric ARF this patient?
is dened as a urine output of greater than 400 mL per day. It
Clinical Presentation and Diagnosis Hyperkalemia

Metabolic acidosis
Urinalysis
While some clinical and laboratory ndings assist in the gen- Sediment
eral diagnosis of ARF, others are used to differentiate between Scant or bland (prerenal or postrenal ARF)
prerenal, intrinsic, and postrenal ARF. For example, patients Brown, muddy granular casts (highly indicative of ATN)
with prerenal ARF typically demonstrate enhanced sodium Proteinuria (glomerulonephritis or allergic interstitial nephritis)
reabsorption, which is reected by a low urine sodium con- Eosinophiluria (acute interstitial nephritis)
centration and a low fractional excretion of sodium. Urine is Hematuria/red blood cell casts (glomerular disease or
typically more concentrated with prerenal ARF and there is a bleeding in urinary tract)
higher urine osmolality and urine:plasma creatinine ratio White blood cells or casts (acute interstitial nephritis or
compared to intrinsic and postrenal ARF. severe pyelonephritis)
Signs and Symptoms of Uremia
Urinary Indices
Peripheral edema
Weight gain Intrinsic and
Nausea/vomiting/diarrhea/anorexia Postrenal
Mental status changes Prerenal ARF ARF
Fatigue Urine osmolality Greater than Less than
Shortness of breath (concentration of 500 mOsm 350 mOsm
Pruritus solutes in the urine)
Volume depletion (prerenal ARF) Urine sodium Less than 20 Greater than
Weight loss (prerenal ARF) concentration 40
Anuria alternating with polyuria (postrenal ARF) (mEq/L)
Colicky abdominal pain radiating from ank to groin Fractional excretion of Less than 1% Greater than
sodium (FENa) 1%
(postrenal ARF)
Specic gravity Greater than Less than
Physical Examination Findings 1.020 1.015
Hypertension Urine:plasma creatinine
Jugular venous distention ratio Greater than Less than
Pulmonary edema 40:1 20:1
Rales
Asterixis Loop diuretics such as furosemide enhance sodium excretion
Pericardial or pleural friction rub and increase FENa, confounding the interpretation of the test.
Hypotension/orthostatic hypotension (prerenal ARF)
Common Diagnostic Procedures
Rash (acute interstitial nephritis)
Urinary catheterization (insertion of a catheter into a
Bladder distention (postrenal bladder outlet obstruction)
patients bladder; an increase in urine output may occur
Prostatic enlargement (postrenal ARF)
with postrenal obstruction)
Laboratory Tests Renal ultrasound (uses sound waves to assess size, posi-
Elevated serum creatinine concentration (normal range tion, and abnormalities of the kidney; dilatation of the uri-
approximately 0.6 to 1.2 mg/dL [53 to 106 mol/L]) nary tract can be seen with postrenal ARF)
Elevated BUN concentration (normal range approximately Renal angiography (administration of intravenous contrast
8 to 25 mg/dL [2.9 to 8.9 mmol/L]) dye to assess the vasculature of the kidney)
Decreased creatinine clearance (normal 90 to Retrograde pyelography (injection of contrast dye into the
120 mL/minute) ureters to assess the kidney and collection system)
BUN:creatinine ratio (elevated in prerenal ARF) Kidney biopsy (collection of a tissue sample of the kidney
Greater than 20:1 (prerenal ARF) for the purpose of microscopic evaluation; may aid in the
Less than 20:1 (intrinsic or postrenal ARF) diagnosis of glomerular and interstitial diseases)
postrenal ARF can be reversed if the underlying problem is

TREATMENT
promptly identied and corrected, while treatment of intrin-
sic renal failure is more supportive in nature. There is no
Desired Outcomes and Goals
evidence that drug therapy hastens patient recovery in ARF,
A primary goal of therapy is ameliorating any identiable decreases length of hospitalization, or improves survival.13
underlying causes of ARF such as hypovolemia, nephrotoxic Therefore, options are limited to supportive therapy, such as
drug administration, or ureter obstruction. Prerenal and uid, electrolyte, and nutritional support, renal replacement
Patient Encounter, Part 2: The Medical Regular insulin 10 units in the morning and 10 units in the
History, Physical Examination, and evening
Laboratory Tests Allopurinol 100 mg orally daily
Naproxen 275 mg orally every 12 hours
PMH Atenolol 50 mg orally daily
Type 1 diabetes mellitus since the age of 32 ROS
Chronic kidney disease (BUN and serum creatinine were () fever or chills, (+) N, () V/D
30 mg/dL [10.7 mmol/L] and 2.5 mg/dL [221 mol/L],
PE
respectively, on admission)
VS: blood pressure 154/95 mm Hg, pulse 80 beats per minute,
Hypertension
respiratory rate 26/minute, temperature 37.7C, current wt
Gout
79 kg (admission wt 75 kg), ht 510 (178 cm)
Osteoarthritis
Chest: Basilar crackles, inspiratory wheezes
FH CV: S1, S2 normal, no S3
Father with a history of type 2 diabetes mellitus, hyper- MS/Exts: 2+ pedal edema
tension, and stage 5 chronic kidney disease; he died from a
Urinalysis
myocardial infarction at age 68; mother with a history of
Color, yellow; character, hazy; glucose (); ketones ();
hypertension; she died from injuries sustained in a motor
specic gravity 1.020; pH 5.0; (+) protein; coarse granular
vehicle accident at the age of 52
casts, 5 to 10/low-powered eld; white blood cell (WBC)
SH count, 5 to 10/high-powered eld; red blood cell (RBC)
Retired coal miner; no smoking, occasional alcohol use count, 2 to 5/high-powered eld; no bacteria; nitrite ();
Hospital Meds blood small; osmolality 325 mOsm; urinary sodium 77
Gentamicin 120 mg intravenous piggyback every 12 hours mEq/L (77 mmol/L); creatinine 63 mg/dL (5569 mol/L)
(dose discontinued after 3 days) Day 3 Labs
Gentamicin 120 mg intravenous piggyback every 24 hours
(days 4 through 10, discontinued this morning) Gentamicin concentrations
Ampicillin 2 g intravenous piggyback every 8 hours (10-day 3.4 mcg/mL (7.12 mol/L) = trough concentration drawn
course, discontinued this morning) immediately prior to the next dose
Sliding scale insulin 6.4 mcg/mL (13.38 mol/L) = peak concentration drawn
Allopurinol 100 mg orally daily 1 hour after the end of the infusion
Ranitidine 150 mg orally every 12 hours Urine (+) Enterococcus spp.
Atenolol 50 mg orally daily
Enalapril 2.5 mg orally daily Given this additional information, what is your assessment
of the patients condition?
Home Meds Identify your treatment goals for the patient.
NPH insulin 20 units in the morning and 10 units in the
evening
therapy (RRT), and treatment of non-renal complications reports in the literature over the efcacy of loop diuretics.
such as sepsis and gastrointestinal bleeding while regeneration Most studies demonstrate an improvement in urine output,
of the renal epithelium occurs. In addition, prevention of but with no effect on survival or need for dialysis. There are
adverse drug reactions by discontinuing nephrotoxic drugs or some reports that loop diuretics may worsen renal function.14
adjustment of drug dosages based on the patients renal func- This may be due in part to excessive preload reduction that
tion is desired. results in renal vasoconstriction. Thus, loop diuretics are lim-
ited to instances of volume overload and edema and are not
Pharmacologic Therapy intended to hasten renal recovery or improve survival.
Loop diuretics (furosemide, bumetanide, torsemide, and
Loop Diuretics ethacrynic acid) are all equally effective when given in equiva-
There is signicant controversy over the role of loop diuretics lent doses. Therefore, selection is based on the side-effect pro-
in the treatment of ARF. Theoretical benets in hastening le, cost, and pharmacokinetics of the agents. The incidence of
recovery of renal function include decreased metabolic oxy- ototoxicity is signicantly higher with ethacrynic acid com-
gen requirements of the kidney, increased resistance to pared to the other loop diuretics; therefore, its use is limited to
ischemia, increased urine ow rates that reduce intraluminal patients who are allergic to the sulfa component in the other
obstruction and ltrate backleak, and renal vasodilation.6 loop diuretics.15 While ototoxicity is a well-established side
Theoretically, these effects could lead to increased urine out- effect of furosemide, its incidence is greater when administered
put, decreased need for dialysis, improved renal recovery, and by the intravenous route at a rate exceeding 4 mg per minute.16
ultimately, increased survival. However, there are conicting Torsemide has not been reported to cause ototoxicity.
There are several pharmacokinetic differences between Efcacy of diuretic administration can be determined by
loop diuretics. Fifty to sixty percent of a dose of furosemide is comparison of a patients hourly uid balance. Other methods
excreted unchanged by the kidney with the remainder under- to minimize volume overload, such as uid restriction and
going glucuronide conjugation in the kidney.17 In contrast, concentration of IV medications, should be initiated as
liver metabolism accounts for 50% and 80% of the elimina- needed. If urine output does not increase to about 1 mL/kg
tion of bumetanide and torsemide, respectively.17 Thus, per hour, the dosage can be increased to a maximum of 160
patients with ARF may have a prolonged half-life of to 200 mg of furosemide or its equivalent (Fig. 221).18 Other
furosemide. The bioavailability of both torsemide and methods to improve diuresis can be initiated sequentially,
bumetanide is higher than for furosemide. The intravenous such as: (1) shortening the dosage interval; (2) adding
(IV):oral ratio for bumetanide and torsemide is 1:1, bioavail- hydrochlorothiazide or metolazone; and (3) switching to a
ability of oral furosemide is approximately 50%, with a continuous infusion loop diuretic. A loading dose should be
reported range of 10% to 100%.18 administered prior to both initiating a continuous infusion
Furosemide and bumetanide are both available in generic and increasing the infusion rate.17 When high doses of loop
formulations and are generally less expensive than torsemide. diuretics are administered, especially in combination with dis-
The pharmacodynamic characteristics of loop diuretics are tal convoluted tubule diuretics, the hemodynamic and uid
similar when equivalent doses are administered. Because loop status of the patient should be monitored every shift, and the
diuretics exert their effect from the luminal side of the electrolyte status of the patient should be monitored at least
nephron, urinary excretion correlates with diuretic response. daily to prevent profound diuresis and electrolyte abnormali-
Substances that interfere with the organic acid pathway, such ties, such as hypokalemia. Patients will not benet from
as endogenous organic acids which accumulate in renal dis- switching from one loop diuretic to another because of the
ease, competitively inhibit secretion of loop diuretics. similarity in mechanisms of action.
Therefore, large doses of loop diuretics may be required to Thiazide diuretics, when used as single agents, are generally
ensure that adequate drug reaches the nephron lumen. In not effective for uid removal when creatinine clearance is less
addition, loop diuretics have a ceiling effect where maximal than 30 mL/minute. Mannitol is also not recommended for the
natriuresis occurs. Thus, very large doses of furosemide (e.g., treatment of volume overload associated with ARF. Mannitol
1 g) are generally not considered necessary and may unneces- is removed by the body by glomerular ltration. In patients
sarily increase the risk of ototoxicity.16 with renal dysfunction, mannitol excretion is decreased,
Several adaptive mechanisms by the kidney limit effective- resulting in expanded blood volume and hyperosmolality.18
ness of loop diuretic therapy. Postdiuretic sodium retention Potassium-sparing diuretics, which inhibit sodium reabsorp-
occurs as the concentration of diuretic in the loop of Henle tion in the distal nephron and collecting duct, are not suf-
decreases. This effect can be minimized by decreasing the ciently effective in removing uid. In addition, they increase
dosage interval (i.e., dosing more frequently) or by adminis- the risk of hyperkalemia in patients already at risk. Thus,
tering a continuous infusion. Continuous infusion loop loop diuretics are the diuretics of choice for the management of
diuretics may be easier to titrate than bolus dosing, requires volume overload in ARF.
less nursing administration time, and may lead to fewer
adverse reactions. Dopamine
Prolonged administration of loop diuretics can lead to a Low-dose dopamine, in doses ranging from 0.5 to 3 mcg/kg
second type of diuretic resistance. Enhanced delivery of per minute, predominantly stimulates dopamine-1 receptors,
sodium to the distal tubule can result in hypertrophy of distal leading to renal vascular vasodilation and increased renal
convoluted cells.17 Subsequently, increased sodium chloride blood ow. While this effect has been substantiated in healthy,
absorption occurs in the distal tubule which diminishes the euvolemic individuals with normal kidney function, a lack of
effect of the loop diuretic on sodium excretion. Addition of a efcacy data exists in patients with ARF. Although there are
distal convoluted tubule diuretic, such as metolazone or more than 50 published reports evaluating the efcacy of low-
hydrochlorothiazide, to a loop diuretic can result in a syner- dose dopamine in the treatment of ARF, numerous aws in
gistic increase in urine output. There are no data to support their study design limit their applicability to clinical practice.
the efcacy of one distal convoluted tubule diuretic over Most of the studies were retrospective, and lacked randomiza-
another. The common practice of administering the distal tion, blinding, and inclusion of a control group. Lack of concise
convoluted tubule diuretic 30 to 60 minutes prior to the loop endpoints, insufcient power to detect a signicant difference,
diuretic has not been studied, although this practice may rst and concurrent treatment with drugs that can affect study
inhibit sodium reabsorption at the distal convoluted tubule endpoints makes interpretation of the results difcult.
before it is inundated with sodium from the loop of Henle. The most comprehensive study evaluating the efcacy of
A usual starting dose of IV furosemide for the treatment of low-dose dopamine to date is the Australian and New Zealand
ARF is 40 mg (Fig. 221). Reasonable starting doses for Intensive Care Society (ANZICS) Clinical Trials Group study.19
bumetanide and torsemide are 1 mg and 20 mg, respectively.17 Low-dose dopamine was compared to placebo in critically ill
FIGURE 221. Algorithm for treatment of extracellular uid expansion. CrCl, creatinine clearance; ECF, extra-
cellular uid; HCTZ, hydrochlorothiazide; IV, intravenous; PO, oral.
patients with at least one indicator of early renal failure and two decreased incidence of death or dialysis in the fenoldopam-
indicators of the systemic inammatory response. Results indi- treated group. Large, prospective trials are needed before
cate that administration of low-dose dopamine compared to fenoldopam can be recommended. Other agents that are
placebo did not alter peak serum creatinine concentration or under evaluation for the treatment of ARF include atrial
secondary outcome endpoints such as need for renal replace- natriuretic peptide, urodilatin, and nesiritide.
ment therapy (RRT), duration of stay in the intensive care unit
(ICU), or survival to hospital discharge. Use of loop diuretics Nonpharmacologic Treatment
was similar between groups and may have been responsible for
the increase in urine output demonstrated in the study. More Renal Replacement Therapy
than half of the patients in the study were non-oliguric. RRT may be necessary in patients with established ARF to
Therefore, the results cannot be directly extrapolated to the treat volume overload that is unresponsive to diuretics, to
oliguric or anuric patient. minimize the accumulation of nitrogenous waste products,
A recent meta-analysis was performed on all published and to correct electrolyte and acid-base abnormalities while
human trials that used low-dose dopamine in the prevention renal function recovers. Five to thirty percent of patients with
or treatment of ARF.20 A total of 61 studies were identied ARF treated with dialysis will not have recovery of their renal
that randomized more than 3300 patients to low-dose function and will need to remain on long-term dialysis.24 This
dopamine or placebo. Results reveal no signicant difference may be due in part to underlying illnesses, as ARF is often seen
between the treatment and control groups for mortality, in the setting of multiorgan failure. There are two types of
requirement for RRT, or adverse effects. dialysis modalities commonly used in ARF: intermittent
Low-dose dopamine is not without adverse reactions and hemodialysis (IHD) and continuous renal replacement ther-
most studies have failed to evaluate its potential toxicities. apy (CRRT). CRRT is a pump-driven form of dialysis which
Adverse reactions that may be associated with low-dose provides slow uid and solute removal on a continuous,
dopamine include: tachycardia, arrhythmias, myocardial 24-hour basis. IHD is a higher-efciency form of dialysis
ischemia, depressed respiratory drive, and gut ischemia. Low- which is provided for several hours a day at a variable fre-
dose dopamine has also been postulated to impair resistance quency (usually daily or 3 to 5 times per week) at a higher
to infection through a reduction in prolactin concentra- blood ow rate. The primary advantage of CRRT is hemody-
tions.21 Furthermore, signicant overlap in receptor activation namic stability and better volume control, particularly in
occurs. Therefore, doses considered to activate only dopamine patients who are unable to tolerate rapid uid removal. The
receptors may increase cardiac output and blood pressure primary disadvantages associated with CRRT are continuous
through dopamines effect on - or -adrenergic receptors. nursing requirements, continuous anticoagulation, frequent
Based on the results of the ANZICS trial, the lack of conclu- clotting of the dialyzer, patient immobility, and increased cost.
sive evidence in many earlier studies, and several meta-analyses, There is no conclusive evidence that one type of dialysis is pre-
routine use of low-dose dopamine solely for increasing renal ferred to another in terms of mortality and recovery of renal
blood ow is not recommended. While recent surveys con- function.25 Thus, selection of CRRT over IHD is often gov-
tinue to show that low-dose dopamine is used in many ICUs, erned by the critical illness of the patient and by the comfort
benets of low-dose dopamine in the prevention or treatment of level of the institution with one particular type of dialysis.
ARF remain unproven. With either type of dialysis, studies suggest that recovery of
renal function is decreased in ARF patients who undergo dialysis
Fenoldopam compared with those not requiring dialysis. Decreased recovery
Fenoldopam is a selective dopamine-1 receptor agonist that is of renal function may be due to hemodialysis-induced hypoten-
approved for short-term management of severe hypertension. sion causing additional ischemic injury to the kidney. Also, expo-
Because it does not stimulate dopamine-2, -adrenergic, and sure of a patients blood to bioincompatible dialysis membranes
-adrenergic receptors, fenoldopam causes vasodilation in the (cuprophane or cellulose acetate) results in complement and
renal vasculature with potentially fewer non-renal effects than leukocyte activation which can lead to neutrophil inltration
dopamine. In normotensive individuals with normal kidney into the kidney and release of vasoconstrictive substances that
function, intravenous fenoldopam increases renal blood ow can prolong renal dysfunction.26 Synthetic membranes com-
without lowering systemic blood pressure.22 While prelimi- posed of substances such as polysulfone, polyacrylonitrile, and
nary studies in animal models of ARF are encouraging, few polymethylmethacrylate are considered to be more biocompati-
studies are available assessing its effectiveness in the treatment ble and would be less likely to activate complement. Synthetic
of ARF. A prospective randomized study comparing membranes are generally more expensive than cellulose-based
fenoldopam to placebo in early ATN did not nd a difference membranes. Several recent meta-analyses found no difference
in need for dialysis or mortality.23 However, in two separate in mortality between biocompatible and bioincompatible
subset analyses, patients with ATN after cardiothoracic sur- membranes. Whether biocompatible membranes lead to better
gery and patients without diabetes mellitus demonstrated a patient outcomes continues to be debated.
cells, and subsequent cellular uptake and cell death.27 In clin-

Patient Encounter, Part 3 ical practice, all of the aminoglycosides are considered equally
nephrotoxic, and the same precautions should be used for all
the agents. High cumulative drug exposure increases the inci-
dence of aminoglycoside-induced ARF. A prolonged course of
Creating a Care Plan
Based on the information presented, create a care plan for aminoglycoside therapy (typically longer than 7 to 10 days) is
this patients ARF. Your plan should include: (1) a statement a risk factor for the development of ARF, especially in those
of the drug-related need and/or problems, (2) the goals of with preexisting chronic kidney disease and in the elderly.28
therapy, (3) a detailed patient-specic therapeutic plan, and Alternative antibiotics should be selected when culture and sen-
(4) a plan for follow-up to determine whether the goals sitivity reports are available. Methods to minimize drug exposure
have been achieved and adverse effects avoided. include maintaining trough concentrations less than 2 mcg/mL
for gentamicin and tobramycin (less than 10 mcg/mL for
amikacin), minimizing length of therapy, avoiding repeated
Supportive Therapy courses of aminoglycosides, and utilizing extended-interval
Supportive therapy in ARF includes adequate nutrition, cor- dosing methods.29 There is conicting evidence as to whether the
rection of electrolyte and acid-base abnormalities (particularly combination of vancomycin and an aminoglycoside has a
hyperkalemia and metabolic acidosis), uid management, and higher incidence of ARF than aminoglycoside therapy alone.
correction of any hematologic abnormalities. Because ARF is ARF due to aminoglycosides can be mild if the drug is dis-
often associated with multiorgan failure, treatment includes continued, although severe ARF requiring dialysis can occur.
the medical management of infections, cardiovascular and gas- The goal of extended-interval dosing is to provide greater
trointestinal conditions, and respiratory failure. Finally, all efcacy against the microorganism with a lower incidence of
drugs should be reviewed, and dosage adjustments made based toxicity. Because aminoglycosides demonstrate concentration-
on an estimate of the patients glomerular ltration rate. dependent killing and a post-antibiotic effect, extended-interval
dosing of antibiotics can be efcacious in the treatment of
most conditions. Extended-interval aminoglycoside dosing
may reduce the incidence of nephrotoxicity by providing high
PREVENTION OF ACUTE RENAL FAILURE concentrations of drug which saturate proximal tubule uptake
sites. Once saturated, the remaining aminoglycoside mole-
Avoidance cules pass through the proximal tubule and are excreted in the
The best preventive measure for ARF, especially in individuals urine with less tubular accumulation. A primary concern with
at high risk, is to avoid medications that are known to precip- extended-interval dosing is the risk of ototoxicity that can
itate ARF. Nephrotoxicity is a signicant side effect of amino- occur with high aminoglycoside concentrations. However, a
glycosides, angiotensin-converting enzyme inhibitors, consistent nding in studies is that extended-interval amino-
angiotensin receptor antagonists, amphotericin B, non- glycoside dosing is as effective as traditional dosing and is not
steroidal anti-inammatory drugs, cyclosporine, tacrolimus, more toxic, and in some studies is less toxic than traditional
and radiographic contrast agents.6 Unfortunately, an effective, dosing. Extended-interval dosing is not recommended in
non-nephrotoxic alternative may not always be appropriate patients with preexisting renal dysfunction, conditions where
for a given patient and the risks and benets of selecting a high concentrations are not needed (e.g., urinary tract infec-
drug with nephrotoxic potential must be considered. For tions), hyperdynamic patients that may demonstrate increased
example, serious gram-negative infections may require double drug clearance (e.g., burn patients), and others where you
antibiotic coverage, and based on culture and sensitivity would suspect altered pharmacokinetics or increased risk of
reports, aminoglycoside therapy may be necessary. In cases ototoxicity.
such as this, other measures to reduce the risk of ARF should
be instituted. Thus, identifying patients at high risk for Amphotericin B
development of ARF and implementing preventive methods to Amphotericin Binduced ARF occurs in as many as 40% to
decrease its occurrence or severity is critical. 65% of patients treated with the conventional desoxycholate
formulation.30 Nephrotoxicity is due to renal arterial vasocon-
striction and distal renal tubule cell damage. Risk factors
Drug-Induced Acute Renal Failure include high doses, treatment for at least 7 days, preexisting
kidney dysfunction, and concomitant use of other nephro-
Aminoglycosides toxic drugs.31 Three lipid-based formulations of amphotericin
Treatment with aminoglycosides (gentamicin, tobramycin, B have been developed in an attempt to decrease the incidence
and amikacin) can cause non-oliguric intrinsic ARF. Injury is of ARF: amphotericin B lipid complex, amphotericin colloidal
due to the binding of aminoglycosides to proximal tubular dispersion, and liposomal amphotericin B. The range of
nephrotoxicity reported is 15% to 25% for these formulations. saline (0.45%) or to oral hydration.37,38 Isotonic fluid
The mechanism for decreased nephrotoxicity has not been appears to provide the best benefit for prevention of
completely elucidated, but it is thought to be due to preferen- nephropathy. A common regimen is intravenous isotonic
tial release of amphotericin B from macrophages at the site of sodium chloride (1 mL per kilogram of body weight per
infection, with less of an afnity for the kidney.30 Whether hour) administered for 12 hours before and 12 hours after
there are signicant differences in nephrotoxicity between the the procedure. Fluid should be administered cautiously to
three lipid-based formulations remains unclear, as there patients with congestive heart failure (CHF), left ventricular
have been no head-to-head comparisons of the three agents dysfunction, and signicant renal dysfunction. Early evi-
in humans. In one prospective, randomized study, the incidence suggests that hydration plus sodium bicarbonate to
dence of nephrotoxicity was lower with liposomal ampho- alkalize renal tubule uid may reduce free radical forma-
tericin B (14%) compared to amphotericin B lipid complex tion. More studies are needed before bicarbonate can be
(42%) in febrile, neutropenic patients.32 Therefore, large, recommended.
prospective studies comparing the incidence of nephrotoxi- Minimizing the quantity of contrast media administered
city between these agents are needed. Lipid-based formula- may be benecial in preventing nephropathy. Some studies,
tions are recommended in individuals with risk factors for but not all, have directly associated dose of contrast media
development of ARF. In addition, use of alternative anti- and nephrotoxicity. Avoidance of contrast dye with alterna-
fungal agents should be considered in the presence of wors- tive diagnostic procedures should be considered in high-
ening renal function. Administration of intravenous normal risk patients, but may not always be feasible. In addition,
saline may also attenuate nephrotoxicity associated with avoidance of multiple contrast studies in a short time
amphotericin B. period will allow renal function to return to normal between
procedures.
Radiocontrast Agents Because production of reactive oxygen species have been
Intravascular radiographic contrast agents are adminis- implicated in the pathophysiology of contrast-induced ARF,
tered during radiologic studies and carry with them the prophylactic administration of the antioxidant acetylcysteine
well-documented risk of ARF. Patients at risk for developing has been investigated. A dose of 600 mg twice daily the day
ARF include patients with chronic kidney disease, diabetic before and the day of the procedure decreased the incidence of
nephropathy, dehydration, and higher dose of contrast dye.33 renal failure in one small study, although patient outcomes
Contrast agents are water-soluble, triiodinated, benzoic acid such as mortality and length of hospitalization were not
salts that cause an osmotic diuresis due to their osmolality, evaluated.39 Since then, approximately eight additional
which exceeds that of plasma. The mechanism of nephro- studies evaluating the efcacy of oral acetylcysteine have
toxicity is not fully understood; however, direct tubular been conducted, with mixed results. In addition, a series of
toxicity, renal ischemia, and tubular obstruction have been meta-analyses have also analyzed the results of the studies.
implicated.34 Diatrizoate and iothalamate are ionic contrast The studies were varied in terms of study population, sample
agents. Iohexol, iopamidol, ioversol, and iopromide represent size, denition of contrast nephropathy, type of contrast agent
non-ionic agents. The incidence of nephrotoxicity with ionic used, hydration, and formulation of acetylcysteine adminis-
and non-ionic agents is similar in patients at low risk for tered, thus making collective interpretation of the results dif-
developing ARF; however, in high-risk patients, nephrotoxic- cult. Although data are not conclusive, they suggest a bene-
ity is signicantly greater when ionic contrast agents are used. cial effect of oral acetylcysteine in combination with adequate
In diabetic patients with chronic kidney disease and a serum hydration.
creatinine concentration of greater than 1.5 mg/dL, nephro- Fenoldopam does not decrease the incidence of contrast
toxicity occurred in 33.3% and 47.7% of patients receiving nephropathy.40 Due to its hypotensive effect, it may worsen
non-ionic and ionic contrast agents, respectively.35 The cost kidney function.
of non-ionic agents is approximately 10-fold higher, which
may limit their routine use in all patients undergoing radio- Cyclosporine and Tacrolimus
graphic studies. Cyclosporine and tacrolimus are calcineurin inhibitors that are
Therapeutic measures that have been used to decrease the administered as part of immunosuppressive regimens in kidney,
incidence of contrast-induced nephropathy include extracel- liver, heart, lung, and bone marrow transplant recipients. In
lular volume expansion, minimization of the amount of con- addition, they are used in autoimmune disorders such as psori-
trast administered, and treatment with oral acetylcysteine. asis and multiple sclerosis. The pathophysiologic mechanism for
Theophylline, fenoldopam, loop diuretics, mannitol, dopamine, ARF is renal vascular vasoconstriction.41 It often occurs within
and calcium antagonists have no effect or may worsen ARF. the rst 6 to 12 months of treatment, and can be reversible with
The most common therapeutic maneuver to decrease the dose reduction or drug discontinuation. Risk factors include
incidence of contrast-induced nephropathy is extracellular high dose, elevated trough blood concentrations, increased age,
volume expansion.36 Several recent studies have compared and concomitant therapy with other nephrotoxic drugs.41
the efcacy of isotonic sodium chloride (0.9%) to half normal Cyclosporine and tacrolimus are extensively metabolized by
the liver through the cytochrome P-450 (CYP)3A4 pathway

and drugs that inhibit their metabolism (e.g., erythromycin, Patient Encounter, Self-Study Questions
clarithromycin, uconazole, ketoconazole, verapamil, diltiazem,
and nicardipine) can precipitate ARF. Because ARF is dose
dependent, careful monitoring of cyclosporine or tacrolimus
1. What would have been an appropriate gentamicin dosage
trough concentrations can minimize its occurrence; however,
regimen that would have avoided elevated plasma
ARF can develop with normal or low blood concentrations. In concentrations?
addition, there is some evidence that calcium channel blockers 2. Based on the patients renal function, would other drug
have a renoprotective effect through dilation of the afferent arte- therapy recommendations be warranted at this time?
rioles and are often used preferentially as antihypertensive
agents in kidney transplant recipients.
It is often difcult to differentiate ARF from acute rejection Non-steroidal Anti-Inammatory Drugs
in the kidney transplant recipient, as both conditions may Non-steroidal anti-inammatory agents can likewise cause pre-
present with similar symptoms and physical examination renal ARF through inhibition of prostaglandin-mediated renal
ndings. However, fever and graft tenderness are more likely vasodilation. Risk factors are similar to those of ACE inhibitors
to occur with rejection while neurotoxicity is more likely to and ARBs. Additional risk factors include hepatic disease with
occur with cyclosporine or tacrolimus toxicity. Kidney biopsy ascites, systemic lupus erythematosus, and advanced age. The
is often needed to conrm the diagnosis of rejection.42 onset is often within days of initiating therapy and patients typi-
cally present with oliguria. It is usually reversible with drug dis-
Angiotensin-Converting Enzyme Inhibitors and continuation. Agents that preferentially inhibit cyclooxygenase-2
Angiotensin Receptor Blockers pose a similar risk as traditional, non-selective NSAIDs.44
In instances of decreased renal blood ow, production of
angiotensin II increases, resulting in efferent arteriole vasocon- Other Drugs
striction and maintenance of glomerular capillary pressure and Other drugs that are commonly implicated in causing ARF
GFR (Fig. 222). In patients initiated on ACE inhibitors or include acyclovir, adefovir, carboplatin, cidofovir, cisplatin,
ARBs, angiotensin II synthesis decreases thereby dilating effer- foscarnet, ganciclovir, indinavir, methotrexate, pentamidine,
ent arterioles and decreasing glomerular capillary pressure and ritonavir, sulnpyrazone, and tenofovir.45
GFR. Risk factors for developing ARF are preexisting renal dys-
function, severe atherosclerotic renal artery stenosis, volume OUTCOME EVALUATION
depletion, and severe CHF.43 ARF often develops within days,
with a rapid rise in BUN and serum creatinine concentration. Goals of therapy are to maintain a state of euvolemia with
Discontinuation of the drug usually results in return of renal good urine output (at least 1 ml/kg per hour), to return serum
function to baseline, although a small decrease in kidney creatinine and BUN to baseline, and to correct electrolyte and
function may be acceptable in patients with severe CHF who acid-base abnormalities. Vital signs, weight, uid intake, urine
would benet from the hemodynamic effect of ACE inhibitors output, BUN, creatinine, and electrolytes should be assessed
or ARBs. daily in the unstable patient.
FIGURE 222. Normal

glomerular autoregulation
serves to maintain intra-
glomerular capillary hydro-
static pressure, glomerular l-
tration rate (GFR), and ulti-
mately, urine output. This is
accomplished by modulation
of afferent and efferent arteri-
oles. Afferent and efferent
arteriolar vasoconstriction are
primarily mediated by
angiotensin II, whereas affer-
ent vasodilation is primarily
mediated by prostaglandins.
PGE2, prostaglandin E2.
IBW: ideal body weight

Patient Care and Monitoring ICU: intensive care unit
IHD: intermittent hemodialysis
IV: intravenous
JVD: jugular venous distention
1. Assess kidney function by evaluating a patients signs and MDRD: Modication of Diet in Renal Disease (study)
symptoms, laboratory test results, and urinary indices. NSAID: non-steroidal anti-inammatory drug
Calculate a patients creatinine clearance to evaluate the RBC: red blood cell
severity of kidney disease. RRT: renal replacement therapy
2. Obtain a thorough and accurate drug history, including Scr: serum creatinine concentration
the use of non-prescription drugs such as NSAIDs. Ucr: urine creatinine
WBC: white blood cell
3. Evaluate a patients current drug regimen to:
Determine if drug therapy may be contributing to ARF.

Consider not only drugs that can directly cause ARF (e.g., available at www.ChisholmPharmacotherapy.com.
aminoglycosides, amphotericin B, NSAIDs, cyclosporine,
tacrolimus, ACE inhibitors, and ARBs), but also drugs that Log into the website: www.pharmacotherapyprinciples.com
can predispose a patient to nephrotoxicity or prerenal for information on obtaining continuing education credit for
ARF (i.e., diuretics and antihypertensive agents). this chapter.
Determine if any drugs need to be discontinued, or alter-
nate drugs selected, to prevent worsening of renal function.
Adjust drug dosages based on the patients creatinine KEY REFERENCES AND READINGS
clearance or evidence of adverse drug reactions or
interactions. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients
with early renal dysfunction: a placebo-controlled randomized
4. Develop a plan to provide symptomatic care of compli- trial. Australian and New Zealand Intensive Care Society (ANZ-
cations associated with ARF, such as diuretic therapy to ICS) Clinical Trials Group. Lancet 2000;356: 21392143.
treat volume overload. Monitor the patients weight, Bellomo R, Ronco C, Kellum JA, et al. Acute renal failuredenition,
urine output, electrolytes (such as potassium), and blood outcome measures, animal models, uid therapy and informa-
pressure to assess efcacy of the diuretic regimen. tion technology needs; the Second International Consensus
Conference of the Acute Dialysis Quality Initiative (ADQI)
Group. Crit Care 2004;8:R204R212.
Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319:3850.
CONCLUSION Cantarovich F, Rangoonwala B, Lorenz H, et al. High-dose furosemide
for established ARF: a prospective, randomized, double-blind,
ARF is a potentially life-threatening condition that can lead to placebo-controlled, multicenter trial. Am J Kidney Dis 2004;44:
signicant morbidity and mortality. Supportive therapy, prompt 402409.
correction of hypo- or hypervolemia, treatment of underlying Dishart MK, Kellum JA. An evaluation of pharmacological strategies
conditions, and avoidance of nephrotoxic drugs is essential. for the prevention and treatment of acute renal failure. Drugs
2000;59:7991.
Mehta RL, Pascual MT, Soroko S, et al. Diuretics, mortality, and non-
ABBREVIATIONS recovery of renal function in acute renal failure. JAMA 2002;
288;25472553.
ACE: angiotensin-converting enzyme Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast
ANZICS: Australian and New Zealand Intensive Care Society media-associated nephropathy: randomized comparison of 2
ARB: angiotensin receptor blocker hydration regimens in 1620 patients undergoing coronary
ARF: acute renal failure angioplasty. Arch Intern Med 2002;162:329336.
ATN: acute tubular necrosis Tepel M, Van der Giet M, Schwarzfeld C, et al. Prevention of radi-
BUN: blood urea nitrogen ographic contrast agent-induced reduction in renal function by
BW: body weight aceylcysteine. N Engl J Med 2000;343:180184.
CHF: congestive heart failure Tonelli M, Manns B, Feller-Kopman D. Acute renal failure in the
CrCl: creatinine clearance intensive care unit: a systematic review of the impact of dialytic
CRRT: continuous renal replacement therapy modality on mortality and renal recovery. Am J Kidney Dis
CYP: cytochrome P-450 2002;40:875885.
FENa: fractional excretion of sodium Venkataraman R. Prevention of acute renal failure. Crit Care Clin
GFR: glomerular ltration rate 2005;21:281289.
23 CHRONIC AND END-STAGE RENAL DISEASE
Kristine S. Schonder
LEARNING OBJECTIVES
1. List the risk factors for progression of chronic kidney disease (CKD).
2. Explain the mechanisms associated with progression of CKD.
3. Identify the desired outcomes for treatment of CKD.
4. Develop a therapeutic approach to slow progression of CKD, including lifestyle
modications and pharmacologic therapies.
5. Identify specic consequences associated with CKD.
6. Design an appropriate therapeutic approach to specic consequences associated with CKD.
7. Recommend an appropriate monitoring plan to assess the effectiveness of pharmacotherapy
for CKD and specic consequences.
8. Educate patients with CKD about the disease state, the specic consequences, lifestyle
modications, and pharmacologic therapies used for treatment of CKD.
KEY CONCEPTS The management of secondary hyperparathyroidism involves

correction of serum calcium and phosphorus levels, and
Chronic kidney disease is a progressive disease that eventually decreasing parathyroid hormone secretion.
leads to renal failure [end-stage renal disease (ESRD)]. Patient education and planning for dialysis should begin at
Early detection and treatment of CKD are fundamental fac- stage 4 CKD, before end-stage renal disease is reached, to allow
tors in minimizing morbidity and mortality associated with for time to establish appropriate access for dialysis.
CKD. Dialysis involves the removal of metabolic waste products by
Declining renal function disrupts the homeostasis of the sys- diffusion and ultraltration from the bloodstream across a
tems regulated by the kidney, leading to uid and electrolyte semipermeable membrane into an external dialysate solution.
imbalances, anemia, and metabolic bone disease.
Angiotensin-converting enzyme inhibitors (ACEIs) and The kidney is made up of approximately 2 million nephrons that
angiotensin II receptor blockers decrease protein excretion and are responsible for ltering, reabsorbing and excreting solutes
are the drugs of choice for hypertension in patients with CKD. and water. As the number of functioning nephrons declines, the
The most common complication of CKD is anemia, which is primary functions of the kidney that are affected include:
caused by a decline in erythropoietin production by the kid-
neys and can lead to cardiovascular disease. production and secretion of erythropoietin
The goal of anemia management is to increase hemoglobin activation of vitamin D
levels to greater than 11 g/dL (6.82 mmol/L), which generally regulation of uid and electrolyte balance
requires a combination of erythropoiesis-stimulating agents regulation of acid-base balance
and iron supplements.
Renal osteodystrophy stems from disruptions in calcium, Chronic kidney disease (CKD), also known as chronic renal
phosphorus, and vitamin D homeostasis through the interac- insufciency, progressive kidney disease, or nephropathy, is
tion with the parathyroid hormone. dened as the presence of kidney damage or decreased
373
Patient Encounter, Part 1 CV: Regular rate and rhythm, normal S1, S2; no murmurs,
rubs or gallops; lungs clear
Abd: Obese; no organomegaly, bruits or tenderness, (+)
bowel sounds; heme () stool
A 62-year-old obese female with a history of diabetes and Exts: Trace pedal edema bilaterally; decreased sensation in
hypertension presents to clinic for routine follow-up. Her feet to light touch; no lesions
fasting blood sugars have been elevated recently, averaging Labs (fasting)
180 to 250 mg/dL (10 to 13.8 mmol/L). Sodium 145 mEq/L (145 mmol/L); potassium 3.2 mEq/L
PMH (3.2 mmol/L); chloride 112 mEq/L (112 mmol/L); carbon
Diabetes mellitus for 8 years, not currently controlled dioxide 26 mEq/L (26 mmol/L); blood urea nitrogen
Hypertension for 5 years, not currently controlled 20 mg/dL (7.14 mmol/L urea); serum creatinine 1.4 mg/dL
(123.76 mol/L); glucose 240 mg/dL (13.32 mmol/L); total
Hyperlipidemia, currently managed by diet therapy
cholesterol 196 mg/dL (5.07 mmol/L); low-density
FH lipoprotein cholesterol 112 mg/dL (2.90 mmol/L); high-
Mother is alive at age 87 with coronary artery disease; father density lipoprotein cholesterol 28 mg/dL (0.72 mmol/L);
is deceased from diabetes; she has no siblings. triglycerides 280 mg/dL (3.16 mmol/L); hemoglobinA1c (HbA1c)
SH 10% (0.1); urine microalbumin 270 mg/dL (2.7 g/L)
She does not work; she smokes 1 pack of cigarettes per day,
but denies alcohol or illicit drug use; she is sedentary What risk factors does the patient have for the development
of CKD?
Meds What signs and symptoms are consistent with CKD?
Furosemide 20 mg orally daily How would you classify her CKD?
Nifedipine XL 30 mg orally daily Identify your treatment goals for the patient.
Glyburide 10 mg orally daily What lifestyle modications would you recommend for the
ROS patient with CKD?
Unremarkable What pharmacologic alternatives are available for the
patient for treatment of CKD?
PE What other interventions are appropriate to minimize the
VS: Blood pressure 145/92 mm Hg, pulse 82 beats per minute, progression of CKD?
temperature 36.9C (98.4F), Ht 54 (162.5 cm), Wt 190 lb
(86.4 kg)
glomerular ltration rate (GFR) for 3 months or more.1 Because of the slow onset of CKD and the lack of symptoms
Generally, CKD is a progressive decline in kidney function (a in earlier stages, the prevalence of CKD is difcult to determine
decline in the number of functioning nephrons) that occurs until patients reach ESRD. It is estimated that approximately
over a period of several months to years. A decline in kidney 19 million people (11% of the United States population) have
function that occurs more rapidly, over a period of days to some degree of CKD.2 Approximately 8 million people have a
weeks, is known as acute renal failure (ARF), which is discussed GFR less than 60 mL/minute/1.73 m2,2 at which point CKD is
in Chapter 22. The decline in kidney function in CKD is often generally diagnosed as a clinical condition. The prevalence of
irreversible. Therefore, measures to treat CKD are aimed at CKD is correlated with specic demographic factors: increased
slowing the progression to end-stage renal disease (ESRD). age, African-American race, and hypertension.
TABLE 231. NKF-DOQI Classication for Chronic Kidney

EPIDEMIOLOGY AND ETIOLOGY OF CKD Disease
The National Kidney Foundation (NKF) developed a classi- State Glomerular Filtration Rate (mL/minute/1.73 m2)
cation system for CKD (Table 231).1 The staging system 1 Greater than or equal to 90a
denes the stages of CKD based on GFR level, but also 2 6089
accounts for evidence of kidney damage in the absence of 3 3059
changes in GFR, as in stage 1 CKD. The GFR is calculated 4 1529
5 Less than 15 (includes patients on dialysis)
using the abbreviated Modication of Diet in Renal Disease
(MDRD) study equation: a
CKD can be present with a normal or near normal GFR if other markers
of kidney disease are present, such as proteinuria, hematuria, biopsy
results showing kidney damage, or anatomic abnormalities (e.g., cysts).
GFR = 186 (SCr)1.154 (age)0.203 (0.742 if female) NKF-DOQI, National Kidney Foundation-Dialysis Outcome Quality
(1.21 if African-American) Initiative.
CHAPTER 23 / CHRONIC AND END-STAGE RENAL DISEASE 375
CKD is a progressive disease that eventually leads to Minority and low socioeconomic communities may be targets
ESRD. The prevalence of ESRD has increased more than ve- for more widespread CKD screening programs. Other factors,
fold since 1980 to more than 450,000 people in 2003 with such as hyperlipidemia, are not directly proven to cause CKD,
more than 100,000 new cases of ESRD diagnosed in 2003.2 but can be modied by drug therapies.
Although the incidence of ESRD is declining in certain popu-
lations, the incidence of ESRD is increasing in African- Hyperlipidemia
Americans to as much as 44% in patients with diabetes 30 to Patients with CKD have a higher prevalence of dyslipidemia
39 years of age. compared to the general population. The dyslipidemia in
Because of the progressive nature of CKD, determination CKD is manifested as an elevation in total cholesterol (TC)
of risk factors for CKD is difcult. Risk factors identied for levels, low-density lipoprotein cholesterol (LDL-C) levels,
CKD are classied into three categories (Table 232): triglycerides, and lipoprotein(a) levels, and decreases in high-
density lipoprotein cholesterol (HDL-C) levels. The prevalence
Susceptibility factors, which are associated with an within the CKD population appears to be related somewhat to
increased risk of developing CKD, but are not directly the degree of proteinuria. In nephrotic syndrome, with urine
proven to cause CKD. These factors are generally not modi- protein excretion rates that exceed 3 g/24 hours, almost all
able by pharmacologic therapy or lifestyle modications. patients have some degree of dyslipidemia.3 Mounting evi-
Initiation factors, which directly cause CKD. These factors dence suggests that hyperlipidemia can promote renal injury
are modiable by pharmacologic therapy. and subsequent progression of CKD. The mechanism is simi-
Progression factors, which result in a faster decline in kid- lar to that of atherosclerosis, whereby lipid deposition causes
ney function and cause worsening of CKD. These factors activation of macrophages and monocytes, which secrete
may also be modied by pharmacologic therapy or lifestyle growth factors that stimulate cell proliferation and oxidation
modications to slow the progression of CKD. of lipoproteins. These lead to endothelial dysfunction, cellular
injury, and brosis in the kidney.4
Susceptibility Factors
Initiation Factors
Susceptibility factors can be readily used to develop screening
programs for CKD. For example, older patients, those with The three most common causes of CKD in the United States
low kidney mass or birth weight, and those with a family his- are diabetes mellitus, hypertension, and glomerulonephritis.
tory of kidney disease should be routinely screened for CKD. Together these account for about 75% of the cases of CKD
(37% for diabetes, 24% for hypertension, and 14% for glomeru-
lonephritis).2 These are discussed in further detail below.
TABLE 232. Risk Factors Associated with Chronic Kidney Diabetes

Disease Diabetes mellitus (DM) is the most common cause of CKD.2
The risk of developing nephropathy associated with DM is
Susceptibility closely linked to hyperglycemia and is similar for both type 1
Advanced age
Reduced kidney mass and type 2, although it is slightly higher in patients with type 2
Low birth weight DM.5 An estimated 3% of patients with DM will develop
Racial/ethnic minority ESRD, which is 12 times greater than those without DM.6
Family history of kidney disease
Low income or education
Systemic inammation Hypertension
Dyslipidemia The second most common cause of CKD is hypertension.2 It
Initiation is more difcult to determine the true risk of developing CKD
Diabetes mellitus in patients with hypertension because the two are so closely
Hypertension linked, with CKD also being a cause of hypertension. The
Autoimmune disease prevalence of hypertension is correlated with the degree of
Polycystic kidney disease
Drug toxicity renal dysfunction (decreased GFR) with 40% of patients with
Urinary tract abnormalities (infections, obstruction, stones) CKD stage 1, 55% of patients with CKD stage 2, and over
Progression 75% of patients with CKD stage 3 presenting with hyperten-
Hyperglycemia: Poor blood glucose control (in patients with sion.1 The risk of developing ESRD is linked to both systolic
diabetes) and diastolic blood pressure.7 A blood pressure greater than
Hypertension: Elevated blood pressure 210/110 mm Hg is associated with a 22% increased relative
Proteinuria risk of developing ESRD, compared with a blood pressure less
Tobacco smoking
than 120/80 mm Hg.7
Glomerulonephritis The effects of smoking on the kidney are multifactorial and

The etiologic and pathophysiologic features of glomerular occur in both healthy individuals and those with CKD.
diseases vary with the specic disease, making it difcult to Smoking induces glomerular hyperltration, produces an
extrapolate the risk for developing CKD in patients affected antidiuretic action that increases blood pressure, and can
by glomerular diseases. Certain glomerular diseases are damage the proximal tubule, resulting in impaired cationic
known to rapidly progress to ESRD, while others progress transport. Furthermore, systemic complications correlated
more slowly or may be reversible. with tobacco abuse, including increases in blood pressure,
platelet activity, and thromboxane A2 production, can also
Progression Factors negatively impact kidney function.13 These effects are related
to the amount of cigarettes smoked, in terms of pack years.13
Progression factors can be used as predictors of CKD. The
most important predictors of CKD include proteinuria, ele-
vated blood pressure, hyperglycemia, and tobacco smoking.
PATHOPHYSIOLOGY OF CKD
Proteinuria
The presence of protein in the urine is a marker of glomeru- A number of factors can cause initial damage to the kidney.
lar and tubular dysfunction and is recognized as an independ- The resulting sequelae, however, follow a common pathway
ent risk factor for the progression of CKD.8 Furthermore, the that promotes progression of CKD and results in irreversible
degree of proteinuria correlates with the risk for progression damage leading to ESRD (Fig. 231).
of CKD. An increase of 1 g of protein excretion per day is asso- The initial damage to the kidney can result from any of the
ciated with a ve-fold increase in the risk of progression of initiation factors listed in Table 232. Regardless of the cause,
CKD, regardless of the cause of CKD.9 The mechanisms by however, the damage results in loss of nephron mass. The
which proteinuria potentiates CKD are discussed later. resultant effect is hypertrophy of the remaining nephrons to
Microalbuminuria is also linked with vascular injury and compensate for the loss of renal function and nephron mass.
increased cardiovascular mortality.10 These adaptive changes result in an increase in glomerular l-
tration and tubular function, both reabsorption and secre-
Elevated Blood Pressure tion, in the remaining nephrons. Initially, these adaptive
Systemic blood pressure correlates with glomerular pressure changes preserve many of the clinical parameters of renal
and elevations in both systemic blood pressure and glomeru- function, including creatinine and electrolyte excretion.
lar pressure contribute to glomerular damage. The rate of However, as time progresses, glomerular capillary pressure is
GFR decline is related to elevated systolic blood pressure and increased, mediated by angiotensin II, to maintain the hyper-
mean arterial pressure. The decline in GFR is estimated to be ltration state of the functioning nephrons. Angiotensin II is
14 mL/minute per year with a systolic blood pressure of 180 mm a potent vasoconstrictor of both the afferent and efferent arte-
Hg. Conversely, the decline in GFR decreases to 2 mL/minute rioles, but has a preferential effect to constrict the efferent
per year with a systolic blood pressure of 135 mm Hg.11 arteriole, thereby increasing the pressure in the glomerular
capillaries. Increased glomerular capillary pressure expands
Elevated Blood Glucose the pores in the glomerular basement membrane, altering the
The reaction between glucose and protein in the blood pro- size-selective barrier and allowing proteins to be ltered
duces advanced glycosylation end-products (AGEs), which are through the glomerulus.14
metabolized in the proximal tubules. Hyperglycemia increases Protein excretion through the nephron, or proteinuria,
the synthesis of AGEs in patients with diabetes and the corre- increases nephron loss through various complex mechanisms.
sponding increase in metabolism is suspected to be a cause of Filtered proteins are reabsorbed in the renal tubules, which
nephropathy associated with diabetes.12 activates the tubular cells to produce inammatory and
vasoactive cytokines and triggers complement activation.14
Tobacco Smoking These in turn cause interstitial damage and scarring within the
Smoking is an independent risk factor for the development of renal tubules, leading to damage and loss of more nephrons.
microalbuminuria in primary hypertension. In patients with Ultimately, the process leads to progressive loss of nephron
CKD, smoking is also an independent risk factor for progres- mass to the point where the remaining nephrons are no longer
sion to ESRD, with a relative risk ratio of up to 1.69 in heavy able to maintain clinical stability and renal function declines.
smokers, independent of other risk factors for the development
and progression of CKD.13 Patients with DM who smoke have
more than a two- to three-fold increased risk of developing ASSESSMENT FOR CKD
diabetic nephropathy compared to non-smokers.13 In patients
with CKD, smoking increases the risk of developing microal- Because CKD often presents without symptoms, assessment
buminuria, and increases the rate of progression to ESRD.13 for CKD relies on appropriate screening strategies in all
Initial pathogenic injury
Glomerular injury
Diabetes mellitus Reduced filtration area Arteriosclerosis
Adaptive hemodynamic
Formation of advanced Hyperlipidemia
changes
glycation end-products
Increased glomerular Increased glomerular

Systemic hypertension
blood flow capillary pressure
Glomerular hypertrophy Epithelial injury Endothelial injury Mesangial injury
Focal detachment of Proteinuria

epithelial foot processes
Glomerular Microthrombi occluding

hyaline deposition glomerular capillaries Mesangial expansion
Glomerulosclerosis Microaneurysm formation
Progression of
renal disease
FIGURE 231. Proposed mechanisms for progression of renal disease. (From Joy MS, Kshirsagar A, Paparello J. Chronic
kidney disease: Progression-modifying therapies. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A
Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 803, with permission.)
patients with risk factors for developing CKD (Table 232). a urine protein/creatinine ratio greater than 200 mg/g.1
Evaluation for CKD and the subsequent treatment strategies Microalbuminuria is dened as 30 to 300 mg of albumin
are dependent on the diagnosis, comorbid conditions, severity excreted in the urine per day or a urine albumin/creatinine
and complications of disease, and risk factors for the progres- ratio greater than 30 mg/day.1 The NKF recommends routine
sion of CKD. Early treatment of CKD and the associated assessment of proteinuria to detect CKD. A urine dipstick pos-
complications of CKD are the most important factors to decrease itive for the presence of protein warrants quantication of pro-
morbidity and mortality associated with CKD. However, the teinuria. Patients with a urine protein/creatinine ratio greater
probability of patients not diagnosed with CKD to have an than 200 mg/g or urine albumin/creatinine ratio greater than
assessment of serum creatinine or urine protein excretion 30 mg/g should undergo diagnostic evaluation; patients with
ranges from 0.01 to 0.04, depending on insurance coverage.2 values below these levels should be reevaluated routinely.1
Screening for CKD should be performed in all people with an Other markers for structural kidney damage that can be
increased risk for developing CKD, including patients with used in place of proteinuria include abnormalities in urinary
DM, hypertension, genitourinary abnormalities, autoimmune sediment, such as hematuria, or abnormalities in imaging
disease, increased age, or a family history of kidney disease. studies or kidney biopsy.1
The assessment for CKD should include measurement of
serum creatinine, urinalysis, blood pressure, serum elec- Complications of CKD
trolytes, and/or imaging studies. The decline in renal function is associated with a number
The primary marker of structural kidney damage is proof complications, which will be discussed later in the chapter,
teinuria, even in patients with normal GFR. Clinically signif- including:
icant proteinuria is dened as urinary protein excretion
greater than 300 mg/day or greater than 20 mcg/minute in a Fluid and electrolyte disorders
timed urine collection. Signicant proteinuria can also be Anemia
determined by a spot urine dipstick greater than 30 mg/dL or Metabolic bone disease
TREATMENT OF CHRONIC KIDNEY DISEASE

Clinical Presentation of Chronic
Kidney Disease Desired Outcomes
The primary goal is to slow and prevent the progression of
General CKD. This requires early identication of patients at risk for
The development of CKD is usually subtle in onset, often CKD to initiate interventions early in the course of the disease.
with no noticeable symptoms.
Symptoms Nonpharmacologic Therapy
Stages 1 and 2 CKD are generally asymptomatic.
Stages 3 and 4 CKD may be associated with minimal Nutritional Management
symptoms. Reduction in dietary protein intake has been shown to slow
Typical symptoms associated with stage 5 CKD include pru-
the progression of kidney disease.8 However, protein restriction
ritus, dysgeusia, nausea, vomiting, constipation, muscle
must be balanced with the risk of malnutrition in patients
pain, fatigue, and bleeding abnormalities.
with CKD. Patients with a GFR less than 25 mL/minute/ 1.73 m2
Signs received the most benet from protein restriction;8 therefore,
Cardiovascular: Worsening hypertension, edema, dyslipi- patients with a GFR above this level should not restrict pro-
demia, left ventricular hypertrophy, electrocardiographic tein intake. The NKF recommends that patients who have a
changes and chronic heart failure. GFR less than 25 mL/minute/1.73 m2 who are not receiving
Musculoskeletal: Cramping.
dialysis, however, should restrict protein intake to 0.6 g/kg
per day. If patients are not able to maintain adequate dietary
Neuropsychiatric: Depression, anxiety, impaired mental energy intake, protein intake may be increased up to 0.75 g/kg
cognition. per day.15 Malnutrition is common in patients with ESRD for
Gastrointestinal: Gastroesophageal reux disease, gastroin- various reasons, including decreased appetite, hypercatabo-
testinal (GI) bleeding, and abdominal distention. lism, and nutrient losses through dialysis. For this reason,
Genitourinary: Changes in urine volume and consistency, patients receiving dialysis should maintain protein intake of
foaming of urine (indicative of proteinuria), and sexual 1.2 g/kg per day to 1.3 g/kg per day.
dysfunction.
Laboratory Tests Pharmacologic Therapy
Stages 1 and 2 CKD: Increased blood urea nitrogen (BUN)
and serum creatinine (SCr) and decreased GFR Intensive Blood Glucose Control (for Patients with
Stages 3, 4, and 5 CKD: Increased BUN and SCr; decreased Diabetes)
GFR. Intensive insulin therapy, the administration of insulin three
Advanced stages: Increased potassium, phosphorus, and or more times daily to maintain preprandial blood glucose
magnesium; decreased bicarbonate (metabolic acidosis); levels between 70 and 120 g/dL and postprandial blood glu-
calcium levels are generally low in earlier stages of CKD cose levels less than 180 g/dL, has been shown to decrease the
and may be elevated in stage 5 CKD, secondary to the use incidence of proteinuria and albuminuria in patients with
of calcium-containing phosphate binders. diabetes, both with and without documented nephropathy.
Decreased albumin, if inadequate nutrition intake in The development and progression of nephropathy is also
advanced stages. delayed in patients with type 1 DM receiving intensive insulin
Decreased red blood cell (RBC) count, hemoglobin (Hgb) therapy. Continued benets of intensive insulin therapy have
and hematocrit (Hct); iron metabolism may also be altered been demonstrated up to 8 years after the study.16
[iron level, total iron binding capacity (TIBC), serum ferritin
level, and transferrin saturation (TSAT)]. Erythropoietin levels
Optimal Blood Pressure Control
are not routinely monitored and are generally normal to low.
Urine positive for albumin or protein. Reductions in blood pressure are associated with a decrease in
Increased parathyroid hormone (PTH) level; decreased proteinuria, leading to a decrease in the rate of progression of
vitamin D levels (stages 4 or 5 CKD). kidney disease. The NKF recommends a goal blood pressure
Stool may be Hemoccult-positive if GI bleeding occurs from of less than 130/80 mm Hg in patients with stages 1 through
uremia. 4 CKD.17 Stage 5 CKD patients who are receiving hemodialysis
should achieve a goal blood pressure of less than 140/90 mm Hg
Structural abnormalities of kidney may be present on diag- before hemodialysis and less than 130/80 after hemodialysis.17
nostic exams. Because hypertension and kidney dysfunction are linked, blood
pressure control can be more difcult to attain in patients with
CKD compared to patients with normal kidney function. All The NKF suggests that CKD should be classied as a coronary
antihypertensive agents have similar effects on reducing blood heart disease (CHD) risk equivalent and the goal LDL-C level
pressure. However, three or more agents are generally required should be below 100 mg/dL in all patients with CKD.22 The most
to achieve the blood pressure goal of less than130/80 mm Hg frequently used agents for the treatment of dyslipidemias in
in CKD patients. patients with CKD are the 3-hydroxy-3-methylglutaryl coen-
zyme A (HMG-CoA) reductase inhibitors (statins) and the
Reduction in Proteinuria bric acid derivatives. However, other treatments have been
The ability of antihypertensive agents to preserve kidney studied in patients with CKD and should be considered if rst-
function differs. Angiotensin-converting enzyme inhibitors line therapies are contraindicated.
(ACEIs) and angiotensin receptor blockers (ARBs) decrease Another important consideration in treating lipid disorders
glomerular capillary pressure and volume because of their in patients with CKD is management of proteinuria. Protein
effects on angiotensin II. This, in turn, reduces the amount excretion in the nephrotic range (greater than 3 g/day) is asso-
of protein ltered through the glomerulus, independent of ciated with an increase in both total and LDL-C levels.23
the reduction in blood pressure, 18 which ultimately Triglyceride levels can also be elevated in patients with severe
decreases the progression of CKD. The ability of ACEIs proteinuria. Results from clinical trials suggest that the use of
and ARBs to reduce proteinuria is greater than that of other ACEIs to reduce proteinuria can decrease total cholesterol
antihypertensives, up to 35% to 40%,17 making ACEIs and levels.24 While the use of ACEIs is unlikely to decrease choles-
ARBs the antihypertensive agents of choice for all patients with terol to goal levels, reducing proteinuria can aid in cholesterol
CKD. All patients with documented proteinuria should reduction, particularly in patients with nephrotic syndrome
receive an ACE-I or ARB, regardless of blood pressure.17 or severe proteinuria. Conversely, treatment of hyperlipidemia
Because diabetes is associated with an early onset of microal- can reduce protein excretion and subsequent progression
buminuria, all patients with diabetes should also receive an of CKD.4
ACE-I or ARB, regardless of blood pressure.17 When initiat-
ing ACE-I or ARB therapy, the dose should be titrated to the Smoking Cessation
maximum tolerated dose, even if the blood pressure is less While the effects of smoking on renal hemodynamics are well
than130/80 mm Hg. Patients who do not achieve adequate established, as discussed previously, the effect of smoking ces-
reductions in blood pressure or protein excretion may bene- sation on CKD progression has not been studied. Data are
t from combination therapy with an ACE-I and an ARB.17 emerging that suggest that smoking cessation may be a prac-
Figure 232 depicts an algorithm for the treatment of hyper- tical approach to slow the progression of CKD. However,
tension in patients with CKD. smoking cessation does not reverse existing renal dysfunction
The nondihydropyridine calcium channel blockers have in former smokers.
been shown to also decrease protein excretion in patients with
diabetes,20 but the reduction in proteinuria appears to be Anemia Treatment
related to the reductions in blood pressure. The maximal Anemia decreases oxygen delivery to the renal tubules, pro-
effect of nondihydropyridine calcium channel blockers on moting the release of inammatory and vasoactive cytokines,
proteinuria is seen with a blood pressure reduction to less which contribute to the progression of CKD. Treatment of
than 130/80 mm Hg and no additional benet is seen with anemia in patients with CKD reduces the cardiovascular effects
increased doses. Dihydropyridine calcium channel blockers, of anemia and has been demonstrated to decrease morbidity
however, do not have the same effects on protein excretion, and mortality by as much as 20%.25 Studies have demonstrated
and may actually worsen protein excretion.17 that treatment of anemia may slow the progression of CKD.26
The management of anemia will be discussed later.
Other Interventions to Limit Progression of Chronic
Kidney Disease
Outcome Evaluation
Hyperlipidemia Treatment Monitor serum creatinine and potassium levels and blood
Hyperlipidemia plays a role in the development of cardiovas- pressure within 1 week after initiating angiotensin-converting
cular disease (CVD) in patients with CKD. The primary goal enzyme inhibitor or angiotensin II receptor blocker therapy.
of treatment of dyslipidemias is to decrease the risk of ather- Discontinue the medication and switch to another agent if a
osclerotic cardiovascular disease. A secondary goal in patients sudden increase in serum creatinine greater than 30% occurs,
with CKD is to reduce proteinuria and decline in kidney func- hyperkalemia develops, or the patient becomes hypotensive.
tion. Treatment of hyperlipidemia in patients with CKD has Titrate the dose of the ACE-I or ARB every 1 to 3 months to
been demonstrated to slow the decline in GFR by 1.9 mL/minute the maximum tolerable dose. If blood pressure is not reduced
per year of treatment with antihyperlipidemic agents.21 to less than 130/80 mm Hg, add another agent to the regimen.
FIGURE 232. Hypertension management

BLOOD PRESSURE GREATER THAN 130/80 MM HG algorithm for patients with CKD. Dosage
IF BP GREATER THAN 15-20/10 MM HG OVER GOAL, COMBINE STEPS 1 AND 2 adjustments should be made every 2 to
GOAL BP = less than 130/80 mm Hg
4 weeks as needed. The dose of one agent
STEP 1 Recheck Scr and K in 1 week. If Scr
should be maximized before another is
Start ACE-I or ARB or K greater than 30%, discontinue agent. added. ACE-I, angiotensin-converting enzyme
inhibitor; ARB, angiotensin receptor blocker;
BP still not at goal BP, blood pressure; CrCl, creatinine clearance;
(Less than 130/80 mm Hg) K, potassium; Scr, serum creatinine. (From
Joy MS, Kshirsagar A, Paparello J. Chronic
STEP 2 kidney disease: Progression-modifying thera-
Add diuretic pies. In: DiPiro JT, Talbert RL, Yee GC, et al,
(eds.) Pharmacotherapy: A Pathophysiologic
If CrCI greater than or equal to If CrCI less than 30 ml/minute,
30 ml/minute, add thiazide diuretic add loop diuretic
Approach. 6th ed. New York: McGraw-Hill;
BP still not at goal
STEP 3
Add long-acting calcium channel blocker (CCB). May also consider adding
low-dose -blocker instead of CCB at this time if patient has angina, heart
failure, or arrhythmia necessitating their use.
Baseline pulse greater than Baseline pulse

or equal to 84 less than 84
STEP 4 STEP 4
Add low-dose -blocker or /-blocker (if not already Add other subgroup of calcium channel blocker
being used) NOTE: The use of a -blocker and a (e.g., a dihydropyridine CCB if a nondihydropine agent
nondihydropyridine CCB should be avoided in the is being used). NOTE: The use of a -blocker
elderly and those with conduction abnormalities. and a nondihydropyridine CCB should be avoided in
the elderly and those with conduction abnormalities.
STEP 5
Add long-acting -blocker, central -agonist, or
vasodilator. NOTE: Central -agonists (i.e., clonidine)
should not be used with -blockers due to the high
likelihood of severe bradycardia.
Refer the patient to a nephrologist to manage complications with normal kidney function, allowing sodium balance to be
associated with CKD. As CKD progresses to stage 4, begin dis- maintained with a sodium intake of 120 to 150 mEq (120 to
cussion to prepare the patient for renal replacement therapy. 150 mmol) per day. Urine osmolality can range from 50 to
1200 mOsm/L (50 to 1200 mmol/L) with normal kidney
function, allowing for water balance to be maintained with a
CONSEQUENCES OF CHRONIC AND END-STAGE
wide range of uid intake. As nephron mass decreases, the
KIDNEY DISEASE
remaining nephrons increase sodium excretion and FENa may
increase up to 10% to 20%.27 This produces an osmotic diure-
Impaired Sodium and Water Homeostasis
sis which impairs the ability of the kidneys to concentrate and
Sodium and water balance are primarily regulated by the kidney. dilute urine and the urine becomes xed at an osmolality
Reductions in nephron mass decrease glomerular ltration and close to that of the plasma, approximately 300 mOsm/L (300
subsequent reabsorption of sodium and water, leading to edema. mmol/L). The inability of the kidney to concentrate the urine
results in nocturia in patients with CKD, usually presenting as
Pathophysiology early as stage 3 CKD.
Sodium and water balance can be maintained despite wide As nephron mass continues to decline, the sodium load
variations in intake with normal kidney function. The frac- overwhelms the remaining nephrons and total sodium excre-
tional excretion of sodium (FENa) is approximately 1% to 3% tion is decreased, despite the increase in sodium excretion by
used to increase sodium and water excretion. Thiazide diuret-

Clinical Presentation of Impaired ics are ineffective when used alone in patients with a GFR
Sodium and Water Homeostasis less than 30 mL/minute/1.73 m2. As CKD progresses, higher
doses or continuous infusion of loop diuretics may be needed,
or combination therapy with loop and thiazide diuretics to
General
increase sodium and water excretion.
Alterations in sodium and water balance in CKD manifests
as increased edema.
Outcome Evaluation
Symptoms Monitor edema after initiation of diuretic therapy. Monitor
Nocturia can present in stage 3 CKD. uid intake to ensure obligatory losses are being met and avoid
Edema generally presents in stage 4 CKD or later. dehydration. If adequate diuresis is not attained with a single
Signs agent, consider combination therapy with another diuretic.
Cardiovascular: Worsening hypertension, edema.
Genitourinary: Change in urine volume and consistency. Impaired Potassium Homeostasis
Laboratory Tests
Increased blood pressure
Potassium balance is also primarily regulated by the kidney
Sodium levels remain within the normal range via the distal tubular cells. Reduction in nephron mass
Urine osmolality is generally xed at 300 mOsm/L (300 mmol/L) decreases tubular secretion of potassium, leading to hyper-
kalemia. Hyperkalemia is estimated to affect more than 50%
of patients with stage 5 CKD.28
the functioning nephrons. Sodium retention causes uid
retention that manifests as systemic hypertension resulting Pathophysiology
from increased intravascular volume. Severe volume overload The distal tubules secrete 90% to 95% of the daily dietary
can lead to pulmonary edema. intake of potassium. The fractional excretion of potassium
(FEK) is approximately 25% with normal kidney function.29
Treatment The GI tract excretes the remaining 5% to 10% of dietary
potassium intake. Following a large potassium load, extracel-
Nonpharmacologic Therapy lular potassium is shifted intracellularly to maintain stable
The kidney is unable to adjust to abrupt changes in sodium extracellular levels.
intake in patients with severe CKD. Therefore, patients should As nephron mass decreases, both the distal tubular secre-
be advised to refrain from adding salt to their diet, but tion and GI excretion are increased because of aldosterone
should not restrict sodium intake. Changes in sodium intake stimulation. Functioning nephrons increase FEK up to 100%
should occur slowly over a period of several days to allow ade- and GI excretion increases as much as 30% to 70% in CKD,30
quate time for the kidney to adjust urinary sodium content. as a result of aldosterone secretion in response to increased
Sodium restriction produces a negative sodium balance, which potassium levels.30 This maintains serum potassium concen-
causes uid excretion to restore sodium balance. The resulting trations within the normal range through stages 1 to 4 CKD.
volume contraction can decrease perfusion of the kidney and Hyperkalemia begins to develop when GFR falls below 20% of
hasten the decline in GFR. Saline-containing intravenous (IV) normal, when nephron mass and renal potassium secretion is
solutions should be used cautiously in patients with CKD so low that the capacity of the GI tract to excrete potassium
because the salt load may precipitate volume overload. has been exceeded.30
Fluid restriction is generally unnecessary as long as sodium Medications can increase the risk of hyperkalemia in patients
intake is controlled. The thirst mechanism remains intact in with CKD, including angiotensin-converting enzyme inhibitors
CKD to maintain total body water and plasma osmolality near and angiotensin II receptor blockers, used for the treatment of
normal levels. Fluid intake should be maintained at the rate of proteinuria and hypertension. Potassium-sparing diuretics, used
urine output to replace urine losses, usually xed at approxi- for the treatment of edema and chronic heart failure, can also
mately 2 L/day as urine concentrating ability is lost. Signicant exacerbate the development of hyperkalemia, and should be
increases in free water intake orally or intravenously can precip- used with caution in patients with stage 3 CKD or higher.
itate volume overload and hyponatremia. Patients with stage 5
CKD require renal replacement therapy to maintain normal vol- Treatment
ume status. Fluid intake is often limited in patients receiving
hemodialysis to prevent uid overload between dialysis sessions. Nonpharmacologic Therapy
Patients with CKD should avoid abrupt increases in dietary
Pharmacologic Therapy intake of potassium because the kidney is unable to increase
Diuretic therapy is often necessary to prevent volume over- potassium excretion with an acute potassium load, particu-
load in patients with CKD. Loop diuretics are most frequently larly in latter stages of the disease. Hyperkalemia resulting
after administration of SPS, but the maximum effect on

Clinical Presentation of Hyperkalemia potassium levels may not be seen for up to 6 hours, which lim-
its the utility in patients with severe hyperkalemia. Of note,
loop diuretics are often used to decrease potassium levels in
patients with normal or mildly decreased kidney function, but
General
are not useful in patients with stage 5 CKD to decrease potas-
Hyperkalemia is generally asymptomatic in patients with
CKD until serum potassium levels are greater than 5.5 mEq/L
sium concentrations. Fludrocortisone is a mineralocorticoid
(5.5 mmol/L), when cardiac abnormalities present. that mimics the effects of aldosterone and increases potassium
excretion in the distal tubules and through the GI tract.
Symptoms However, udrocortisone causes signicant sodium and water
Mild hyperkalemia is generally not associated with overt
retention, which exacerbates edema and hypertension, and
symptoms.
may not be tolerated by many CKD patients.
Signs
Cardiovascular: Electrocardiogram (ECG) changes Outcome Evaluation
Laboratory Tests Monitor electrocardiogram continuously in patients with
Increased serum potassium levels cardiac abnormalities until serum potassium levels drop
below 5 mEq/L (5 mmol/L) or cardiac abnormalities resolve.
Evaluate serum potassium and glucose levels within 1 hour in
from an acute increase in potassium intake can be more severe patients who receive insulin and dextrose therapy. Evaluate
and prolonged. Patients who develop hyperkalemia should serum potassium levels within 2 to 4 hours after treatment
restrict dietary intake of potassium to 50 to 80 mEq (50 to 80 with SPS or diuretics. Repeat doses of diuretics or SPS if nec-
mmol) per day. Dialysate potassium concentrations can also essary until serum potassium levels fall below 5 mEq/L
be altered in patients receiving hemodialysis and peritoneal (5 mmol/L). Monitor blood pressure and serum potassium
dialysis to manage hyperkalemia. Because GI excretion of levels in 1 week in patients who receive udrocortisone.
potassium plays a large role in potassium homeostasis in
patients with stage 5 CKD, a good bowel regimen is essential Anemia of CKD
to minimize constipation, which can occur in 40% of patients
receiving hemodialysis.29 Severe hyperkalemia is most effec- The progenitor cells of the kidney produce 90% of the hor-
tively managed by hemodialysis. mone erythropoietin (EPO), which stimulates red blood cell
(RBC) production. Reduction in nephron mass decreases
Pharmacologic Therapy renal production of EPO, which is the primary cause of anemia
Patients with acute hyperkalemia usually require other thera- in patients with CKD. The development of anemia of CKD
pies to manage hyperkalemia until dialysis can be initiated. results in decreased oxygen delivery and utilization, leading to
Patients who present with cardiac abnormalities caused by increased cardiac output and left ventricular hypertrophy
hyperkalemia should receive calcium gluconate or chloride (LVH), which increase the cardiovascular risk and mortality in
(1 g intravenously) to reverse the cardiac effects. Temporary patients with CKD.
measures can be employed to shift extracellular potassium into
the intracellular compartment to stabilize cellular membrane Epidemiology and Etiology
effects of excessive serum potassium levels. Such measures Current NKF guidelines dene anemia as a hemoglobin
include the use of regular insulin (5 to 10 units intravenously) (Hgb) level less than 11 g/dL (6.8 mmol/L).31 A number of
and dextrose (5% to 50% intravenously), or nebulized factors can contribute to the development of anemia, includ-
albuterol (10 to 20 mg). Sodium bicarbonate should not be ing deciencies in vitamin B12 or folate, hemolysis, bleeding,
used to shift extracellular potassium intracellularly in patients or bone marrow suppression. Many of these can be detected
with CKD unless severe metabolic acidosis (pH less than 7.2) by alterations in RBC indices, which should be included in the
is present. These measures will decrease serum potassium evaluation for anemia. A complete blood cell count is also
levels within 30 to 60 minutes after treatment, but potassium helpful in evaluating anemia to determine overall bone mar-
must still be removed from the body. Shifting potassium to row function.
the intracellular compartment, however, decreases potassium The prevalence of anemia is correlated with the degree of
removal by dialysis. Often, multiple dialysis sessions are renal dysfunction. More than 26% of patients with a GFR greater
required to remove potassium that is redistributed from the than 60 mL/minute/1.73 m2 are estimated to have anemia, and
intracellular space back into the serum. the number increases to 75% in patients with a GFR less than
Sodium polystyrene sulfonate (SPS, 15 to 30 g orally), a 15 mL/minute/1.73 m2.32 The risk of developing anemia also
sodium-potassium exchange resin, promotes potassium excre- increases as GFR declines, doubling for patients with stage 3
tion from the GI tract. The onset of action is within 2 hours CKD, increasing to 3.8-fold in patients with stage 4 CKD, and
plasma concentration of EPO increases exponentially. As

Patient Encounter, Part 2 nephron mass decreases, EPO production also decreases. Thus,
as Hgb, Hct, and tissue oxygenation decrease in patients with
CKD, plasma EPO levels remain constant within the normal
range, but low relative to the degree of hypoxia present. The
The patient returns to your clinic 2 years later with complaints
result is a normochromic, normocytic anemia.
of feeling tired all of the time. She had been trying to exer-
cise more, but has not had enough energy to exercise for the Several other factors also contribute to the development of
past 6 months or so. She also complains that she feels cold all anemia in patients with CKD. Uremia, a result of declining
of the time, despite increasing the temperature in her house. renal function, decreases the lifespan of RBCs from a normal
of 120 days to as low as 60 days in patients with stage 5 CKD.
Current Meds
Iron deciency and blood loss from regular laboratory testing
Furosemide 80 mg orally daily
Lisinopril 40 mg orally daily and hemodialysis also contribute to the development of ane-
Metoprolol 50 mg orally twice daily mia in patients with CKD.
Insulin glargine 25 units subcutaneously at bedtime
Insulin lispro subcutaneously per sliding scale with meals Treatment
ROS
Slightly pale skin color; fatigue daily in the afternoon; General Approach to Therapy
otherwise unremarkable Studies have demonstrated that initiation of treatment for
anemia before stage 5 CKD decreases mortality in patients
PE
with ESRD receiving dialysis, particularly in the elderly.33 The
VS: Blood pressure 135/85 mm Hg, pulse 72 beats per
treatment of anemia can decrease morbidity, increase exercise
minute, temperature 35.9C (96.6F); Wt 175 lb (79.5 kg)
Chest: Regular rate and rhythm, normal S1, S3 present. capacity and tolerance, and slow the progression of CKD if
Abd: Obese; no organomegaly, bruits or tenderness, (+) target Hgb levels are achieved.34
bowel sounds; heme () stool Patients with CKD should be evaluated for anemia when
Exts: 1+ pedal edema bilaterally; decreased sensation in feet; the GFR falls below 60 mL/minute or if the serum creatinine
small lesion on left ankle that appears to be healing slowly rises above 2 mg/dL (176.8 mmol/L). If the Hgb is less than
Labs 11 g/dL (6.8 mmol/L), an anemia work-up should be per-
Sodium 142 mEq/L (142 mmol/L); potassium 4.8 mEq/L formed. The work-up for anemia should rule out other
(4.8 mmol/L); chloride 103 mEq/L (103 mmol/L); carbon potential causes for anemia (see Chapter 63). Abnormalities
dioxide 20 mEq/L (20 mmol/L); BUN 58 mg/dL (20.71 mmol/L found during the anemia work-up should be corrected
urea); SCr 3.2 mg/dL (282.88 mol/L); glucose 130 mg/dL before initiating erythropoiesis-stimulating agents (ESA),
(7.28 mmol/L); WBC 4.8 103 cells/m3 (4.8 109/L); RBC
2.5 103 cells/m3 (2.5 1012/L); Hgb 8.0 g/dL (4.96 mmol/L);
Hct 25% (0.25); mean corpuscular volume (MCV) 88 fL; Clinical Presentation of Anemia of CKD
mean corpuscular hemoglobin concentration (MCHC)
35 g/dL (350 g/L); platelets 250 103 cells/m3 (250 109/L);
iron 35 mcg/dL (6.26 mmol/L); TIBC 150 mcg/dL
(26.85 mol/L); ferritin 75 ng/mL (168 pmol/L); TSAT General
15% (0.15); HbA1c 7.5% (0.075) Anemia of CKD generally presents with fatigue and
decreased quality of life.
What signs and symptoms are consistent with anemia of CKD?
What additional information could you request to deter- Symptoms
mine other causes of anemia in this patient? Anemia of CKD is associated with symptoms of cold
What treatment would you recommend for this patient for intolerance, shortness of breath, and decreased exercise
treatment of anemia? capacity.
How would you evaluate the effectiveness of treatment of Signs
anemia? Cardiovascular: Left ventricular hypertrophy, ECG changes,
congestive heart failure
Neurologic: Impaired mental cognition
to 10.5-fold for patients with stage 5 CKD, compared to stages Genitourinary: Sexual dysfunction
1 and 2 CKD.32
Laboratory Tests
Decreased RBC count, Hgb, and Hct
Pathophysiology Decreased serum iron level, TIBC, serum ferritin, and TSAT
The primary cause of anemia in patients with CKD is a Decreased erythropoietin levels relative to the degree of
decrease in EPO production. With normal kidney function, as hypoxia that is present
Hgb, hematocrit (Hct), and tissue oxygenation decrease, the
particularly iron deciency, as iron is an essential component levels between 100 and 500 ng/mL (225 to 1123.5 pmol/L) in
of RBC production. If Hgb is still below the goal level when all patients not receiving hemodialysis and between 200 and
other causes of anemia have been corrected, EPO deciency 500 ng/mL (449.4 to 1123.5 pmol/L) in patients receiving
should be assumed. EPO levels are not routinely measured and hemodialysis and TSAT greater than 20% (0.2).31 The approach
have little clinical signicance in monitoring progression and to the management of anemia of CKD with ESA and iron
treatment of anemia in patients with CKD. supplementation is illustrated in Figs. 233 and 234.
Generally, treatment requires a combination of ESA and
iron supplementation. The goal of treatment for anemia of CKD Nonpharmacologic Therapy
is to increase Hgb levels greater than 11 g/dL (6.8 mmol/L). The Sufcient dietary iron intake must be maintained in patients
goal for iron supplementation is to maintain serum ferritin with anemia of CKD. Approximately 1 to 2 mg of iron is
Monitor Anemia Status

Consider and treat as appropriate
Iron deficiency (see Figure 234) Infection, inflammatory disease

Hyperparathyroidism Aluminum toxicity
Vitamin B12 or folate deficiency Hypertension
Blood loss Hemolysis
Hgb less than 11 g/dL; Hgb 1112 g/dL; Hct 33%36%a Hgb greater than 12 g/dL;
Hct less than 33%a AT GOAL Hct greater than 36%a
No change in regimen, If on erythropoietin therapy,b

monitor Hgb/Hct 12 times reduce the dose by 25%
per month
If nave to erythropoietic therapy

Epoetin alfa (SC preferred):
80120 units/kg/week SC in 2 or 3 divided doses
120180 units/kg/week IV in 2 or 3 divided doses
Darbepoetin alfa (IV or SC):
0.45 mcg/kg once weekly Monitor
Hgb/Hct 12 times per week until stable, then
If on erythropoietic therapy 12 times per month
Epoetin alfa: 25%50% increase in dose Adjust erythropoietic doses no more than every
Darbepoetin alfa: 25% increase in dose 34 weeks
Iron indices monthly for 3 months, then every
3 months (see Figure 234)
Desired outcomes
Rise in Hgb of 1 g/dL after 24 weeks
(rise in Hct of 12 points per week but
no more than 4 points in 2 weeks)
Hgb 1112 g/dL; Hct 33%36% Is there a poor response in Hgb/Hct?
Ferritin 100500 ng/mL
TSat 20%50%
Yes No
Yes Is there a functional iron No Are there reasons for

See Figure 234 deficiency (TSat less than 20% resistance to erythropoietic Monitor as above
with normal ferritin)? therapy?
No Yes
Increase dose of
Treat underlying cause(s)
erythropoietic agent by 25%
a
Use Hgb as primary parameter to assess anemia.
b Epoetin alfa or darbepoetin alfa.
FIGURE 233. Guidelines for erythropoietic therapy in the management of anemia of CKD. (Adapted
from Joy MS, Kshirsagar A, Paparello J. Chronic kidney disease: Progression-modifying therapies. In:
DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed.
Measure Iron Indices

TSat and Ferritin
TSat 2050%
TSat less than 20% TSat greater than 50%
Ferritin less than 100 ng/mL Ferritin greater than 800 ng/mL
AT GOAL
Administer supplemental iron Administer maintenance iron Hold IV iron doses

IV: 1 g in divided doses (iron dextran, HD: 50 mg IV iron sucrose or if receiving iron
sodium ferric gluconate, or iron sucrose)a iron dextran per week or 62.5 supplementation
mg IV ferric gluconate per week until below upper
(titrate doses) threshold levels
Early CKD or PD: Attempt Consider erythropoietic
oral iron therapy.b Change to IV therapy c
therapy if necessary
Consider erythropoietic
therapy c TSat less than 20%
(Functional iron deficiency?)
If not responding to erythropoietic

At goal iron indices? therapy increase dose and/or
frequency of maintenance iron
Change to IV iron if patient on oral
Yes No therapy
Administer maintenance iron Administer 1 g course of IV iron

as described above Once at target iron indices, administer
Consider erythropoietic therapy c maintenance iron as described above
Consider erythropoietic therapy c
Monitor iron indices monthly for 3 months,

then every 3 months if Hgb/Hct stable
a IV iron regimen may be divided over 810 HD sessions (depending on product used) or given in larger
doses (eg, up to 500 mg iron dextran, 300 mg iron sucrose, 250 mg ferric gluconate) over a prolonged
administration time for patients with early CKD or on PD.
b The dose of oral iron should be 200 mg elemental iron per day in divided doses.
c Initiate erythropoietic therapy as indicated based on Hgb/Hct (see Figure 233).
FIGURE 234. Guidelines for iron therapy in the management of anemia of CKD. (Adapted from Joy MS, Kshirsagar A,
Paparello J. Chronic kidney disease: Progression-modifying therapies. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.)
absorbed daily from the diet. This small amount is generally before the availability of ESAs, but are now reserved as third-
not adequate to preserve adequate iron stores to promote RBC line agents because of toxicity; namely, hepatotoxicity.
production. RBC transfusions have been used in the past as
the primary means to maintain Hgb and Hct levels in patients Erythropoiesis-Stimulating Agents (ESAs) Erythropoietin is a
with anemia of CKD. This treatment is still utilized today in growth factor that acts on erythroblasts formed from stem
patients with severe anemia, but is considered a third-line cells in the bone marrow, stimulating proliferation and differ-
therapy for anemia of CKD. entiation into normoblasts, then reticulocytes, which are
released into the bloodstream to eventually mature into ery-
Pharmacologic Therapy throcytes (mature RBCs). The ESAs currently available in the
The rst-line treatment for anemia of CKD involves replace- United States are: epoetin alfa (distributed as Epogen by
ment of erythropoietin with erythropoiesis-stimulating Amgen, Inc., Thousand Oaks, CA; and Procrit by Ortho
agents (ESAs). Use of ESAs increases the iron demand for RBC Biotech, Johnson & Johnson, Raritan, NJ) and darbepoetin
production and iron deciency is common, requiring iron alfa (Aranesp by Amgen, Inc.). Epoetin alfa and epoetin beta,
supplementation to correct and maintain adequate iron stores which is available outside the United States, have the same
to promote RBC production. Androgens were used extensively biological activity as endogenous EPO. Darbepoetin alfa
differs from epoetin alfa by the addition of carbohydrate side Shirley, NY); sodium ferric gluconate (Ferrlecit by Watson
chains that increase the half-life of darbepoetin alfa compared Pharmaceuticals, Inc., Corona, CA); and iron sucrose (Venofer
to epoetin alfa and endogenous EPO, allowing for less fre- by American Reagent, Inc., Shirley, NY). Initiation of IV iron
quent dosing than that of epoetin alfa. All ESAs are equivalent should be based on evaluation of iron stores. A serum ferritin
in their efcacy and have a similar adverse-effect prole. level less than 100 ng/mL in conjunction with a TSAT level less
The most common adverse effect seen with ESA is increased than 20% indicates absolute iron deciency and is a clear indica-
blood pressure, which can occur in up to 23% of patients.31 tion for the need for iron replacement.31 When TSAT is less than
Antihypertensive agents may be required to control blood pres- 20% in conjunction with normal or elevated serum ferritin lev-
sure in patients receiving ESAs. Caution should be used when els, treatment should be based on the clinical picture of the
initiating an ESA in patients with very high blood pressures patient, as serum ferritin is an acute phase reactant, which may
(greater than 180/100 mm Hg). If blood pressures are refractory become elevated with inammation and stress. Iron supplemen-
to antihypertensive agents, ESAs may need to be withheld. tation may be indicated if Hgb levels are below the goal level.
Subcutaneous (SC) administration of ESA produces a When replacing iron stores in patients receiving ESA ther-
more predictable and sustained response than IV administra- apy, the general approach to treatment is to give a total of 1 g of
tion, and is therefore the preferred route of administration for IV iron, administered in smaller, sequential doses. Because iron
both agents. Intravenous administration is often utilized in stores deplete quickly in patients who do not receive iron sup-
patients who have established IV access or are receiving plementation, maintenance doses are often used, particularly in
hemodialysis. Starting doses of ESAs depend on the patients patients receiving hemodialysis. Maintenance doses consist of
Hgb level, the target Hgb level, the rate of Hgb increase and smaller doses of iron administered weekly or with each dialysis
clinical circumstances.31 The initial increase in Hgb should be session (e.g., iron dextran or iron sucrose 20 to 100 mg per
12 g/dL (0.62061.2404 mmol/L) per month. The starting doses week; sodium ferric gluconate 62.5 to 125 mg per week).
of epoetin alfa previously recommended are 80 to 120 units/kg Intravenous iron preparations are equally effective in
per week for SC administration and 120 to 180 units/kg per increasing iron stores. Iron dextran has been associated with
week for IV administration, divided two to three times per side effects, including anaphylactic reactions and delayed reac-
week. The starting dose of darbepoetin alfa is 0.45 mcg/kg tions, such as arthralgias and myalgias. A test dose of 25 mg
administered SC or IV once weekly (Table 233). iron dextran should be administered 30 minutes before the full
dose to monitor for potential anaphylactic reactions. However,
Iron Supplementation Use of ESAs can lead to iron deciency if patients should be monitored closely when receiving iron dex-
iron stores are not adequately maintained. If serum ferritin and tran, as anaphylactic reactions can occur in patients who safely
TSAT fall below the goal levels, iron supplementation is required. received prior doses of iron dextran. For this reason, use of
Oral iron supplements are less costly than IV supplements and iron dextran has decreased dramatically in CKD patients in
are generally the rst-line treatment for iron supplementation. favor of the newer iron preparations, sodium ferric gluconate
When administering iron by the oral route, 200 mg of elemental and iron sucrose, which are associated with fewer severe reac-
iron should be delivered daily to maintain adequate iron stores. tions. The most common side effects seen with these prepara-
Oral iron supplementation is generally not effective in main- tions include hypotension, ushing, nausea, and injection site
taining adequate iron stores in patients receiving ESAs because reactions. A test dose is not required prior to the administra-
of poor absorption and an increased need for iron with ESA tion of either sodium ferric gluconate or iron sucrose.
therapy, making the IV route necessary for iron supplementa-
tion. The IV iron products currently available are: iron dextran Outcome Evaluation
(distributed as INFeD by Watson Pharmaceuticals, Inc., Evaluate Hgb every 1 to 2 weeks when ESA therapy is initiated
Morristown, NJ, and Dexferrum by American Reagent, Inc., or the dose is adjusted until Hgb is greater than 11 g/dL
(6.82 mmol/L). Once goal Hgb is attained, evaluate Hgb every
TABLE 233. Estimated Starting Doses of Darbepoetin Alfa 2 to 4 weeks thereafter. While the patient is receiving ESA
Based on Previous Epoetin Alfa Dose therapy, monitor iron stores monthly in patients who are not
receiving iron supplements or every 3 months in patients who
Previous Epoetin Alfa Dose Weekly Darbepoetin Alfa are receiving iron supplements. When the goal Hgb is reached,
(units/week) Dose (mcg/week) monitor iron stores every 3 months.
Less than 2500 6.25
25004999 12.5
500010,999 25
Secondary Hyperparathyroidism and Renal
11,00017,999 40 Osteodystrophy
18,00033,999 60
34,00059,999 100 Epidemiology and Etiology
60,00089,999 150 Increases in parathyroid hormone (PTH) occur early as renal
Greater than or equal to 90,000 200
function begins to decline. The actions of PTH on bone
more aggressive treatment of hyperparathyroidism. The

Patient Encounter, Part 3 development of ROD can dramatically affect morbidity in
patients with CKD.
Pathophysiology
The patient returns to your clinic 1 year later for routine As renal function declines in patients with CKD, decreased
follow-up. She has no complaints at this time. phosphorus excretion disrupts the balance of calcium and
Current Meds phosphorus homeostasis. The parathyroid glands release
Furosemide 80 mg orally daily PTH in response to decreased serum calcium and increased
Lisinopril 40 mg orally daily serum phosphorus levels. The actions of PTH include:
Metoprolol 75 mg orally twice daily
Insulin glargine 28 units subcutaneously at bedtime Increasing calcium resorption from bone
Insulin lispro subcutaneously per sliding scale with meals Increasing calcium reabsorption from the proximal tubules in
Darbepoetin 60 mcg subcutaneously weekly the kidney
ROS Decreasing phosphorus reabsorption in the proximal tubules in
Unremarkable the kidney
PE Stimulating activation of vitamin D by 1-a-hydroxylase to cal-
VS: Blood pressure 128/75 mm Hg, pulse 68 beats per citriol (1,25-dihydroxyvitmin D3) to promote calcium absorp-
minute, temperature 36.5C (97.9F); Wt 170 lb (77.3 kg) tion in the GI tract and increased calcium mobilization from
Chest: Regular rate and rhythm, normal S1, S3 present bone
Abd: Obese; no organomegaly, bruits, tenderness, (+) bowel
sounds; heme () stool All of these actions are directed at increasing serum cal-
Exts: 2+ edema bilaterally; decreased sensation to light cium levels and decreasing serum phosphorus levels, although
touch in feet; no lesions the activity of calcitriol also increases phosphorus absorption
Labs in the GI tract and mobilization from the bone, which can
Sodium 144 mEq/L (144 mmol/L); potassium 5.0 mEq/L worsen hyperphosphatemia. Calcitriol also decreases PTH
(5.0 mmol.L); chloride 105 mEq/L (105 mmol/L); carbon levels through a negative feedback loop. These measures are
dioxide 18 mEq/L (18 mmol/L); BUN 75 mg/dL (26.78 mmol/L sufcient to correct serum calcium levels in the earlier stages
urea); SCr 4.8 mg/dL (424.32 mol/L); glucose 115 mg/dL of CKD.
(6.38 mmol/L); calcium 8.6 mg/dL (2.15 mmol/L); phosphate As kidney function continues to decline and the GFR falls
7.8 mg/dL (2.52 mmol/L); albumin 3.0 mg/dL (30 g/L); intact less than 60 mL/minute/1.73 m2, phosphorus excretion contin-
parathyroid hormone (iPTH) 538 pg/mL (538 ng/L); WBC
ues to decrease and calcitriol production decreases, causing
6.0 103 cells/mm3 (6.0 109/L); RBC 3.5 103 cells/mm3
PTH levels to begin to rise signicantly, leading to secondary
(3.5 1012/L); Hgb 10.5 g/dL (6.51 mmol/L); Hct 32% (0.32);
platelets 350 103 cells/mm3 (350 109/L) hyperparathyroidism (sHPT). The excessive production of
PTH leads to hyperplasia of the parathyroid glands, which
What signs are consistent with secondary decreases the sensitivity of the parathyroid glands to serum cal-
hyperparathyroidism? cium levels and calcitriol feedback, further promoting sHPT.
What information would you request to determine if the The most dramatic consequence of sHPT is alterations in
patient has renal osteodystrophy? bone turnover and the development of ROD. Other complica-
How would you determine whether treatment is neces- tions of CKD can also promote ROD. Metabolic acidosis
sary for this patient? decreases bone formation and aluminum toxicity causes alu-
What treatment would you recommend for secondary minum uptake into bone in place of calcium, weakening the
hyperparathyroidism?
bone structure. The pathogenesis of sHPT and ROD are
depicted in Fig. 235.
The increased serum phosphorus binds to calcium in the
serum, which leads to deposition of hydroxyapatite crystals
turnover lead to renal osteodystrophy (ROD). As many as throughout the body. The calcium-phosphorus (Ca-P)
75% to 100% of patients with stage 3 CKD have ROD.35 The product reects serum solubility. A Ca-P product greater than
type of bone disease can vary based on the degree of bone 75 mg2/dL2 promotes crystal deposition in the joints and eye,
turnover. High bone turnover is the most common cause of leading to arthritis and conjunctivitis, respectively. Soft tissue
bone abnormalities in patients with CKD, present in as many deposition primarily affects the coronary arteries of the heart,
as 75% of patients receiving dialysis,35 and is generally medi- lungs, and vascular tissue and is associated with a Ca-P product
ated by high levels of PTH. Adynamic bone disease, character- greater than 55 mg2/dL2.36 The Ca-P product has been associ-
ized by low bone turnover, is less common, although the ated with increased mortality37 and is a risk factor for calcica-
prevalence appears to be increasing,35 which may be related to tion of vascular and soft tissues.35
Nephron loss
Decreased production
Impaired phosphate of 1,25-
excretion dihydroxyvitamin D3
Increased [Ca] [PO4] Phosphate retention

product
Decreased intestinal Impaired bone
calcium absorption mineralization
Increased PTH production
Soft tissue calcification Hypocalcemia Secondary
hyperparathyroidism Hypocalcemia
Increased calcium *Increased renal *Decreased renal

mobilization from bone calcium reabsorption tubular reabsorption of
phosphate
Osteitis fibrosa Renal

cystica osteodystrophy Osteomalacia
Metabolic acidosis Aluminum overload
FIGURE 235. Pathogenesis of secondary hyperparathyroidism and renal osteodystrophy in patients with CKD.
*These adaptations are lost as renal failure progresses. [Ca] [PO4] calcium-phosphorus product. (From Joy MS,
Kshirsagar A, Paparello J. Chronic kidney disease: Progression-modifying therapies. In: DiPiro JT, Talbert RL, Yee GC, et al,
(eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 834, with permission.)
Metabolic acidosis, a common complication of CKD, also

Clinical Presentation of Secondary contributes to ROD by altering the solubility of hydroxyapatite,
Hyperparathyroidism and Renal promoting bone dissolution. Additionally, metabolic acidosis
Osteodystrophy inhibits the activity of osteoblasts, which promote bone forma-
tion, while stimulating osteoclasts to promote bone resorption.
General Finally, metabolic acidosis can worsen sHPT by reducing the
Onset of sHPT and ROD is subtle and may not be associ- sensitivity of the parathyroid gland to serum calcium levels.38
ated with symptoms.
Symptoms Treatment
sHPT and ROD are usually asymptomatic in early disease.
Calcication in the joints can be associated with decreased General Approach
range of motion. Diagnosis and management of bone disease in CKD is
Conjunctival calcications are associated with a gritty sen- based on corrected serum levels of calcium and phosphorus, the
sation in the eyes, redness, and inammation. Ca-P (using corrected calcium levels), and intact PTH levels
Signs (iPTH).39 The target levels of each vary with the stage of CKD
Cardiovascular: Increased stroke index, heart rate, and dias- and are listed in Table 234. The primary target for treatment
tolic and mean arterial pressures is control of serum phosphorus levels, as this is the initial
Musculoskeletal: Bone pain, muscle weakness parameter that disrupts homeostasis. However, serum phos-
Dermatologic: Pruritus phorus can be difcult to control, particularly in the latter
Laboratory Tests stages of CKD. Management of sHPT often requires supple-
Increased serum phosphorus levels mental treatment in addition to phosphorus management.
Low to normal serum calcium levels
Increased Ca-P product Nonpharmacologic Therapy
Increased PTH levels The rst-line treatment for the management of hyperphos-
Decreased vitamin D levels phatemia is dietary phosphorus restriction to 800 to 1000 mg
Diagnostic Tests per day in patients with stage 3 CKD or higher who have
Radiographic studies show calcium-phosphate deposits in phosphorus levels at the upper limit of the normal range or
joints and/or cardiovascular system elevated iPTH levels.39 Foods high in phosphorus are also high
Bone biopsy of the iliac crest in protein, which can make it difcult to restrict phosphorus
intake while maintaining adequate protein intake to avoid
TABLE 234. Target Levels for Calcium, Phosphorus, Calcium-Phosphorus Product, and
Intact Parathyroid Hormone
Parameter Stage 3 CKD Stage 4 CKD Stage 5 CKD

Corrected calcium Normal Normal 8.49.5 mg/dL
(2.12.37 mmol/L)
Phosphorus 2.74.6 mg/dL 2.74.6 mg/dL 3.55.5 mg/dL
(0.871.49 mmol/L) (0.871.49 mmol/L) (1.131.78 mmol/L)
Ca-P product Less than 55 mg2/dL2 Less than 55 mg2/dL2 Less than 55 mg2/dL2
Intact PTH 3570 pg/mL 70110 pg/mL 150300 pg/mL
(3570 ng/L) (70110 ng/L) (150300 ng/L)
Ca-P, calcium-phosphorus product; CKD, chronic kidney disease; PTH, parathyroid hormone.
malnutrition. Hemodialysis and peritoneal dialysis can decreasing serum phosphorus levels. The drugs used for
remove up to 2 to 3 g of phosphorus per week. However, this binding dietary phosphate are listed in Table 235. These
is insufcient to control hyperphosphatemia and pharmaco- agents should be administered with each meal and can be tai-
logic therapy is necessary in addition to dialysis treatment. lored to the amount of phosphorus that is typically ingested
Other nonpharmacologic strategies to manage sHPT and during each meal. For example, patients can take a smaller
ROD in patients with CKD include restriction of aluminum dose with smaller meals or snacks, and a larger dose with
exposure and parathyroidectomy. Ingestion of aluminum- larger meals.
containing antacids and other aluminum-containing prod- Calcium-based phosphate binders, including calcium car-
ucts should be avoided in patients with stage 4 CKD or higher bonate and calcium acetate, are effective in decreasing serum
(GFR less than 30 mL/minute/1.73m2) because of the risk of phosphate levels, as well as increasing serum calcium levels.
aluminum toxicity and potential uptake into the bone. Calcium acetate binds more phosphorus than the carbonate
Purication techniques for dialysate solutions also minimize salt, making it a more potent agent for binding dietary phos-
the risk of exposure to aluminum. phate. Calcium citrate is usually not used as a phosphate-
Parathyroidectomy is a treatment of last resort for sHPT, binding agent because the citrate salt can increase aluminum
but should be considered in patients with persistently ele- absorption. The calcium-containing phosphate binders also
vated iPTH levels above 800 pg/mL (800 ng/L) that is refrac- aid in the correction of metabolic acidosis, another complica-
tory to medical therapy to lower serum calcium and/or tion of renal failure. Caution should be used with these agents
phosphorus levels.39 A portion or all of the parathyroid tis- if serum calcium levels are near the upper end of the normal
sue may be removed, and in some cases a portion of the range or are elevated because of the risk of increasing the
parathyroid tissue may be transplanted into another site, Ca-P product and potentiating vascular and soft tissue calci-
usually the forearm. Bone turnover can be disrupted in cations. The dose of calcium-based phosphate binders should
patients undergoing parathyroidectomy whereby bone pro- not provide more than 1500 mg of elemental calcium per day,
duction outweighs bone resorption. The syndrome, known and the total elemental calcium intake per day should not
as hungry bone syndrome, is characterized by excessive exceed 2000 mg, including medication and dietary intake.39
uptake of calcium, phosphorus, and magnesium for bone The most common adverse effects of calcium-containing
production, leading to hypocalcemia, hypophosphatemia, phosphate binders are constipation and hypercalcemia.
and hypomagnesemia. Serum ionized calcium levels should Phosphate-binding agents that do not contain calcium,
be monitored frequently (every 4 to 6 hours for the rst 48 magnesium, or aluminum include sevelamer hydrochloride
to 72 hours) in patients receiving a parathyroidectomy. and lanthanum carbonate. These agents are particularly useful
Calcium supplementation is usually necessary, administered in patients with hyperphosphatemia who have elevated serum
IV initially, then orally (with vitamin D supplementation) calcium levels or who have vascular or soft tissue calcications.
once normal calcium levels are attained for several weeks to Sevelamer is a cationic polymer that is not systemically
months after the procedure. absorbed and binds to phosphate in the GI tract, and prevents
absorption and promotes excretion of phosphate through the
Pharmacologic Therapy GI tract via the feces. Sevelamer has an added benet of reduc-
ing LDL-C by up to 30% and increasing HDL-C levels.39 The
Phosphate-Binding Agents When serum phosphorus lev- most common side effects of sevelamer are GI complaints,
els cannot be controlled by restriction of dietary intake, including nausea, constipation, and diarrhea. The cost of seve-
phosphate-binding agents are used to bind dietary phosphate lamer is signicantly higher compared to calcium-containing
in the GI tract to form an insoluble complex that is excreted phosphate binders, however, which often makes sevelamer a
in the feces. Phosphorus absorption is decreased, thereby second-line agent for controlling phosphorus levels.
TABLE 235. Phosphate-Binding Agents Used in the Treatment of Hyperphosphatemia in CKD
Compound Elemental Calcium

Compound Trade Name Content (mg) Content (mg) Starting Dose Comments
Calcium carbonate Tums 500, 750, 200, 300, 0.51 g First-line agent; dissolution
(40% elemental 1000, 1250 400, 500 (elemental characteristics and phosphorus-
calcium) Oscal-500 1250 500 calcium) binding effect may vary from
Caltrate 600 1500 600 three times a product to product; try to limit
Nephro-Calci 1500 600 day with meals daily intake of elemental calcium
LiquiCal 1200 480 to 1500 mg/day
CalciChew 1250 500 Approximately 39 mg phosphorus
bound per 1 g calcium carbonate
Calcium acetate Phos-Lo 667 167 0.51 g First-line agent; comparable efcacy
(25% elemental (elemental to calcium carbonate with one-half
calcium) calcium) the dose of elemental calcium; do
three times not exceed 1500 mg elemental
a day calcium intake per day
with meals Approximately 45 mg phosphorus
bound per 1 g calcium acetate
By prescription only
Sevelamer Renagel 400, 800 800 mg three First-line agent; lowers LDL-C
times a day More expensive than calcium
with meals products; preferred in patients at
risk for extraskeletal calcication
May require large doses to control
phosphorus levels
Lanthanum Fosrenol 250, 500 7501500 mg Second-line agent; more expensive
chewable three times than calcium products; preferred in
tablets a day patients at risk for extraskeletal
with meals calcication
Most patients require 15003000
mg per day to control phosphorus
Aluminum Alterna GEL 600 mg/5 mL 300600 mg Third-line agents; do not use
hydroxide Amphojel 300, 600 (tablet) three times concurrently with citrate-
320 mg/5 mL a day containing products
(suspension) with meals Reserve for short-term use (4 weeks)
Alu-Cap 400 in patients with hyperphosphatemia
not responding to other binders
Aluminum Basaljel 500 (tablet, 450500 mg Same as for aluminum hydroxide
carbonate capsule) three times
400 mg/5 mL a day
(suspension) with meals
Magnesium Mag-Carb 70 (capsule) 70 mg three Third-line agent; diarrhea
carbonate times a day common; monitor serum
with meals magnesium
Magnesium Milk of 300, 600 (tablet) 300400 mg Same as for magnesium carbonate
hydroxide Magnesia 400 mg/5 mL, three times a
800 mg/5 mL day with
(suspension) meals
Magnesium MagneBind 200 mg 160 200 mg three Same as for calcium carbonate and
carbonate/calcium 200 (elemental times a day magnesium carbonate
carbonate magnesium) with meals
LDL-C, low-density lipoprotein cholesterol.
Lanthanum is a naturally occurring trivalent rare earth ele- from the GI tract.40 Side effects of lanthanum include nausea,
ment (atomic number 57). Lanthanum carbonate quickly dis- peripheral edema, and myalgias.
sociates in the acidic environment of the stomach, where the Aluminum- and magnesium-containing phosphate-binding
lanthanum ion binds to dietary phosphorus, forming an insol- agents are not recommended for chronic use in patients with
uble compound that is excreted in the feces. Lanthanum has CKD to minimize the risk of aluminum and magnesium
been shown to remove more than 97% of dietary phosphorus accumulation. Aluminum-containing agents may be used for
a short course of therapy (less than 4 weeks) if phosphorus intestinal calcium and phosphorus absorption, while retaining
levels are signicantly elevated greater than 7 mg/dL (2.26 the effects on parathyroid gland hyperplasia and PTH synthesis
mmol/L), but should be replaced by other phosphate-binding and secretion.41 This makes paricalcitol more useful in patients
agents after no more than 4 weeks.39 In addition to the risk of with an elevated Ca-P product. Doxercalciferol, on the other
magnesium accumulation, the use of magnesium-containing hand, has similar effects as calcitriol on vitamin D receptors in
agents is also limited by the GI side effects, primarily diarrhea. the parathyroid glands and intestines. Like calcitriol, calcium and
phosphorus levels and the Ca-P product should be within the
Vitamin D Therapy Exogenous vitamin D compounds that normal range for the stage of CKD prior to starting doxercalcif-
mimic the activity of calcitriol act directly on the parathyroid erol. Recommendations for vitamin D analog therapy depend on
gland to decrease PTH secretion. This is particularly useful the stage of CKD (Table 236).39
when reduction of serum phosphorus levels does not suf- It is important to monitor vitamin D therapy aggressively to
ciently reduce PTH levels. The most active form of vitamin D is assure that PTH levels are not oversuppressed. Oversuppression
calcitriol (1,25-dihydroxyvitamin D3), which is available com- of PTH levels can induce adynamic bone disease, which man-
mercially as an oral formulation (Rocaltrol by Roche ifests as decreased osteoblast and osteoclast activity, decreased
Laboratories, Inc., Nutley, NJ) and an injectable formulation bone formation, and low bone turnover.
(Calcijex by Abbott Laboratories, North Chicago, IL). The
effects of calcitriol are mediated by upregulation of the vitamin Calcimimetics
D receptor in the parathyroid gland, which decreases parathy- Cinacalcet is a calcimimetic that increases the sensitivity of
roid gland hyperplasia and PTH synthesis and secretion. receptors on the parathyroid gland to serum calcium levels to
However, vitamin D receptor upregulation also occurs in the reduce PTH secretion. Cinacalcet may be benecial in patients
intestines, which increases calcium and phosphorus absorption, with an increased Ca-P product who have elevated PTH levels
increasing the risk of hypercalcemia and hyperphosphatemia. It and cannot use vitamin D therapy. Because the effects of
is important that serum calcium and phosphorus levels are cinacalcet on PTH can reduce serum calcium levels and result
within the normal range for the stage of CKD and the Ca-P prod- in hypocalcemia, cinacalcet should not be used if serum cal-
uct is less than 55 mg2/dL2 prior to starting calcitriol therapy. cium levels are below normal.
Other vitamin D analogs available in the United States include
paricalcitol (19-nor-1,25-dihydroxyvitamin D2, Zemplar by Reversal of Metabolic Acidosis
Abbott Laboratories, North Chicago, IL) and doxercalciferol Studies have demonstrated that reversal of metabolic acidosis
(1--hydroxyvitamin D2, Hectoral by Bone Care International, can improve bone disease associated with CKD.38 Serum
Middleton, WI). Alfacalcidiol (1--hydroxyvitamin D3) is only bicarbonate levels should be maintained at 22 mEq/L (22
available outside the United States. Paricalcitol has less effect on mmol/L) in patients with bone disease associated with CKD.39
vitamin D receptors in the intestines, decreasing the effects on The treatment of metabolic acidosis is described below.
TABLE 236. Dosing Recommendations for Vitamin D in Patients with CKD
Serum PTH (pg/mL) Calcitriol Dose Paricalcitol Dose Doxercalciferol Dose

Stage 3 or 4 CKD
70300a 0.25 mcg orally daily Not recommended 2.5 mg orally 3 times weekly
Stage 5 CKD on
hemodialysis
300600b 0.51.5 mcg 2.55 mcg intravenously per HD 5 mcg orally per HD
PO or intravenously per HD 2 mcg intravenously per HD
6001000b 14 mcg orally per HD 610 mcg intravenously per HD 510 mcg orally per HD
13 mcg intravenously per HD 24 mcg intravenously per HD
Greater than 1000c 37 mcg orally per HD 1015 mcg intravenously per HD 1020 mcg orally per HD
35 mcg intravenously per HD 48 mcg intravenously per HD
Stage 5 CKD on
peritoneal dialysis
Greater than 300b 0.25 mcg orally daily Not recommended 2.55 mcg orally 23 times weekly
0.51 mcg orally 23 times weekly
a
If serum calcium less than 9.5 mg/dL (2.37 mmol/L), phosphorus less than 4.6 mg/dL (1.49 mmol/L), and Ca-P product less than 55 mg2/dL2
b
If serum calcium less than 9.5 mg/dL (2.37 mmol/L), phosphorus less than 5.5 mg/dL (1.78 mmol/L), and Ca-P product less than 55 mg2/dL2
c
If serum calcium less than 10 mg/dL (2.5 mmol/L), phosphorus less than 5.5 mg/dL (1.78 mmol/L), and Ca-P product less than 55 mg2/dL2
CKD, chronic kidney disease; HD, hemodialysis; PO, orally; PTH, parathyroid hormone.
Outcome Evaluation Nonpharmacologic Therapy

Monitor serum calcium and phosphorus levels regularly in Treatment of metabolic acidosis in CKD requires pharmaco-
patients receiving phosphate-binding agents. When initiating logic therapy. Other disorders that may contribute to meta-
therapy, monitor serum levels every 1 to 4 weeks, depending bolic acidosis should also be addressed. Altering bicarbonate
on the severity of hyperphosphatemia. Titrate doses of phos- levels in the dialysate uid in patients receiving dialysis may
phate binders to achieve the target levels of serum calcium and assist with the treatment of metabolic acidosis, although phar-
phosphorus and the Ca-P product (Table 234). Once target macologic therapy may still be required.
levels are achieved, monitor serum calcium and phosphorus
levels every 1 to 3 months. Monitor intact PTH levels monthly Pharmacologic Therapy
while initiating vitamin D therapy, then every 3 months once Pharmacologic therapy with sodium bicarbonate or
stable iPTH levels are achieved. When starting or increasing citrate/citric acid preparations may be needed in patients with
the dose of cinacalcet, monitor serum calcium and phosphorus stage 3 CKD or higher to replenish body stores of bicarbonate.
levels within 1 week and iPTH levels should be monitored Calcium carbonate and calcium acetate, used to bind phos-
within 1 to 4 weeks. Once target levels are achieved, decrease phorus in sHPT, also aid in increasing serum bicarbonate lev-
monitoring to every 3 months. els, in conjunction with other agents.
Sodium bicarbonate tablets are administered in increments
of 325 and 650 mg tablets. A 650 mg tablet of sodium bicar-
Metabolic Acidosis bonate contains 7.7 mEq (7.7 mmol) each of sodium and
bicarbonate. Sodium retention associated with sodium bicar-
Epidemiology and Etiology bonate can cause volume overload, which can exacerbate
Approximately 80% of patients with a GFR less than 20 to 30 hypertension and chronic heart failure. Patient tolerability of
mL/minute develop metabolic acidosis.38 Metabolic acidosis sodium bicarbonate is low because of carbon dioxide produc-
can increase protein catabolism and decrease albumin synthe- tion in the GI tract that occurs during dissolution.
sis, which promote muscle wasting, and alter bone metabo- Solutions that contain sodium citrate/citric acid (Shohls
lism. Other consequences associated with metabolic acidosis solution and Bicitra) provide 1 mEq/L (1 mmol/L) each of
in CKD include worsening cardiac disease, impaired glucose sodium and bicarbonate. Polycitra is a sodium/potassium
tolerance, altered growth hormone and thyroid function, and citrate solution that provides 2 mEq/L (2 mmol/L) of bicar-
inammation.38 bonate, but contains 1 mEq/L (1 mmol/L) each of sodium
and potassium, which can promote hyperkalemia in
Pathophysiology patients with severe CKD. The citrate portion of these
The kidneys play a key role in the management of acid-base preparations is metabolized in the liver to bicarbonate,
homeostasis in the body by regulating excretion of hydrogen while the citric acid portion is metabolized to CO2 and
ions. With normal kidney function, bicarbonate that is freely l- water, increasing tolerability compared to sodium bicarbon-
tered through the glomerulus is completely reabsorbed via the ate. Sodium retention is also decreased with these prepara-
renal tubules. Hydrogen ions are generated at a rate of 1 mEq/kg tions. However, these products are liquid preparations,
(1 mmol/kg) per day during metabolism of ingested food and which may not be palatable to some patients. Citrate can
are excreted at the same rate by the kidney via buffers in the also promote aluminum toxicity by augmenting aluminum
urine created by ammonia generation and phosphate excre- absorption in the GI tract.
tion. As a result, the pH of body uids is maintained within a When determining the dose of bicarbonate replacement,
very narrow range. the goal for therapy is to achieve a normal serum bicarbonate
As kidney function declines, bicarbonate reabsorption is level of 24 mEq/L (24 mmol/L). The dose is usually deter-
maintained, but hydrogen excretion is decreased because the mined by calculating the base decit: [0.5 L/kg (body
ability of the kidney to generate ammonia is impaired. The weight)] [(normal CO2) (measured CO2)]. Because of the
positive hydrogen balance leads to metabolic acidosis, which is risk of volume overload resulting from the sodium load
characterized by a serum bicarbonate level of 15 to 20 mEq/L administered with bicarbonate replacement, the total base
(15 to 20 mmol/L). This picture is generally seen when the decit should be administered over several days. Once the goal
GFR declines below 20 to 30 mL/minute.38 serum bicarbonate level is attained, a maintenance dose of
bicarbonate is necessary and should be titrated to maintain
Treatment serum bicarbonate levels.
Serum electrolytes should be monitored in patients with CKD
for the development of metabolic acidosis. Metabolic acidosis Outcome Evaluation
in patients with CKD is generally characterized by an elevated Monitor serum electrolytes and arterial blood gases regularly.
anion gap greater than 17 mEq/L (17 mmol/L), due to the Correct metabolic acidosis slowly to prevent the development
accumulation of phosphate, sulfate, and other organic anions. of metabolic alkalosis or other electrolyte abnormalities.
Other Therapeutic Considerations in CKD depleting stores of von Willebrand factor. Side effects of
DDAVP include ushing, dizziness, and headache.
Uremic Bleeding Estrogens have also been used to decrease bleeding time. The
Uremia can lead to a number of alterations in clotting ability, onset of action is slower than that of DDAVP, but more sus-
resulting in hemorrhage. Bleeding complications associated tained, and depends on the route of administration. Intravenous
with CKD include ecchymoses, prolonged bleeding from doses of 0.6 mg/kg per day for 4 to 5 days decreases bleeding
mucous membranes and puncture sites used for blood collec- time within 6 hours of administration, and produces an effect
tion and hemodialysis, GI bleeding, intramuscular bleeding, that lasts up to 2 weeks after stopping therapy. The onset of
and others. Most bleeding complications associated with CKD action with oral doses of 50 mg/kg daily is within 2 days of treat-
are mild. However, serious bleeding events, including GI ment and is sustained for 4 to 5 days after stopping therapy.
bleeds and intracranial hemorrhage, can occur. Transdermal patches providing 50 to 100 mcg per day have also
been shown to be effective in decreasing bleeding time.42 Side
effects of estrogen use include hot ashes, uid retention, and
Pathophysiology hypertension.
Uremia alters a number of mechanisms that contribute to
bleeding. Platelet function and aggregation is altered through
Pruritus
decreased production of thromboxane.42 Plateletvessel wall
Pruritus can affect 25% to 86% of patients with advanced
interactions are also altered in patients with uremia because
stages of CKD, and is not related to the cause of renal failure.43
of decreased activity of von Willebrand factor.42 and are
Pruritus can be signicant and has been linked to mortality in
exacerbated by anemia in CKD patients. With a normal RBC
patients receiving hemodialysis.43
count in the plasma, platelets skim the surface of the
endothelial tissue in the blood vessels. In patients with ane-
Pathophysiology
mia, RBC count is decreased and platelets circulate closer to
The cause of pruritus is unknown, although several mecha-
the center of the vessels, which decreases the interaction with
nisms have been proposed. Vitamin A is known to accumulate
the vessel wall. The risk of bleeding is increased in patients
in the skin and serum of patients with CKD, but a denite cor-
receiving hemodialysis. Anticoagulants administered to pre-
relation with pruritus has not been established. Histamine
vent or treat clotting during hemodialysis or in vascular
may also play a role in the development of pruritus, which
access sites, including heparin, warfarin, aspirin, and clopi-
may be linked to mast cell proliferation in patients receiving
dogrel, exacerbate the risk of bleeding in these patients.
hemodialysis. Hyperparathyroidism has also been suggested
as a contributor to pruritus, despite the fact that serum PTH
Treatment levels do not correlate with itching. Accumulation of divalent
ions, specically magnesium and aluminum, may also play a
Nonpharmacologic Therapy The incidence and severity of role in pruritus in patients with CKD. Other theories that have
bleeding associated with uremia has decreased since dialysis been proposed include inadequate dialysis, dry skin, periph-
has become the mainstay of treatment for ESRD. Dialysis ini- eral neuropathy, and opiate accumulation.43
tiation improves platelet function and reduces bleeding
time.42 Improved care of the patient with ESRD, with anemia Treatment
treatment and improvement in nutritional status, are also
likely contributors to decreased uremic bleeding. Nonpharmacologic Therapy Pruritus associated with CKD is
difcult to alleviate. It is important to evaluate other potential
Pharmacologic Therapy Treatments used to decrease bleeding dermatologic causes of pruritus to maximize the potential for
time in patients with uremic bleeding include cryoprecipitate, relief. Adequate dialysis is generally the rst line of treatment
which contains various components important in platelet in patients with pruritus. However, this has not been shown to
aggregation and clotting, such as von Willebrand factor and decrease the incidence of pruritus signicantly. Maintaining
brinogen. Cryoprecipitate decreases bleeding time within 1 proper nutritional intake, especially with regard to dietary
hour in 50% of patients. However, cost and the risk of infec- phosphorus and protein intake, may lessen the degree or
tion have limited the use of cryoprecipitate. occurrence of pruritus. Patients who do not attain relief from
Desmopressin (DDAVP) increases the release of factor VIII other measures may benet from ultraviolet B phototherapy.
(von Willebrand factor) from endothelial tissue in the vessel
wall. Bleeding time is promptly reduced, within 1 hour of Pharmacologic Therapy Topical emollients have been used as
administration, and is sustained for 4 to 8 hours.42 Doses used treatment for pruritus in patients with dry skin, but are often
for uremic bleeding are 0.3 to 0.4 mcg/kg intravenously over not effective in relieving pruritus associated with CKD.
20 to 30 minutes, 0.3 mcg/kg subcutaneously, or 2 to 3 mcg/kg Antihistamines, such as hydroxyzine 25 to 50 mg or diphen-
intranasally. Repeated doses can cause tachyphylaxis by hydramine 25 to 50 mg orally or intravenously, are used as
rst-line oral agents used to treat pruritus. Cholestyramine

has also been used at doses of 5 g twice daily. Oral activated Patient Encounter, Part 4
charcoal has also been used in doses of 1 to 1.5 g four times
daily with some demonstrated efcacy. Other therapies that
are often used in combination with other agents include oral
The patient presents to clinic several years later and com-
ondansetron or naltrexone and topical capsaicin. Each has
plains that she feels lousy. She states that she doesnt
been reported to have efcacy in the treatment of pruritus feel like eating and has lost 20 pounds (9 kg) in the last
associated with CKD. 6 months.
Current Meds
Vitamin Replacement
Furosemide 80 mg orally twice daily
Water-soluble vitamins removed by hemodialysis (HD) con- Metolazone 5 mg orally twice daily
tribute to malnutrition and vitamin deciency syndromes. Lisinopril 40 mg orally daily
Patients receiving HD often require replacement of water- Metoprolol 75 mg orally twice daily
soluble vitamins to prevent adverse effects. The vitamins that Insulin glargine 30 units subcutaneously at bedtime
may require replacement are ascorbic acid, thiamine, biotin, Insulin lispro subcutaneously per sliding scale with meals
folic acid, riboavin, and pyridoxine. Patients receiving HD Darbepoetin 100 mcg subcutaneously weekly
should receive a multivitamin B complex with vitamin C Iron polysaccharide 150 mg orally daily
supplement, but should not take supplements that include Sevelamer 800 mg orally three times daily with meals
fat-soluble vitamins, such as vitamins A, E, or K, which can Calcitriol 0.25 mcg orally daily
Sodium bicarbonate 1300 mg orally three times daily
accumulate in patients with renal failure.
ROS
Unremarkable
RENAL REPLACEMENT THERAPY PE
VS: Blood pressure 160/85 mm Hg, pulse 70 beats per
Patients who progress to ESRD require renal replacement minute, temperature 36.8C (98.2F), Wt 150 lb (68.2 kg)
therapy (RRT). The modalities that are used for RRT are dial- Chest: Regular rate and rhythm, normal S1, S3 and S4 both
ysis, including HD and peritoneal dialysis (PD), and kidney present; slight pericardial friction rub
Exts: 3+ bilateral lower extremity edema which is present
transplantation. The United States Renal Data Service
half-way up her calf
(USRDS) reported that the number of patients with ESRD
was 452,957, with 102,567 new cases being diagnosed in Labs
2003.2 The most common form of RRT is dialysis, accounting Sodium 142 mEq/L (142 mmol/L); potassium 5.8 mEq/L
for 72% of all patients with ESRD. The principles and com- (5.8 mmol/L); chloride 102 mEq/L (102 mmol/L); carbon
dioxide 16 mEq/L (16 mmol/L); BUN 85 mg/dL
plications associated with dialysis are discussed below.
(30.34 mmol/L urea); SCr 9.5 mg/dL (839.8 mol/L);
Chapter 52 discusses the principles of kidney transplantation.
glucose 112 mg/dL (6.22 mmol/L); calcium 8.2 mg/dL
(2.05 mmol/L); phosphate 5.8 mg/dL (1.87 mmol/L); iPTH
438 pg/mL (1.87 ng/L); WBC 5.3 103 cells/mm3
Indications for Dialysis
(5.3 109/L); RBC 3.2 103 cells/mm3 (3.2 1012/L);
Planning for dialysis should begin when creatinine clear- Hgb 9.8 g/dL (6.08 mmol/L); Hct 29% (0.29); platelets
ance falls less than 30 mL/minute/1.73 m2 (stage 4 CKD),1 when 390 103 cells/mm3 (390 109/L)
progression to ESRD is inevitable, to allow time to educate the
patient and family on the treatment modalities and establish the What indications does the patient have for dialysis?
What alternatives for renal replacement therapy exist for
appropriate access for the modality of choice. Ideally, initiation
the patient?
of dialysis should be done at a point when the patient is ready
What are the advantages and disadvantages of each
to undergo treatment, rather than when the patient is in modality for renal replacement?
emergent need of dialysis.
Initiation of dialysis is dependent on the patients clinical
status. Symptoms that may indicate the need for dialysis
include persistent anorexia, nausea, vomiting, fatigue, and guide for the initiation of dialysis, but should not be the
pruritus. Other criteria that indicate the need for dialysis absolute indicator. Dialysis is initiated in most patients when
include declining nutritional status, declining serum albumin the GFR falls below 15 mL/minute/1.73 m2.1 Patient should
levels, uncontrolled hypertension, and volume overload, determine which modality of dialysis to use based on their
which may manifest as chronic heart failure, and electrolyte own preferences. Advantages and disadvantages of hemodial-
abnormalities, particularly hyperkalemia. Blood urea nitrogen ysis and peritoneal dialysis are listed in Tables 237 and 238,
(BUN) and serum creatinine (SCr) levels may be used as a respectively.
TABLE 237. Advantages and Disadvantages of Hemodialysis TABLE 238. Advantages and Disadvantages of Peritoneal
Dialysis
Advantages
1. Higher solute clearance allows intermittent treatment. Advantages
2. Parameters of adequacy of dialysis are better dened and there- 1. More hemodynamic stability (blood pressure) due to slow
fore underdialysis can be detected early. ultraltration rate.
3. The techniques failure rate is low. 2. Increased clearance of larger solutes, which may explain good
4. Even though intermittent heparinization is required, hemostasis clinical status in spite of lower urea clearance.
parameters are better corrected with hemodialysis than peri- 3. Better preservation of residual renal function.
toneal dialysis. 4. Convenient intraperitoneal route of administration of drugs
5. In-center hemodialysis enables closer monitoring of the such as antibiotics and insulin.
patient. 5. Suitable for elderly and very young patients who may not toler-
ate hemodialysis well.
Disadvantages
6. Freedom from the machine gives the patient a sense of inde-
1. Requires multiple visits each week to the hemodialysis center,
pendence (for continuous ambulatory peritoneal dialysis).
which translates into loss of control by the patient.
7. Less blood loss and iron deciency, resulting in easier manage-
2. Dysequilibrium, dialysis, hypotension, and muscle cramps are
ment of anemia or reduced requirements for erythropoietin and
common. May require months before patient adjusts to
parenteral iron.
hemodialysis.
8. No systemic heparinization requirement.
3. Infections in hemodialysis patients may be related to the
9. Subcutaneous versus intravenous erythropoietin or darbepoetin is
choice of membranes, the complement-activating membranes
usual, which may reduce overall doses and be more physiologic.
being more deleterious.
4. Vascular access is frequently associated with infection and Disadvantages
thrombosis. 1. Protein and amino acid losses through the peritoneum and
5. Decline of residual renal function is more rapid compared to reduced appetite owing to continuous glucose load and sense
peritoneal dialysis. of abdominal fullness predispose to malnutrition.
2. Risk of peritonitis.
From Elwell RJ, Foote EF. Hemodialysis and peritoneal dialysis. In:
3. Catheter malfunction, and exit site and tunnel infection.
DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A
Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 4. Inadequate ultraltration and solute dialysis in patients with a
852, with permission. large body size, unless large volumes and frequent exchanges
are employed.
5. Patient burnout and high rate of technique failure.
6. Risk of obesity with excessive glucose absorption.
7. Mechanical problems such as hernias, dialysate leaks, hemor-
The goals of dialysis are to remove toxic metabolites to rhoids, or back pain may occur.
decrease uremic symptoms, correct electrolyte abnormalities, 8. Extensive abdominal surgery may preclude peritoneal dialysis.
restore acid-base status, and maintain volume status to ulti- 9. No convenient access for intravenous iron administration.
mately improve quality of life and decrease the morbidity and From Elwell RJ, Foote EF. Hemodialysis and peritoneal dialysis. In:
mortality associated with ESRD. DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A
Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 853,
with permission.
Hemodialysis
Principles of Hemodialysis
Hemodialysis (HD) involves the exposure of blood to a bloodstream. Conventional (standard) membranes have small
semipermeable membrane (dialyzer) against which a physiologic pores, which limit solute removal to relatively small mole-
solution (dialysate) is owing. The dialyzer is composed of thou- cules, such as creatinine and urea. High-efciency membranes
sands of capillary bers made up of the semipermeable mem- also have small pores, but have a higher surface area that
brane, which are enclosed in the dialyzer, to increase the surface increases removal of small molecules, such as water, urea, and
area of blood exposure to maximize the efciency of removing creatinine from the blood. High-ux membranes have larger
substances. The dialysate is composed of puried water and pores that allow for the removal of high-molecular-weight
electrolytes, and is run through the dialyzer countercurrent to substances, including some drugs, such as vancomycin.
the blood on the other side of the semipermeable membrane. Three primary processes are utilized for the removal of
The process allows for the removal of several substances from substances from the blood. Diffusion is the movement of a
the bloodstream, including water, urea, creatinine, uremic tox- solute across the dialyzer membrane from an area of higher
ins, and drugs. Although the dialysate is not sterilized, the concentration (usually the blood) to a lower concentration
membrane prevents bacteria from entering into the blood- (usually the dialysate). This process is the primary means for
stream. However, if the membrane ruptures during hemodialy- small molecules to be removed from the bloodstream, such as
sis, infection becomes a major concern for the patient. electrolytes. At times, solutes can be added to the dialysate that
Three types of membranes used for dialysis are classied by are diffused into the bloodstream. Changing the composition
the size of the pores and the ability to remove solutes from the of the dialysate allows for control of the amount of electrolytes
that are being removed. Ultraltration is the movement of promotes redistribution of uids from extracellular spaces
solvent (plasma water) across the dialyzer membrane by into the plasma. However, decreased serum albumin levels
applying hydrostatic or osmotic pressure, and is the primary and removal of solutes from the bloodstream decrease the
means for removing water from the bloodstream. Changing osmotic pressure of the plasma relative to the extracellular
the hydrostatic pressure applied to the dialyzer or the osmotic spaces, slowing redistribution during hemodialysis.45 The
concentration of the dialysate allows for control of the decreased plasma volume causes hypotension. Other factors
amount of water being removed. Convection is the movement that can contribute to hypotension include antihypertensive
of dissolved solutes across the dialyzer membrane by drag- medications prior to HD, a target dry weight that is too low,
ging the solutes along a pressure gradient with a uid trans- diastolic or autonomic dysfunction, low dialysate calcium or
port and is the primary means for larger molecules to be sodium, high dialysate temperature, or ingesting meals prior
removed from the bloodstream, such as urea. Changing the to HD.
pore size of the dialyzer membrane alters the efciency of Risk factors that may increase the potential for hypoten-
convection and allows for control of the amount of water sion include elderly age, diabetes, autonomic neuropathy, ure-
removed in relation to the amount of solute being removed. mia, and cardiac disease.46 The symptoms associated with
hypotension during dialysis include dizziness, nausea, vomit-
Vascular Access ing, sweating, and chest pain.
Long-term permanent access to the bloodstream is a key
component of HD. There are three primary techniques used Treatment Nonpharmacologic management of acute hypoten-
to obtain permanent vascular access in patients receiving HD. sion that occurs during dialysis involves placing the patient in
Arteriovenous stula (AVF) is the preferred access method the Trendelenburg position (with the head lower than the
because it has the longest survival rate and the fewest compli- feet) and decreasing the ultraltration rate. Pharmacologic
cations.44 An AVF is made by creating an anastomosis management of acute hypotension during dialysis includes
between an artery and a vein, usually in the forearm of the administration of normal saline (100 to 200 mL), hypertonic
non-dominant arm. An arteriovenous graft (AVG) results in a saline (23.4%, 10 to 20 mL), or mannitol (12.5 g) to restore
similar access site, but uses a synthetic graft, usually made of intravascular volume.
polytetrauoroethylene, to connect the artery and vein in the Preventive measures for patients who may be prone to
forearm. The advantages of the AVG is that it is able to be used hypotension include accurate determination of the dry
within 2 to 3 weeks, compared to 2 to 3 months for an AVF. weight and maintaining a constant ultraltration rate.
However, AVGs are complicated by stenosis, thrombosis, and Midodrine is an -adrenergic agonist that is effective in
infections, which lead to a shorter survival time of the graft. reducing hypotension in patients with autonomic dysfunction
Double-lumen venous catheters, placed in the femoral, sub- that is taken with each dialysis session or as chronic therapy.
clavian, or jugular vein, are often used as temporary access Midodrine can be administered at doses of 2.5 to 10 mg prior
while waiting for the AVF or AVG to mature. The catheters are to HD or 5 mg twice daily for chronic hypotension. Side
tunneled beneath the skin to an exit site to reduce the risk of effects of midodrine include pruritus and paresthesias.
infection. Venous catheters can also be used as permanent Hypotension may be related to alterations in levocarnitine
access in patients in whom arteriovenous access cannot be levels during dialysis. Patients who have low levels of levocar-
established. nitine may benet from supplementation. Levocarnitine is
administered as doses of 20 mg/kg intravenously at the end of
each dialysis session. However, levocarnitine should not be
Complications of Hemodialysis
used as a rst-line agent for the treatment of hypotension
Complications associated with HD include hypotension,
because of the signicant cost associated with the treatment.
myalgia, thrombosis, and infection.
Patients receiving levocarnitine should be evaluated every
3 months for response to therapy.47 Other preventive measures
Hypotension
that have not been well studied include caffeine, sertraline, or
Hypotension is the most common complication seen during
udrocortisone.
hemodialysis. It has been reported to occur with approxi-
mately 10% to 30% of dialysis sessions, but may be as frequent
as 50% of sessions in some patients.46 Muscle Cramps
Pathophysiology Hypotension associated with hemodialysis Pathophysiology Muscle cramps can occur with up to 20% of
manifests as a symptomatic sudden drop of more than 30 dialysis sessions.48 The cause is often related to excessive ultra-
mm Hg in mean arterial or systolic pressure or a systolic ltration, which causes hypoperfusion of the muscles. Other
pressure drop to less than 90 mm Hg during the dialysis ses- contributing factors to the development of muscle cramps
sion. The primary cause is uid removal from the blood- include hypotension and electrolyte and acid-base imbalances
stream. Ultraltration removes uid from the plasma, which that occur during hemodialysis sessions.
Treatment Nonpharmacologic treatments of muscle cramping bacteremia. As with thrombosis, venous catheters are most
that occurs during hemodialysis include decreasing the ultra- commonly infected, followed by synthetic AV grafts, and nally
ltration rate and accurately determining the dry weight. AV stulas.
Pharmacologic measures include vitamin E, which is admin- Blood cultures should be obtained for any patient receiving
istered at doses of 400 IU daily. Other options that are not as hemodialysis who develops a fever. Nonpharmacologic man-
well studied include oxazepam and prazosin. agement of infections involves preventive measures with sterile
technique, proper disinfection, and minimizing the use and
Thrombosis duration of venous catheters for hemodialysis access.
Thrombosis associated with hemodialysis most commonly Pharmacologic management of infections should cover the
occurs in patients with venous catheter access for dialysis and gram-positive organisms that most frequently cause access-
is a common cause of catheter failure. However, thrombosis related infections. Patients who have positive blood cultures
can occur in synthetic grafts and less frequently in AV stulas. should receive treatment tailored to the organism isolated.
Nonpharmacologic management of thrombosis in a Preventive measures for access-related infections include
hemodialysis catheter involves saline ushes. Smaller clots mupirocin at the exit site and povidone-iodine ointment. The
may be managed by balloon angioplasty to mechanically open recommendations of the NKF for treatment of infections
the catheter. In severe cases in whom clots cannot be removed associated with hemodialysis are listed in Table 239.
by either mechanical or pharmacologic therapy, the catheter
may require replacement.
Peritoneal Dialysis
Pharmacologic management of thrombosis includes local
administration of thrombolytic agents. Alteplase (2 mg per port) Principles of Peritoneal Dialysis
and reteplase (0.5 unit per port) are the two most commonly Peritoneal dialysis (PD) utilizes similar principles as
used agents today. Urokinase has been used in the past, but after hemodialysis in that blood is exposed to a semipermeable
its reintroduction to the United States market, the larger dosed membrane against which a physiologic solution is placed. In
vial size makes it less cost effective than the newer agents. the case of PD, however, the semipermeable membrane is the
peritoneal membrane, and a sterile dialysate is instilled into
Infection the peritoneal cavity. The peritoneal membrane is composed
Infections are an important cause of morbidity and mortality of a continuous single layer of mesothelial cells that covers the
in patients receiving hemodialysis. The cause of infection is abdominal and pelvic walls on one side of the peritoneal cav-
usually related to organisms found on the skin, namely ity, and the visceral organs, including the GI tract, liver, spleen,
Staphylococcus epidermidis and S. aureus. Other organisms have and diaphragm on the other side. The mesothelial cells are
also been found to cause access-related infections. The greatest covered by microvilli that increase the surface area of the peri-
risk to patients receiving hemodialysis is the development of toneal membrane to approximate body surface area (1 to 2 m2).
TABLE 239. Management of Hemodialysis Access Infections
AV stula Treat as subacute bacterial endocarditis for 6 weeks

Initial antibiotic choice should always cover gram-positive organisms (e.g., vancomycin 20 mg/kg
intravenously with serum concentration monitoring or cefazolin 20 mg/kg intravenously 3 times
per week)
Gram-negative coverage is indicated for patients with diabetes, HIV infection, prosthetic valves, or
those receiving immunosuppressive agents (gentamicin 2 mg/kg intravenously with serum
concentration monitoring).
Synthetic Grafts (AVG)
Local infection Empiric antibiotic coverage for gram-positive, gram-negative, and Enterococcus (e.g., gentamicin
plus vancomycin, then individualize after culture results become available); continue for
24 weeks
Extensive infection Antibiotics as above plus total resection
Access less than 1 month old Antibiotics as above plus removal of the graft
Tunneled Cuffed Catheters
(Internal Jugular, Subclavian)
Infection localized to No drainage: topical antibiotics (e.g., mupirocin ointment)
catheter exit site Drainage present: gram-positive coverage (e.g., cefazolin 20 mg/kg IV 3 times per week)
Bacteremia with or Gram-positive coverage as above
without systemic If stable and asymptomatic, change catheter and provide culture-specic
signs or symptoms antibiotic coverage for a minimum of 3 weeks.
AV, arteriovenous; HIV, human immunodeciency virus; IV, intravenous.

Blood vessels that supply the abdominal organs, muscle, and is generally tunneled under the abdominal wall and subcuta-
mesentery serve as the blood component of the system. neous tissue where it is held in place by cuffs that provide sta-
The gaps between the mesothelial cells allow for large bility and mechanical support to the catheter. The proximal
solutes to pass through into the bloodstream. Both the inter- portion of the catheter exits the abdomen near the umbilicus.
stitium and endothelial cells of the blood vessels provide Placement and handling of the catheter during PD exchanges
resistance to limit the solute size that is removed from the requires a sterile environment to minimize the risk of infec-
blood. Diffusion is the most important component of solute tious complications.
transport in PD, which is enhanced by the large surface area
and volume of dialysate, as well as contact time with the peri- Complications of Peritoneal Dialysis
toneal membrane. Ultraltration is achieved in PD by creat- Complications associated with PD include mechanical prob-
ing an osmotic pressure gradient between the dialysate and lems related to the PD catheter, metabolic problems associated
the blood. Traditionally, glucose has been used to create the with the components of the dialysate uid, damage to the peri-
osmotic gradient, but the solutions are not biocompatible toneal membrane, and infections (Table 2310). Strategies to
with the peritoneal membrane, resulting in cytotoxicity of the manage infectious complications of PD are discussed below.
cells. More recently, polymeric glucose derivatives, such as
icodextrin, have been used to create a colloid-driven osmosis Peritonitis
that results in ultraltration and convection of solute removal. Peritonitis is a leading cause of morbidity in PD patients,
In PD, prewarmed dialysate is instilled into the peritoneal which often leads to loss of the catheter and subsequent
cavity where it dwells for a specied length of time (usually change to HD as the treatment modality. However, recent
one to several hours, depending on the type of PD) to ade- advances with connectors used during instillation and
quately clear metabolic waste products. At the end of the dwell drainage of dialysate and delivery systems have dramatically
time, the dialysate is drained and replaced with fresh dialysate. decreased the incidence of peritonitis. Peritonitis can be
The continuous nature of PD provides for a more physiologic caused by chemical irritation or microorganisms.
removal of waste products from the bloodstream, which mim-
ics endogenous renal function by decreasing the uctuations TABLE 2310. Common Complications during Peritoneal
seen in serum concentrations of the waste products. Similarly, Dialysis
water is removed at a more constant rate, lessening the uctu-
ations in intravascular uid balance and providing for more Mechanical Complications
hemodynamic stability. Kinking in catheter
Catheter migration
There are several types of PD that are used. The most com-
Catheter adherence to peritoneal tissue
mon is continuous ambulatory peritoneal dialysis (CAPD), Excessive movement of catheter at exit site
which requires the patient to exchange 1 to 3 L of dialysate Peritoneal Damage
four to six times per day. Exchanges are generally done every Alterations in permeability of the peritoneal membrane
4 to 6 hours throughout the day with a longer dwell time Sclerosis of the peritoneal membrane
overnight. Automated peritoneal dialysis (APD) procedures Pain
involve the use of a cycler machine that performs sequential Impingement of the catheter tip on visceral organs
exchanges overnight while the patient is sleeping. Continuous Instillation pain
Rapid inow of dialysate
cycling PD (CCPD) performs three to ve exchanges through-
Acidic pH of dialysate
out the night. The nal exchange remains in the peritoneal Chemical irritation from dialysate additives (e.g., antibiotics)
cavity to dwell for the duration of the day. Nightly intermit- Low dialysate temperature
tent PD (NIPD) performs six to eight exchanges throughout Infections
the night. The nal exchange of dialysate is drained in the Peritonitis
morning and the peritoneal cavity remains empty throughout Exit-site infections
the day. Nocturnal tidal PD (NTPD) is similar to NIPD, with Tunnel infections
the exception that only a portion of the dialysate is exchanged Metabolic Complications
Exacerbation of diabetes mellitus from glucose load
throughout the night. The nal exchange is drained in the
Fluid overload
morning and the peritoneal cavity remains empty throughout Exacerbation of chronic heart failure
the day. Edema
Pulmonary congestion
Electrolyte abnormalities
Peritoneal Access Malnutrition
Access to the peritoneal cavity requires placement of an Albumin and amino acid loss
indwelling catheter. There are several types of indwelling Muscle wasting
catheters available, but all require placement of the distal end Increased adipose tissue
Fibrin formation in dialysate
into the peritoneal cavity. The central portion of the catheter
Pathophysiology Gram-positive organisms, namely S. epider- infections, which are difcult to treat and often require
midis, are the most common cause of peritonitis. Other removal of the catheter. Rifampin 600 mg orally daily (in a
pathologic organisms include S. aureus, streptococcal species, single or divided dose) may be added to IP vancomycin for the
enterococcus species, gram-negative organisms including treatment of methicillin-resistant S. aureus (MRSA), but
Escherichia coli and Pseudomonas species, and fungal organ- should be limited to duration of 1 week to minimize the
isms. Peritonitis should be presumed if cloudy uid is drained development of resistance. Two antibiotics are required for
from the peritoneal cavity and the uid should be evaluated treatment of P. aeruginosa peritonitis.49 If multiple organisms
by cultures. Antibiotic treatment should be initiated immedi- are cultured, treatment should cover all of the organisms,
ately, until cell counts and cultures prove otherwise.49 Patients including anaerobic organisms, and the patient should be
with peritonitis may also complain of abdominal pain, evaluated for other intra-abdominal pathologies.49
although pain may be absent in some cases. Peritonitis caused by fungal organisms is associated with
mortality in 25% of patients,49 which can be reduced by remov-
ing the catheter after fungal organisms are identied. Empiric
Treatment The International Society of Peritoneal Dialysis
treatment should include amphotericin B and ucytosine.49
(ISPD) revised the recommendations for the treatment of
Although amphotericin penetration into the peritoneal cavity
PD-related infections in 2005.49 Drug selection for empiric
is poor with IV administration, IP administration is associ-
treatment of peritonitis should cover both gram-positive and
ated with chemical irritation and pain. Fluconazole, voricona-
gram-negative organisms specic to the dialysis center and be
zole, or caspofungin may be suitable alternatives, depending
based on the protocols and sensitivity patterns of organisms
on culture results.
known to cause peritonitis, as well as the history of infections
in the patient. First-generation cephalosporins, such as cefa-
zolin, or vancomycin are recommended for empiric coverage Catheter-Related Infections
of gram-positive organisms. Appropriate coverage for gram- Catheter-related infections generally occur at the exit site or
negative organisms includes third- or fourth-generation the portion of the catheter that is tunneled in the subcuta-
cephalosporins, such as ceftazidime or cefepime, or aminogly- neous tissue. Previous infections increase the risk and inci-
cosides. Alternatives for gram-negative coverage include dence of catheter-related infections.
amikacin and oral uoroquinolones. An example of an
appropriate empiric treatment for peritonitis includes cefa- Pathophysiology The major pathologic organisms responsible
zolin in combination with ceftazidime, cefepime, or an for causing catheter-related infections are S. aureus and P.
aminoglycoside. If the patient has a cephalosporin allergy, aeruginosa. These organisms also cause the most serious
vancomycin in combination with an aminoglycoside is an catheter-related infections. S. epidermidis is found in less than
alternative empiric treatment.49 20% of catheter-related infections. Other organisms include
The preferred route of administration is intraperitoneal diphtheroids, anaerobic bacteria, Legionella, and fungi.49
(IP) rather than IV to achieve maximum concentrations at the Exit-site infections present with purulent drainage at the
site of infection. Antibiotics can be administered IP intermit- site. Erythema may or may not be present with an exit-site
tently as a single large dose in one exchange per day or con- infection. Tunnel infections are generally an extension of the
tinuously as multiple smaller doses with each exchange. exit-site infection and rarely occur alone. Symptoms of a tun-
Intermittent administration requires at least 6 hours of dwell nel infection may include tenderness, edema, and erythema
time in the peritoneal cavity to allow for adequate systemic over the tunnel pathway, but are often asymptomatic.
absorption and provides adequate levels to cover the 24-hour Ultrasound can be used to detect tunnel infections in asymp-
period. However, continuous administration is better suited tomatic patients. Exit-site infections caused by S. aureus and P.
for PD modalities that require more frequent exchanges (less aeruginosa often spread to tunnel infections and are the most
than 6-hour dwell time). The reader should refer to the ISPD common causes of catheter-infectionrelated peritonitis.
guidelines for dosing recommendations for IP antibiotics in
CAPD and automated PD patients.49 The dose of the antibi- Treatment Exit-site infections may be treated immediately
otics should be increased by 25% for patients with residual with empiric coverage, or treatment may be delayed until cul-
renal function who are able to produce more than 100 mL tures return. Empiric treatment of catheter-related infections
urine output per day. should cover S. aureus. Coverage for P. aeruginosa should also
Once the organism has been identied and sensitivities be included if the patient has a history of infections with this
are known, drug selection should be adjusted to reect the organism.49 Cultures and sensitivity testing are particularly
susceptibilities of the organism. Streptococcal, staphylococcal, important in tailoring antibiotic therapy for catheter-related
and enterococcal species sensitive to -lactam antibiotics infections to ensure eradication of the organism and prevent
should be treated with continuous IP dosing to increase ef- recurrence or related peritonitis.
cacy and minimize resistance.49 Peritonitis caused by S. aureus Less severe infections may be treated with topical antibiotic
or P. aeruginosa are often associated with catheter-related cream, although this practice is controversial. Oral antibiotics
are also effective for treatment of catheter-related infections.

Empiric or routine use of vancomycin for gram-positive Patient Care and Monitoring
infections should be avoided unless the infection is caused by
MRSA. Rifampin may be added to therapy for severe infec-
tions or slowly-resolving S. aureus infections, but monother-
1. Assess the patient to determine if the patient should be
apy is not recommended.49 Oral uoroquinolones are used as
evaluated for CKD. Does the patient have any risk fac-
rst-line agents to treat P. aeruginosa, which can be difcult to tors for CKD?
treat and require prolonged treatment. If the infection is slow
2. Review any available laboratory data to determine the
to resolve or if it recurs, IP ceftazidime or a second agent
staging of CKD.
should be added.49 Treatment of catheter-related infections
3. Obtain a thorough medical and medication history
should be continued until the exit site appears normal with no
from the patient. Does the patient have any concomi-
erythema or drainage. Generally, at least 2 weeks of therapy or
tant diseases, such as diabetes or hypertension, that
longer are required to ensure complete eradication of the should be treated to prevent the progression of CKD?
organism and prevent future recurrence, which is common
4. Determine if an ACE-I or ARB is appropriate for the
with S. aureus and P. aeruginosa. Infections that do not resolve
patient. Does the patient have proteinuria?
may require replacement of the PD catheter. Catheter-related
5. Develop a plan to assess and optimize treatment of CKD.
infections that present in conjunction with or progress to
peritonitis with the same organism require removal of the PD 6. Determine if the patient requires medical treatment for
catheter until the peritonitis is resolved.49 electrolyte imbalances. Does the patient have edema?
Does the patient have an arrhythmia?
7. Educate the patient on dietary changes to manage elec-
Prophylaxis of Peritonitis and Catheter-Related trolyte imbalances associated with CKD.
Infections
8. Assess the patient for the presence of anemia. Do the labo-
Prevention of peritonitis and catheter-related infections starts ratory tests suggest the patient requires medical treatment?
when the catheter is placed. The exit site should be properly cared
9. Develop a plan to assess and optimize treatment for
for until it is well healed before it can be used for PD. Patients
anemia.
should receive proper instructions for care of the catheter during
10. Determine if the patient requires medical intervention
this time period, which can last up to 2 weeks. Patients should
to prevent the development of or treatment for secondary
also be instructed on the proper techniques to use for dialysate
hyperparathyroidism.
exchanges to minimize the risk of infections during exchanges,
11. Develop a plan to assess and optimize treatment for
which is the most common cause of peritonitis.
secondary hyperparathyroidism.
Intranasal S. aureus increases the risk of S. aureus exit-site
infections, tunnel infections, peritonitis, and subsequent 12. Establish if the patient requires renal replacement therapy.
catheter loss.49 Several measures have been used to decrease the 13. Evaluate the patient for complications associated with
risk of peritonitis caused by S. aureus, including mupirocin dialysis. Does the patient develop hypotension or cramps
cream applied daily around the exit site, intranasal mupirocin during hemodialysis? Does the patient have symptoms
consistent with peritonitis or a catheter infection?
cream twice daily for 5 days each month, or rifampin 300 mg
orally twice daily for 5 days, repeated every 3 months.49 14. Develop a plan to assess and optimize treatment for
Mupirocin use is preferred over rifampin to prevent the devel- complications associated with dialysis.
opment of resistance to rifampin, although mupirocin resist- 15. Stress the importance of adherence with the treatments for
ance has also been reported.49 Other measures that have been CKD and associated complications, including lifestyle
used to decrease both S. aureus and P. aeruginosa infections modications and medications. Recommend a therapeutic
regimen that is easy for the patient to accomplish.
include gentamicin cream applied twice daily and ciprooxacin
otic solution applied daily to the exit site.49 16. Provide patient education with regard to CKD and the
associated complications, lifestyle modications, and
drug therapy:
Outcome Evaluation
Clinical improvement should be seen within 48 hours of ini-
What causes CKD and what things to avoid.
tiating treatment for peritonitis or catheter-related infections. Possible complications of CKD and symptoms associ-
Perform daily inspections of peritoneal uid or the exit site to ated with the complications.
determine clinical improvement. Peritoneal uid should When to take medications.
become clear with improvement of peritonitis and erythema What potential adverse effects may occur.
and discharge should remit with improvement of catheter- Which drugs may interact with therapy.
related infections. If no improvement is seen within 48 hours, Warning signs to report to the physician (edema,
obtain additional cultures and cell counts to determine the irregular heart beat, fatigue, unusual bleeding).
appropriate alterations in therapy.
ABBREVIATIONS RRT: renal replacement therapy

SC: subcutaneous
ACE-I: angiotensin-converting enzyme inhibitor SCr: serum creatinine
AGE: advanced glycosylation end-product sHPT: secondary hyperparathyroidism
APD: automated peritoneal dialysis SPS: sodium polystyrene sulfonate
ARB: angiotensin receptor blocker TC: total cholesterol
ARF: acute renal failure TIBC: total iron binding capacity
AVF: arteriovenous stula TSAT: transferrin saturation
AVG: arteriovenous graft USRDS: United States Renal Data Service
Ca-P: calcium-phosphorus product Reference lists and self-assessment questions and answers are
CAPD: continuous ambulatory peritoneal dialysis available at www.ChisholmPharmacotherapy.com.
CCPD: continuous cycling peritoneal dialysis
CHD: coronary heart disease Log into the website: www.pharmacotherapyprinciples.com
CKD: chronic kidney disease for information on obtaining continuing education credit for
CVD: cardiovascular disease this chapter.
DDAVP: desmopressin
DM: diabetes mellitus
ECG: electrocardiogram
EPO: erythropoietin
ESA: erythropoiesis-stimulating agent KEY REFERENCES AND READINGS
ESRD: end-stage renal disease
FEK: fractional excretion of potassium Agarwal R, Curley TM. The role of statins in chronic kidney disease.
FENa: fractional excretion of sodium Am J Med Sci 2005;333:6981.
GFR: glomerular ltration rate Bakris GL. A practical approach to achieving recommended blood
GI: gastrointestinal pressure goals in diabetic patients. Arch Intern Med
HbA1c: hemoglobinA1c 2001;161:26612667.
Hct: hematocrit Bakris GL, Williams M, Sworkin L, et al. for the National Kidney
HD: hemodialysis Foundation Hypertension and Diabetes Executive Committees
HDL-C: high-density lipoprotein cholesterol Working Group. Preserving renal function in adults with hyper-
Hgb: hemoglobin tension and diabetes: a consensus approach. Am J Kidney Dis
HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A 2000;36:646661.
IP: intraperitoneal de Francisco ALM. Secondary hyperparathyroidism: review of the
iPTH: intact parathyroid hormone disease and its treatment. Clin Ther 2004;26:19761993.
ISPD: International Society of Peritoneal Dialysis Hudson JQ, Schonder KS. Advances in anemia management in
IV: intravenous chronic kidney disease. J Pharm Pract 2002;15:437455.
LDL-C: low-density lipoprotein cholesterol National Kidney Foundation. KDOQI Clinical Practice Guidelines
LVH: left ventricular hypertrophy and Clinical Practice Recommendations for Anemia in
MCHC: mean corpuscular hemoglobin concentration Chronic Kidney Disease. Am J Kidney Dis 2006; 47 (suppl 3):
MCV: mean corpuscular volume S1S146.
MDRD: Modication of Diet in Renal Disease (study) Piraino B, Bailie GR, Bernardini J, et al. ISPD guidelines/recommen-
MRSA: methicillin-resistant Staphylococcus aureus dations: peritoneal dialysis-related infections recommenda-
NIPD: nightly intermittent peritoneal dialysis tions: 2005 update. Perit Dial Int 2005;25:107131.
NKF: National Kidney Foundation Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies.
NKF-DOQI: National Kidney Foundation-Dialysis Outcome N Engl J Med 1998;339:14481456.
Quality Initiative Remuzzi G, Ruggenenti P, Perico N. Chronic renal diseases: renopro-
NTPD: nocturnal tidal peritoneal dialysis tective benets of renin-angiotensin system inhibition. Ann
PD: peritoneal dialysis Intern Med 2002;136:604615.
PTH: parathyroid hormone Uhlig K, Sarnak MJ, Singh AK. New approaches to the treatment of cal-
RBC: red blood cell cium and phosphorus abnormalities in patients on hemodialysis.
ROD: renal osteodystrophy Curr Opin Nephrol Hypertens 2001;10:793798.
24 FLUIDS AND ELECTROLYTES
Mark A. Malesker and Lee E. Morrow
LEARNING OBJECTIVES
1. Estimate the volumes of various body uid compartments.

2. Calculate the daily maintenance uid requirement for patients given their age, weight, and
gender.
3. Differentiate among currently available uids for volume resuscitation.
4. Identify the electrolytes primarily found in the extracellular and intracellular uid
compartments.
5. Describe the unique relationship between serum sodium concentration and total body water.
6. Review the etiology, clinical presentation, and management for disorders of sodium,
potassium, calcium, phosphorus, and magnesium.
KEY CONCEPTS Concentrated electrolytes (potassium chloride, potassium

phosphate, and sodium chloride greater than 0.9%) should
Total body water (TBW) is approximately 50% of lean body not be stored in patient care areas as a patient safety measure.
weight in the normal female and 60% of lean body weight in Serum magnesium levels do not correlate well with total
males. TBW is comprised of the intracellular uid (two-thirds body magnesium stores. For this reason, magnesium sup-
of TBW) and the extracellular uid (one-third of TBW). The plementation is often given empirically to critically ill
extracellular uid is made up of two major uid subcompart- patients.
ments: the interstitial space and the intravascular space.
Therapeutic uids include crystalloid and colloid solutions.
The most commonly used crystalloids include normal saline, BODY FLUID COMPARTMENTS
hypertonic saline, and lactated Ringers solution. Examples of
colloids include albumin, the dextrans, hetastarch, and fresh A thorough understanding of the fundamentals of uid and
frozen plasma. electrolyte homeostasis is essential given the frequency with
The calculated serum osmolality helps determine deviations which clinical disturbances are seen and the profound effects
in TBW content. these disturbances can have on various aspects of patient care.
Hyponatremia is a very common nding in hospitalized patients However, the interplay of body uids, serum electrolytes, and
and is dened as a serum sodium level below 136 mEq/L clinical monitoring is complex, and a thorough command of
(136 mmol/L). these issues is a challenging task even for advanced practitioners.1
Intravenous potassium infusions running at rates of greater Practitioners must be familiar with the key concepts of body
than 10 mEq/hour require cardiac monitoring. compartment volumes, calculation of daily uid requirements,
Calcium gluconate is the preferred peripherally infused calcium and the various types of uid available for replacement. The
supplement because it is less irritating to the veins. Calcium management of disorders of sodium, potassium, calcium,
chloride must be infused via a central line. phosphorus, and magnesium integrates these concepts with
In the critical care setting, hypophosphatemia can result in issues of dose recognition and patient safety.
impaired diaphragmatic contractility and acute respiratory The most fundamental concept to grasp is an assessment of
failure. total body water (TBW), which is directly related to body
403
weight. TBW constitutes approximately 50% of lean body

weight in healthy females and 60% of lean body weight in males. Patient Encounter 1, Body Fluid
The percentage of TBW decreases as body fat increases and/or Compartments
with age (75% to 85% of body weight is water for newborns).
Unless the patient is obese (body weight greater than 120% of
Calculate the TBW, ICF, and ECF in a 70-kg male.
ideal body weight), clinicians typically use a patients actual TBW = 0.5 body weight (kg) for females and 0.6 body
body weight when calculating TBW.2 In this instance, it is cus- weight (kg) for males
tomary to estimate TBW using lean body weight as calculated by ICF = 2/3 TBW
the Devine-Devine method: males lean body weight = 50 kg + ECF = 1/3 TBW
[2.3 kg/inch (height in inches 60)] and females lean body
Example
weight = 45.5 kg + [2.3 kg/inch (height in inches 60)].35 TBW = 0.6 70 kg = 42 L
Note that 1 kg is equivalent to 2.2 pounds and 1 inch is equi- ICF = 2/3 TBW = 0.67 42 L = 28 L
valent to 2.54 cm. One liter of water weighs 1 kg (2.2 lb). ECF = 1/3 TBW = .33 42 L = 14 L
The intracellular uid (ICF) represents the water contained Interstitial uid = 3/4 ECF or 25% TBW = .25 42 L = 11 L
within cells and is rich in electrolytes such as potassium, mag- Plasma uid = 1/4 ECF or 8% TBW = .08 42 L = 3 L
nesium, phosphates, and proteins. The ICF is approximately TBW, total body water; ICF, intracellular uid; ECF, extra-
two-thirds of TBW regardless of gender. For a 70-kg man, this cellular uid.
would mean that the TBW is 42 L and the ICF is approxi-
mately 28 L. For a 70-kg woman, these values would be 35 L
and 24 L, respectively. Note that ICF represents approximately
40% of total body weight in men and approximately 33% of a normal adult on an average diet, ingested uids are easily
total body weight in women. measured and average 1400 mL per day. Other uid inputs,
The extracellular uid (ECF) is the uid outside the cell such as those from ingested foods and the water by-product of
and is rich in sodium, chloride, and bicarbonate. The ECF is oxidation, are not directly measurable. Fluid outputs such as
approximately one-third of TBW (14 L in a 70-kg man or 12 L in urinary and stool losses are also easily measured and are
a 70-kg woman) and is subdivided into two compartments: the referred to as sensible losses. Other sources of uid loss, such
interstitial uid and the intravascular uid. The interstitial as evaporation of uid through the skin and/or lungs, are not
uid (also known as lymphatic uid) represents the uid readily measured and are called insensible losses. Table 241
occupying the spaces between cells, and is about 25% of TBW shows the estimated ins and outs (I&Os) for a healthy 150-lb
(10.5 L in a 70-kg man or 8.8 L in a 70-kg woman). The (68-kg) man.6 The measurable ins and outs are routinely
intravascular uid (also known as plasma) represents the uid measured in hospitalized patients and are used to estimate
within the blood vessels and is about 8% of TBW (3.4 L in a total uid balance for each 24-hour period. It is important to
70-kg man or 2.8 L in a 70-kg woman). The ECF is approxi- realize that in hospitalized patients, multiple other forms of
mately one-third of TBW or 14 L in a 70-kg male. Because the uid loss must be considered. These include losses from
exact percentages are cumbersome to recall, many clinicians enteric suctioning [most commonly, nasogastric (NG) tubes],
accept that the ECF represents roughly 20% of body weight from surgical drains (e.g., chest tubes, nephrostomy tubes,
(regardless of gender) with 15% in the interstitial space and and pancreatic drains), via stulous tracts, and enhanced
5% in the intravascular space.6 Note that serum electrolytes evaporative losses (burns and fever).
are routinely measured from the ECF. ECF depletion tends to occur acutely. In this setting, rapid
The transcellular uid includes the viscous components of and aggressive uid replacement is required to maintain ade-
the peritoneum, pleural space, and pericardium, as well as the quate organ perfusion. Because ECF depletion is generally
cerebrospinal uid, joint space uid, and the gastrointestinal due to the loss of isotonic uid (proportional losses of
(GI) digestive juices. Although the transcellular uid normally sodium and water), major disturbances of plasma osmolality
accounts for about 1% of TBW, this amount can increase sig-
nicantly during various illnesses favoring uid collection in
one of these spaces (e.g., pleural effusions or ascites in the TABLE 241. Ins and Outs for a Healthy 150-lb (68-kg) Man
peritoneum). The accumulation of uid in the transcellular
space is often referred to as third spacing. To review the cal- Input mL/day Output mL/day
culations of the body uid compartments in a representative Ingested uid a
1400 Urine a
1500
patient, see Patient Encounter 1. Fluid in food 850 Skin losses 500
To maintain uid balance, the total amount of uid gained Water of oxidation 350 Respiratory tract losses 400
throughout the day (input, or ins) must equal the total amount Stool 200
Total 2600 Total 2600
of uid lost (output, or outs). Although most forms of the
bodys input and output can be measured, several cannot. For a
Readily quantiable.
CHAPTER 24 / FLUIDS AND ELECTROLYTES 405
are not common. ECF depletion manifests clinically as signs

and symptoms associated with decreased tissue perfusion: Patient Encounter 2, Fluid
dizziness, orthostasis, tachycardia, decreased urine output, Requirements
increased hematocrit, decreased central venous pressure,
and/or hypovolemic shock. Common causes of ECF depletion
Calculate the daily uid requirement for a 70-kg adult
include external uid losses (burns, hemorrhage, diuresis, GI
male. Use the equation from Table 242: Adult uid
losses, and adrenal insufciency) and third-spacing of uids requirement = 1500 mL + 20 mL for each kg greater than 20
(septic shock, anaphylactic shock, or abdominal ascites). The uid requirements for a 70-kg adult would be 1500 mL +
TBW depletion (often referred to as dehydration) is typ- 20 mL (50 kg) = 2500 mL
ically a more gradual, chronic problem compared to ECF
depletion. Because TBW depletion represents a loss of hypo-
tonic uid (proportionally more water is lost than sodium)
from all body compartments, a primary disturbance of osmo- Therapeutic Fluids
lality is usually seen. The signs and symptoms of TBW deple- Therapeutic intravenous (IV) uids include crystalloid
tion include CNS disturbances (mental status changes, seizures, solutions, colloidal solutions, and oxygen-carrying resuscitation
and coma), excessive thirst, dry mucous membranes, decreased solutions. Crystalloids are composed of water and electrolytes,
skin turgor, elevated serum sodium, increased plasma osmolality, all of which pass freely through semipermeable membranes
concentrated urine, and acute weight loss. Common causes of and remain in the intravascular space for shorter periods of
TBW depletion include insufcient oral intake, excessive insen- time. As such, these solutions are very useful for correcting
sible losses, diabetes insipidus, excessive osmotic diuresis, and electrolyte imbalances but result in smaller hemodynamic
impaired renal concentrating mechanisms. Long-term care res- changes for a given unit of volume.
idents are frequently admitted to the acute care hospital with Fluids can be classied further according to their tonicity.
TBW depletion secondary to lack of adequate oral intake, often Isotonic solutions (i.e., normal saline or 0.9% sodium chloride
with concurrent excessive insensible losses. [NaCl]) have a tonicity equal to that of the ICF (approximately
The volume of uid required to correct TBW depletion 310 mEq/L or 310 mmol/L) and do not shift the distribution
equals the basal uid requirement plus ongoing exceptional of water between the ECF and the ICF. Because hypertonic
losses plus the uid decit. Basal daily uid requirements are solutions (i.e., hypertonic saline or 3% NaCl) have greater
calculated using the formulas in Table 242. For an adult, this tonicity than the ICF (greater than 376 mEq/L or 376 mmol/L),
represents 1500 mL for the rst 20 kg of body weight plus 20 they draw water from the ICF into the ECF. In contrast, hypo-
mL for each additional kg. The volume of replacement uids tonic solutions (i.e., 0.45% NaCl) have less tonicity than the ICF
required for a given patient (the uid decit) can be esti- (less than 250 mEq/L or 250 mmol/L) leading to an osmotic
mated by the acute weight change in the patient (1 kg = 1 L pressure gradient that pulls water from the ECF into the ICF.
of uid). Because the precise weight change is not typically The tonicity, electrolyte content, and glucose content of selected
known, it is often calculated as follows: uid decit = normal uids are shown in Table 243.
TBW present TBW. Normal TBW is estimated based on the The tonicity of crystalloid solutions is directly related to their
patients height using the formulas in Table 242, and the sodium concentration. The most commonly used crystalloids
present TBW is estimated based on the patients current body include normal saline, hypertonic saline, and lactated Ringers
weight. solution. Excessive administration of any uid replacement
Once TBW has been restored, the volume of maintenance therapy, regardless of tonicity, can lead to uid overload, partic-
uid equals the basal uid requirement plus ongoing excep- ularly in patients with cardiac or renal insufciency.
tional losses. If the pathophysiologic process leading to TBW
depletion has not been identied and corrected (or accounted Normal Saline (0.9% NaCl)
for in the calculation of maintenance uid requirements), Normal saline is an isotonic uid composed of water, sodium,
TBW depletion will quickly recur. To review the concepts and chloride. It provides primarily ECF replacement and can
involved in the calculation of replacement uids for a repre- be used for virtually any cause of TBW depletion. Common
sentative patient (see Patient Encounter 2). uses of normal saline include: perioperative uid administra-
tion; volume resuscitation of shock, hemorrhage, or burn
patients; uid challenges in hypotensive or oliguric patients;
TABLE 242. Useful Calculations for the Estimate of Patient and hyponatremia.
Maintenance Fluid Requirements
Neonate (110 kg) = 100 mL/kg Half-Normal Saline (0.45% NaCl)

Child (1020 kg) = 1000 mL + 50 mL for each kg greater than 10 Half-normal saline is a hypotonic uid that provides free
Adult (greater than 20 kg) = 1500 mL + 20 mL for each kg greater water in relative excess when compared to the sodium con-
than 20
centration. This crystalloid is typically used to treat patients
TABLE 243. Electrolyte and Dextrose Content of Selected Crystalloid Fluids
Dextrose Sodium Potassium Calcium Chloride Lactate

Osmolarity (g/L) (mEq/L) (mEq/L) (mEq/L) (mEq/L) (mEq/L)
IV Solution (mOsm) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L)
5% Dextrose 250 50
2.78
10% Dextrose 505 100
5.55
0.9% NaCl 308 154 154
0.45% NaCl 154 77 77
3% NaCl 1025 513 513
D5% and 405 50 77 77
0.45% NaCl 2.78
D5% and 329 50 34 34
0.2% NaCl 2.78
Ringers injection 310 147 4 5 156
2.5
Lactated Ringers 274 130 4 3 109 28
1.5
Lactated Ringers 525 50 130 4 5 109 28
and D5% 2.78 2.5
D, dextrose; NaCl, sodium chloride.
who are hypertonic with primary depletion of the ECF. It is commonly used to treat severe hypernatremia. D5W is
Because half-normal saline is hypotonic, serum sodium must used in small volumes (100 mL) to dilute many IV medica-
be closely monitored during administration. tions or at a low infusion rate (10 to 15 mL/hour) to keep the
vein open (KVO) for IV medications.
Hypertonic Saline (3% NaCl) Colloids do not dissolve into a true solution, and therefore
Hypertonic saline is obviously hypertonic and provides a sig- do not pass readily across semipermeable membranes. As such,
nicant sodium load to the intravascular space. This solution colloids effectively remain in the intravascular space and
is utilized very infrequently given the potential to cause sig- increase the oncotic pressure of the plasma. This effectively
nicant shifts in the water balance between the ECF and the shifts uid from the interstitial compartment to the plasma
ICF. It is typically considered to treat patients with severe compartment. In clinical practice, these theoretical benets are
hyponatremia who have symptoms attributable to low serum generally short lived and for most patients there is little thera-
sodium. peutic advantage of colloids over crystalloids or vice-versa.
Examples of colloids include 5% albumin, 25% albumin, the
Ringers Lactate dextrans, hetastarch, and fresh frozen plasma. Note that each of
This isotonic volume expander contains sodium, potassium, these agents contains a substance (proteins and complex sugars)
chloride, and lactate that approximates the uid and elec- that will ultimately be metabolized. When this ultimately occurs,
trolyte composition of the blood. Ringers lactate (also known the oncotic agent will be lost and only the remaining hypotonic
as lactated Ringers or LR) provides ECF replacement and is uid delivery agent will remain. As such, use of large volumes of
most often used in the perioperative setting, and for patients colloidal agents is more likely to induce uid overload com-
with lower GI uid losses, burns, or dehydration. The lactate pared to crystalloids. Although smaller volumes of colloids have
component of LR works as a buffer to increase the pH. Large equal efcacy as larger volumes of crystalloids, they generally
volumes of LR may cause metabolic alkalosis. Because patients must be infused more slowly. Often the net result is that the
with signicant liver disease are unable to metabolize lactate time to clinical benet is the same regardless of which class of
sufciently, Ringers lactate administration in this population fluid is utilized. For example, 500 mL of normal saline is
may lead to accumulation of lactate with iatrogenic lactic aci- required to increase the systolic blood pressure to the same
dosis. The lactate is not metabolized to bicarbonate in the degree as seen with approximately 250 mL of albumin; how-
presence of liver disease and lactic acid can result. ever, the normal saline can be administered twice as fast.
5% Dextrose in Water (D5W) Albumin

D5W is a solution of free water and dextrose that provides a Albumin is a protein derived from fractionating human
modest amount of calories but no electrolytes. Although it is plasma. Because albumin infusion is expensive and may be
technically isotonic, it acts as a hypotonic solution in the body. associated with adverse events, it should be used for acute
volume expansion and not as a supplemental source of protein acidosis may arise with massive or prolonged infusions. In
calories. Historically, albumin was used indiscriminately in severe cases, a colloid or blood product may be indicated to
the intensive care unit until anecdotal publications suggested increase oncotic pressure within the vascular space. Once iso-
that albumin may cause immunosuppression. However, the volemia is achieved, patients may be switched to a more
recently completed Safety After Fifty Evaluation (SAFE) trial hypotonic solution (0.45% NaCl) at a rate that delivers esti-
randomized nearly 7000 hypovolemic patients to either albumin mated daily needs.
or normal saline therapy and found that the mortality for The clinical scenario and the severity of the volume abnor-
those who received albumin was the same as for those who mality dictate monitoring parameters during uid replacement
received normal saline.7 This nding conrmed the results of therapy. These may include a subjective sense of thirst, mental
several previous reviews and meta-analyses of studies using status, skin turgor, orthostatic vital signs, pulse rate, weight
human albumin versus normal saline therapy for resuscitation changes, blood chemistries, uid input and output, central
of critically ill patients.810 Albumin combined with furosemide venous pressure, pulmonary capillary wedge pressure, and car-
has been demonstrated to improve uid balance, oxygenation, diac output. Fluid replacement requires particular caution in
and hemodynamics in the subset of patients with acute lung patient populations at risk of uid overload, such as those with
injury who have low serum protein.11 renal failure, cardiac failure, hepatic failure, or the elderly. Other
While albumin is the most commonly used colloid, the complications of IV uid therapy include inltration, infection,
other products are not without their own risks and benets. phlebitis, thrombophlebitis, and extravasation.
Hetastarch (various manufacturers) contains 6% starch and In summary, the settings in which uid replacement is used
0.9% sodium chloride. This product has no oxygen-carrying are: hypovolemic patients (e.g., sepsis or pneumonia); hyper-
capacity and is administered intravenously as a plasma volemic patients [e.g., congestive heart failure (CHF), cirrho-
expander. Limitations of this product include acquisition cost, sis, or renal failure]; euvolemic patients who are unable to take
hypersensitivity reactions, and bleeding. Dosing should be oral uids in proportion to insensible losses (e.g., the periop-
reduced in the presence of renal dysfunction. Low-molecular- erative period); and patients with electrolyte abnormalities
weight dextran (various manufacturers) and high-molecular- (see below).
weight dextran (various manufacturers) are polysaccharide
plasma expanders. Anaphylactic reactions and prolonged
bleeding times have historically limited the use of these prod-
ELECTROLYTES
ucts. Fresh frozen plasma (FFP) has been used in cases of
excessive blood loss (surgery or trauma) and to prevent bleed-
Normally, the number of anions and cations in each uid com-
ing in the presence of abnormal coagulation studies. Fresh
partment are equal. Cell membranes play the critical role of
frozen plasma is now rarely used for volume expansion. Risks
maintaining distinct ICF and ECF spaces which are biochemi-
of fresh frozen plasma include anaphylaxis, the potential for
cally distinct. Serum electrolyte concentrations reect the
viral transmission through plasma, hepatitis, and an increased
stores of ECF electrolytes rather than that of ICF electrolytes.
nosocomial infection rate in the intensive care setting.
Table 244 lists the chief cations and anions along with their
normal concentrations in the ECF and ICF. The principal
cations are sodium, potassium, calcium, and magnesium, while
Fluid Management Strategies
the key anions are chloride, bicarbonate, and phosphate. In the
Classic indications for IV uid include maintenance of blood ECF, sodium is the most common cation and chloride is the
pressure, restoring the ICF volume, replacing ongoing renal or most abundant anion; while in the ICF, potassium is the primary
insensible losses when oral intake is inadequate, and the need cation and phosphate is the main anion. Normal serum elec-
for glucose as a fuel for the brain.12 Although large volumes of trolyte values are listed in Table 245.
uid are given during the resuscitation of most trauma Osmolality is a measure of the number of osmotically
patients, a recent analysis reported uncertainty about the use active particles per unit of solution, independent of the weight
of early large-volume uid replacement in patients with active or nature of the particle. Equimolar concentrations of all sub-
bleeding, calling into question our understanding of the need stances in the undissociated state exert the same osmotic pres-
for uids in various patient populations.13 sure. Although the normal serum osmolality is 280 to 300
When determining the appropriate uid to be utilized, it is mOsm/kg (280 to 300 mmol/kg), multiple scenarios exist
important to rst determine the type of uid problem (TBW where this value becomes markedly abnormal. The calcu-
versus ECF depletion), and start therapy accordingly. For lated serum osmolality helps determine deviations in TBW
patients demonstrating signs of impaired tissue perfusion, content. As such, it is often useful to calculate the serum
the immediate therapeutic goal is to increase the intravascular osmolality as follows:
volume and restore tissue perfusion. The standard therapy is
normal saline given at 150 to 500 mL/hour until perfusion is Serum osmolality (mOsm/L) = 2 [Na+] + [glucose
optimized. Although LR is a therapeutic alternative, lactic (mg/dL)]/18 + [blood urea nitrogen]/2.8
TABLE 244. Normal Cation and Anion Concentrations in the ECF and ICF
ECF ICF
Plasma Interstitial Fluid
Ion Species (mEq/L) (mEq/L) Ion Species mEq/L
Cations Cations
Na+ 142 144 K+ 135
K+ 4 4 Mg2+ 43
Ca2+ 5 2.5
Mg2+ 3 1.5
Total 154 152 Total 178
Anions Anions
Cl 103 114 PO42 90
HCO3 27 30 Protein 70
PO42 2 2 SO42 18
SO42 1 1
Organic acid 5 5
Protein 16 0
Total 154 152 Total 178
ECF, extracellular uid; ICF, intracellular uid.
Note: For glucose, multiply by a factor of 0.055 to convert con- aggressive interventions including the use of concentrated
ventional glucose units (mg/dL) to SI glucose units (mmol/L). electrolytes. However, these solutions are a frequent source
Because the body regulates water to maintain osmolality, of medical errors with signicant potential for patient harm.
deviations in serum osmolality are used to estimate TBW As such, the 2005 National Patient Safety Goals published by
stores. Water moves freely across all cell membranes, making the Joint Commission on Accreditation of Healthcare Organizations
serum osmolality an accurate reection of the osmolality (JCAHO) recommends that concentrated electrolyte solutions
within all body compartments. An increase in osmolality is (potassium chloride, potassium phosphate, and sodium chloride
equated with a loss of water greater than the loss of solute greater than 0.9%) be removed from patient care areas. In addi-
(TBW depletion). A decrease in serum osmolality is seen tion, JCAHO recommends standardizing and limiting the
when water is retained in excess of solute (congestive heart number of drug concentrations available in each institution
failure or hepatic cirrhosis). The difference between the meas- so as to further reduce the risk of medication errors and
ured serum osmolality and the calculated serum osmolality, improve outcomes.14
using the equation above, is referred to as the osmolar
gap. Under normal circumstances the osmolar gap should be
10 mOsm/L or less. An increased osmolar gap suggests the Patient Encounter 3, Calculate the
presence of a small, osmotically active agent and is most com- Plasma Osmolality
monly seen with the ingestion of alcohols (ethanol, methanol,
ethylene glycol, or isopropyl alcohol) or during mannitol
therapy. Patient Encounter 3 illustrates the utility of serum A 50-year-old homeless man is brought to the emergency
osmolality in a clinical setting. department staggering and smelling like beer. Rapid respira-
Many of the electrolyte disturbances discussed in the remain- tion, tachycardia, and a BP of 90/60 mm Hg were noted.
der of this chapter represent medical emergencies that call for The sodium is 142 mEq/L (142 mmol/L), potassium 3.6
mEq/L (3.6 mmol/L), chloride 100 mEq/L (100 mmol/L),
bicarbonate 12 mEq/L (12 mmol/L), glucose 180 mg/dL
(9.99 mmol/L), and BUN 28 mg/dL (9.99 mol/L). The meas-
TABLE 245. Normal Ranges for Serum Electrolyte Concentrations ured osmolarity is 360 mOsm/L.
Sodium 136145 mEq/L or 136145 mmol/L Calculate the osmolality.
Potassium 3.55.0 mEq/L or 3.55.0 mmol/L (2 Na) + (glucose/18) + (BUN/2.8) = (2 142) + (180/18) +
Chloride 98106 mEq/L or 98106 mmol/L (28/2.8) = 304 mOsm/L
Bicarbonate 2130 mEq/L or 2130 mmol/L Calculate the osmolar gap.
Magnesium 1.41.8 mEq/L or 0.70.9 mmol/L 360 304 = 56 mOsm/L for gap
Calcium
Total 4.45.2 mEq/L (910.5 mg/dL) or 2.252.5 mmol/L What is the likely cause of an increased gap in this patient?
Ionized 2.22.8 mEq/L (4.55.6 mg/dL) or 1.11.4 mmol/L Ethanol content of the ingested beer
Phosphorus 34.5 mg/dL (1.01.4 mmol/L)
Sodium wound drainage, burns, GI losses (vomiting or diarrhea),

hypoadrenalism (low cortisol and low aldosterone), and renal
The bodys normal daily sodium requirement is 1.0 to 1.5
tubular acidosis. Treatment includes the administration of
mEq/kg (80 to 130 mEq, which is 80 to 130 mmol) to maintain
sodium to correct the sodium decit and water to correct the
a normal serum sodium concentration of 136 to 145 mEq/L
TBW decit. The sodium decit can be calculated with the
(136 to 145 mmol/L).15 Sodium is the predominant cation of
following equation:2
the ECF and largely determines ECF volume. Sodium is also
the primary factor in establishing the osmotic pressure rela- Sodium decit (mEq) = (TBW)(desired Na+ concentration
tionship between the ICF and ECF. All body uids are in
current Na+ concentration)
osmotic equilibrium and changes in serum sodium concentra-
tion are associated with shifts of water into and out of body
Although both water and sodium are required in this instance,
fluid compartments. When sodium is added to the intravas-
sodium needs to be provided in excess of water to fully correct
cular uid compartment, uid is pulled intravascularly from
this abnormality. As such, hypertonic saline (3% NaCl) is
the interstitial uid and the ICF until osmotic balance is
often used. One can estimate the change in serum sodium
restored. As such, a patients measured sodium level should not
concentration after 1 L of 3% NaCl infusion using the follow-
be viewed as an index of sodium need because this parameter
ing equation:16
reects the balance between total body sodium content and
TBW. Disturbances in the sodium level most often represent
Change in serum Na+ = (infusate Na+ serum Na+)/(TBW + 1)
disturbances of TBW. Sodium imbalances cannot be properly
assessed without rst assessing the body uid status.
In this formula, TBW is increased by 1 to account for the addi-
Hyponatremia is very common in hospitalized patients tion of the liter of 3% NaCl. Patient Encounters 4 and 5 illus-
and is dened as a serum sodium concentration below 136 mEq/L trate the concepts of calculating and correcting the sodium
(136 mmol/L). Clinical signs and symptoms appear at concen- decit.
trations below 120 mEq/L (120 mmol/L) and typically consist Depending on the severity of the hyponatremia, 0.9%, 3%,
of agitation, fatigue, headache, muscle cramps, and nausea. or 5% NaCl can be utilized. Most patients can be adequately
With profound hyponatremia (less than 110 mEq/L [110 managed with normal saline rehydration, which is generally
mmol/L]), confusion, seizures, and coma may be seen. Because the safest agent. Hypertonic saline (3% or 5% NaCl) is gener-
therapy is also inuenced by volume status, hyponatremia is ally reserved for patients with severe hyponatremia (less than
further dened as: (1) hypertonic hyponatremia; (2) hypotonic 120 mEq/L [120 mmol/L]) accompanied by coma, seizures, or
hyponatremia with an increased ECF volume; (3) hypotonic high urinary sodium losses. Roughly one-third of the sodium
hyponatremia with a normal ECF volume; and (4) hypotonic decit can be replaced over the rst 12 hours as long as the
hyponatremia with a decreased ECF volume.16 replacement rate is less than 0.5 mEq/hour (0.5 mmol/L). The
Hypertonic hyponatremia is usually associated with signif- remaining two-thirds of the decit can be administered over
icant hyperglycemia. Glucose is an osmotically active agent several days. Overly aggressive correction of symptomatic
that leads to an increase in TBW with little change in total hyponatremia (greater than 12 mEq/L [12 mmol/L] per day)
body sodium. For every 60 mg/dL (3.33 mmol/L) increase in can result in central pontine myelinolysis.17 Given the potential
serum glucose above 200 mg/dL (11.1 mmol/L), the sodium is
expected to decrease by approximately 1 mEq/L (1 mmol/L).
Appropriate treatment of the hyperglycemia will return the
serum sodium to normal.15 Patient Encounter 4, Calculation of
Hypotonic hyponatremia with an increase in ECF is also Sodium Decit
known as dilutional hyponatremia. In this scenario, patients
have an excess of total body sodium and TBW; however, the
excess in TBW is greater than the excess in total body sodium. Calculate the sodium decit for a 75-kg male with a serum
sodium of 123 mEq/L (123 mmol/L).
Common causes include CHF, hepatic cirrhosis, and nephrotic
Sodium decit (mEq) = (TBW) (desired current
syndrome. Treatment includes sodium and uid restriction in
Na concentration)
conjunction with treatment of the underlying disorderfor TBW = 0.6 75 kg = 45 L
example, salt and water restrictions are used in the setting of Desired sodium = 140 mEq/L (140 mmol/L)
CHF along with loop diuretics, angiotensin-converting Current sodium = 123 mEq/L (123 mmol/L)
enzyme inhibitors, and spironolactone.15
Example
In hypotonic hyponatremia with a decreased ECF volume,
patients usually have a decit of both total body sodium and Sodium decit = (45 L)(140 mEq/L 123 mEq/L)
TBW, but the sodium decit exceeds the TBW decit. = 765 mEq (or 765 mmol)
Common causes include diuretic use, profuse sweating,
loss, decreased skin turgor, intracranial bleeding, or coma.

Patient Encounter 5, Estimate the Many coexisting disorders and medications may complicate
Anticipated Change in Serum Sodium the diagnosis.
The classic causes of hypernatremia are associated with
TBW depletion. These include dehydration from loss of hypo-
Estimate the anticipated change in serum sodium concen-
tonic uid from the respiratory tract or skin, decreased water
trations after the infusion of 1 L of 3% sodium chloride in a
75-kg male with a serum sodium of 123 mEq/L (123 mmol/L). intake, osmotic diuresis (e.g., mannitol, available as generic),
and diabetes insipidus (e.g., decreased ADH; phenytoin, avail-
(Infusate sodium serum sodium) able as generic; lithium, available as generic). Hypernatremia
Change in serum Na+ =
TBW + 1 in hospitalized patients occurs secondary to inappropriate
Example uid management in patients at risk for increased free water
losses and impaired thirst or restricted water intake.20
512 123 389
Change in serum Na+ = = Iatrogenic hypernatremia is occasionally caused by the
(0.6 L/kg)(75 kg) + 1 46
administration of excessive hypertonic saline. Treatment of
= 8.45 mEq (or 8.45 mmol) hypernatremia includes calculation of the TBW decit fol-
lowed by the administration of hypotonic uids as previously
described. The uid volume should be replaced over 48 to
72 hours depending on the severity of symptoms and the
degree of hypertonicity.21 For asymptomatic patients, the rate of
for irreversible neurologic damage if untreated or if improperly
correction should not exceed 0.5 mEq/L per hour (0.5 mmol/L
treated, acute hyponatremia is an urgent condition that should
per hour). One rule of thumb is to replace half the calculated
be promptly treated with careful attention to monitoring serial
TBW decit over 12 to 24 hours and the other half of the decit
sodium values and adjusting therapeutic infusions accordingly.18
over the next 24 to 48 hours.2,19 Excessively rapid correction
In hypotonic hyponatremia with a normal ECF volume,
of hypernatremia may lead to cerebral edema and death.
patients have an excess of TBW with relatively normal
Patient Encounters 6 and 7 reinforce the concepts of calculating
sodium content. In essence, there is a presence of excess free
TBW decit and expected changes in serum sodium concen-
water. This is most frequently seen in patients with the syn-
tration with therapy.
drome of inappropriate antidiuretic hormone secretion
(SIADH). Common causes of SIADH include carcinomas
(e.g., lung or pancreas), pulmonary disorders (e.g., pneumo- Potassium
nias or tuberculosis), central nervous system disorders (e.g., The bodys normal daily potassium requirement is 0.5 to
meningitis, stroke, tumor, or trauma), and medications (e.g., 1 mEq/kg (0.5 to 1 mmol/kg) or 40 to 80 mEq (40 to 80 mmol)
sulfonylureas, antineoplastic agents, barbiturates, morphine, to maintain a serum potassium concentration of 3.5 to 5 mEq/L
antipsychotics, tricyclics, non-steroidal anti-inammatory (3.5 to 5 mmol/L). Potassium is the most abundant cation in the
agents, selective serotonin reuptake inhibitors, dopamine ICF, balancing the sodium contained in the ECF and maintain-
agonists, and general anesthetics). These types of medica- ing electroneutrality of bodily uids. Because the majority of
tions can stimulate the release of antidiuretic hormone from potassium is intracellular, serum potassium concentration is not
the pituitary gland. When antidiuretic hormone is released, the a good measure of total body potassium; however, clinical mani-
body retains water and the sodium concentration drops. festations of potassium disorders correlate well with serum
Treatment generally consists of fluid restriction alone. potassium. The acid-base balance of the body affects serum
Hypertonic saline is used only when the sodium concentra- potassium concentrations. Hyperkalemia is routinely seen in
tion is less than 110 mEq/L (110 mmol/L) and/or severe
symptoms (e.g., seizures) are present. Refractory SIADH may
respond to demeclocycline (Declomycin, ESP Pharma)
dosed at 900 to 1200 mg/day. Patient Encounter 6, Calculate Water
Hypernatremia is a serum sodium concentration greater Decit
than 145 mEq/L (145 mmol/L) and can occur in the absence
of a sodium decit (pure water loss) or in its presence (hypo-
Calculate the water decit in a 75-kg male with a serum
tonic uid loss).19 The signs and symptoms of hypernatremia are
sodium of 154 mEq/L (154 mmol/L).
the same as those found in TBW depletion. Symptoms of hyper- Water decit (L) = TBW [(serum sodium/140) 1]
natremia are evident with a serum concentration greater than
160 mEq/L (160 mmol/L) and usually consist of thirst, men- Example
tal slowing, and dry mucous membranes. Signs and symptoms Water decit = (0.6 L/kg)(75 kg) [154/140 1] = 45 0.1
become more profound as hypernatremia worsens, with the = 4.5 L
patient demonstrating confusion, hallucinations, acute weight
TABLE 246. Potassium Content in Various Potassium Salt

Patient Encounter 7, Calculate the Preparations
Anticipated Change in Serum Sodium
Potassium Salt mEq/g (mmol/L)
Potassium gluconate 4.3
Calculate the anticipated change in serum sodium concen- Potassium citrate 9.8
tration after IV infusion of 1 L of 5% dextrose in a 75-kg Potassium bicarbonate 10.0
male with a serum sodium of 156 mEq/L (156 mmol/L). Potassium acetate 10.2
Potassium chloride 13.4
(Infusate Na serum Na)
Change in serum Na+ = Hypokalemia and alkalosis: Use potassium chloride
TBW + 1
Hypokalemia and acidosis: Use potassium bicarbonate, potassium
citrate, potassium acetate, or potassium gluconate salts
Example
0 156 156
Change in serum Na+ = =
45 + 1 46 (200 to 400 mmol) reduction in serum concentration.
Potassium repletion should be guided by close monitoring of
= 3.39 mEq(or 3.39 mmol)
serum concentrations instead of using empirically chosen
predened amounts. Of the ve potassium salts available,
potassium acetate (10.2 mEq/K+ per gram or 10.2 mmol/K+
per gram) and potassium chloride (13.4 mEq/K+ per gram or
patients with decreased pH (acidosis). Potassium regulation is 13.4 mmol/K+ per gram) are the most commonly used forms.
primarily under the control of the kidneys with excess dietary When hypokalemia occurs in the setting of alkalosis, potassium
potassium being excreted in the urine. Although mild abnormal- chloride is the preferred agent; in acidosis, potassium should be
ities of serum potassium are considered a nuisance, severe hyper- provided in the form of acetate, citrate, bicarbonate, or glu-
kalemia and hypokalemia can be life-threatening.22,23,32 conate salt. Table 246 outlines the potassium content of each
Hypokalemia (serum potassium less than 3.5 mEq/L potassium salt preparation, and Table 247 lists each of the
[3.5 mmol/L]) is a common clinical problem. Signs and symp- oral potassium replacement products. Potassium acetate and
toms of hypokalemia include cramps, muscle weakness, chloride are available for IV infusions as premixed solutions.
polyuria, electrocardiogram (ECG) changes (attened T-waves The usual dose of these agents is 10 to 20 mEq (10 to 20 mmol)
and presence of U-waves), and cardiac arrhythmias (bradycar- diluted in 1000 mL of normal saline.2,24,25
dia, heart block, atrial utter, premature ventricular contrac- Moderate hypokalemia is dened as a serum potassium of
tions, and ventricular brillation). Causes of hypokalemia 2.5 to 3.5 mEq/L (2.5 to 3.5 mmol/L) without ECG changes.
include GI losses (vomiting, diarrhea, or NG tube suction), renal In this setting, potassium replacement can usually be given
losses (high aldosterone and low magnesium), inadequate orally at a dose of 40 to 120 mEq/day (40 to 120 mmol/day).
potassium intake (in IV uids or PO), or alkalosis. Many med- Anecdotally, oral potassium supplementation (see Table 247)
ications can precipitate hypokalemia. 2-Agonists (albuterol is often more effective in repleting moderate hypokalemia. For
available as generic) and insulin (multiple product formula- patients with an ongoing source of potassium loss, chronic
tions) lower potassium via cellular redistribution. The use of replacement therapy should be considered. The potassium
loop diuretics (furosemide [Lasix], also available as generic),
thiazide diuretics (hydrochlorothiazide, available as generic),
high-dose antibiotics (penicillin, available as generic), and corti- TABLE 247. Oral Potassium Replacement Productsa
costeroids (prednisone, available as generic) cause a renal potas-
Product Salt Strength
sium wasting. In addition, amphotericin B (available as generic),
cisplatin (available as generic), and foscarnet (Foscavir, Extended/controlled- Chloride 8 mEq (600 mg)
AstraZeneca) can also produce hypokalemia secondary to deple- release tablets 10 mEq (750 mg)
15 mEq (1125 mg)
tion of magnesium. Hypomagnesemia diminishes intracellular 20 mEq (1500 mg)
potassium concentration and produces potassium wasting.
Effervescent tablets Chloride and 20 mEq
Given the potential for signicant morbidity and mortality, bicarbonate 25 mEq
serum potassium concentrations should be monitored closely 50 mEq
for patients with known (or suspected) hypokalemia.2,24,32 Liquid Chloride 20 mEq/15mL (10%)
Hypokalemia is a risk factor for digitalis toxicity. 30 mEq/15mL (15%)
A 1 mEq/L (1 mmol/L) fall in serum potassium (i.e., from 40 mEq/15mL (20%)
4 mEq/L to 3 mEq/L [4 mmol/L to 3 mmol/L]) represents a loss Powder packets Chloride 15 mEq
of approximately 200 mEq (200 mmol) of potassium. However, 20 mEq
25 mEq
when the serum potassium is below 3 mEq/L (3 mmol/L), each
1 mEq/L fall in serum potassium represents a 200 to 400 mEq For potassium, 1 mEq = 1 mmol.
a
decit is a rough approximation of the amount of potassium Increased potassium intake results from excessive dietary
needed to be replaced and can be estimated as follows: potassium (salt substitutes), excess potassium in IV uids, and
other select medications (potassium-sparing diuretics or
Potassium decit(mEq) = (4.0 current serum potassium) 100 cyclosporine, available as generic), angiotensin-converting
enzyme inhibitors, non-steroidal anti-inammatory agents,
Severe hypokalemia is dened as a serum potassium less pentamidine (available as generic), unfractionated heparin,
than 2.5 mEq/L (2.5 mmol/L) or hypokalemia of any severity and low-molecular-weight heparins. Decreased potassium
that is associated with ECG changes (e.g., attening of T wave excretion results from acute renal failure, chronic renal failure,
or elevation of U wave) and cardiac arrhythmias. In these situa- or Addisons disease. Excess potassium release from cells
tions, IV replacement should be initiated urgently. Potassium results from tissue breakdown (surgery, trauma, hemolysis, or
infusion at rates exceeding 10 mEq/hour requires cardiac mon- rhabdomyolysis), blood transfusions, and metabolic acidosis.
itoring given the potential for cardiac arrhythmias. Although In addition to discontinuing all potassium supplements,
the maximally concentrated solution for potassium replace- potassium-sparing medications, and potassium-rich salt sub-
ment is 80 mEq/L (80 mmol/L), the maximum infusion rate stitutes, management of hyperkalemia addresses three concur-
is 40 mEq/hour (40 mmol/hour), and must be administered rent strategies: (1) agents to antagonize the pro-arrhythmic
via a central line. Table 248 outlines current IV potassium effects of hyperkalemia; (2) agents to drive potassium into the
replacement guidelines. intracellular space and acutely lower the serum potassium; and
Caution must be exercised when repleting potassium with (3) agents that will denitively (but more gradually) lower the
IV agents given possible vein irritation and/or throm- total body potassium content.28 If the serum potassium con-
bophlebitis. The risk of these complications is minimized by centration is greater than 7 mEq/L (7 mmol/L) and/or ECG
using less concentrated solutions and by giving infusions via changes are present, IV calcium is provided to stabilize the
central access if possible. Administration of potassium in myocardium. Depending on the acuity of the situation, 1 g of
vehicles containing glucose is discouraged, as glucose facili- calcium chloride (13.5 mEq or 6.75 mmol) is administered by
tates the intracellular movement of potassium. Post-therapy direct injection or diluted in 50 mL of D5W and delivered IV
improvements in serum potassium may be transient and con- over 15 minutes. Clinical effects are seen within 1 to 2 minutes
tinuous monitoring is required. Patients with a low serum of infusion and persist for 10 to 30 minutes. Repeat doses may
magnesium will have exaggerated potassium losses from the be administered as necessary. Because most patients with
kidneys and GI tract leading to refractory hypokalemia. In clinically signicant hyperkalemia receive multiple boluses of
this situation, the magnesium decit must be corrected in calcium directed by electrocardiogram ndings, iatrogenic
order to successfully treat the concurrent potassium de- hypercalcemia is a potential complication of hyperkalemia
ciency. In the hypokalemic patient with concurrent acidosis, treatment. As such, total calcium concentration is commonly
potassium is often given as acetate, which is metabolized to checked with each potassium concentration measurement.
bicarbonate. In the patient with depleted phosphorus and Ionized calcium measurements should be obtained in patients
potassium, therapy with potassium phosphate is the natural who have comorbid conditions that would lead to inconsis-
choice.22,26,27 tency between total serum calcium and free calcium (abnormal
Hyperkalemia is dened as a serum potassium concentration albumin, protein, or immunoglobulin concentrations).
greater than 5 mEq/L (5 mmol/L). Manifestations of hyper- Dextrose and insulin (with or without sodium bicarbonate)
kalemia include muscle weakness, paresthesias, hypotension, are typically given at the time of calcium therapy in order to
ECG changes (e.g., peaked T waves, shortened QT intervals, and redistribute potassium into the intracellular space. Dextrose 50%
wide QRS complexes), cardiac arrhythmias, and a decreased pH. (25 g in 50 mL) can be given by slow IV push over 5 minutes or
Causes of hyperkalemia fall into three broad categories: dextrose 10% with 20 units of regular insulin can be given by
(1) increased potassium intake; (2) decreased potassium excre- continuous IV infusion over 1 to 2 hours. The onset of action for
tion; and (3) potassium release from the intracellular space. this combination is 30 minutes and the duration of clinical effects
TABLE 248. Recommended Potassium Dosage/Infusion Rate Guidelinesa
Maximum Maximum Maximum

Clinical Scenario Infusion Rate Concentration 24-hour Dose
K+ greater than 2.5 mEq/L AND 10 mEq/hour 40 mEq/L 200 mEq
No ECG changes of hypokalemia
K+ less than 2.5 mEq/L OR 40 mEq/hour 80 mEq/L 400 mEq
ECG changes of hypokalemia
a
For potassium, 1 mEq = 1 mmol.
is 2 to 6 hours. High-dose inhaled 2-agonists (e.g., albuterol, the facial nerve (adjacent to the ear). This will produce a brief
available as generic) may also be used to acutely drive potassium spasm of the upper lip, eye, nose, or face in hypocalcemic
into the intracellular space. patients.
It is critically important to recognize that the treatments of Causes of hypocalcemia include hypoparathyroidism,
hyperkalemia discussed thus far are transient, temporizing hypomagnesemia, alcoholism, hyperphosphatemia, blood
measures. They are intended to provide time to institute product infusion (due to chelation by the citrate buffers),
denitive therapy aimed at removing excess potassium from chronic renal failure, vitamin D deciency, acute pancreatitis,
the body. Agents that increase potassium excretion from the alkalosis, and hypoalbuminemia. Medications that cause
body include sodium polystyrene sulfonate, loop diuretics, hypocalcemia include phosphate replacement products, loop
and hemodialysis or hemoltration (used only in patients diuretics, phenytoin (Dilantin, available as generic), pheno-
with renal failure). Sodium polystyrene sulfonate (Kayexalate, barbital (available as generic), corticosteroids, aminoglycoside
various manufacturers) can be given orally, via NG tube, or as antibiotics, and acetazolamide (available as generic).34,39,42
a rectal retention enema and is dosed at 15 to 60 grams in four Oral calcium replacement products include calcium car-
divided doses per day. bonate (OsCal, GlaxoSmithKline and various generics;
Tums, GlaxoSmithKline and various generics) and calcium
Calcium citrate (Citrical, Mission Pharmacal, and various generics).
IV calcium replacement products include calcium gluconate
More than 99% of total body calcium is found in bone; the and calcium chloride (both products available as generic).
remaining less than 1% is in the ECF and ICF. Calcium plays Calcium gluconate is preferred for peripheral use because it is
a critical role in the transmission of nerve impulses, skeletal less irritating to the veins; it may also be given intramuscularly.
muscle contraction, myocardial contractions, maintenance of Each 10 mL of a 10% calcium gluconate solution provides
normal cellular permeability, and the formation of bones and 90 mg (4.5 mEq or 2.25 mmol) of elemental calcium. Calcium
teeth. There is a reciprocal relationship between the serum chloride is associated with more venous irritation and is gen-
calcium concentration (normally 8.6 to 10.2 mg/dL [2.15 to erally reserved for administration via central line. Each 10 mL
2.55 mmol/L]) and the serum phosphate concentration that is of a 10% calcium chloride solution contains 270 mg (13.5 mEq
regulated by a complex interaction between parathyroid hor- or 6.75 mmol) of elemental calcium. IV calcium products are
mone, vitamin D, and calcitonin. About one-half of the serum given as a slow push or added to 500 to 1000 mL of 0.9%
calcium is bound to plasma proteins; the other half is free ion- normal saline for slow infusion.37,42
ized calcium. Given that the serum calcium has signicant For acute symptomatic hypocalcemia, 200 to 300 mg of
protein binding, the serum calcium concentration must be elemental calcium is administered IV and repeated until
corrected in patients who have low albumin concentrations symptoms are fully controlled. This is achieved by infusing
(the major serum protein). The most commonly used formula 1 g of calcium chloride or 2 to 3 grams of calcium at a rate no
adds 0.8 mg/dL (0.2 mmol/L) of calcium for each gram of faster than 30 to 60 mg of elemental calcium per minute.
albumin deciency as follows: More rapid administration is associated with hypotension,
bradycardia, or cardiac asystole. Total calcium concentration
Corrected [Ca] = Measured [Ca mg/dL] + [0.8 (4 is commonly monitored in critically ill patients. Under nor-
measured albumin)]2931 mal circumstances, about half of calcium is loosely bound to
serum proteins while the other half is free. Total calcium con-
Note: To convert conventional units (mg/dL) to SI calcium centration measures bound and free calcium. Ionized cal-
units multiply by a factor of 0.25. cium measures free calcium only. Under usual circumstances,
Hypocalcemia is caused by inadequate intake (vitamin a normal calcium level implies a normal free ionized calcium
deciency, poor dietary calcium sources, and alcoholism) or level. Ionized calcium should be obtained in patients with
excessive losses (hypoparathyroidism, renal failure, alkalosis, comorbid conditions that would lead to inconsistency
and pancreatitis). Clinical manifestations of hypocalcemia are between total calcium and free serum calcium (abnormal
seen with total serum concentrations less than 6.5 mg/dL albumin, protein, or immunoglobulin concentrations). For
(1.63 mmol/L) and include: tetany, circumoral tingling, mus- chronic asymptomatic hypocalcemia, oral calcium supple-
cle spasms, hypoactive reexes, anxiety, hallucinations, ments are given at doses of 2 to 4 g/day of elemental calcium.
hypotension, myocardial infarction, seizures, lethargy, stupor, Many patients with calcium deciency have concurrent
and Trousseaus sign or Chvosteks sign.32,37 Trousseaus sign vitamin D deciency that must also be corrected in order to
is elicited by inating a blood pressure cuff on the patients restore calcium homeostasis.2,37,38
upper arm, whereby hypocalcemic patients will experience Hypercalcemia is dened as a calcium concentration
tetany of the wrist and hand as evidenced by thumb adduction, greater than 10.2 mg/dL (2.55 mmol/L). It may be categorized
wrist exion, and metacarpophalangeal joint exion. Chvosteks as mild if total serum calcium is 10.3 to 12 mg/dL (2.575 to
sign is elicited by tapping on the proximal distribution of 3 mmol/L), moderate if total serum calcium is 12.1 to 13 mg/dL
(3.025 to 3.25 mmol/L), or severe when serum concentration is ECF. Note that phosphorus is the major anion within the cells.
greater than 13 mg/dL (3.25 mmol/L). Causes of hypercalcemia Given this distribution, serum phosphate concentration does
include hyperparathyroidism, malignancy, Pagets disease, granu- not accurately reect total body phosphorus stores.
lomatous diseases (e.g., tuberculosis, sarcoidosis, or histoplasmo- Phosphorus is expressed in milligrams (mg) or millimoles
sis), hyperthyroidism, immobilization, multiple bony fractures, (mmol), not as milliequivalents (mEq). Because phosphorus
acidosis, and milk-alkali syndrome. Multiple medications cause is the source of phosphate for adenosine triphosphate (ATP)
hypercalcemia and include thiazide diuretics, estrogens, lithium and phospholipid synthesis, manifestations of phosphorus
(available as generic), tamoxifen (Nolvadex, available as imbalance are variable.
generic), vitamin A, vitamin D, and calcium supplements.2,33,37,42 Dietary intake, parathyroid hormone levels, and renal
Because the severity of symptoms and the absolute serum function are the major determinants of the serum phosphorus
concentration are poorly correlated in some patients, institu- concentration, which is normally 2.7 to 4.5 mg/dL (0.87 to
tion of therapy should be dictated by the clinical scenario. All 1.45 mmol/L).2,3537 Hypophosphatemia is dened by a serum
patients with hypercalcemia should be treated with aggressive phosphorus concentration less than 2.5 mg/dL (0.81 mmol/L);
rehydration: normal saline at 200 to 300 mL/hour is a routine severe hypophosphatemia occurs when the phosphorus concen-
initial uid prescription. For patients with mild hypocalcemia, tration is less than 1 mg/dL (0.323 mmol/L). Hypophosphatemia
hydration alone may provide adequate therapy. The moderate can be caused by increased distribution to the ICF (hyper-
and severe forms of hypercalcemia are more likely to have sig- glycemia, insulin therapy, or malnourishment), decreased
nicant manifestations and require prompt initiation of addi- absorption (starvation, excessive use of phosphorus-binding
tional therapy. These patients may present with anorexia, con- antacids, vitamin D deciency, diarrhea, or laxative abuse) or
fusion, and/or cardiac manifestations (bradycardia and increased renal loss (diuretic use, diabetic ketoacidosis, alcohol
arrhythmias with ECG changes). Total calcium concentrations abuse, hyperparathyroidism, or burns).38,39 In the critical care
greater than 13 mg/dL (3.25 mmol/L) are particularly worri- setting, hypophosphatemia can result in impaired diaphragmatic
some, as these levels can unexpectedly precipitate acute renal contractility and acute respiratory failure. Medications that cause
failure, ventricular arrhythmias, and sudden death. hypophosphatemia include diuretics (acetazolamide [Diamox,
Once uid administration has repleted the ECF, forced diure- available as generic], furosemide [Lasix, available as generic],
sis (with associated calcium loss) can be initiated with a loop hydrochlorothiazide [Hydrodiuril, available as generic]),
diuretic. For this approach to be successful, normal kidney sucralfate (Carafate, available as generic), corticosteroids,
function is required. In renal failure patients, the alternative cisplatin (available as generic), antacids (aluminum carbonate,
therapy is emergent hemodialysis. Other treatment options calcium carbonate, and magnesium oxide [antacids all available
include bisphosphonates (zoledronic acid [Zometa, Novartis], as generic]), foscarnet (Foscavir, Astra Zeneca), phenytoin
pamidronate [Aredia, available as generic]), hydrocortisone (Dilantin, available as generic), phenobarbital (available as
(available as generic), mithramycin (Mithracin), calcitonin, generic), and phosphate binders (sevelamer [Renagel, Genzyme
and gallium. Given their efcacy and favorable side-effect prole, Corp.], and calcium acetate [PhosLo, Nabi]).
bisphosphonates are typically the agents of choice. Table 249 Signs and symptoms of hypophosphatemia include pares-
outlines the treatment options for hypercalcemia including time thesias, muscle weakness, myalgias, bone pain, anorexia, nau-
to onset of effect, duration of effect, and efcacy.2,34,37,38 sea, vomiting, RBC hemolysis, acute respiratory failure,
seizures, and coma.38,40 For mild hypophosphatemia, patients
should be encouraged to eat a high-phosphorus diet including
Phosphorus
eggs, nuts, whole grains, meat, sh, poultry, and milk prod-
Phosphorus is primarily found in the bone (80% to 85%) and ucts. For moderate hypophosphatemia (1 to 2.5 mg/dL)
ICF (15% to 20%): the remaining less than 1% is found in the (0.323 to 0.808 mmol/L), oral supplementation of 1.5 to 2 g/day
TABLE 249. Selected Treatment Options for the Management of Hypercalcemia
Therapy Dose Onset Duration Efcacya

Normal saline 36 L/day Hours Hours 12 mg/dL
Furosemide (Lasix, available as generic) 80160 mg/day Hours Hours 12 mg/dL
Hydrocortisone (available as generic) 200 mg/day Hours Days Mild
Calcitonin (Miacalcin, Novartis) 48 units/kg Hours Hours 12 mg/dL
Mithramycin (Mithracin) 25 mcg/kg 12 hours Days 15 mg/dL
Pamidronateb (Aredia, available as generic) 3090 mg/week Days 14 weeks 15 mg/dL
Zoledronic acid (Zometa, available as generic) 48 mg Days Weeks 15 mg/dL
Gallium (Ganite, Genta Inc.) 200 mg/m2 Days DaysWeeks 15 mg/dL
a
Expected decrease in serum Ca.
b
Preferred bisphosphonate.
(30 to 60 mmol/day) is usually adequate. Diarrhea may be a Magnesium

dose-limiting side effect with oral phosphate replacement
The bodys normal daily magnesium requirement is 300 to
products. Injectable phosphate products are reserved for
350 mg/day to maintain a serum magnesium concentration
patients with severe hypophosphatemia or those in the inten-
of 1.5 to 2.4 mg/dL (0.75 to 1.2 mmol/L). Because magnesium
sive care unit.41 The available agents are provided as sodium or
is the second most abundant ICF cation, serum concentrations
potassium salts; however, unless concurrent hypokalemia is
are a relatively poor measure of total body stores. Magnesium
present, sodium phosphate is usually used. Empirically, if the
catalyzes and/or activates more than 300 enzymes, provides
serum phosphorus is 2.3 to 2.7 mg/dL (0.74 to 0.87 mmol/L), the
neuromuscular stability, and is involved in myocardial contrac-
corresponding IV phosphorus dose is 0.08 to 0.16 mmol/kg; for
tion. Magnesium is generally not part of standard chemistry
a serum phosphorus of 1.5 to 2.2 mg/dL (0.48 to 0.71 mmol/L), panels, and therefore must be ordered separately.2,37,42,44,45
the replacement dose is 0.16 to 0.32 mmol/kg; and the dose is Hypomagnesemia is dened as a serum magnesium less
0.32 to 0.64 mmol/kg when the serum phosphorus is less than than 1.5 mg/dL (0.75 mmol/L), and is most frequently seen in
1.5 mg/dL (0.48 mmol/L).2 IV phosphorus preparations are usu- the intensive care and postoperative settings. Hypomagnesemia
ally infused over 4 to 12 hours. Table 2410 compares the avail- results from inadequate intake (alcoholism, dietary restriction, or
able phosphate replacement products. inadequate magnesium in total parenteral nutrition [TPN]),
Hyperphosphatemia is dened by a serum phosphorus inadequate absorption (steatorrhea, cancer, malabsorption
concentration greater than 4.5 mg/dL (1.45 mmol/L). The syndromes, or excess calcium or phosphorus in the GI tract),
manifestations of hyperphosphatemia include ndings of excessive GI loss of magnesium (diarrhea, laxative abuse, NG
hypocalcemia (see above), paresthesias, ECG changes (pro- tube suctioning, or acute pancreatitis), or excessive urinary loss
longed QT interval and prolonged ST segment), and meta- of magnesium (primary hyperaldosteronism, certain medica-
static calcications. Causes of hyperphosphatemia include tions, diabetic ketoacidosis, and renal disorders). Medications
impaired phosphorus secretion (hypoparathyroidism or renal that potentially can cause hypomagnesemia include aminogly-
failure), redistribution of phosphorus to the ECF (acid-base coside antibiotics, amphotericin B (available as generic), cisplatin
imbalance, rhabdomyolysis, muscle necrosis, or tumor lysis (available as generic), insulin, cyclosporine (available as generic),
during chemotherapy), and increased phosphorus intake (var- loop diuretics, and thiazide diuretics. There is also a strong cor-
ious medications).38 Medications that can cause hyperphos- relation between hypokalemia and hypomagnesemia.38,42,46
phatemia include enemas containing phosphorus (e.g., Fleet, The ndings of hypomagnesemia include muscle weak-
Fleet), laxatives containing phosphate or phosphorus, oral or ness, cramps, agitation, confusion, tremor, seizures, ECG
parenteral phosphorus supplements (e.g., Neutra-Phos, changes (increased PR interval, prolonged QRS complex, and
Ortho McNeil), vitamin D supplements, and the bisphospho- increased QT interval), ndings of hypocalcemia (see above),
nates (e.g., pamidronate, various manufacturers).42 refractory hypokalemia (see above), metabolic alkalosis, and
Hyperphosphatemia is generally benign and rarely needs digoxin toxicity.42,47,48
aggressive therapy. Dietary restriction of phosphate and pro- Asymptomatic mild magnesium deciencies (1 to 1.5 mg/dL)
tein is effective for most minor elevations. Phosphate (0.5 to 0.75 mmol/L) can be managed with increased oral
binders such as aluminum-based antacids, calcium carbonate, intake of magnesium-containing foods or with oral supple-
calcium acetate (PhosLo, Nabi), sevelamer (Renagel, mentation. Magnesium oxide (MagOx, Blaine Pharmaceuticals
Genzyme), and lanthanum carbonate (Fosrenol, Shire) may and various manufacturers) 400 mg tablets contain 241 mg
be necessary for some patients.43 If patients exhibit ndings of (20 mEq or 10 mmol) of magnesium. Diarrhea is often a dose-
hypocalcemia (tetany), IV calcium should be administered limiting side effect of oral supplementation. Severely decient
empirically. patients (less than 1.0 mg/dL) (0.5 mmol/L) and all decient
TABLE 2410. Phosphate Replacement Products
mmol mEq (mmol) mEq (mmol)

Product Route mg PO4 PO4 Na+ K+
Potassium phosphate (KPO4/mL), IV 94 3 0 4.4
available as generic
Sodium phosphate (NaPO4/mL), IV 94 3 4 0
available as generic
Neutra-Phos Powder, Ortho McNeil PO 250 8 7.1 7.1
Neutra-Phos-K Powder, Ortho McNeil PO 250 8 0 14.3
K-Phos, Beach PO 125 4 2.9 1.4
K-Phos Neutral Tablets, Beach PO 250 8 13.1 1.4
IV = intravenous; PO = oral.
critically ill patients should be managed with IV magnesium

sulfate. Ten milliliters of a 10% magnesium sulfate solution Patient Encounter 8
contains 1 g of magnesium, which is equivalent to 98 mg
(8.12 mEq or 4.06 mmol) of elemental magnesium. Because
magnesium concentration does not correlate well with total body TO, a 77-year-old male nursing home resident is admitted to
magnesium stores, magnesium is often administered empirically the hospital with a 3-day history of altered mental status. The
to critically ill patients.2,37 Intravenous magnesium has been patient was unable to give a history or review of systems. On
utilized for the treatment of acute asthma in the emergency physical examination the vital signs revealed a blood pres-
department in patients not responding to standard therapy. sure of 100/60 mm Hg, pulse 110 beats per minute, respira-
High doses of IV magnesium sulfate are effective in reducing tions 14/minutes, and a temperature of 101F (38.3C). Rales
the risk of eclampsia in women with pre-eclampsia and is rou- and dullness to percussion were noted at the posterior right
tinely administered in this setting. base. The cardiac exam was signicant for tachycardia. No
edema was present. Laboratory studies included: sodium
The most common causes of hypermagnesemia are renal
160 mEq/L (160 mmol/L), potassium 4.6 mEq/L (4.6 mmol/L),
failure, often in conjunction with magnesium-containing med-
chloride 120 mEq/L (120 mmol/L), bicarbonate 30 mEq/L
ications (cathartics, antacids, or magnesium supplements), (30 mmol/L), glucose 104 mg/dL (5.77 mmol/L), BUN
and lithium therapy (available as generic). Hypermagnesemia 34 mg/dL (12.14 mmol/L), and creatinine 2.2 mg/dL (194.5
is dened as a serum magnesium concentration greater than mol/L). The CBC was within normal limits. Chest x-ray
2.4 mg/dL (1.2 mmol/L). Mild hypermagnesemia is present if indicated a right lower lobe pneumonia.
the serum magnesium concentration is between 2.5 and 4 mg/dL The patient is 510 (152.4 cm) and currently weighs 160
(1.25 to 2 mmol/L) and manifests as nausea, vomiting, cuta- lb (72.6 kg). His normal weight is 170 pounds (77.1 kg).
neous vasodilation, and bradycardia. Moderate hypermagne-
semia is present if the serum magnesium concentration is What is the likely cause for the increased sodium con-
between 4 and 12 mg/dL (2 to 6 mmol/L) and may manifest centration in this patient?
Increased insensible losses (from his fever caused by bac-
with hyporeexia, weakness, somnolence, hypotension, and
terial pneumonia) and lack of access to water (from his
ECG changes (increased QRS interval). Severe hypermagne-
altered level of consciousness)
semia is present if the serum magnesium concentration is
greater than 13 mg/dL (6.5 mmol/L) and can manifest as muscle Calculate the TBW, ICF and ECF for this patient.
paralysis, complete heart block, asystole, respiratory failure, IBW = 73 kg. Normal weight = 77 kg (170 lb)
refractory hypotension, and death.2,49 TBW = 77 kg 0.6 = 46 L
All patients with hypermagnesemia should have all mag- ICF = 46 L 0.33 = 15 L
nesium supplements or magnesium-containing medications ECF = 46 L 0.67 = 31 L
discontinued.2,37 Mild hypermagnesemia and moderate Calculate TOs uid decit if one is present.
hypermagnesemia without cardiac ndings can be treated 170 160 = 10/2.2 = 4.5 L, or using the sodium equation
with normal saline infusion and furosemide therapy 0.6 (77) [160/140 1] = 6.6 L
The uid decit is between 4.5 and 6.6 L. We will base our
(assuming the patient has normal renal function). Moderate
calculations upon a 5 L decit
hypermagnesemia with cardiac irritability and severe hyper-
In the next 24 hours, the medical team wants to give 50% of
magnesemia require IV calcium gluconate to reverse the neuro- the uid decit plus an extra 240 mL to account for insensible
muscular and cardiovascular effects. Calcium gluconate given losses in addition to the patients maintenance needs. Using the
at typical doses of 1 to 2 g IV will have transient effects and can equation (1500 mL + 20 mL for each kg greater than 20 kg),
be repeated as clinically indicated. Hemodialysis may be neces- calculate the rate of uid administration for the total uids
sary for those with severely compromised renal function. needed in this 24-hour period and over the next 48 hours.
Calculate TOs daily maintenance uids.
1500 mL + (20 mL/kg 57 kg) = 2640 mL
CONCLUSION Calculate TOs uids for the rst 24 hours.
0.5(5000) + 2640 + 240 = 5380 mL
Because disturbances in uid balance are routinely encountered 5380/24 = 225 mL per hour 24 hours
in clinical medicine, it is essential to have a thorough under- Calculate TOs uids for the next 48 hours.
standing of body uid compartments and the therapeutic use 0.5(5000) + 2(2640) + 2(240) = 82,600 mL
of uids. Similarly, disturbances in serum sodium, potassium, 8260/48 = 175 mL per hour 48 hours
calcium, phosphorus, and magnesium are ubiquitous and must
be mastered by all clinicians. Dysregulation of uid and/or elec- What type of uid should be used to treat TOs uid
trolyte status has serious implications regarding the concepts disorder?
of drug absorption, volumes of distribution, and toxicity. Hypotonic solution such as dextrose 5% and 1/2 normal
Similarly, many medications can disrupt uid and/or elec- saline or similar uid
trolyte balance as an unintended consequence.
ATP: adenosine triphosphate Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000;342:
BUN: blood urea nitrogen 14931499.
CHF: congestive heart failure Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:
Cl: chloride 15811589.
CNS: central nervous system Adrogue HJ, Madias N, Halperin ML. Potassium. Lancet 1998;352:
D5W: dextrose 5% water 135140.
ECF: extracellular uid Bilezikian JP. Clinical review 51. Management of hypercalcemia. J
ECG: electrocardiogram Clin Endocrinol Metab 1993;77:14451449.
FFP: fresh frozen plasma Bushinsky DA, Monk RD. Calcium. Lancet 1998;352:14931499.
GI: gastrointestinal Faber MD, Kupin WL, Heligi CW, Narins RG. Common uid-
ICF: intracellular uid electrolyte and acid-base problems in the intensive care unit:
I&Os: ins and outs selected issues. Semin Nephrol 1994;14:822.
IV: intravenous Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451458.
JCAHO: Joint Commission on Accreditation of Healthcare Kraft MD, Btaiche IF, Sacks GS, Kudsk KA. Treatment of electrolyte
Organizations disorders in adult patients in the intensive care unit. Am J
K+: potassium Health-Syst Pharm 2005;62:16631682.
kg: kilogram The SAFE Study Investigators. A comparison of albumin and saline
KVO: keep the vein open for uid resuscitation in the intensive care unit. N Engl J Med
L: liter 2004;350:22472256.
LR: lactated Ringers (solution)
mEq: milliequivalent
mg: milligram
mL: milliliter
mmol: millimole
Na: sodium
NG: nasogastric
NS: normal saline
PO: per mouth
SIADH: syndrome of inappropriate ADH secretion
TBW: total body water
TPN: total parenteral nutrition


this chapter.
25 ACID-BASE DISTURBANCES
Lee E. Morrow and Mark A. Malesker
LEARNING OBJECTIVES
1. Dene primary acid-base disturbances within the human body.

2. Apply simple formulas in order to determine the etiology of simple acid-base disturbances
and the adequacy of compensation.
3. Integrate the supplemental concepts of the anion gap and the excess gap to help assess
complex acid-base disturbances.
4. Discuss the most common causes of each primary acid-base irregularity.
5. Determine the appropriate management for patients with acid-base disorders.
KEY CONCEPTS Metabolic acidosis and alkalosis result from primary distur-
bances in the serum HCO3 concentration. Respiratory com-
Acid-base homeostasis is tightly regulated by the complex, but pensation of metabolic disturbances begins within minutes
predictable, interactions of the kidneys, the lungs, and various and is complete within 12 hours.
buffer systems. The kidneys control serum bicarbonate Metabolic acidosis is characterized by a decrease in serum
(HCO3) concentration through the excretion or reabsorp- HCO3. The anion gap is used to narrow the differential diag-
tion of ltered HCO3, the excretion of metabolic acids, and nosis, as this acidosis may be caused by addition of acids
synthesis of new HCO3. The lungs control arterial carbon (increased anion gap) or loss of HCO3 (normal anion gap).
dioxide levels through changes in the depth and/or rate of The compensation for metabolic acidosis is an increase in ven-
respiration. tilation with a decrease in arterial CO2.
Respiratory acidosis and alkalosis result from primary distur- Metabolic alkalosis is characterized by an increase in serum
bances in the arterial carbon dioxide (CO2) levels. Metabolic HCO3. This disorder requires loss of uid that is low in
compensation of respiratory disturbances is a slow process, HCO3 from the body or addition of HCO3 to the body. The
often requiring days for the serum HCO3 to reach the steady compensation for metabolic alkalosis is a decrease in ventila-
state. tion with an increase in arterial CO2.
Respiratory acidosis is caused by respiratory insufciency Arterial blood gases, serum electrolytes, physical examination
resulting in an increased arterial CO2 concentration. The com- ndings, the medical history, and the patients recent medica-
pensation for respiratory acidosis (if present for prolonged tions must be reviewed in order to establish the etiology of a
periods) is an increase in serum HCO3. given acid-base disturbance.
Respiratory alkalosis is caused by hyperventilation resulting It is critical to treat the underlying causative process to effec-
in a decreased arterial CO2 concentration. The compensation tively resolve most observed acid-base disorders. However,
for respiratory alkalosis (if present for prolonged periods) is a supportive treatment of the pH and electrolytes is often
decrease in serum HCO3. needed until the underlying disease state is improved.
419
Given its reputation for complexity and the need to memorize imbalances occur. Conversely, cessation of breathing for min-
innumerable formulas, acid-base analysis intimidates many utes results in profound acid-base disturbances.1
health care providers. In reality, acid-base disorders always The best way to assess a patients acid-base status is to
obey well-dened biochemical and physiologic rules. The pH review the results of an arterial blood gas (ABG) specimen.
determines a patients acid-base status and an assessment of Blood gas analyzers directly measure the pH and PaCO2 while
the bicarbonate (HCO3) and arterial carbon dioxide (PaCO2) the HCO3 value is calculated using the Henderson-
values identies the underlying process. This makes them easy Hasselbalch equation. A more direct measure of serum HCO3
to recognize and interpret if a practical strategy is rigorously is obtained by measuring the total venous carbon dioxide
applied. This chapter will outline a clinically useful approach (tCO2). Because dissolved carbon dioxide is almost exclusively
to acid-base abnormalities and then apply this approach in a in the form of HCO3, tCO2 is essentially equivalent to the
series of increasingly complex clinical scenarios. measured serum HCO3 concentration. This value is routinely
Disturbances of acid-base equilibrium occur in a wide vari- reported on basic chemistry panels. In the remainder of this
ety of illnesses and are among the most commonly encoun- chapter the pH and PaCO2 values should be assumed to come
tered disorders in critical care medicine. The importance of a from an arterial blood gas while HCO3 values should be con-
thorough command of this content cannot be overstated given sidered to be measured serum concentrations.
that acid-base disorders are remarkably common and may
result in signicant morbidity and mortality. Although severe
derangements may affect virtually any organ system, the most BASIC PATHOPHYSIOLOGY
serious clinical effects are cardiovascular (arrhythmias and
impaired contractility), neurologic (coma and seizures), pul- Under normal circumstances the arterial pH is tightly regu-
monary (dyspnea, impaired oxygen delivery, and respiratory lated between 7.35 and 7.45. Acidemia is an abnormally low
fatigue), and/or renal (hypokalemia). Changes in acid-base sta- arterial blood pH (less than 7.35) while acidosis is a patho-
tus also affect multiple aspects of pharmacokinetics (clearance logic process that acidies body uids. Similarly, alkalemia is
and protein binding) and pharmacodynamics. an abnormally high arterial blood pH (less than 7.45) while
alkalosis is a pathologic process that alkalinizes body uids.
As such, although a patient can simultaneously have acidosis
ACID-BASE HOMEOSTASIS
and alkalosis, the end result will be acidemia or alkalemia.
Changes in the arterial pH are driven by changes in the
Acid-base homeostasis is responsible for maintaining blood
PaCO2 and/or the serum HCO3. Carbon dioxide is a volatile
hydrogen ion concentration [H+] near normal despite the daily
acid that is regulated by the depth and rate of respiration.
acidic and/or alkaline loads derived from the intake and
Because CO2 can be either blown off or retained by the
metabolism of foods. Acid-base status is traditionally repre-
respiratory system, it is referred to as being under respiratory
sented in terms of pH, the negative logarithm of [H+]. Because
control. A respiratory acid-base disorder is a pH disturbance
[H+] is equal to 24 times the ratio of PaCO2 to HCO3, the pH
caused by pathologic alterations of the respiratory system or its
can be altered by a change in either the bicarbonate concentra-
central nervous system control. Such an alteration may
tion or the dissolved carbon dioxide. A critically important
result in the accumulation of PaCO2 beyond normal limits
concept is that [H+] is dependent only on the ratio of PaCO2 to
(greater than 45 mm Hg or 6 kPa), a situation termed respira-
HCO3 and not the absolute amount of either. As such, a nor-
tory acidosis, or it may result in the loss of PaCO2 beyond nor-
mal PaCO2 or HCO3 alone does not guarantee that the pH
mal limits (less than 35 mm Hg or 4.7 kPa), a condition termed
will be normal. Conversely, a normal pH does not imply that
respiratory alkalosis. Variations in respiratory rate and/or depth
either the PaCO2 or HCO3 will be normal.
allow the lungs to achieve changes in the PaCO2 very quickly
Blood pH is normally tightly regulated by three distinct (within minutes).
mechanisms: Bicarbonate is a base that is regulated by renal metabolism
via the enzyme carbonic anhydrase. As such, bicarbonate is
1. Extracellular bicarbonate and intracellular protein buffering often referred to as being under metabolic control. A meta-
systems bolic acid-base disorder is a pH disturbance caused by derange-
2. Pulmonary regulation of PaCO2, effectively allowing carbonic ment of the pathways responsible for maintaining a normal
acid to be eliminated by the lungs as CO2 HCO3 level. This may result in a pathologic accumulation
3. Renal reclamation or excretion of HCO3 and excretion of of HCO3 (greater than 26 mEq/L or mmol/L), a condition
acids such as ammonium. termed metabolic alkalosis, or it may result in the loss of HCO3
beyond normal (less than 22 mEq/L or mmol/L), a condition
Because the kidneys excrete less than 1% of the estimated termed metabolic acidosis. In contrast to the lungs rapid effects
13,000 mEq of H+ ions generated in an average day, renal failure on CO2, the kidneys change the HCO3 very slowly (hours to
can be present for prolonged periods before life-threatening days).
CHAPTER 25 / ACID-BASE DISTURBANCES 421
TABLE 251. The Six Simple Acid-Base Disorders
Type of Disorder pH PaCO2d HCO3

1. Metabolic Decreasedb Decreaseda
acidosis PaCO2 = (1.5 HCO3) + 8
2. Metabolic Increasedb Increaseda
alkalosis PaCO2 = (0.9 HCO3) + 15
3. Acute respiratory Increaseda ~Normal
acidosis HCO3 = 0.1 PaCO2d
4. Chronic respiratory Increaseda Increasedc
acidosis HCO3 = 0.35 PaCO2d
5. Acute respiratory Decreaseda ~Normal
alkalosis HCO3 = 0.2 PaCO2d
6. Chronic respiratory Decreaseda Decreasedc
alkalosis HCO3 = 0.4 PaCO2d
a
Primary disorder.
b
Respiratory compensation: If inappropriate, see Table 252.
c
Metabolic compensation: If inappropriate, see Table 252.
d
PaCO2 in millimeters of mercury.
Respiratory and metabolic derangements can occur in iso- expected compensatory responses. Although it isnt manda-
lation or in combination. If a patient has an isolated primary tory to memorize these formulas in order to interpret acid-
acid-base disorder that is not accompanied by another pri- base problems, they can be helpful tools. If the measured val-
mary acid-base disorder, a simple (uncomplicated) disorder ues differ markedly from the calculated values (the measured
is present. The most common clinical disturbances are simple serum HCO3 is greater than 2 mEq/L from the calculated
acid-base disorders. If two or three simple acid-base disorders value or the measured PaCO2 is more than 4 mm Hg from the
are simultaneously present the patient has a mixed (compli- calculated value), a second acid-base disorder is present as
cated) disorder. More complex clinical situations lead to outlined in Table 252.
mixed acid-base disturbances.
Because CO2 is a volatile acid, it can rapidly be changed by
the respiratory system. If a respiratory acid-base disturbance APPLICATION OF BASIC PATHOPHYSIOLOGY
is present for minutes to hours it is considered an acute dis-
order while if it is present for days or longer it is considered a When given an ABG for interpretation, it is essential to use an
chronic disorder. By denition, the metabolic machinery that approach that is focused yet comprehensive. An algorithm
regulates HCO3 results in slow changes in serum bicarbonate illustrating this concept is shown in Fig. 251. The rst step is
and all metabolic disorders are chronic. This means that there to identify all abnormalities in the pH, PaCO2, and/or HCO3
are six simple acid-base disorders as outlined in Table 251.2 and then decide which abnormal values are primary and
Changes that follow the primary disorder and attempt to which are compensatory. This is best done by rst looking at
restore the blood pH to normal are referred to as compensa- the pH. Whichever side of 7.40 the pH is on, the process that
tory changes. It should be stressed that compensation never
normalizes the pH. Because all metabolic acid-base disorders
are chronic and the normal respiratory system can quickly alter TABLE 252. Diagnosis of Concurrent Acid-Base Disturbances
the PaCO2, essentially all metabolic disorders are accompanied when Compensation Is Inappropriate
by some degree of respiratory compensation.3 Similarly,
Primary Acid-Base Assessment of Concurrent Acid-Base
chronic respiratory acid-base disorders are typically accompa-
Disturbance Compensation Disturbance
nied by attempts at metabolic compensation.4,5 However, with
acute respiratory acid-base disorders there is insufcient time for Metabolic acidosis PaCO2 too low Respiratory alkalosis
PaCO2 too high Respiratory acidosis
the metabolic pathways to compensate signicantly.6 As such, Metabolic alkalosis PaCO2 too low Respiratory alkalosis
acute respiratory derangements are essentially uncompensated. PaCO2 too high Respiratory acidosis
The amount of compensation (metabolic or respiratory) Respiratory acidosis HCO3 too low Metabolic acidosis
can be reliably predicted based on the degree of derangement HCO3 too high Metabolic alkalosis
in the primary disorder. Table 251 outlines the simple acid- Respiratory alkalosis HCO3 too low Metabolic acidosis
HCO3 too high Metabolic alkalosis
base disorders and provides formulas for calculating the
FIGURE 251. An algorithmic approach to acid-base disorders. Normal values: pH 7.35 to

7.45, PaCO2 35 to 45 mm Hg (4.7 to 6 kPa), HCO3 22 to 26 mEq/L (mmol/L), anion gap
less than 12 mEq/L (mmol/L). Note that PaCO2 should be in millimeters of mercury to use
the equations in the gure. Cl, chloride ion; HCO3, bicarbonate; Na+, sodium ion; PaCO2,
partial pressure of arterial carbon dioxide.
caused it to shift to that side is the primary abnormality. If the (greater than 25 mEq/L or mmol/L, metabolic alkalosis)
arterial pH is lower than 7.40 (acidemia), an elevated PaCO2 would be the primary abnormality. Once the primary disorder
(greater than 45 mm Hg or 6 kPa, respiratory acidosis) or a is established, the second step is to apply the formulas from
lowered HCO3 (less than 22 mEq/L or mmol/L, metabolic Table 251 to assess whether compensation is appropriate and
acidosis) would be the primary abnormality. If the arterial pH to look for concurrent processes.2
is higher than 7.40 (alkalemia), a decreased PaCO2 (less than An alternative to a diagnostic algorithm is use of a graphic
35 or 4.7 kPa, respiratory alkalosis) or an increased HCO3 nomogram. Nomograms are plots of the pH, PaCO2, and
HCO3 that allow the user to rapidly determine whether arte- Acid-base disturbances are always manifestations of under-
rial blood gas values are consistent with one of the six simple lying clinical disorders. It is useful to specically dene the
primary acid-base disturbances. Although nomograms are primary acid-base abnormality, as each disorder is caused by
commonly used to identify acid-base disturbances in clinical a limited number of disease processes. Establishing the spe-
practice, only individuals who fully comprehend the concepts cic disease process responsible for the observed acid-base
of acid-base assessment should use these tools. Furthermore, disorder is clinically important because treatment of a given
nomograms have limited utility when dealing with complex acid-base disorder will only be accomplished by correcting the
acid-base derangements. underlying disease process.
Patient Encounters 1 through 5: Case Study 3

Application of Basic Pathophysiology Now consider a patient whose ABG shows a pH of 7.50, a
PaCO2 of 29 mm Hg (3.86 kPa), and an HCO3 of 22 mEq/L
(mmol/L). Because this person is alkalemic, the low PaCO2 is
Case Study 1 the primary disturbance. Again, this degree of metabolic
First, consider a patient with a pH of 7.16, a PaCO2 of 70 mm compensation (2 mEq/L or mmol/L) is appropriate. Because
Hg (9.3 kPa), and an HCO3 of 27 mEq/L (mmol/L). This person the PaCO2 has decreased by 11 mm Hg (1.46 kPa) and the
is acidemic (the pH is less than 7.35) with an increased PaCO2 expected HCO3 is 0.2 x PaCO2 (in millimeters of mer-
(greater than 45 mm Hg or 6 kPa) and an HCO3 that is mini- cury) (see Table 251) the HCO3 is expected to change by
mally elevated (normal range 22 to 26 mEq/L or mmol/L). This 0.2 x 11 or ~2 mEq/L (mmol/L). This ABG represents acute
appears to represent an acute respiratory acidosis with meta- respiratory alkalosis with minimal metabolic compensation.
bolic compensation. To ensure that the value of the serum These blood gases were obtained from a normal, healthy
HCO3 represents appropriate compensation, the formulas individual who was having an ABG collected as part of a
shown in Table 251 are applied. Because the PaCO2 has research protocol. Anxiety caused by the anticipation of an
increased by 30 mm Hg (4 kPa) and the expected change () arterial puncture for blood gas collection often causes hyper-
in the HCO3 is 0.1 x PaCO2 (in millimeters of mercury), our ventilation with acute respiratory alkalosis.
expected HCO3 is 3 mEq/L or mmol/L (0.1 x 30 mEq/L or
mmol/L). By adding this expected compensation (3 mEq/L or Case Study 4
mmol/L) back to a normal HCO3 (24 mEq/L or mmol/L), it This patient has an ABG with the following values: pH of
becomes evident that this patients measured HCO3 of 7.50, a PaCO2 of 47 mm Hg (6.3 kPa), and an HCO3 of 36
27 mEq/L (or mmol/L) is consistent with metabolic compen- mEq/L (mmol/L). Again, both the PaCO2 and the HCO3 are
sation. These blood gases were obtained from a patient who elevated, two abnormalities with opposite effects on the pH.
had overdosed on heroin, a potent respiratory depressant. Because the pH is higher than 7.40 the primary disorder is
the elevated HCO3 (a metabolic alkalosis). In this instance
Case Study 2 the elevated PaCO2 is consistent with respiratory compensa-
The next patient has a pH of 7.34, a PaCO2 of 70 mm Hg tion. From Table 251, the formula for the expected compen-
(9.3 kPa), and an HCO3 of 35 mEq/L (mmol/L). Now both satory level of the PaCO2 is (0.9 x HCO3) + 15. In this case
the PaCO2 and the HCO3 are signicantly elevated, two the predicted PaCO2 would be (0.9 x 36) + 15, or 47 mm Hg
abnormalities with opposite effects on the pH. Because the (6.3 kPa). These blood gases are from a patient with conges-
pH is lower than 7.40, the primary disorder is the elevated tive heart failure who is on chronic diuretic therapy that has
PaCO2again a respiratory acidosis. The markedly elevated caused her metabolic alkalosis. Although respiratory com-
bicarbonate and the near-normal pH suggest that metabolic pensation has occurred, this compensation did not (and
compensation has occurred and that the respiratory acidosis should not) return the pH entirely to normal.
is chronic. Again, this degree of compensation (11 mEq/L or
mmol/L) is appropriate. Because the PaCO2 has increased by Case Study 5
30 mm Hg (4 kPa) and the expected HCO3 is 0.35 x The nal patient in this section has an ABG with a pH of
PaCO2 (in millimeters of mercury) (see Table 251), the 7.20, a PaCO2 of 20 mm Hg (2.7 kPa), and an HCO3 of 8
expected HCO3 is 0.35 x 30 or ~11 mEq/L (mmol/L). mEq/L (mmol/L). Because the patient is acidemic the low
The changes in this patients pH and HCO3 should be bicarbonate is the primary abnormality and a metabolic aci-
compared with the values from the patient in Case Study 1. dosis is present. The PaCO2 is consistent with respiratory
It is critical to differentiate acute and chronic respiratory compensation, as the expected value is PaCO2 = (1.5 x
acidosis, as the acute form is often a medical emergency that HCO3) + 8 which equals (1.5 x 8) + 8, or 20 mm Hg (2.7
requires intubation and mechanical ventilation, whereas the kPa) (see Table 251). These blood gases came from a patient
chronic form is typically a stable condition. The blood gases in with chronic renal insufciency who was hospitalized for
Case Study 2 came from a patient with advanced emphysema gastroenteritis with profound diarrhea. In this instance, the
who is a CO2 retainer due to ineffective ventilation. Because patient had lost extensive amounts of HCO3 in her stool and
this patients disease is chronic, the elevated PaCO2 developed was unable to adequately regenerate HCO3 given her under-
very slowly and allowed for metabolic compensation. lying renal disease.
ADVANCED PATHOPHYSIOLOGY PaCO2, and HCO3; (2) assessment of the adequacy of com-
pensation; (3) calculation of the anion gap; and (4) calcula-
The concepts in this section will be used to further expand the tion of the excess gap.
diagnostic algorithm shown in Fig. 251. Under normal cir-
cumstances the serum is in the isoelectric state. This means that
the positively charged entities reported in a standard chemistry ETIOLOGY AND TREATMENT
panel (cations: sodium and potassium) should be exactly bal-
anced by the negatively charged entities (anions: chloride and After an acid-base disorder has been completely charac-
bicarbonate). However, this relationship is consistently incor- terized, the patients medical history, physical exam, and med-
rect, as the measured cations are higher than the measured ications should be reviewed in order to establish the etiology
anions by 10 to 12 mEq/L (mmol/L). This discrepancy results of the given disorder. Tables 253 through 257 outline the
from the presence of unmeasured anions (e.g., circulating pro- most commonly encountered causes of the primary acid-
teins, phosphates, and sulfates). This apparent difference in base disorders. The therapeutic approach to each of these
charges, the serum anion gap, is calculated as follows: acid-base derangements should emphasize a search for the
cause, as opposed to immediate attempts to normalize the pH.
Anion gap = sodium (chloride + bicarbonate) Although supportive measures to prevent the sequelae of
marked acid-base abnormalities is often required, these therapies
Because the serum potassium content is relatively small and is will be required indenitely if the causative process is not also
tightly regulated, it is generally omitted from the calculation. identied and corrected.7,8
It is important to realize that the serum HCO3 concentra- All patients with signicant disturbances in their acid-base
tion may be affected by the presence of unmeasured endoge- status require continuous cardiovascular and hemodynamic
nous acids (lactic acidosis or ketoacidosis). Bicarbonate will monitoring. Because frequent assessment of the patients
attempt to buffer these acids, resulting in a 1 mEq loss of response to treatment is critical, an arterial line is often placed
serum HCO3 for each 1 mEq of acid titrated. Because the to minimize patient discomfort with serial ABG collections. If
cation side of the equation is not affected by this transaction,
the loss of serum HCO3 results in an increase in the calcu-
lated anion gap. Identication of an increased anion gap is
very important for identifying the etiology of the acid-base
TABLE 253. Common Causes of Metabolic Acidosis
disorder. The concept of the increased anion gap will be
applied later in the case studies section. Elevated Anion Gapa Normal Anion Gapa
Any time an ABG is analyzed it is wise to concurrently
Intoxications Bowel stula
inspect the serum chemistry values to calculate the anion gap. Methanol Diarrhea
The body does not generate an anion gap to compensate for a Ethylene glycol Dilutional acidosis
primary disorder. As such, if the calculated anion gap exceeds Salicylates Drugs
12 mEq/L (mmol/L) there is a primary metabolic acidosis Paraldehyde Acetazolamideb
Isoniazid Ammonium chlorideb
regardless of the pH or the serum HCO3 concentration. The
Ketoacidosis Amphotericin Bb
anion gap may be articially lowered by decreased serum albu- Diabetic Arginine hydrochloridec
min, multiple myeloma, lithium intoxication, or a profound Ethanol Cholestyramineb
increase in the serum potassium, calcium, or magnesium. Starvation Hydrochloric acidb
Calculation of the anion gap also facilitates determination Lactic acidosis Lithiumb
Carbon monoxide poisoning Parenteral nutritionb
of the excess gap or the degree to which the calculated anion
Drugs Topiramateb
gap exceeds the normal anion gap. The excess gap is calculated IV lorazepam (due to vehicle)c Zonisamideb
as follows: Metforminb Lead poisoning
Nitroprusside (due to Renal tubular acidosis
Excess gap = [sodium (chloride + bicarbonate)] 12 cyanide accumulation)b Surgical drains
Nucleoside reverse Ureteral diversion
transcriptase inhibitorsb Villous adenomas (some)
The excess gap represents the amount of HCO3 that has been Propofolc
lost due to buffering unmeasured cations. The excess gap can be Seizures
added back to the measured HCO3 to determine what the Severe hypoxemia
patients bicarbonate would be if these endogenous acids were Shock
Renal failure
not present. This is a very valuable tool that can be used in nar-
rowing the differential diagnosis of certain acid-base disorders as a
Anion gap = serum sodium concentration (serum chloride
well as in uncovering occult or mixed acid-base disorders. concentration + serum bicarbonate concentration). Under normal
circumstances the anion gap should be 10 mEq/L (mmol/L) or less.
In summary, the approach to assessment of acid-base sta- b
May be observed with therapeutic doses or overdoses.
tus involves four key steps: (1) initial inspection of the pH, c
Typically observed only with overdoses.
Patient Encounters 6 through 10: Case Study 8

Application of Advanced This intoxicated patient has a pH of 7.50, a PaCO2 of 20 mm
Pathophysiology Hg (2.7 kPa), an HCO3 of 15 mEq/L (mmol/L), a sodium con-
centration of 145 mEq/L (mmol/L), and a chloride level of 100
Case Study 6 mEq/L (mmol/L). Here the pH is high, the PaCO2 and HCO3
Now consider a psychiatric patient who presents with a pH are low, and there is an anion gap of 30 mEq/L (mmol/L).
of 7.50, a PaCO2 of 20 mm Hg (2.7 kPa), an HCO3 of 16 Because the patient is alkalemic, the low PaCO2 is the primary
mEq/L (mmol/L), a sodium concentration of 140 mEq/L disturbance and the patient has a respiratory alkalosis. By de-
(mmol/L), and a chloride level of 103 mEq/L (mmol/L). nition, the increased anion gap is consistent with a metabolic
Because this person is alkalemic, the low PaCO2 is the pri- acidosis. The excess gap is 18 mEq/L (mmol/L), indicating that
mary disturbance and represents respiratory alkalosis. If this the patients original HCO3 was 33 mEq/L (mmol/L), indicat-
disturbance is a chronic respiratory alkalosis with metabolic ing a concurrent metabolic alkalosis. Despite this triple disor-
compensation, the expected HCO3 is 0.4 x PaCO2 (in der, the pH is only mildly abnormal. This man had alcoholic
millimeters of mercury) or 0.4 x 20, which is 8 mEq/L ketoacidosis (causing the anion gap metabolic acidosis), with
(mmol/L). As such, the predicted HCO3 concentration persistent vomiting (causing metabolic alkalosis), and an aspi-
should be 24 mEq/L (mmol/L) [normal] 8 mEq/L (mmol/L) ration pneumonia (causing respiratory alkalosis). Triple disor-
[expected compensation] or 16 mEq/L (16 mmol/L). ders represent the most complex acid-base derangements. A
Given the ABG values shown, most clinicians would stop patient cannot have four primary acid-base disorders, as it is
at this point and erroneously conclude that the patient has a impossible to simultaneously hyperventilate (respiratory alkalo-
chronic respiratory alkalosis with metabolic compensation. sis) and hypoventilate (respiratory acidosis).
However, calculation of the anion gap reveals a hidden Case Study 9
disorder. The anion gap for this patient is 140 (103 + 16) = The next labs are from a patient who was brought to the hos-
21 mEq/L (mmol/L). The presence of this abnormally large pital unconscious and was quickly intubated. The blood work
anion gap indicates that a second primary disorder (an anion drawn prior to intubation shows a pH of 7.10, a PaCO2 of 50
gap metabolic acidosis) is also present. The excess anion gap mm Hg (6.7 kPa), an HCO3 of 15 mEq/L (mmol/L), a sodium
(21 12 = 9 mEq/L [mmol/L]) should be added back to the concentration of 145 mEq/L (mmol/L), and a chloride level of
measured serum HCO3 (16 mEq/L [mmol/L]) to tell us the 100 mEq/L (mmol/L). This person is acidemic and has an ele-
patients baseline HCO3 level (before buffering the acid that vated PaCO2 with a low bicarbonate. Furthermore, the anion
has widened the anion gap). Doing so provides a normal gap is markedly abnormal at 30 mEq/L. As such, the patient
starting HCO3 of 25 mEq/L (mmol/L), indicating that no fur- has a respiratory acidosis and an anion gap metabolic acido-
ther primary abnormalities are present. sis as primary disorders. Adding the excess gap (18 mEq/L or
This patient had ingested a large quantity of aspirin result- mmol/L) to the measured HCO3 (15 mEq/L or mmol/L) gives
ing in the classic ndings of a salicylate overdose: a centrally a starting bicarbonate of 33 mEq/L. This represents a concur-
mediated respiratory alkalosis with a concurrent anion gap rent primary metabolic alkalosis and the presence of a triple
metabolic acidosis. disorder. This patient had diabetic ketoacidosis (anion gap
metabolic acidosis) with prominent vomiting (metabolic alka-
Case Study 7
losis) who became obtunded and was hypoventilating (respi-
These values come from an unconscious man in the intensive
ratory acidosis).
care unit: pH of 7.40, PaCO2 of 40 mm Hg (5.3 kPa), HCO3
of 24 mEq/L (mmol/L), sodium concentration of 145 mEq/L Case Study 10
(mmol/L), and chloride level of 100 mEq/L (mmol/L). In this The nal patient is a young woman with a pH of 7.15, a
case, all of the ABG and electrolyte values are surprisingly PaCO2 of 15 mm Hg (2 kPa), an HCO3 of 5 mEq/L (mmol/L),
normal. However, the anion gap is elevated [145 (100 + a sodium concentration of 140 mEq/L (mmol/L) , and a chlo-
24) = 21 mEq/L or mmol/L]. The increased anion gap identi- ride level of 110 mEq/L (mmol/L). She is acidemic with a low
es a metabolic acidosis even though the pH is normal. The PaCO2, a low bicarbonate, and an increased calculated
excess anion gap is 21 12 = 9 mEq/L (mmol/L). Adding the anion gap (25 mEq/L or mmol/L). The expected PaCO2 with
excess gap back to the measured HCO3 (24 mEq/L or respiratory compensation is (1.5 x HCO3) + 8 or 15.5 mm
mmol/L) gives a baseline HCO3 value of 33 mEq/L (mmol/L). Hg (2.1 kPa). As such, these values look like a simple anion
This abnormally high value tells us that the patient has a con- gap metabolic acidosis with respiratory compensation.
current metabolic alkalosis. This patient had end-stage kidney However, after adding the excess gap (13 mEq/L or mmol/L)
disease and after missing several dialysis sessions developed back to the measured serum bicarbonate (5 mEq/L or
increasing uremia (causing the anion gap metabolic acidosis) mmol/L) it is apparent that this patient had a baseline HCO3
with intense vomiting (causing the metabolic alkalosis). The of 18 mEq/L (mmol/L). This patient has a concurrent anion
acute alkalosis from his vomiting offset his chronic acidosis gap metabolic acidosis and a non-anion gap metabolic aci-
of renal failure, resulting in a normal pH. This is another dosis. This woman was in the recovery phase of diabetic
example of a hidden acid-base derangement that would ketoacidosis. During this period, a non-anion gap acidosis
routinely be missed by clinicians who do not utilize a sys- can be present due to the kidneys inability to regenerate
tematic approach to ABG interpretation. bicarbonate from the ketoacids lost in the urine.
the anion gap was initially abnormal, serial chemistries should TABLE 255. Common Causes of Metabolic Alkalosis
be followed to ensure that the anion gap resolves with treat-
Urine Cl less than 10 mEq/L Urine Cl greater than 10 mEq/L
ment. Specic treatment decisions depend on the underlying (less than10 mmol/L) (greater than10 mmol/L)
pathophysiologic state (e.g., dialysis for renal failure, insulin
Alkali administration Drugsa
for diabetic ketoacidosis, or improving tissue perfusion and
IV bicarbonate therapy Corticosteroid therapy
oxygenation for lactic acidosis). Oral alkali therapy Diuretics
Parenteral nutrition with Hypokalemia
acetate Mineralocorticoid excess
Metabolic Acidosis Contraction alkalosis Hyperaldosteronism
Metabolic acidosis is characterized by a reduced arterial pH, post-diuretic use
Decreased chloride intake
Bartters syndrome
Cushings syndrome
a primary decrease in the HCO3 concentration, and a compen- Loss of gastric acid
satory reduction in the PaCO2. The etiologies of metabolic aci- Vomiting
dosis are divided into those that lead to an increase in the anion Nasogastric suction
gap and those associated with a normal anion gap and are listed Post-hypercapnia
Villous adenomas (some)
in Table 253. Although there are numerous mnemonics to
recall the differential diagnosis of metabolic acidosis, two sim- a
ple ones are shown in Table 254. High anion gap metabolic
acidosis is most frequently caused by lactic acidosis, ketoaci-
dosis, and/or renal failure. Although there is considerable chloride. Because of this, normal anion gap metabolic acido-
variation, the largest anion gaps are caused by ketoacidosis, sis is often referred to as hyperchloremic acidosis.
lactic acidosis, and methanol or ethylene glycol ingestion.9 In patients with a normal anion gap metabolic acidosis it is
Symptoms of metabolic acidosis are attributable to often helpful to calculate the urine anion gap (UAG). The
changes in the cardiovascular, musculoskeletal, neurologic, or UAG is calculated as follows:
pulmonary function. Respiratory compensation requires
marked increases in minute ventilation and may lead to dysp- UAG = (Urine Na+ + Urine K+) Urine Cl
nea. Acidemia predisposes to ventricular arrhythmias and
reduces cardiac contractility, each of which can result in pul-
monary edema and/or systemic hypotension. Neurologic TABLE 256. Common Causes of Respiratory Acidosis
symptoms range from lethargy to coma and are usually pro-
portional to the severity of the pH derangement. Chronic Central nervous system disease Pneumonia
Brain stem lesions Pneumonitis
metabolic acidosis leads to a variety of musculoskeletal prob- Central sleep apnea Pulmonary edema
lems including impaired growth, rickets, osteomalacia, or Infection Restrictive lung disease
osteopenia. These changes are believed to be caused by the Intracranial hypertension Ascites
release of calcium and phosphate during bone buffering of Trauma Chest wall disorder
excess H+ ions. Tumor Fibrothorax
Vascular Kyphoscoliosis
As previously discussed, in anion gap metabolic acidosis, Drugsa Obesity
the isoelectric state is maintained because unmeasured anions Aminoglycosides Pleural effusion
are present. With a normal anion gap metabolic acidosis, the Anesthetics Pneumoconiosis
isoelectric state is maintained by an increase in the measured -Blockers Pneumothorax
Botulism toxin Progressive systemic
Hypnotics sclerosis
Narcotics Pulmonary brosis
TABLE 254. Mnemonics for the Differential Diagnoses of Neuromuscular blocking agents Spinal arthritis
Metabolic Acidosis Organophosphates Smoke inhalation
Sedatives Upper airway obstruction
Elevated Anion Gapa Normal Anion Gapa Neuromuscular disease Foreign body
M Methanol U Ureteral diversion Guillain-Barr syndrome Laryngospasm
U Uremia S Saline infusion Muscular dystrophy Obstructive sleep apnea
D Diabetic ketoacidosis E Exogenous acid Myasthenia gravis Others
P Paraldehyde D Diarrhea Polymyositis Abdominal distention
I Isoniazid Pulmonary disease Altered metabolic rate
L Lactic acidosis C Carbonic anhydrase inhibitors Lower airway obstruction Congestive heart failure
E Ethylene glycol A Adrenal insufciency Chronic obstructive Hypokalemia
S Salicylates R Renal tubular acidosis pulmonary disease Hypothyroidism
Foreign body Inadequate mechanical
a
Anion gap = serum sodium concentration (serum chloride Status asthmaticus ventilation
concentration + serum bicarbonate concentration). Under normal
circumstances the anion gap should be 10 mEq/L (mmol/L) or less. a
TABLE 257. Common Causes of Respiratory Alkalosis hyperosmolarity, overshoot alkalemia, and/or hypokalemia.
The calculated HCO3 decit reects only the present situa-
Central nervous system disease Pulmonary disease
Infection Early restrictive lung disease
tion and does not account for ongoing H+ production and
Trauma Infection HCO3 loss. When giving HCO3 therapy, serial blood gases
Tumor Pneumothorax are needed to monitor therapy.
Vascular Pulmonary edema Another option for patients with severe acidemia is
Drug- or toxin-induceda Pulmonary embolism tromethamine (THAM). This inert amino alcohol buffers
Catecholamines Tissue hypoxia
Doxapram Burn injury
acids and CO2 through its amine (NH2) moiety:
Methylphenidate Excessive mechanical
THAM-NH2 + H+ = THAM-NH3+
Methylxanthines ventilation
Nicotine Fever THAM-NH2 + H2O + CO2 = THAM-NH3+ + HCO3
Progesterone Hepatic failure
Salicylates Hypoxemia Protonated THAM (with Cl or HCO3) is excreted in the
Psychiatric disease Pain urine at a rate that is slightly higher than creatinine clearance.
Anxiety Post-metabolic acidosis
Hyperventilation Pregnancy As such, THAM augments the buffering capacity of the blood
Hysteria Severe anemia without generating excess CO2. THAM is less effective in
Panic disorder Thyrotoxicosis patients with renal failure and toxicities may include hyper-
a
kalemia, hypoglycemia, and possible respiratory depression.
The normal UAG ranges from 0 to 5 mEq/L (mmol/L) and rep- Metabolic Alkalosis
resents the presence of unmeasured urinary anions. In metabolic
acidosis, the excretion of NH4+ and concurrent Cl should Metabolic alkalosis is characterized by an increased arte-
increase markedly if renal acidication is intact. This results in rial pH, a primary increase in the HCO3 concentration, and a
UAG values from 20 to 50 mEq/L (mmol/L). This occurs compensatory increase in the PaCO2. Patients will always
because the urinary Cl concentration now markedly exceeds hypoventilate to compensate for metabolic alkalosiseven if
the urinary Na+ and K+ concentrations. Diagnoses consistent it results in profound hypoxemia. For a metabolic alkalosis to
with an excessively negative UAG include proximal (type 2) persist there must concurrently be a process that elevates
renal tubular acidosis, diarrhea, or administration of acetazo- serum HCO3 concentration (gastric or renal loss of acids)
lamide or hydrochloric acid (HCl). Excessively positive values and another that impairs renal HCO3 excretion (hypo-
of the UAG suggest a distal (type 1) renal tubular acidosis. volemia, hypokalemia, or mineralocorticoid excess). The eti-
In order to effectively treat metabolic acidosis, the causative ologies of metabolic alkalosis are listed in Table 255.
process must be identied and treated.17 The role of adjunctive Patients with metabolic alkalosis rarely have symptoms
therapy with sodium bicarbonate (NaHCO3) is not universally attributable to alkalemia. Rather, complaints are usually
agreed upon. However, most individuals would agree that related to volume depletion (muscle cramps, positional dizzi-
NaHCO3 is indicated when renal dysfunction precludes ade- ness, and weakness) or to hypokalemia (muscle weakness,
quate regeneration of HCO3 or when severe acidemia (pH less polyuria, and polydipsia).
than 7.10) is present. The metabolic acidosis seen with lactic aci- In order to effectively treat metabolic alkalosis, the
dosis and ketoacidosis generally resolves with therapy targeted at causative process must be identied and treated. The major
the underlying cause and NaHCO3 may be unnecessary regard- causes of metabolic alkalosis are often readily apparent after
less of the pH. The metabolic acidosis of renal failure, renal carefully reviewing the patients history and medication list.
tubular acidosis, or intoxication with ethylene glycol, methanol, Always look for administration of compounds such as citrate
or salicylates is much more likely to require NaHCO3 therapy. in blood products and acetate in parenteral nutrition that can
If NaHCO3 is used, the plasma HCO3 should not be cor- raise the HCO3 level. If the etiology of the metabolic alkalo-
rected entirely. Instead, aim at increasing HCO3 above an sis is still unclear, measurement of the urinary chloride may be
absolute value of 10 mEq/L. The total HCO3 decit can be useful. Some processes leading to metabolic alkalosis (vomit-
calculated from the current bicarbonate level (HCO3curr), the ing, nasogastric suction losses, and factitious diarrhea) will
desired bicarbonate level (HCO3post), and the body weight (in have low urinary Cl levels (less than 25 mEq/L or mmol/L),
kilograms) as follows: while others (diuretics, hypokalemia, and mineralocorticoid
excess) will have higher urinary Cl levels (greater than 40
HCO3 decit = [(2.4/HCO3curr) + 0.4] weight mEq/L or mmol/L).
(HCO3curr HCO3post) In general, contributing factors such as diuretics, nasogas-
tric suction, and corticosteroids should be discontinued if
No more than half of the calculated HCO3 decit should be possible. Any uid decits should be treated with IV normal
given initially to avoid volume overload, hypernatremia, saline. Recognize that patients with varieties of metabolic
alkalosis with high urine Cl (though rather uncommon) will alveolar ventilation is required. This can often be achieved by
be resistant to saline loading. Potassium supplementation controlling the underlying disease (e.g., bronchodilators and
should always be given if it is also decient. corticosteroids in asthma) and/or physically augmenting
In patients with mild or moderate alkalosis who require ventilation.
ongoing diuresis but have rising HCO3 levels, the carbonic Although their precise role and mechanisms of action are
anhydrase inhibitor acetazolamide can be used to reduce the unclear, agents such as medroxyprogesterone, theophylline,
HCO3 concentration. Acetazolamide is typically dosed at 250 and doxapram stimulate respiration and have been used to
mg every 6 to 12 hours as needed to maintain the pH in a clin- treat mild to moderate respiratory acidosis. Moderate or severe
ically acceptable range. If alkalosis is profound and potentially respiratory acidosis requires assisted ventilation. This can be
life-threatening (due to seizures or ventricular tachyarrhyth- provided to spontaneously breathing patients via bilevel posi-
mias) consideration can be given to hemodialysis or transient tive airway pressure (BiPAP) delivered via a tight-tting mask,
HCl infusion. The hydrogen ion decit (in milliequivalents or or by intubation followed by mechanical ventilation. In
millimoles) can be estimated from the current bicarbonate mechanically ventilated patients, respiratory acidosis is treated
level (HCO3curr), the desired bicarbonate level (HCO3post), by increasing the minute ventilation. This is achieved by
and the body weight (in kilograms) as follows: increasing the respiratory rate and/or tidal volume.
As with the treatment of metabolic acidosis, the role of
H+ decit = 0.4 weight (HCO3curr HCO3post) NaHCO3 therapy is not well dened for respiratory acidosis.
Realize that administration of NaHCO3 can paradoxically
After estimating the H+ decit, 0.1 to 0.2 N HCl is infused at 20 result in increased CO2 generation (HCO3 + H+ H2CO3
to 50 mEq/hour (mmol/hour) into a central vein. Arterial pH H2O + CO2) and worsened acidemia. Careful monitoring of
must be monitored at least hourly and the infusion stopped as the pH is required if NaHCO3 therapy is started for this indi-
soon as clinically feasible. Ammonium chloride and arginine cation. The use of THAM in respiratory acidosis (see meta-
hydrochloride, agents that result in the formation of HCl, should bolic acidosis, above) has unproven safety and benet.
not be given, as they may lead to signicant toxicity. Ammonium The goals of therapy in patients with chronic respiratory
chloride causes accumulation of ammonia and is associated with acidosis are to maintain oxygenation and to improve alveolar
encephalopathy. Arginine hydrochloride can induce life-threat- ventilation if possible. Because of the presence of renal com-
ening hyperkalemia through unclear mechanisms. pensation it is usually not necessary to treat the pH, even in
patients with severe hypercapnia. Although the specic treat-
ment varies with the underlying disease, excessive oxygen and
Respiratory Acidosis sedatives should be avoided, as they can worsen CO2 retention.
Respiratory acidosis is characterized by a reduced arterial
pH, a primary increase in the arterial PaCO2 and, when present
for sufcient time, a compensatory rise in the HCO3 concentra- Respiratory Alkalosis
tion. Because increased CO2 is a potent respiratory stimulus, Respiratory alkalosis is characterized by an increased arte-
respiratory acidosis represents ventilatory failure or impaired rial pH, a primary decrease in the arterial PaCO2 and, when
central control of ventilation as opposed to an increase in CO2 present for sufcient time, a compensatory fall in the HCO3
production. As such, most patients will have hypoxemia in concentration. Respiratory alkalosis represents hyperventila-
addition to hypercapnia. The most common etiologies of res- tion and is remarkably common. The most common etiolo-
piratory acidosis are listed in Table 256. gies of respiratory acidosis are listed in Table 257 and range
Severe, acute respiratory acidosis produces a variety of from benign (anxiety) to life-threatening (pulmonary
neurologic abnormalities. Initially these include headache, embolism). Some causes of hyperventilation and respiratory
blurred vision, restlessness, and anxiety. These may progress acidosis are remarkably common (hypoxemia or anemia).
to tremors, asterixis, somnolence, and/or delirium. If The symptoms produced by respiratory alkalosis result
untreated, terminal manifestations include peripheral vasodi- from increased irritability of the central and peripheral nervous
lation leading to hypotension and cardiac arrhythmias. systems. These include light-headedness, altered consciousness,
Chronic respiratory acidosis is typically associated with cor distal extremity paresthesias, circumoral paresthesia, cramps,
pulmonale and peripheral edema. carpopedal spasms, and syncope. Various supraventricular
In order to effectively treat respiratory acidosis, the and ventricular cardiac arrhythmias may occur in extreme
causative process must be identied and treated. If a cause is cases, particularly in critically ill patients. An additional nd-
identied, specic therapy should be started. This may ing in many patients with severe respiratory alkalosis is
include naloxone for opiate-induced hypoventilation or hypophosphatemia, reecting a shift of phosphate from the
bronchodilator therapy for acute bronchospasm. Because res- extracellular space into the cells. Chronic respiratory alkalosis
piratory acidosis represents ventilatory failure, an increase in is generally asymptomatic.
It is imperative to identify serious causes of respiratory gap are useful tools that can identify hidden disorders. This
alkalosis and institute effective treatment. In spontaneously rigorous assessment of the patients acid-base status, incorpo-
breathing patients, respiratory alkalosis is typically only mild rated with the available clinical data, increases the likelihood
or moderate in severity and no specic therapy is indicated. that the clinician will successfully determine the cause of each
Severe alkalosis generally represents respiratory acidosis identied disorder. Although supportive therapy is often
imposed on metabolic alkalosis and may improve with seda- required for profound acid-base disturbances, denitive ther-
tion. Patients receiving mechanical ventilation are treated with apy must target the underlying process that has led to the
reduced minute ventilation achieved by decreasing the respira- observed derangements.
tory rate and/or tidal volume. If the alkalosis persists in the
ventilated patient, high-level sedation or paralysis is effective.
ABBREVIATIONS
SUMMARY ABG: arterial blood gas

BiPAP: bilevel positive airway pressure
Acid-base disturbances are common clinical problems that are Cl: chloride ion
not difcult to analyze if approached in a consistent manner. CO2: carbon dioxide
(delta): change
The pH, PaCO2, and HCO3 should be inspected to identify all
H+: hydrogen ion
abnormal values. This should lead to an assessment of which
HCl: hydrochloric acid
deviations represent the primary abnormality and which rep- HCO3: bicarbonate
resent compensatory changes. The serum electrolytes should HCO3curr: current bicarbonate
always be used to calculate the anion gap. In cases in which the HCO3post: post-therapy bicarbonate
anion gap is increased, the excess anion gap should be added Hg: mercury
back to the measured HCO3. The anion gap and the excess K+: potassium ion
kg: kilogram
kPa: kilopascal
L: liter
Patient Care and Monitoring mEq: milliequivalent
mm: millimeter
mmol: millimole
Na+: sodium ion
1. Every patient with a suspected acid-base disturbance
NaHCO3: sodium bicarbonate
should have an arterial blood gas and a serum chemistry
NH2: terminal amine group
panel drawn concurrently. The results of these tests
NH4+: ammonium
should be reviewed using a systematic approach to
pH: logarithm of the hydrogen ion concentration
ensure proper interpretation.
PaCO2: partial pressure of arterial carbon dioxide
2. What is the primary disorder? Has compensation occurred? tCO2: total venous carbon dioxide
3. Is the anion gap excessively large? If so, does calculation THAM: tromethamine
of the excess gap identify another acid-base disorder? UAG: urine anion gap
4. Continuous cardiovascular and hemodynamic monitoring
should be used for signicant pH disturbances, as the most Reference lists and self-assessment questions and answers are
serious sequelae of acid-base disorders include electrolyte available at www.ChisholmPharmacotherapy.com.
abnormalities, cardiac dysrhythmias, and systemic
hypotension. Log into the website: www.pharmacotherapyprinciples.com
5. All acid-base abnormalities result from underlying disease for information on obtaining continuing education credit for
processes. Denitive therapy for these disturbances this chapter.
requires treatment of the illness that has disrupted the pH
equilibrium.
6. Review each patients history, physical exam, and current KEY REFERENCES AND READINGS
medication list for potential causes of the observed acid-
base disorder. Abelow B. Understanding Acid-Base. Baltimore: Williams & Wilkins,
7. Serial arterial blood gases and serum chemistries should 1998:229.
be compared, as every patients acid-base status is con- Adrogu HJ, Madias NE. Management of life-threatening acid-base
tinuously changing based on the underlying disease state disorders. First of two parts. N Engl J Med 1998;338:2634.
and any therapy initiated. Adrogu HJ, Madias NE. Management of life-threatening acid-base
disorders. Second of two parts. N Engl J Med 1998;338:107111.
Gennari FJ, Goldstein MB, Schwartz WB. The nature of the renal adap- Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte
tation to chronic hypocapnia. J Clin Invest 1972;51:17221730. Disorders. 5th ed. New York: McGraw-Hill, 2001:299.
Hood FL, Tannen RL. Protection of acid-base balance by pH regula- Schlichtig R, Grogono A, Severinghaus J. Human PaCO2 and stan-
tion of acid production. N Engl J Med 1998;339:819826. dard base excess for compensation of acid-base imbalances. Crit
Pierce NF, Fedson DS, Brigham KL, et al. The ventilatory response to Care Med 1998;26:11731179.
acute base decit in humans. Time course during development van Yperselle de Striho C, Brasseur L, de Coninck JD. The carbon
and correction of metabolic acidosis. Ann Intern Med dioxide response curve for chronic hypercapnia in man. N Engl
1970;72:633640. J Med 1966;275:117122.
Polak A, Haynie GD, Hays RM, Schwartz WB. Effects of chronic
hypercapnia on electrolyte and acid-base equilibrium. J Clin
Invest 1961;40:12231237.
Section 5. Neurologic Disorders
26 MULTIPLE SCLEROSIS
Melody Ryan
LEARNING OBJECTIVES
1. Identify risk factors for multiple sclerosis.

2. Describe pathophysiologic ndings of multiple sclerosis.
3. Recognize common presenting symptoms of multiple sclerosis.
4. Distinguish between the forms of multiple sclerosis based on the patient presentation and
course of disease.
5. Compare and contrast multiple sclerosis disease-modifying treatment choices for a specic
patient.
6. Determine appropriate symptomatic treatment choices and a detailed therapeutic plan for a
specic patient.
7. Develop a monitoring plan for a patient placed on specic medications.
KEY CONCEPTS Multiple sclerosis (MS) is a complex inammatory disease of

the central nervous system (CNS) that is variable in terms of
Multiple sclerosis symptoms are a function of the position of symptoms and presentation. The name refers to two features
lesions within the central nervous system (CNS). of the disease: multiple describes the number of CNS lesions;
The McDonald criteria allow the clinician to use the clinical and sclerosis refers to the demyelinated lesions. Today, these
exam in combination with magnetic resonance imaging (MRI) lesions are usually called plaques, rather than scleroses.
and cerebrospinal uid data to make a diagnosis sooner, and Although scientic understanding of MS has progressed at a
thus begin treatment earlier. rapid pace, there are still many areas of evolving knowledge.
The clinical course of multiple sclerosis has been described in
four basic patterns: relapsing remitting, secondary progres-
sive, primary progressive, and progressive relapsing.
Acute relapses are treated with corticosteroids to speed recov- Patient Encounter, Part 1
ery of the patient.
Disease-modifying therapies are used to decrease the number of
relapses, prevent permanent neurologic damage, and prevent
disability. CN is a 28-year-old woman who complains of a 2-day
Symptomatic treatment minimizes the impact of multiple history of weakness and tingling in her right arm and leg.
sclerosis on quality of life. These symptoms began over a 4-hour period. She also
reports an episode 2 years ago of right eye pain and blurred
Dose-response curves have been observed with the beta vision that resolved over 1 month. She was diagnosed with
interferons. optic neuritis at that time. Following an MRI, she is diag-
There is no consensus on the best medication for initial nosed with relapsing remitting MS today.
therapy.
Mitoxantrone should be reserved for patients with rapidly What is optic neuritis?
advancing disease who have failed other therapies. Why was her MS classied as relapsing remitting?
Multiple sclerosis patients must be treated with agents specic How would you treat the episode today?
for upper motor neuron spasticity.
431
432 SECTION 5 / NEUROLOGIC DISORDERS
EPIDEMIOLOGY AND ETIOLOGY bloodbrain barrier by attachment to upregulated adhesion

molecules and production of matrix metalloproteinases that
Epidemiology cause bloodbrain barrier breakdown. In the CNS, the T cells
come into contact with antigen-presenting cells and prolif-
Approximately 400,000 Americans have MS. Most are diag- erate. The T-helper cells differentiate into proinammatory
nosed with MS between the ages of 20 and 50 years. Twice as T helper-1 (Th1) cells and anti-inammatory T helper-2
many women as men develop MS.1 Risk factors associated (Th2) cells.7 T helper-1 cells secrete cytokines that enhance
with developing MS include: family history of MS, autoim- macrophage and microglial cells that may attack myelin.7
mune diseases, or migraine; and personal history of autoim- B cells likely cross previously damaged sections of the
mune diseases or migraine.2 bloodbrain barrier to arrive in the CNS, an area normally
MS prevalence decreases with decreases in latitude.3 The geo- free of B cells. Autoreactive T cells cause B cells to form
graphic risk of developing MS is not xed. When people move autoantibodies to myelin. B-cell antibodies also initiate the
from a higher- to a lower-risk area, the migrants MS risk is inter- complement cascade which causes myelin degradation.7
mediate between the risk of the original and the new areas.
However, when individuals move from a lower- to higher-risk Axonal Transection
area, there is not much change in the migrants MS risk.3
Furthermore, future risk of developing MS may depend on the Transection or severing of the axon disrupts nerve signals
age at the time of the move; adolescence is the critical time completely and irreversibly.8 There is growing evidence that
period.3 cytotoxic (CD8+) T cells cause axonal injury.5 Axonal transec-
tion begins as early as 2 weeks after diagnosis and continues
throughout the course of the disease.9
Etiology
Inheritance Theory CLINICAL PRESENTATION, DIAGNOSIS, AND

MS probably has a genetic component; there is a 5% risk for fam- CLINICAL COURSE
ily members of MS patients. Monozygotic twins, who share the
same genetic material, are at highest risk, with a 25% to 30% Diagnosis
concordance rate.4 However, a straightforward inheritance pat-
tern cannot fully explain the etiology of MS, because only a small MS diagnostic criteria were revised in 2001 and are known as
proportion of patients have a known family member with MS.4 the McDonald criteria (Fig. 262).1820 MS diagnosis requires
that plaques be disseminated in time and space. Previously,
Environment Theory diagnosis relied heavily on clinical examination. The
Over 20 infectious agents have been incriminated as etiologic McDonald criteria allow the clinician to use the clinical exam in
agents; for many the causal relationship has been disproved, and combination with magnetic resonance imaging (MRI) and cere-
for others there is conicting evidence. Human herpesvirus brospinal uid (CSF) data to make a diagnosis sooner, and thus
6 (HHV-6) is currently the most likely causative virus. HHV-6 begin treatment earlier (Table 261).
may initiate the autoimmune processes of MS in one of two
ways. First, HHV-6 is structurally similar to myelin basic pro- Clinical Course
tein. When T cells become sensitive to HHV-6, the cells may The clinical course of MS has been described in four basic
attack myelin basic protein. Second, HHV-6 may directly stimu- patterns: relapsing remitting, secondary progressive, primary pro-
late the complement cascade, activating autoimmune processes.5 gressive, and progressive relapsing (Fig. 263). Relapsing remit-
Infection with HHV-6 alone cannot fully explain MS, because ting MS develops into secondary progressive MS in 50% of
HHV-6 is found in 75% of all people, but MS is much more rare. patients within 10 years and 75% of patients within 25 years of
initial diagnosis.22 Rating scales used to assess the clinical
PATHOPHYSIOLOGY effects of MS are shown in Table 262. MS reduces overall life
expectancy 6 to 7 years.24 Suicide is disproportionately high in
While the actual causative agent of MS is not clear, the nal MS patients, accounting for about 15% of MS-related deaths.25
result is the development of an autoimmune disorder with
areas of CNS demyelination and axonal transection.
TREATMENT
Demyelination Desired Outcomes and General Approach

to Treatment
An unknown antigen presented by the major histocompatibil-
ity complex (MHC) class II molecules causes T cells to become The overall goal of MS treatment is to prevent permanent
autoreactive (Fig. 261). Once activated, T cells penetrate the neurologic damage. There are three general approaches to
Systemic immune
BBB Central nervous system
compartment
APC
1 6
T
Reactivation
and expansion
TH1 M
IL-4
IL-6 4
IL-10
3 TGF-
Abs Abs
B
TH2 B
2 5
1: Antigen presentation 2: B-cell activation & 3: Chemotoxis, adhesion

& T-cell activation antibody formation & migration
Antigen presenting cell CCRs

CXCRs
MHC
B7 CD28
Ag CD40L CAMs
B
CD40
TCR
CD5
Abs Chemokines
T lymphocyte MMPs
4: Macrophage activation 5: Axonal degeneration 6: Programmed cell
& demyelination & loss of trophic support deathapoptosis
No
TNF- Na+ channel
T Mitochondrial
C5b-9 MMPs upregulation
dysfunction
LT
TNF-
M
Ca2+ influx
Ca2+
Cytoskeleton disintegration IL-2
FIGURE 261. Synoptic view of the immune response in the pathogenesis of multiple sclerosis. Autoreactive T cells recognize with
their TCR a specic autoantigen presented by MHC class II molecules and the simultaneous delivery of co-stimulatory signals (CD 28,
B7, CD40, CD 40L) on the cell surface of APCs, such as macrophages, in the systemic immune compartment (panel 1). Activated T
lymphocytes can cross the BBB in order to enter the CNS. The mechanisms of transendothelial migration is mediated by the complex
interplay of CAMs, chemokines, and their receptors (CCRs, CXCRs) and MMPs (panel 3). Within the CNS, T cells activate microglia
cells/macrophages (M) to enhanced phagocytic activity; production of cytokines, such as TNF- and LT; and the release of toxic
mediators, such as NO, propagating demyelination and axonal loss. Abs crossing the BBB or locally produced by B cells or mast cells
(B*) contribute to this process. Autoantibodies activate the complement cascade resulting in the formation of the membrane-attack
complex (C5b-9) and its subsequent lysis of the target structure (panels 2 and 4). The upregulation of Na+ and Ca2+ channels on the
axon as well as mitochondrial dysfunction and loss of trophic support contribute to axonal disintegration and degeneration (panel 5).
The inammatory response is regulated by anti-inammatory cytokines, such as IL-10 or TGF-, as well as IL-2, inducing programmed
cell death (apoptosis) in immunoreactive T lymphocytes (panel 6). Abs, autoantibodies; Ag, antigen; APC, antigen-presenting cells;
BBB, bloodbrain barrier; CAM, cellular adhesion molecule; CNS, central nervous system; IL, interleukin; LT, lymphotoxin; MHC,
major histocompatibility complex; MMP, matrix metalloproteinases; NO, nitric oxide; T, T cell; TCR, T-cell receptor; TGF, transforming
growth factor; TNF, tumor necrosis factor. (From Wiendl H, Kieseier BC, Disease-modifying therapies in multiple sclerosis: An update
on recent and ongoing trials and future strategies. Expert Opin Investig Drugs 2003;12:689712, with permission.)
433
FIGURE 262. McDonald diagnostic criteria for MS. MRI evidence of dissemination over time is a gadolinium-enhancing lesion on
a MRI done at least 3 months following onset of clinical attack at a site different from the initial attack, or a gadolinium-enhancing
lesion or new T2-weighted lesion 6 months following onset of clinical attack. Positive CSF is oligoclonal immunoglobulin G bands
in CSF but not serum or elevated immunoglobulin G index. Positive evoked potentials are delayed, but maintain a well-preserved
wave form.
Dissemination in space by MRI evidence of nine or more T2-weighted brain lesions, or two or more cord lesions, or four to eight
brain and one cord lesion, or positive visual evoked potentials with four to eight MRI lesions, or positive visual evoked potentials
with less than four brain lesions plus one cord lesion.
MRI, magnetic resonance imaging; CSF, cerebrospinal uid.
treatment. First, acute relapses are treated with corticos- Pharmacologic Treatment
teroids to speed recovery. Second, disease-modifying therapies
Treatment of Acute Relapses
are used to decrease the number of relapses, prevent permanent
The mechanism of action of corticosteroids used for acute
neurologic damage, and prevent disability. Third, sympto-
relapses is not completely clear, but may involve the following
matic treatment minimizes the impact of MS on quality of life.
actions:
TABLE 261. Diagnostic Tests for MS21 Prevention of inammatory cytokine activation;
Inhibition of T-cell activation;
Test Findings in Multiple Sclerosis
Prevention of immune cells from entering the CNS; and
Magnetic resonance imaging Increased death of activated immune cells.26
T2 weighted Demyelinated plaques, both
active and inactive
Gadolinium enhanced Active demyelinating plaques Corticosteroids hasten functional recovery after
Cerebrospinal uid analysis Oligoclonal bands of relapses.27 Intravenous adrenocorticotropic hormone, intra-
immunoglobulin G venous methylprednisolone, or oral prednisone are used for
Elevated immunoglobulin G index treatment of relapses. Generally, intravenous methylpred-
Evoked potentials Slowed nerve impulse conduction
nisolone is considered the drug of choice for acute relapses.28
CHAPTER 26 / MULTIPLE SCLEROSIS 435
Recent studies show equal efcacy of equivalent doses of Clinical improvement usually begins during corticosteroid
intravenous and oral dosage forms.30,31 Some clinicians are treatment. No standard exists for the administration of an oral
now using oral prednisone for patients experiencing relapses prednisone taper after the intravenous methylprednisolone treat-
to avoid the discomfort, inconvenience, and expense of ment. If a taper is given, it is usually completed over 1 to 2 weeks.
intravenous therapy.
Outcome Evaluation
Monitor the patient for improvement of relapse symptoms.
Adverse Effects Educate the patient regarding possible adverse effects of
Short-term use of corticosteroids is not associated with most acute use of corticosteroids and have her or him report any
of the adverse effects of chronic steroid use. The most com- unexpected occurrences.
mon adverse effects encountered are gastrointestinal upset,
insomnia, and mood swings.28
Disease-Modifying Therapies
Dosing and Administration A number of agents have been used to modify the disease
Methylprednisolone is usually given 1 g/day intravenously as one course of MS. This chapter will focus on the ve agents that
or divided doses for 3 to 5 days. Oral prednisone 1250 mg/day have an indication for use in MS: subcutaneous interferon beta
provides an equivalent dose. 1a (Rebif); intramuscular interferon beta 1a (Avonex); interferon
Clinical Presentation1017
MS symptoms are a function of the position of lesions within the CNS. Because
myelin increases the speed of nerve impulse transmission, demyelination slows the speed
of transmission. No impulses can be transmitted if the axon is transected. The primary
symptoms of MS are caused by this delay or cessation of impulses. Secondary symptoms
of MS result from the primary symptoms.
Frequency Related Secondary
Primary Symptoms of Occurrence Symptoms
Urinary symptoms 90%
Incontinence Decubitus ulcers
Urinary retention Urinary tract infections
Spasticity 60% Falls, care difculties, pain,
gait problems
Visual symptoms
Optic neuritis 55% Falls, care difculties
Diplopia
Bowel symptoms
Incontinence 2951% Decubitus ulcers
Constipation 3554% Pain
Depression 50% Suicide
Cognitive decits 50% Care difculties
Weakness Falls, care difculties, gait problems
Fatigue 7692%
Uhthoffs phenomenon 80%
Sexual dysfunction
Erectile dysfunction 70%
Female sexual dysfunction 72%
Tremor 25%
Pain
Trigeminal neuralgia 2%
Lhermittes sign 9%
Dysesthetic pain 18%
MS Type Definition Patients Affected Example
Relapsing Episodes of acute worsening of neurologic 85%
% Health
Remitting function (relapses) followed by a varying degree
of recovery, with a stable course between attacks
(remissions)
Time
Primary Gradual, nearly continuous, worsening with 10%
% Health
Progressive minor fluctuations but no distinct relapses
Time
Secondary Initial relapsing-remitting disease course 50% of relapsing

Progressive followed by progression with or without remitting patients
% Health
occasional relapses, minor remissions, within 10 years of
and plateaus diagnosis
Time
Progressive Progressive disease from onset, with clear 5%
% Health
Relapsing acute relapses, with or without recovery,
with periods between relapses characterized
by continuing progression
Time
FIGURE 263. Comparison of clinical course of multiple sclerosis by type.
beta 1b (Betaseron); glatiramer acetate (Copaxone); and mitox- Decrease in T-cell activation, decreasing cytokine secretion
antrone (Novantrone). A broad look across all studies of these and preserving myelin;
immunomodulators shows about 30% reduction in relapses.32 Prevention of upregulation of adhesion molecules on activated
T cells, limiting the number of T cells that can get into the brain;
Beta Interferons Suppression of matrix metalloproteinases, maintaining the
Pharmacology and Mechanism of Action The mechanism of integrity of the bloodbrain barrier;
action of beta interferons is complex and not completely under- Decrease in microglial proliferation, preserving myelin;
stood. The following properties are thought to be important to Promotion of formation of Th-2 cells rather than Th-1 cells,
the mechanism of action: decreasing inammation; and
Inhibition of viruses, important if MS has a viral etiology.7,33
Efcacy Patients with relapsing remitting MS: A meta-analysis

Patient Encounter, Part 2 of all beta interferons determined that treated patients were
27% and 19% less likely to have a relapse during the rst and
second years of treatment, respectively, than those who had
CN begins to improve after 2 days of methylprednisolone
1 g intravenously daily. The treatment team wants to begin TABLE 262. Clinical Rating Scales Used in MS23
a disease-modifying treatment.
Expanded Disability Status Scale (EDSS)
Do you agree that she should be on a disease-modifying Rates functional systems from 0 (normal) to 10 (death due to MS)
treatment? Why? Emphasis is on ambulation over other symptoms
If so, which treatment would you choose? Recommend a Multiple Sclerosis Functional Composite (MSFC)
dosing regimen. Three-part tool rating ambulation, limb function, and cognitive
How should the patient be counseled on the chosen treatment? function
Develop a care plan for the patient. Composite score is compared to standardized population
Correlates better with magnetic resonance imaging data than EDSS
TABLE 263. Comparison of Disease-Modifying Therapies27,3840,43,46
Drug Dose Route Frequency Adverse Effects

Interferon beta 1a 30 mcg IM Weekly Flu-like symptoms 61%
(Avonex) Anemia 8%
Interferon beta 1a 44 mcg SQ Three times Flu-like symptoms 28%
(Rebif) per week Injection site reactions 66%
Leukopenia 22%
Increased aspartate aminotransferase/
alanine transaminase 1727%
Interferon beta 1b 0.25 mg SQ Every other day Flu-like symptoms 6076%
(Betaseron) Injection site reactions 5085%
Asthenia 49%
Menstrual disorder 17%
Leukopenia 1016%
Increased aspartate aminotransferase/
alanine transaminase 419%
Glatiramer acetate 20 mg SQ Daily Injection site reaction 90%
(Copaxone) Systemic reaction 15%
Mitoxantrone 12 mg/m2 IV Every 3 months Nausea 76%
(Novantrone) up to 140 mg/m2 Alopecia 61%
Menstrual disorders 61%
Urinary tract infection 32%
Amenorrhea 25%
Leukopenia 19%
-Glutamyl transpeptidase increase 15%
received placebo.34 Early treatment after a rst clinical attack can transiently worsen MS symptoms.39 Injection site reactions
delayed time to a second attack by 9 to 13 months compared to can range from redness to necrosis. There are preventative and
placebo.35,36 Patients with secondary progressive MS who treatment measures for injection site reactions (see Table 264).
experience relapses: Beta interferons have mixed results for At the threshold laboratory values shown in Table 264, inter-
slowing disease progression in secondary progressive MS. The feron should be temporarily discontinued. When values return
MS Therapy Consensus Group states that treatment is most to normal, interferon can be resumed with gradual dose
likely to be effective if clinical relapses or MRI signs of inam- increases and careful monitoring.39 Alpha and gamma interfer-
matory activity are present.37 ons have been associated with depression. MS patients also com-
monly are depressed, even without beta interferon treatment.
Adverse Effects Adverse effects are common with the beta inter- Because of conicting data, it is difcult to determine whether
ferons (Table 263). Commonly, ulike symptoms consist of beta interferons cause or worsen MS-related depression.15
fever, fatigue, muscle aches, malaise, and chills. Symptoms begin
a few hours after the injection and dissipate 8 to 24 hours Neutralizing Antibodies Antibodies to beta interferons can
later.38 Preventive measures can be employed (Table 264). In form over time and reduce the clinical effect of beta interferons.40
temperature-sensitive patients, beta interferoninduced fever The clinical effect of neutralizing antibodies is seen 18 to
TABLE 264. Prevention or Treatment Strategies for Beta Interferon Adverse Effects38,39
Flu-like Symptoms Injection Site Reaction Laboratory Abnormalitiesa

Inject dose in the evening Bring medication to room Hemoglobin less than 9.4 g/dL (94 g/L or 5.8 mmol/L)
temperature White blood cells less than 3 103/mm3 (less than
Begin at 1/4 1/2 dose for 2 Ice injection site prior 3 103/L or less than 3 109/L)
weeks of treatment, then to the injection Absolute neutrophil count less than 1.5 103/mm3
increase to a full dose Rotate injection sites (less than 1.5 103/L or less than 1.5 109/L)
Use ibuprofen 200 mg before If severe, use Platelets less than 75 103/mm3 (less than 75 103/L
and 6 and 12 hours after hydrocortisone 1% or less than 75 109/L)
injection cream on the site Bilirubin greater than 2.5 times baseline
Alternatives to ibuprofen If necrotic: temporarily AST/ALT greater than 5 times baseline
include acetaminophen, discontinue; consult Alkaline phosphatase greater than 5 times baseline
prednisone taper, and dermatologist; do not use
pentoxifylline topical corticosteroids
a
At these threshold values, beta interferon should be temporarily discontinued and laboratory values monitored.
ALT, alanine aminotransferase; AST, aspartate aminotransferase.
24 months after treatment begins.40 Neutralizing antibodies Choosing Therapy There is no consensus on the best medica-
can form against all of the beta interferons, but frequency tion for initial therapy. Comparative beta interferon trials indi-
and route of administration affect neutralizing antibody devel- cate better efcacy with more frequent and/or higher dosing.37
opment: 28% to 47% for subcutaneous interferon beta-1b; This consideration must be balanced with neutralizing anti-
12% to 28% for subcutaneous interferon beta-1a; and 2% to body development and patient acceptance and tolerance.
6% for intramuscular interferon beta-1a.40
Many issues surrounding neutralizing antibodies remain Patient Education Refer to Table 265 for key components of
such as standardization of the neutralizing antibody assay, test- patient education for self-injection.
ing recommendations, and treatment recommendations for
positive tests.41 Neutralizing antibodies may disappear even with Mitoxantrone
continued treatment. Neutralizing antibodies exhibit cross-reac-
tivity with the other beta interferons.41 Pharmacology and Mechanism of Action Mitoxantrone is an
anthracenedione antineoplastic that is indicated for multiple
Dosing and Administration Dose, frequency, and route of sclerosis. The mechanisms of action thought to be important
administration differ between the beta interferon products (see for MS are as follows:
Table 263). Dose-response curves have been observed with the
beta interferons. However, it is not known if the total weekly dose Causes apoptosis in T and antigen-presenting cells, prevent-
or the frequency of administration is most important.37 ing initial T cell activation;
Inhibits DNA and RNA synthesis, decreasing the prolifera-
Glatiramer Acetate tion of T cells, B cells, and macrophages;
Decreases cytokine release, preventing inammation; and
Pharmacology and Mechanism of Action The mechanism of Inhibits macrophages, preventing myelin degradation.45
action of glatiramer acetate is not fully known; however, the
following properties have been observed: Efcacy Mitoxantrone is indicated for secondary progres-
sive MS, progressive relapsing MS, and for patients with
Binds to MHC class II, blocking the activation of T cells; worsening relapsing remitting MS. It reduces the clinical
Activates Th-2 cells, preventing inammation; and attack rate and attack-related MRI outcome measures in
Activated Th-2 cells secrete brain-derived neurotrophic factor, patients with relapsing disease. Because of signicant
which may be neuroprotective.7,33 potential for toxicities, mitoxantrone should be reserved for
patients with rapidly advancing disease who have failed other
Efcacy Glatiramer acetate reduces relapses by 28% each year therapies.27
compared to placebo. Additionally, relapses occurred later
compared to placebo (322 days versus 219 days).42 Adverse Effects Adverse effects are seen regularly in patients given
mitoxantrone (see Table 263). Patients often experience bluish
Adverse Effects Patients commonly report pain, redness, itch- discoloration of the sclera and the urine for 24 hours after infu-
ing, swelling, and bruising at injection sites (see Table 263). sion.46 Transient leukopenia and neutropenia are common with
Icing the injection site before and after the injection improves a nadir 10 to 14 days after the infusion. Patients should avoid
these reactions. If the patient experiences signicant pain at exposure to infectious individuals during this time.46 Patients
the injection site, topical anesthetics can be used. The systemic taking mitoxantrone should not receive live virus vaccines; other
reaction may involve ushing, chest tightness, palpitations, vaccines should be held for 4 to 6 weeks after a mitoxantrone
anxiety, and shortness of breath. This reaction usually occurs dose.46 Amenorrhea, caused by a direct toxic effect on the ovary,
within 30 minutes of the injection and lasts no longer than may be permanent, an important consideration because the MS
30 minutes. Many patients may experience this reaction population includes women of childbearing potential.27
only once. If desired, doses can be reduced by 75% for the
week following the reaction, then increased by 25% per TABLE 265. Patient Education for Self-Injection
week until the patient returns to the full dose.43
Keep all non-refrigerated supplies together and out of the reach of
Issues with Self-Injected Disease-Modifying Therapies children and pets
Allow medications to warm to room temperature
Wash hands thoroughly
Adherence Adherence and continuation of these injectable Choose injection site, rotating between sites
medications can be a signicant problem. Overall, there is no Ice area to be injected for no more than 15 minutes, if desired
signicant difference between the rates of discontinuation for Clean injection site thoroughly with alcohol or soap and water
the products (17% to 41%). The main reasons for discontin- Administer injection
uation are adverse effects and lack of efcacy. Realistic expec- Ice injection site for no more than 15 minutes after injection, if
desired
tations regarding therapy improve adherence rates.44
Cardiotoxicity is a serious, rare adverse effect of mitox-

antrone. The incidence of congestive heart failure was 0.15% in Patient Encounter, Part 3
patients with normal left ventricular ejection fraction and
2.18% in those who had asymptomatic left ventricular ejection
fraction of less than 50% at baseline.46 Therefore, mitoxantrone
After 3 years of treatment, CN has had one additional
should not be used in patients with baseline cardiomyopathy,
relapse, but otherwise is doing fairly well. At her routine
even if asymptomatic. The risk of cardiotoxicity is dose-related. clinic appointment, she describes some difculty walking
The maximum lifetime dose of mitoxantrone is 140 mg/m2, or due to leg spasticity and urinary incontinence episodes that
about 3 years of MS therapy. The use of cyclooxygenase-2 occur about twice a week.
inhibitors should be avoided in patients receiving mitoxantrone
because of a potential for worsening cardiac toxicity.46 What treatment options are available for spasticity, and
Acute myelogenous leukemia has been observed in 0.07% which would you choose?
of MS patients treated with mitoxantrone.46 This form of acute Should this patients incontinence be treated?
leukemia appears within 2 to 4 years of initiating mitoxantrone If so, what medication would you recommend?
and is generally responsive to standard antileukemic therapy. Recommend a dosing regimen and monitoring plan.
Dosing and Administration Mitoxantrone is infused intra-

venously over 30 minutes to reduce the chance of cardiotoxi- these will be discussed in more depth. Other important symp-
city.46 Mitoxantrone is administered every 3 months, if cardiac toms such as urinary incontinence, pain, and depression, are
function and laboratory values are normal (Table 266). discussed only briey because there are other chapters in this
text devoted to the management of these symptoms.
Monitoring Disease-Modifying Therapies
Fatigue
Assess the patient periodically for changes in primary or sec- There are nonpharmacologic and pharmacologic strategies
ondary symptoms. for decreasing the impact of fatigue on the lifestyle of MS
Monitor the patient for adverse effects according to the spe- patients (Table 267). Pharmacologic management of fatigue
cic medication (see Tables 263 and 266). may include amantadine or stimulants; however, evidence of
Assess regularly for adherence with appointments and all efcacy from randomized controlled trials is limited.
components of therapy.
Spasticity
Symptomatic Therapies The goals of treating spasticity can be patient-specic. For
MS patients develop many symptoms that require treatment. ambulatory patients, reducing spasticity may improve mobility.
The symptoms most unique to MS are fatigue and spasticity; For bed-bound patients, treating spasticity may relieve pain and
TABLE 266. Monitoring Disease-Modifying Therapies
Therapy Tests Frequency

Beta interferons Complete blood count, Baseline, 46 weeks, 12 weeks,
(Avonex, bilirubin, electrolytes, then every 3 months
Betaseron, AST, ALT, -glutamyl
Rebif) transferase, alkaline
phosphatase
EDSS, MSFC, neurologic Every 3 months during the rst year
history and examination of therapy then every 6 months
Mitoxantrone Complete blood count, bilirubin, Before each infusion
(Novantrone) AST, ALT, alkaline phosphatase,
pregnancy test
Electrocardiogram Baseline
Echocardiogram or multiple gated Baseline and every 612 months;
acquisition (MUGA) scan prior to each infusion after
100 mg/m2
EDSS, MSFC, neurologic history Every 3 months during the rst year
and examination of therapy then every 6 months
Glatiramer acetate EDSS, MSFC, neurologic history Every 3 months during the rst year
(Copaxone) and examination of therapy then every 6 months
ALT, alanine aminotransferase; AST, aspartate aminotransferase; EDSS, Expanded Disability Status Scale;
MSFC, Multiple Sclerosis Functional Composite.
TABLE 267. Pharmacologic and Nonpharmacolgic Treatments for Fatigue47
Nonpharmacologic Pharmacologic
Appropriate rest:activity ratio First-line therapies:
Use of assistive devices to conserve energy Amantadine 100 mg orally every morning
Environmental modications to make and early afternoon
activities more energy-efcient Modanil 200 mg orally daily
Cooling strategies to avoid the fatigue Second-line therapies:
caused by elevations in core body temperature Pemoline 75140 mg/day divided into
due to heat, exercise-related exertion, and fever 23 doses
Regular aerobic exercise, geared to the Methylphenidate 1020 mg every morning
persons ability, to promote cardiovascular and noon
health, strength, improved mood, and
reduce fatigue
Stress management techniques
ease transfers and care. Physical therapy is a nonpharmacologic caused by neurogenic detrusor overactivity. First-line treatment
treatment for spasticity.11 is anticholinergics such as oxybutynin, tolterodine, avoxate, or
MS patients usually have upper motor neuron spasticity. tricyclic antidepressants with antimuscarinic properties.
This type of spasticity cannot be treated with muscle relaxants Bowel symptoms in MS patients can include both fecal
such as carisoprodol. MS patients must be treated with incontinence and constipation. Fecal incontinence is difcult
agents specic for upper motor neuron spasticity (Table 268).48 to treat. Some patients may have improvement if they use a
MS spasticity is classied as focal or generalized. If the spas- regular schedule for emptying the bowel with laxative sup-
ticity primarily involves only one muscle group, it is focal and positories or enemas. Alternatively, antidiarrheal medications
may benet from botulinum toxin administration.11 Systemic such as loperamide can be used.14
medications are used for generalized spasticity. No clear con- Desipramine and sertraline are efcacious for MS-related
clusion can be reached regarding the superiority in efcacy of depression.15 If beta interferon treatment appears to be caus-
one antispasticity agent over another; medication selection is ing depression, discontinuation could be considered.
usually based on adverse effects (see Table 268).11,48 Phosphodiesterase 5 inhibitors such as sildenal are effec-
tive for MS-induced erectile dysfunction.14 In women, vaginal
dryness or dyspareunia may respond to lubricating jellies.
Other Symptoms
Two types of urinary tract symptoms are commonly seen in MS: Outcome Evaluation
incomplete bladder emptying and incontinence. Incomplete Assess patient for improvement of primary and secondary
bladder emptying is due to dyscoordination of the external ure- symptoms.
thral sphincter and detrusor activity.14 Most patients who Monitor for adverse effects of prescribed medications.
develop this condition require intermittent or permanent uri- Monitor for adherence with regimen.
nary catheterization.14 Incontinence in most MS patients is Monitor for emergence of symptoms of depression
TABLE 268. Comparison of Antispasticity Agents11
Place in Therapy Medication Mechanism of Action Dose

First-line Baclofen Pre- and postsynaptic 5 mg orally three times daily,
-aminobutyric acid increase by 5 mg/dose every 3 days to a
receptor blocker maximum of 80 mg/day
Tizanidine Centrally-acting 2-receptor agonist 4 mg orally daily, increase by 24 mg 34 times
daily to a maximum of 36 mg/day
Second-line Dantrolene Direct inhibitor of muscle 25 mg orally daily, increase to 25 mg 34 times
contraction by decreasing the daily, then increase by 25 mg every 47 days
release of calcium from skeletal to a maximum of 400 mg/day
muscle sarcoplasmic reticulum
Diazepam -Aminobutyric acid agonist 210 mg orally 34 times/day
Third-line Intrathecal baclofen Pre- and postsynaptic -aminobutyric Titrated individually, usual range 62749 mcg/day
acid receptor blocker
Focal spasticity Botulinum toxin Prevents release of acetylcholine Individualized
in the neuromuscular junction
MHC: major histocompatibility complex

Patient Care and Monitoring MMP: matrix metalloproteinase
MRI: magnetic resonance imaging
MS: multiple sclerosis
MSFC: Multiple Sclerosis Functional Composite
1. Once diagnosed, work with the patient to select either a MUGA: multiple gated acquisition
beta interferon or glatiramer acetate, considering: NO: nitric oxide
TCR: T-cell receptor
Route of administration TGF: transforming growth factor
Frequency of administration Th-1: T helper-1 cells
Adverse-effect prole and other concerns (e.g., neutralizing Th-2: T helper-2 cells
antibodies and concomitant depression) TNF: tumor necrosis factor
2. Obtain the required baseline laboratory studies Reference lists and self-assessment questions and answers are
(Table 266). available at www.ChisholmPharmacotherapy.com.
3. Educate the patient regarding self-injection (Table 265).
4. Assess the patient for symptomatic treatment needs. Log into the website: www.pharmacotherapyprinciples.com
5. Initiate needed symptomatic treatments. for information on obtaining continuing education credit for
6. Refer the patient to the National MS Society for information,
this chapter.
newsletters, and local support groups (www.nmss.org).
7. Instruct the patient to contact the clinician for any sud-
den changes in symptoms that may suggest a relapse. KEY REFERENCES AND READINGS
8. Monitor the patient for efcacy and adverse effects of
Bayas A, Reickmann P. Managing the adverse effects of interferon-
disease-modifying and symptomatic therapies every
therapy in multiple sclerosis. Drug Saf 2000;22:149159.
3 months for the rst year and every 6 months thereafter
Cohen BA, Mikol DD. Mitroxantrone treatment of multiple sclerosis:
and as required for selected therapy (Table 266).
safety considerations. Neurology 2004;63:S28S32.
9. Treat any relapses with methylprednisolone intravenously DasGupta R, Fowler CJ. Bladder, bowel and sexual dysfunction in
or prednisone orally. multiple sclerosis: management strategies. Drugs 2003;63:
153166.
Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying
therapies in multiple sclerosis: report of the Therapeutics and
Technology Assessment Subcommittee of the American
ABBREVIATIONS Academy of Neurology and the MS Council for Clinical Practice
Guidelines. Neurology 2002;58:169178.
Abs: autoantibodies Hartung HP, Bar-Or A, Zoukos Y. What do we know about the mech-
ALT: alanine aminotransferase anism of action of disease-modifying treatments in MS? J Neurol
APC: antigen-presenting cell 2004; 251(Suppl 5):V/12V/29.
AST: aspartate aminotransferase Hartung HP, Munschauer F, Schellekens H. Signicance of neu-
BBB: bloodbrain barrier tralizing antibodies to interferon beta during treatment of mul-
CAM: cellular adhesion molecule tiple sclerosis: expert opinions based on the Proceedings of an
CNS: central nervous system International Consensus Conference. Eur J Neurol 2005;12:
CSF: cerebrospinal uid 588601.
EDSS: Expanded Disability Status Scale McDonald WI, Compston A, Edan G, et al. Recommended diagnos-
HHV-6: human herpesvirus 6 tic criteria for multiple sclerosis: guidelines from the interna-
IL: interleukin tional panel on the diagnosis of multiple sclerosis. Ann Neurol
LT: lymphotoxin 2001;50:121127.
27 EPILEPSY
Timothy E. Welty and Edward Faught
LEARNING OBJECTIVES
1. Describe the epidemiology and social impact of epilepsy.

2. Dene terminology related to epilepsy, including seizure, convulsion, and epilepsy.
3. Describe the basic pathophysiology of seizures.
4. Describe the basic pathophysiology of epilepsy.
5. Differentiate and classify seizure types when provided a description of the clinical
presentation of the seizure and electroencephalogram.
6. Identify key therapeutic decision points in the treatment of epilepsy.
7. Establish therapeutic goals for pharmacotherapy in a patient with epilepsy.
8. Discuss nonpharmacologic treatments for epilepsy.
9. Recommend an appropriate pharmacotherapeutic regimen for the treatment of epilepsy.
10. Select appropriate monitoring parameters for a pharmacotherapeutic regimen of epilepsy.
11. Devise a plan for switching a patient from one antiepileptic regimen to a different
regimen.
12. Recognize complications of pharmacotherapy for epilepsy.
13. Analyze potential drug interactions with antiepileptic drugs.
14. Determine when and how to discontinue antiepileptic drug therapy.
15. Educate a patient or caregiver on epilepsy and pharmacotherapy for this disorder.
KEY CONCEPTS acute adverse effects, chronic adverse effects, and possible
drug interactions.
A distinction between convulsions, a single seizure, pseudo- Antiepileptic drug therapy should usually be initiated
seizure, and epilepsy should be made in patients presenting carefully using a titration schedule to minimize adverse
with possible seizures. events.
Selection of appropriate pharmacotherapy is dependent upon Changes in antiepileptic drug regimens should be done in a
distinguishing, identifying, and understanding different stepwise fashion, keeping in mind drug interactions that may
seizure types. be present and necessitate dosage changes in concomitant
Prior to starting pharmacologic therapy, it is essential to deter- drugs.
mine the risk of the patient having a subsequent seizure. Discontinuation of antiepileptic drugs should be done gradu-
Mechanisms of action, effectiveness for specic seizure types, com- ally, only after the patient has been seizure-free for 2 to 5 years
mon adverse effects, and potential for drug interactions are key ele- and with careful consideration of factors predictive of seizure
ments in selecting medications for individual patients. recurrence.
Patients receiving antiepileptic drugs for seizures should have Children and women with epilepsy have unique problems
regular monitoring for seizure frequency, seizure patterns, related to the use of antiepileptic drugs.
443
EPIDEMIOLOGY, SOCIAL IMPACT, Isolated seizures that are not epilepsy can be caused by stroke,
AND ETIOLOGY central nervous system trauma, central nervous system infections,
metabolic disturbances (e.g., hyponatremia and hypoglycemia),
Epidemiology and hypoxia. If these underlying causes of seizures are not cor-
rected, they may lead to the development of recurrent seizures
Epilepsy is a disorder that aficts approximately 2 million indi- or epilepsy. Medications can also cause seizures. Some drugs that
viduals in the United States, with an age-adjusted prevalence of are commonly associated with seizures include tramadol,
approximately 4 to 7 cases per 1000 persons.1 The incidence of bupropion, theophylline, some antidepressants, some antipsy-
epilepsy in the United States is estimated at 35 to 75 cases per chotics, amphetamines, cocaine, imipenem, lithium, excessive
100,000 persons per year, which is similar to that of other devel- doses of penicillins or cephalosporins, and sympathomimetics
oped countries.2,3 In developing countries, the incidence is or stimulants.
higher at 100 to 190 cases per 100,000 persons per year, possibly
related to poor health care and prenatal care, increased risk of
neurologic trauma, and increased rates of infections. About 8%
of the United States population will experience a seizure during PATHOPHYSIOLOGY
their lifetime. New-onset seizures occur most frequently in
infants below 1 year of age and in adults after age 55.4 However, Seizures
the largest number of patients suffering from epilepsy is between Regardless of the underlying etiology, all seizures involve a sud-
the ages of 15 and 64 years. den electrical disturbance of the cerebral cortex. A population
of neurons res rapidly and repetitively for seconds to minutes.
Social Impact Cortical electrical discharges become excessively rapid, rhyth-
mic, and synchronous. This phenomenon is presumably related
Epilepsy is a disorder with profound impact on a patients to an excess of excitatory neurotransmitter action, a failure of
lifestyle. All states limit driving for individuals who have recently inhibitory neurotransmitter action, or a combination of the
had a seizure with impaired consciousness and restrictions vary two. In the individual patient, however, it is usually impossible
from state to state.5 Patients who live in communities without to identify which neurochemical factors are responsible.
adequate public transportation face major impediments to sim-
ple activities of daily life, such as purchasing groceries or getting
to a job. Education is also problematic for patients with Neurotransmitters
epilepsy.6,7 Individuals with persistent seizures have poor school The major excitatory neurotransmitter in the cerebral cortex is
attendance. Fifty percent of patients with epilepsy complain of glutamate.9 When glutamate is released from a presynaptic
cognitive difculties and believe their seizures interfere with neuron, it attaches to one of several receptor types on the post-
learning. Additionally, patients with epilepsy score 50% lower on synaptic neuron. The result is opening of membrane channels
standardized examinations and have lower graduation rates to allow sodium or calcium to ow into the postsynaptic neu-
from high school and college. Transportation and educational ron, thus depolarizing it and transmitting the excitatory signal.10
difculties combine with persistent seizures to cause patients Many antiepileptic drugs (e.g., phenytoin, carbamazepine,
with epilepsy to be unemployed or underemployed. Thus, this and lamotrigine) work by interfering with this mechanism,
group of patients faces multiple nancial difculties and often either by blocking the release of glutamate or by blocking the
does not have health insurance. sodium or calcium channels, thus preventing excessive excita-
Finally, patients with epilepsy are often dependent upon care- tion.11 These drugs typically do not block normal neuronal
givers to assist with medications, transportation, and ensuring signaling, only the excessively rapid ring characteristic of a
their safety. Caregivers should be informed of the patients med- seizure. For this reason they do not usually affect normal brain
ical needs and how to assist should a seizure occur. function.
The major inhibitory neurotransmitter in the cerebral cor-
tex is -aminobutyric acid (GABA). It attaches to neuronal
Etiology
membranes and opens chloride channels. When chloride
For nearly 80% of patients with epilepsy, the underlying etiology is ows into the neuron, it becomes hyperpolarized and less
unknown.8 The most common recognized causes of epilepsy are excitable. This mechanism is probably critical for shutting off
head trauma and stroke. Developmental and genetic defects are the seizure activity by controlling the excessive neuronal ring.
cause of about 5% of cases of epilepsy. Central nervous system Some antiepileptic drugs, primarily barbiturates and benzodi-
(CNS) tumors, central nervous system infections, and neurodegen- azepines, work by enhancing the action of GABA.
erative diseases are other common causes. Other important causes Cortical function is modulated by many other neurotrans-
of epilepsy are human immunodeciency virus infection or neuro- mitters. However, their role in the pathophysiology of epilepsy
cysticercosis infection, primarily occurring in Latin America. and in the action of antiepileptic drugs is not yet well known.
CHAPTER 27 / EPILEPSY 445
Neuronal Mechanisms inhibitory connections, making the occurrence of future

Seizures originate in a group of neurons which do not have nor- seizures more likely. Additionally, epilepsy is associated with an
mal electrical behavior.12 Individual neuronal ring is prolonged increased mortality rate.13 For these reasons, an argument can be
and repetitive. This long, abnormal depolarization is called a made for controlling epileptic seizures with medications as
paroxysmal depolarizing shift (PDS). early as possible. This may reduce the possibility of permanent
The excessive electrical discharges can spread to other neu- changes in brain function, although this hypothesis is
rons, either adjacent ones or distant ones connected by ber unproven.
tracts. The seizure thus spreads to other areas of the brain,
recruiting them into the uncontrolled ring pattern. The neu- Genetic Factors
rons involved may not be abnormal themselves, but are Patients with seizures may be concerned that their children or
diverted from their normal functioning to participate in the other family members will inherit epilepsy. This fear is usually
wildly excessive discharges. The degree of spread and the loca- unfounded. Patients with acquired causes of seizures, such as
tion of brain areas involved determine the clinical manifesta- head trauma or stroke, will not transmit the problem. There is
tions of the seizure. a group of patients, however, who apparently have epilepsy on
Nearly all seizures stop spontaneously, because after sec- a genetic basis. Most of these individuals have primary gener-
onds to minutes brain inhibitory mechanisms become strong alized epilepsy.14,15 Usually these patients develop seizures
enough to shut off the abnormal excitation. during childhood. However, the hereditary tendency is not
strong. Complex inheritance patterns are usually seen, indi-
cating the likely involvement of several abnormal genes or
Epilepsy other factors for seizures to be clinically expressed in off-
Epilepsy is the tendency to have seizures on a chronic, recur- spring. Thus, most patients can be reassured that their children
rent basis. This implies that there is a permanent change in and siblings are unlikely to develop epilepsy. Increasing num-
cortical function which renders neurons more likely to partic- bers of epilepsy syndromes are being identied as being of
ipate in a seizure discharge. This process is referred to as genetic origin, and once the specic genes are identied it may
epileptogenesis, and the exact way in which it occurs is not be possible to target drug therapies more specically toward
known. A process thought to be similar to epileptogenesis in individual biochemical defects.
humans occurs after prolonged, intermittent electrical stimu-
lation of animal brains and is known as kindling. Epilepsy may
develop days, months, or many years after an insult to the cor-
SEIZURE CLASSIFICATION AND PRESENTATION
tex. It may be that an originally small group of abnormal neu-
rons causes adjacent or connected neurons to gradually
General Principles
become abnormal as well, by bombarding them over time with Careful diagnosis and identication of seizure types is essential to
frequent, repeated electrical impulses. When the network of proper treatment of epilepsy. Numerous schemes and descrip-
abnormal neurons becomes sufciently large, it becomes capa- tions of seizures exist, but the International League Against
ble of sustaining an excessive ring pattern for at least several Epilepsy (ILAE) has established the currently accepted standard
seconds: a seizure. This hyperexcitable network of neurons is for classifying epileptic seizures (Fig. 271) and epilepsies or
then the seizure focus. epilepsy syndromes (Table 271).16,17 Classication of epileptic
If the change in cortical electrical characteristics is perma- seizures is based upon electroencephalographic (EEG) ndings
nent, why dont seizures occur all the time? This is probably combined with the clinical ndings or semiology of the seizure
because the occurrence of an individual seizure depends upon events. Clinical presentations of seizures vary widely, depending
an interplay of environmental and internal brain factors which on the region and amount of brain involved in the seizure.
from time to time result in loss of the normal mechanisms that
contain and control abnormal neuronal ring. Some common
Primary Generalized Seizures
factors are sleep loss and fatigue, but it is impossible to deter-
mine what sets off a particular seizure in most patients. If the entire cerebral cortex is involved in the seizure from the
In some patients, epilepsy worsens over time, with the onset of the seizure, the seizure is classied as primary gener-
seizures becoming more frequent as patients grow older. This alized. The following are types of primary generalized
does not occur in most patients with epilepsy. In those so seizures.
affected, it is possible that the seizures themselves may cause
some damage to the cortex; loss of neurons, especially Tonic-clonic: Characterized by a sudden loss of conscious-
inhibitory neurons, has been demonstrated in tissue from ness accompanied by tonic extension and rhythmic clonic
seizure foci. Other changes occur in brain areas affected by contractions of all major muscle groups. The duration of the
seizures: reorganization of connections between groups of neu- seizure is usually 1 to 3 minutes. These seizures are often
rons may strengthen excitatory connections and weaken described as grand mal.
FIGURE 271. International League Against

Seizures Epilepsy classication of epileptic seizures.
Data from reference 16.
Primary Generalized Partial
Tonic-Clonic Simple
(No altered consciousness)
Absence Complex
(Altered consciousness)
Myoclonic Secondarily Generalized
Atonic
Absence: Sudden and brief (i.e., several seconds in duration) will fall when they are not lying down or sitting in a chair.
losses of consciousness without muscle movements. These These seizures may be described as falling out.
seizures are often described as daydreaming or blanking out
episodes. A common term for these seizures is petit mal.
Partial Seizures
Myoclonic: Single and very brief jerks of all major muscle
groups. Patients with these may not lose consciousness, due When the seizure begins in a localized area of the brain, it is
to the seizure lasting less than 3 to 4 seconds. Patients may dened as partial. There are three types of partial seizures in
describe these seizures as shoulder shrugs or spinal chills. the current classication system.
Myoclonic seizures may cluster and build into a generalized
tonic-clonic seizure. Simple: The patient will have a sensation or uncontrolled
Atonic: The patient loses consciousness and muscle tone. muscle movement of a portion of their body without an
No muscle movements are typically noted, and the patient alteration in consciousness. The type of sensation or move-
ment is dependent on the location of seizure in the brain.
TABLE 271. International League Against Epilepsy Classication Complex: Although the seizure is localized in a specic area
Scheme for Epilepsies and Epilepsy Syndromes of the brain, like a simple partial seizure, this seizure causes
an alteration in the patients level of consciousness.
I. Localization-related (focal, local, or partial) epilepsies and Secondarily generalized: Seizures that start as a simple or
epileptic syndromes complex partial seizure and spread to involve the entire
A. Idiopathic with age-related onset
1. Benign childhood epilepsy with centrotemporal spikes
brain. Patients may report a warning or aura, and these are
2. Childhood epilepsy with occipital paroxysms actually the start of the seizure.
B. Symptomatic
II. Generalized epilepsies and epileptic syndromes
A. Idiopathic and age-related onset Epilepsy Syndromes
1. Benign neonatal epilepsy
Classication of epilepsies and epilepsy syndromes is helpful
2. Childhood absence epilepsy (pyknolepsy)
3. Juvenile myoclonic epilepsy (impulsive petit mal) in determining appropriate pharmacotherapy. This classica-
4. Juvenile absence epilepsy with generalized tonic-clonic tion scheme is based on the type of seizures a patient has and
seizure on awakening an attempt to identify the etiology of the epilepsy or epilepsy
B. Secondary (idiopathic or symptomatic) syndrome.
1. West syndrome (infantile spasms)
2. Lennox-Gastaut syndrome
C. Symptomatic Idiopathic epilepsies: These syndromes are thought to be due
1. Nonspecic etiology (early myoclonic encephalopathy) to genetic alterations, but the underlying etiology is not
2. Specic syndromes (epileptic seizures that may complicate identied. Neurologic functions are completely normal
many diseases, e.g., Ramsay-Hunt syndrome, Unverrichts apart from the occurrence of seizures.
disease)
Symptomatic epilepsies: There is an identiable cause for the
Data from reference 17. seizures, such as trauma or hypoxia.
Cryptogenic epilepsies: In these epilepsies the seizures are the

Clinical Presentation and Diagnosis result of an underlying neurologic disorder that is often ill-
dened or undocumented. Neurologic functions are often
abnormal or developmentally delayed in patients with cryp-
General togenic epilepsies.
Typically, health care providers are not able to observe a
patients seizures, and for most types of seizures the patient A complete description of a patients epilepsy should
has no memory of the event. It is important to obtain a include the seizure type with the epilepsy or syndrome type
careful history from the patient and any individuals who (i.e., idiopathic, symptomatic, or cryptogenic).
witnessed the seizures. Commonly encountered epilepsy syndromes are:
Common Descriptions of Seizures
The clinical presentation of seizures will vary from patient Juvenile myoclonic epilepsy (JME): A primary generalized
to patient depending on the portion of brain involved in the epilepsy syndrome that usually starts in the early to middle
seizure. Events will tend to be stereotypical for an individ- teenage years and has a strong familial component. Patients
ual patient. have myoclonic jerks and tonic-clonic seizures and may also
Patients who experience seizures may complain of paroxys- have absence seizures.
mal spells of: Lennox-Gastaut syndrome (LGS): Patients with this syn-
Blanking out spells, lapses in memory, periods of altered drome have cognitive dysfunction and mental retardation.
consciousness Their seizures usually consist of a combination of tonic-
Warnings or auras consisting of various sensations or clonic, absence, atonic, and myoclonic seizures.
automatic, uncontrolled movements Mesial temporal lobe epilepsy (MTLE): A type of epilepsy that
Daydreaming consists of partial seizures arising from the mesial temporal
Jerks, shoulder shrugs, and sudden chills of the spine lobe of the brain. Often this type of epilepsy is associated
Falling out with an anatomic change described as hippocampal sclero-
Associated Symptoms sis. Patients with this type of epilepsy often have excellent
Incontinence, usually of urine outcomes with surgery for epilepsy.
Tongue biting Infantile spasms: A seizure syndrome that occurs in infants
Traumatic injuries, usually associated with falling during
less than 1 year of age. It is characterized by a specic EEG
a seizure
pattern and spasms or jitters and is also known as Wests
Diagnosis syndrome. Infants with infantile spasms often develop other
Description of events: The patient and any witnesses to the
seizure types and epilepsies later in life.
seizures should be carefully interviewed to obtain a full and
complete description of typical seizures.
Neurologic examination: Usually, the neurologic physical
Other Classications
examination is completely normal. Any neurologic decits that The ILAE is proposing a new classication system that
are identied should be fully investigated, because seizures do improves the description of the seizure type and epilepsy.18,19
not usually cause permanent, detectable neurologic decits. The proposed scheme revolves around ve axes:
Electroencephalogram
A routine EEG can be helpful if epileptiform discharges are Axis 1: description of the seizure event
seen. However, the EEG may be normal between seizures, Axis 2: epileptic seizure type or types
and most routine EEGs are not performed during a seizure.
Axis 3: any syndrome type
Maneuvers such as sleep deprivation, photic stimulation,
Axis 4: etiology when known
hyperventilation, or prolonged monitoring can help reveal
EEG changes consistent with epilepsy. Axis 5: degree of impairment by the epilepsy.
Neuroimaging (preferably a magnetic resonance imaging
[MRI] scan of the brain): Imaging of the brain is important This classication system is undergoing nal review and
to rule out obvious causes of seizures such as stroke or should become the standard in the near future.
tumors. An MRI is also helpful in detecting mesial temporal
sclerosis, a nding often associated with mesial temporal Diagnosis
lobe epilepsy and predictive of positive surgical outcomes.
Video-EEG monitoring: A procedure consisting of continuous Determining a correct and accurate diagnosis is essen-
video monitoring of the patient with a simultaneous EEG. tial prior to any consideration of pharmacotherapy. When a
Usually a patient is monitored in the hospital for 4 to 5 days. patient complains of paroxysmal, stereotypical spells that may
This procedure is used to determine if the patient is truly be seizures, it must be determined if the spells are really
having seizures, to determine the specic type of seizures seizures. Numerous other disorders, including syncope, psy-
the patient is having, and to localize the area of the brain chogenic nonepileptic events (i.e., pseudoseizures), anxiety
that is the origin for the seizures. attacks, cardiac arrhythmias, hypoglycemia, transient ischemic
attacks, tics, and complicated migraine headaches, are often Structural CNS lesion
mistaken for seizures by patients and caregivers. Abnormal EEG
A proper diagnostic workup of a patient presenting with Partial seizure type
seizures should include the following elements: Positive family history
Postictal motor paralysis21
Thorough neurologic examination
Electroencephalogram If no risk factors are present, the risk of another seizure is 10%
Laboratory tests (CBC, LFT, and serum chemistry) to 15%. However, if two or more risk factors are present, the
Neuroimaging (preferably magnetic resonance imaging) risk of another seizure is 100%.
When sufcient evidence is available to determine that the
Patients with epilepsy may have completely normal ndings in patient has real seizures and is at risk for another seizure,
these assessments. Many of the tests are done to rule out other pharmacotherapy is usually started (Fig. 272). The patient
causes of seizures (e.g., infection or electrolyte imbalance). should be in agreement with the plan, be willing to take the
Often the EEG appears normal between seizures.20 Several medication, and be able to monitor seizure frequency and
manipulations can be done in an attempt to capture seizure or adverse drug effects in some way. Design of an appropriate
seizure-like activity on the EEG. These include sleep deprivation, pharmacotherapeutic plan is based on the patients seizure
photic stimulation, prolonged (greater than 20 minutes) EEG type, the common adverse-effect prole of possible AEDs, and
recording, and 24-hour EEG monitoring with video correlation. economic factors (e.g., cost of the drug, insurance formulary,
and ability to pay). Other patient factors such as gender, con-
comitant drugs, age, and lifestyle also need to be considered.
TREATMENT
Nonpharmacologic Treatment
Desired Outcomes
Several nonpharmacologic treatments for epilepsy are avail-
The ultimate outcome goal for any patient with epilepsy is
able. For some patients, surgery is the treatment approach with
elimination of all seizures without any adverse effects of the
the greatest probability of achieving a seizure-free state.22 The
treatment. An effective treatment plan would allow the patient
most common surgical approach for epilepsy is temporal
to pursue a normal lifestyle with complete control of seizures.
lobectomy. When the seizure focus can be localized and it is in
Specically, the treatment should enable the patient to drive,
a region of the brain that is not too close to critical areas, such
perform well in school, hold a reasonable job, and function
as those responsible for speech or muscle control, surgical
effectively in the family and community. However, due to the
removal of the focus can result in 80% to 90% of patients
intractability of the seizures or sensitivity to antiepileptic drugs
becoming seizure-free. According to a National Institutes of
(AEDs), many patients are not able to achieve these outcomes.
Health Consensus Conference, three criteria should be met for
In these cases, the goal of therapy is to provide a tolerable bal-
patients to be candidates for surgery.23 These criteria are a def-
ance between reduced seizure severity and/or frequency and
inite diagnosis of epilepsy, failure of adequate drug therapies,
medication adverse effects that optimizes the individuals abil-
and denition of the electroclinical syndrome (i.e., localization
ity to have a lifestyle as nearly normal as possible.
of the seizure focus in the brain). Other surgical procedures,
that are less likely to make a patient seizure-free, include cor-
General Approach to Treatment pus callosotomy and extra-temporal lesion removal.
Vagal nerve stimulation is another nonpharmacologic
Once it is concluded that the patient has seizures, the type approach to treating seizures.24 In this treatment, a unit that
of seizure and epilepsy syndrome, if any, must be determined.
generates an intermittent electrical current is placed under the
Proper identication and classication of the seizure type is most
skin in the chest. A wire is tunneled under the skin to the left
helpful in selecting appropriate pharmacotherapy. Without an
vagus nerve in the neck. The unit generates a small electrical
accurate classication of the seizure type, it is possible to select a
current that stimulates the vagus nerve every 5 minutes.
medication that is ineffective or even harmful to the patient.
Additional stimulations can be initiated by the patient swiping
Additionally, the risk of a subsequent seizure must be a magnet over the device located in the chest. This treatment
determined. If there is an underlying treatable cause, such as approach is essentially equivalent in efcacy to starting a new
hyponatremia or a CNS infection, the risks of another seizure medication, but the precise mechanism for its effect has not
and the development of epilepsy are very small. In these cases, been elucidated. Approximately 25% to 50% of patients who
the only pharmacotherapy that is necessary is to correct the have a vagal nerve stimulator placed will experience at least a
underlying problem and possibly short-term use of an AED. 50% reduction in seizure frequency. However, fewer than 10%
Risk factors for repeated seizures in patients without an become seizure-free. Adverse effects include hoarseness, swal-
underlying disorder include: lowing difculties, tingling or vibration in the neck, infection
FIGURE 272. Treatment algorithm for management of seizure disorders.
or bleeding due to surgery, and rarely laryngeal spasms. Vagal Pharmacologic Therapy
nerve stimulation is usually reserved for patients who do not
respond to several drugs and are not surgical candidates. Special Considerations
One of the oldest nonpharmacologic treatments is the Use of the AEDs presents some unique challenges, some
ketogenic diet. 25 Modern use of the diet was started in the of which relate to their pharmacokinetic properties, which
1920s. This diet produces a ketoacidotic state through the need to be clearly understood.26
elimination of nearly all carbohydrates. To initiate the diet,
patients undergo 24 to 48 hours of fasting until ketones are
detected in the urine. The diet consisting of dietary fats (e.g., Michaelis-Menten Metabolism
butter, heavy cream, and fatty meats) and protein with no Phenytoin metabolism is capacity-limited, meaning the max-
added sugar is started. Daily urinalysis for ketones is per- imum capacity of hepatic enzymes to metabolize the drug is
formed to ensure that the patient remains in ketosis. Any reached within the normal dosage range. This is dened as
inadvertent consumption of sugar results in the need to reini- Michaelis-Menten metabolism or Michaelis-Menten pharma-
tiate the diet. Pharmacists have an important role in main- cokinetics. The clinical signicance is that small changes in
taining the diet, by determining the sugar or carbohydrate doses result in disproportionate and large changes in serum
content of medications the patient is taking. This diet is typ- concentrations. The patient is at risk of sudden toxicity if too
ically used only in children with difcult-to-control seizures. large a dose increase is made, or a breakthrough seizure may
In certain patients the diet can be extremely effective, result- occur if too large a reduction in dose is made. Due to individ-
ing in complete seizure control and reduction of AEDs. ual differences in metabolism, each patient follows a different
However, it is hard to maintain a ketotic state, and palatabil- curve in the relationship between dose and serum concentra-
ity of the diet is a concern. Additionally, there are concerns tions. These differences can be dened only by careful use of
about growth retardation in children and hypercholes- serum concentration and dosing data. There are numerous
terolemia with prolonged use of the diet. schemes for determining appropriate dosage adjustments of
phenytoin, and these are discussed in pharmacokinetics text- 30

books. For routine clinical practice, dosage adjustments for No Titration Titration
adults with normal protein binding of phenytoin and a 25
Serum Concentration
steady-state serum concentration can be made using the fol-
20
lowing plan.
15
For serum concentrations less than 7 mcg/mL (28 mol/L)
10
the total daily dose is increased by 100 mg.
For serum concentrations of 7 to 12 mcg/mL (2848 mol/L) 5
the total daily dose is increased by 50 mg.
For serum concentrations greater than 12 mcg/mL (48 mol/L) 0
1st Week 2nd Week 3rd Week 4th Week
the total daily dose is increased by no more than 30 mg.27
FIGURE 273. Serum concentrations of carbamazepine in the
Protein Binding presence and absence of appropriate dose titration.
Carbamazepine induces its own metabolism, so maintenance
Some AEDs, especially phenytoin and valproate, are highly dose requirements are much greater than starting doses. To
bound to plasma proteins. When interpreting a reported con- avoid excessive adverse effects, starting doses should be 25% to
centration for these drugs, it is important to remember that 30% of the target maintenance doses and increased gradually
the value represents the total (i.e., bound and unbound) con- to the target maintenance dose, usually over 3 to 4 weeks.
centration in the blood. Because of differences in the metabo-
lism of these drugs, the clinical effects of altered protein bind-
ing are different for different drugs. is increased over time to compensate for the enzyme induction
Normally, 88% to 92% of phenytoin is bound to plasma (Fig. 273). Most dosage regimens for carbamazepine call for a
protein, leaving 8% to 12% unbound. The unbound compo- starting dose that is 25% to 30% of the typical maintenance
nent is able to leave the blood to produce the clinical effect in dose of 15 mg/kg per day. The dosage is increased weekly until
the CNS, produce dose-related side effects in the CNS and at the target maintenance dose is achieved within 3 to 4 weeks.
other sites, distribute to other peripheral sites, and be metab- Titration of the carbamazepine dose lessens the risk for severe
olized. Certain patient groups are known to have decreased dose-related adverse effects when carbamazepine is rst started.
protein binding, resulting in an increased percentage of drug
that is unbound. These patient groups include: Drug Selection and Seizure Type
The key to selecting effective pharmacotherapy is to base the
Those with renal failure decision on the seizure type. Several consensus treatment
Those with hypoalbuminemia guidelines from the Scottish Intercollegiate Guidelines
Neonates Network, the National Institute for Clinical Excellence in the
Pregnant women United Kingdom, and the American Academy of Neurology all
Those taking multiple highly protein-bound drugs use determination of seizure type as the basis for selection of
Patients in critical care pharmacotherapy (Table 272).2830 While the guidelines make
recommendations for specic drugs to be used in certain
Due to the Michaelis-Menten metabolism of phenytoin, seizure types, the consensus recommendations utilize only data
alterations in its protein binding will result in increased sever- available from the medical literature. In many cases, a recom-
ity of dose-related adverse effects. In patients with suspected mendation is not made, because there are no published data on
changes in protein binding, it is useful to measure unbound which to make an evidence-based decision. Therefore, a drug
phenytoin concentrations. may not currently be recommended for a seizure type simply
When valproate protein binding is altered, the risk for because it has not been studied for that seizure type. Absence of
severe dose-related adverse effects is much less compared to a recommendation should not be taken to mean that the drug
phenytoin. Michaelis-Menten metabolism is not a factor with is ineffective for a specic seizure type.
valproate, so hepatic enzymes are able to efciently metabo- Outside of the evidence-based guidelines, other pharmaco-
lize the additional unbound portion. logic treatments are commonly used or avoided. For initial
treatment of absence seizures, ethosuximide and valproate are
Autoinduction commonly used, not only in the United Kingdom, but also in
Carbamazepine is a potent inducer of hepatic microsomal the United States. Zonisamide may be also used for initial treat-
enzymes. Not only does it increase the rate of metabolism for ment of absence and myoclonic seizures. In absence and
many other drugs, it increases the rate of its own metabolism. myoclonic seizures, carbamazepine, oxcarbazepine, gabapentin,
Hepatic enzymes become maximally induced over several tiagabine, and pregabalin should be avoided, as they have been
weeks, necessitating a small initial dose of carbamazepine that associated with an exacerbation of these types of seizures.
TABLE 272. Evidence-Based Guidelines for Initial Monotherapy Treatment of Epilepsy
United Kingdom National

American Academy Scottish Intercollegiate Institute for Clinical
Seizure Type of Neurology Guidelines Network Excellence
Primary generalized Carbamazepinea Lamotrigine Carbamazepine
tonic-clonic Lamotriginea Valproate Lamotrigine
Oxcarbazepinea Topiramate
Phenobarbitala Valproate
Phenytoina Second-line:
Topiramatea Clobazamb
Valproatea Levetiracetam
Oxcarbazepine
Absence Lamotrigine Ethosuximide Ethosuximide
(children) Lamotrigine Lamotrigine
Valproate Valproate
Second-line:
Clobazamb
Clonazepam
Topiramate
Myoclonic Not mentioned Lamotrigine Valproate
Valproate Topiramate
(children with
severe myoclonic
epilepsy of infancy)
Second-line:
Clobazamb
Clonazepam
Lamotrigine
Levetiracetam
Piracetamb
Topiramate
Tonic Not mentioned Not mentioned Lamotrigine
Valproate
Second-line:
Clobazamb
Clonazepam
Levetiracetam
Topiramate
Atonic Not mentioned Not mentioned Lamotrigine
Valproate
Second-line:
Clobazamb
Clonazepam
Levetiracetam
Topiramate
Partial with or Carbamazepine Phenytoin Carbamazepine
without Gabapentin Carbamazepine Lamotrigine
secondary Lamotrigine Valproate Oxcarbazepine
generalization Oxcarbazepine Lamotrigine Valproate
Phenobarbital Oxcarbazepine Topiramate
Phenytoin Second-line:
Topiramate Clobazamb
Valproate Gabapentin
Levetiracetam
Phenytoin
Tiagabine
a
Based upon data from newly diagnosed epilepsy patients of multiple seizure types.
b
Not currently available in the United States.
Data from references 27, 28, 29, 30.
effects occur with AEDs: dose-related (Table 273) and idio-

Patient Encounter 1, New-Onset syncratic. Concentration-related adverse effects happen with
Seizures increasing frequency and severity as the dose or concentration
of a drug is increased. For many AEDs, common concentra-
tion-related adverse effects include sedation, ataxia, and
AG, a 20-year-old male college student, is seen by his physi-
diplopia. When selecting an AED, these adverse effects should
cian 4 days after an apparent seizure during nals week.
According to his roommate, he suddenly fell to the oor and be carefully considered and used as one of the selection criteria.
had a generalized tonic-clonic seizure. This seizure lasted for For example, if a patient has a job that requires mental
1 to 2 minutes. The patient was incontinent for urine during alertness, it is best to choose an AED that is less likely to cause
the seizure. He was sleepy and confused when the para- sedation (e.g., lamotrigine).
medics arrived 10 minutes later. Due to nal examinations he Idiosyncratic adverse effects are not dose- or concentration-
reports being sleep-deprived. His physical exam is completely related and will almost always result in the AED being discon-
normal and no focal neurologic decits were observed. tinued. Rash, hepatotoxicity, and hematologic toxicities are
the most common idiosyncratic reactions seen with AEDs.
What diagnostic tests should be done at this time? Because many of these adverse effects are life-threatening or
Should these tests be performed prior to starting medications?
potentially life-threatening, the AED should be discontinued
His MRI is normal, and focal epileptiform activity originating
immediately when the reaction is observed. Carbamazepine,
from his left temporal lobe is observed on the EEG.
Should an AED be started at this point? phenytoin, phenobarbital, valproate, lamotrigine, oxcar-
If you decide to treat, what drug and dose would you use? bazepine, and felbamate are most likely to cause these types of
How should that drug be monitored? reactions. Many of these reactions are thought to occur pri-
marily on an immunologic basis, which raises the possibility
Three months later he has another seizure, but this time it is of cross-reactivity. This is especially true for carbamazepine,
characterized by a rising feeling in his stomach followed by phenytoin, phenobarbital, and oxcarbazepine, for which 15%
confused speech, lip smacking, repetitive movements of his to 25% of patients who have an idiosyncratic reaction to one
right hand, and unresponsiveness. This episode lasts for 2 to drug will have a similar reaction to the other drugs.
3 minutes, and it takes 15 minutes for his speech to return
to normal.
Chronic Adverse Reactions
If he is receiving an AED, should a second AED be started Because AEDs are administered for long periods of time,
at this time? adverse effects due to prolonged drug exposure are of con-
What tests and evaluations should you do before starting cern. Some chronic adverse effects that have been associated
a second AED?
with AEDs include peripheral neuropathy and cerebellar atro-
If a second drug is started, what drug and dose would
you use?
phy. Other chronic adverse effects are extensions of acute
adverse effects, for example weight gain.
One chronic adverse effect that is of concern is osteoporosis.32,33
Carbamazepine, phenytoin, phenobarbital, oxcarbazepine,
Refractory seizure (i.e., unresponsive to at least two rst-line and valproate have all been shown to decrease bone mineral
AEDs) treatment is somewhat different. According to the density, even after only 6 months of treatment. Data on the
American Academy of Neurology (AAN) Practice Parameter, relationship between other AEDs and osteoporosis are not
topiramate is useful as monotherapy for primary generalized currently available. Multiple studies have shown the risk of osteo-
tonic-clonic seizures, and there is insufcient evidence to make porosis due to chronic AED use to be similar to the risk with
any recommendation regarding gabapentin, lamotrigine, chronic use of corticosteroids. Patients taking carbamazepine,
oxcarbazepine, tiagabine, levetiracetam, or zonisamide.31 phenytoin, phenobarbital, or valproate for longer than 6 months
Combinations of drugs are not addressed by the AAN, but may should take supplemental calcium and vitamin D. Additionally,
be useful in patients with difcult-to-control primary general- routine monitoring for osteoporosis should be performed
ized seizures. This practice parameter also gives the highest rec- every 2 years, and patients should be instructed on ways to
ommendation to oxcarbazepine and topiramate as monother- protect themselves from fractures.
apy in patients with refractory partial epilepsy. Additionally,
lamotrigine is noted to be effective as monotherapy for refrac-
tory partial seizures, but was associated with a high dropout Practical Issues
rate in the clinical trials. All AEDs, except ethosuximide, are
effective in combination therapy for partial seizures. Comorbid Disease States
Patients with epilepsy often have comorbid disease states.
Complications of Pharmacotherapy Disorders such as chronic headaches and asthma are fre-
Adverse effects of AEDs are frequently dose-limiting or quent problems. For patients who also have asthma, care
can cause a drug to be discontinued. Two types of adverse must be taken to identify drug interactions between AEDs
TABLE 273. Characteristics of Common Antiepileptic Drugs
Mechanism of Pharmacokinetic Usual Serum Dose-Related Idiosyncratic

Drug Action Dose Parameters Concentration Range Adverse Effects Adverse Effects
Carbamazepine Modulate sodium Loading dose: Half-life: 412 mcg/mL Diplopia, drowsiness, Aplastic anemia,
channels Not recommended due 1025 hours with (1751 mol/L) nausea, sedation hyponatremia,
to excessive dose- chronic dosing leukopenia,
related toxicity Apparent volume osteoporosis, rash
Maintenance dose: of distribution:
Titrate dosage to target 0.81.9 L/kg
over 34 weeks Protein binding:
Adults: 1020 mg/kg per 6781%
day as a divided dose Primary elimination
Children: 2030 mg/kg per route:
day as a divided dose Hepatic
Clonazepam Enhance GABA Loading dose: Half-life: Not established Ataxia, memory
activity Not recommended due to 3040 hours impairment,
increased adverse effects Apparent volume of sedation, slowed
Maintenance dose: distribution: thinking
Initiate at 0.5 mg one 3.2 L/kg
to three times daily, Protein binding:
titrate dose to effectiveness 4780%
usually 35 mg daily Primary elimination
in 2 to 3 divided doses route:
Hepatic
Ethosuximide Modulate calcium Loading dose: Half-life: 60 hours 40100 mcg/mL Ataxia, sedation Hepatotoxicity,
channels Not recommended due to 60 hours (283708 mol/L) neutropenia, rash
increased adverse effects Apparent volume of
Maintenance dose: distribution:
Initiate at 250 mg twice 0.60.7 L/kg
daily and titrate to Protein binding:
5001000 mg twice daily None
Primary elimination
route:
Hepatic
Felbamate Inhibit glutamate Loading dose: Half-life: Not established Anxiety, Anorexia, aplastic
activity Not recommended due to Monotherapy: 20 hours insomnia, anemia, headache,
increased adverse effects Concurrent enzyme nausea hepatotoxicity,
Maintenance dose: inducers: 1116 hours weight loss
12003600 mg/day in Apparent volume of
34 divided doses distribution:
0.70.8 L/kg
Protein binding: 2535%
Primary elimination
route:
Hepatic
(Continued )
453
454
TABLE 273. Characteristics of Common Antiepileptic Drugs (Continued)

Gabapentin Modulate calcium Loading dose: Half-life: Not established Drowsiness, sedation Peripheral edema,
channels and Not recommended 57 hours (proportional to weight gain
enhance GABA due to short half-life creatinine clearance)
activity Maintenance dose: Apparent volume of
9003600 mg/day in distribution:
34 divided doses 0.60.8 L/kg
(doses up to 10,000 mg/day Protein binding: less than 10%
have been tolerated) Primary elimination
route:
Renal
Lamotrigine Modulate sodium Loading dose: Half-life: Not established Ataxia, drowsiness, Rash
channels Not recommended due to Monotherapy: 24 hours headache,
increased risk of rash Concurrent enzyme insomnia,
Maintenance dose: inducers: 1215 hours sedation
150800 mg/day in 23 Concurrent enzyme
divided doses. Doses inhibitors: 5560 hours
should be initiated and Apparent volume of
titrated according to the distribution:
manufacturers 1.1 L/kg
recommendations to Protein binding: 55%
reduce the risk of rash Primary elimination route:
Hepatic
Levetiracetam Unknown Loading dose: Half-life: Not established Somnolence, Depression
Not recommended 68 hours Apparent dizziness
due to excessive volume of distribution:
adverse effects 0.50.7 L/kg
Maintenance dose: Protein binding: less than 10%
10003000 mg/day. Primary elimination
Start at 1000 mg/day and route:
titrate upward as 70% renal
indicated by response 30% hepatic
Oxcarbazepine Modulate sodium Loading dose: Half-life: Not established Diplopia, dizziness, Hyponatremia,
channels Not recommended due to Parent drug ~2 hours; somnolence 2530% cross
excessive adverse effects 10-monohydroxy sensitivity in
Maintenance dose: metabolite ~9 hours patients with
6001200 mg/day. Start at Apparent volume of hypersensitivity to
300 mg twice daily and distribution: carbamazepine
titrate upward as indicated 0.50.7 L/kg
by response Protein binding: 40%
Primary elimination route:
Hepatic
Phenobarbital Modulate sodium Loading dose: Halflife: 1540 mcg/mL Ataxia, drowsiness, Attention decit,
channels 1020 mg/kg as Adults: 49120 hours (65172 mol/L) sedation cognitive
single or divided Children: 3773 hours impairment,
intravenous infusions Neonates: ~115 hours hyperactivity,
or orally in divided Volume of distribution: osteoporosis,
doses over 2448 hours 0.71 L/kg passive-aggressive
Maintenance dose: Protein binding: ~50% behavior
Adults: 14 mg/kg per Primary elimination
day, as a single or divided route:
dose Hepatic
Children: 36 mg/kg
per day, as divided dose
Neonates: 13 mg/kg per day,
as divided dose
Phenytoin Modulate sodium Loading dose: Half-life: 1020 mcg/mL Ataxia, diplopia, Anemia, gingival
channels Adults: 1520 mg/kg single Follows capacity-limited (4079 mol/L) drowsiness, hyperplasia,
intravenous dose or or Michaelis-Menten total concentration sedation hirsutism,
divided oral dose pharmacokinetics 12 mcg/mL lymphadenopathy,
Infants less than 3 months: 1015 Half-life increases as the (48 mol/L) osteoporosis, rash
mg/kg single intravenous dose dose and serum unbound
Neonates: 1520 mg/kg single concentration increases concentration
intravenous dose Volume of distribution:
Maintenance dose: Adults: 0.7 L/kg
Adults: 57 mg/kg per day, Children: 0.8 L/kg
as single or divided dose Neonates: 1.2 L/kg
Children: 615 mg/kg per day, Protein binding:
as divided dose Adults, children:
Neonates: 38 mg/kg per day, 8892%
as divided dose Neonates: 65%
Hepatic
Pregabalin Modulate calcium Loading dose: Half-life: Not established Ataxia, blurred Edema, weight gain
channels Not recommended due 6.3 hours, proportional to vision, dizziness,
to increased adverse effects creatinine clearance dry mouth,
Maintenance dose: Apparent volume of somnolence
Initiate at 150 mg/day in 23 distribution: 0.5 L/kg
divided doses and titrate Protein binding:
to a maximum dose Negligible
of 600 mg/day Primary elimination
route:
Renal
Tiagabine Enhance GABA Loading dose: Half-life: Not established Dizziness,
activity Not recommended Monotherapy: 79 hours somnolence,
due to excessive Concurrent enzyme irritability,
adverse effects inducers: 2.54.5 hours slowed thinking
Maintenance dose: Apparent volume of
3256 mg/day in four distribution:
divided doses 0.60.8 L/kg
Doses should be titrated Protein binding: 96%
upward over 6 weeks, Primary elimination
starting at 4 mg/day route:
455
Hepatic
(Continued)
456
TABLE 273. Characteristics of Common Antiepileptic Drugs (Continued )

Topiramate Modulate sodium Loading dose: Half-life: Not established Ataxia, dizziness, Acute glaucoma,
channels; inhibit Not recommended Monotherapy: 21 hours drowsiness, metabolic acidosis,
glutamate activity; due to excessive Concurrent enzyme slowed thinking oligohidrosis,
enhance GABA adverse effects inducers: 1116 hours paresthesias, renal
activity Maintenance dose: Apparent volume of calculi, weight loss
100400 mg/day in distribution:
23 divided doses 0.550.8 L/kg
Doses should be started Protein binding: 1317%
at 2550 mg/day and Primary elimination
gradually titrated upward route:
over 36 weeks to avoid 60% renal
excessive adverse effects 40% hepatic
Valproic acid/ Modulate sodium Loading dose: Half-life: 50100 mcg/mL Drowsiness, nausea, Hepatotoxicity,
divalproex channels 2040 mg/kg Adults: 815 hours (346693 mol/L); sedation, tremor osteoporosis,
sodium Maintenance dose: Children: 415 hours children may pancreatitis,
Adults: 1545 mg/kg Infants less than 2 months: require concentrations weight gain
per day in 24 divided 65 hours up to 150 mcg/mL
doses Volume of distribution: (1040 mol/L)
Children: 560 mg/kg 0.10.5 L/kg
per day in 24 Protein binding:
divided doses 90% (decreases with
increasing serum
concentrations)
Hepatic
Zonisamide Modulate sodium Loading dose: Half-life: Not established Dizziness, Metabolic acidosis,
and calcium Not recommended due ~63 hours somnolence oligohidrosis,
channels to excessive adverse effects Apparent volume of paresthesias,
Maintenance dose: distribution: renal calculi
100600 mg/day; start 1.45 L/kg
at 100 mg/day and titrate Protein binding: 40%
upward as indicated Primary elimination
by response route:
Hepatic
GABA, -aminobutyric acid.

Data from references 25, 35, 36, 37, 38.
and medications used for asthma. These interactions may neces- Stopping Therapy
sitate close monitoring for changes in efcacy or increased Epilepsy is generally considered to be a lifelong disorder
toxicity, and dosage changes of other drugs may be necessary that requires ongoing treatment. However, many patients who
when an AED is added or removed. Patients with chronic are seizure-free may desire to discontinue their medications.35
headaches need special attention in the selection of an AED. Patients who become seizure-free following surgery for their
Agents known to prevent headache (e.g., valproate and topi- epilepsy may have medications slowly tapered starting 1 to
ramate) may be preferred among several choices, and agents 2 years after their surgery. Many patients will choose to stay on
associated with increased headaches (e.g., lamotrigine and fel- at least one medication following successful surgery to ensure
bamate) may be a secondary or tertiary alternative. that they remain seizure-free. Five criteria must be met before
Depression is a common problem in patients with epilepsy, considering the discontinuation of AEDs.36 They are:
with approximately 30% having symptoms of major depression at
some point.34 Patients with epilepsy should be routinely assessed for No seizures for 2 to 5 years
signs of depression, and treatment should be initiated if necessary. Normal neurologic examination
Certain AEDs may exacerbate depression, for example levetirac- Normal intelligence quotient
etam and phenytoin. Other AEDs (e.g., lamotrigine, carba- Single type of partial or generalized seizure
mazepine, and oxcarbazepine) may be useful in treating depression. Normal EEG with treatment
Changes in mood can be precipitated by addition or discontinua-
tion of an AED. If treatment for depression is necessary, caution Individuals who fulll all of these criteria have a 61%
should be exercised in choosing an agent that does not increase chance of remaining seizure-free after AEDs are discontinued.
seizure frequency and does not interact with AEDs. Additionally, there is a direct relationship between the dura-
tion of seizure freedom while taking medications and the
Switching Drugs chance of being seizure-free after medications are withdrawn.
Changing from one AED to another can be a complex Withdrawal of AEDs is done slowly, usually with a tapering
process. If the rst drug is stopped too abruptly breakthrough dose over at least 3 months.
seizures may occur. Stopping or adding a drug can introduce
various problems with drug interactions which should be con- Dosing
sidered in any regimen change. Typically the new drug is started Dosing of AEDs is determined by general guidelines and
at a low initial dose and gradually increased over several weeks. response of the patient. Serum concentrations may be helpful
Once the new drug is at a minimally effective dose, the drug to in benchmarking a specic response. Therapeutic ranges that
be discontinued is gradually tapered while the dose of the new are often quoted are broad guidelines for dosing, but should
drug continues to be increased to the target dose. During a never replace careful evaluation of the patients response. It is
transition between drugs, patients should be cautioned about not unusual for a patient to be well managed with serum con-
the possibility of increased seizures or adverse reactions. centrations or doses outside the typical ranges.
Patient Encounter 2, Switching a

Patient to a Different Antiepileptic
Drug Patient Encounter 3, Discontinuing
Antiepileptic Drug Therapy
BC, a 22-year-old woman, was diagnosed 2 years ago with
juvenile myoclonic epilepsy. She has been treated with val-
proate 1500 mg/day. Since starting valproate she has gained The consultant pharmacist is reviewing the care of AN, who
45 pounds (20.5 kg), continues to have occasional myoclonic is a 79-year-old male resident of a long-term care facility.
jerks, had a generalized tonic-clonic seizure 3 months ago, According to his records, he has received phenytoin and
and is sexually active. Additionally, she complains of easily phenobarbital ever since suffering a stroke 12 years ago.
falling asleep during the day. Due to adverse effects, poor There is no record of a seizure in his chart, and the nursing
seizure control, and the risk of birth defects with valproate, the staff has not observed a seizure since he arrived at the facility
decision is made to switch to a different antiepileptic drug. 2 years ago. His family recalls that he had 1 seizure around
the time of his stroke, but has not had any more seizures.
What drug would be the optimal alternative drug for this
patient? Can his antiepileptic medications be discontinued?
How should the new drug be started and the valproate What additional information would be helpful to determine
discontinued? the possibility of discontinuing his antiepileptic drugs?
What instructions should be given to the patient regarding If the antiepileptic drugs are stopped, how should they be
the switch to another drug? discontinued?
Drug Interactions than those seen in adults. When treating a child it is imperative
AEDs are associated with many different drug interactions.3739 to control seizures as quickly as possible to avoid interference
These interactions are primarily in relation to absorption, with development of the brain and cognition. Antiepileptic
metabolism, and protein binding. Tube feedings and antacids drug doses are increased rapidly, and frequent changes in the
are known to reduce the absorption of phenytoin and carba- regimen are made to maximize control of seizures. Due to
mazepine. Phenytoin, carbamazepine, and phenobarbital are the rapid metabolic rates seen in children, doses of AEDs are
potent inducers of various cytochrome P-450 (CYP450) typically higher on a milligram-per-kilogram basis com-
isoenzymes, increasing the clearance of other drugs metabo- pared to those for adults, and serum concentrations are used
lized through these pathways (Table 274). In contrast, val- more extensively to help ensure an adequate trial of a drug
proate is a CYP450 isoenzyme inhibitor and reduces the has been given.
clearance of some drugs. Phenytoin and valproate are highly For women, the treatment of epilepsy poses challenges,
protein-bound and can be displaced when taken concur- including teratogenicity, interactions between AEDs and
rently with other highly protein-bound drugs. For example, hormonal contraceptives, and reduced fertility. 40,41
when phenytoin and valproate are taken together, there may Recommendations for managing women of child-bearing
be increased dose-related adverse effects within several potential and who are pregnant have been developed
hours of dosing. This can be avoided by staggering doses or (Table 275). Several AEDs have been implicated in caus-
giving smaller doses more frequently during the day. ing both minor and serious birth defects. 42 Of special
Whenever a change in a medication regimen occurs, drug concern are neural tube defects (e.g., spina bifida, micro-
interactions should be considered and appropriate adjust- cephaly, and anencephaly), associated most commonly
ments in dose made. with valproate and possibly carbamazepine. All women of
child-bearing potential who have epilepsy should be tak-
ing 1 to 4 mg daily of supplemental folic acid to reduce the
Special Populations risk of these defects. Even with drugs like valproate, more
Children and women present special challenges in the than 90% of pregnancies will produce a completely nor-
management of epilepsy and use of AEDs. In children, devel- mal infant. Therefore, use of valproate is not contraindi-
opmental changes occur rapidly, and metabolic rates are greater cated in women who may become pregnant, but it may be
TABLE 274. Common Drug Interactions with Antiepileptic Drug3638
Enzyme Substrate Common Inducers Common Inhibitors

CYP1A2 Carbamazepine Carbamazepine Cimetidine
Phenytoin Ciprooxacin
Phenobarbital Erythromycin
Rifampin Clarithromycin
CYP2C9 Phenobarbitala Carbamazepine Amiodarone
Phenytoina Phenytoin Cimetidine
Carbamazepine Phenobarbital Fluconazole
Valproate Rifampin Valproate
CYP2C19 Phenobarbital Felbamate
Phenytoin Ticlopidine
Valproate Topiramate
Zonisamide
CYP2D6 Zonisamide Carbamazepine
CYP3A4 Carbamazepinea Carbamazepine Amiodarone
Tiagabinea Phenytoin Erythromycin
Zonisamidea Phenobarbital Propoxyphene
Rifampin Ketoconazole
Uridine diphosphate Lamotriginea Lamotrigine Valproate
glucuronyl-transferase Carbamazepine Phenobarbital
Phenytoin
a
Primary route of metabolism.
CYP450, cytochrome P-450 isoenzyme.
Data from references 36, 37, 38.
TABLE 275. Management of Antiepileptic Drugs during

Pregnancy Patient Encounter 4, Hormonal
Contraceptives and Interactions with
Give supplemental folic acid, 14 mg daily, to all women of Antiepileptic Drugs
child-bearing potential
Use monotherapy whenever possible LJ, a 25-year-old-woman with complex partial seizures,
Use the lowest doses that control seizures
presents a prescription to the pharmacy for a triphasic oral
Continue pharmacotherapy that best controls seizures prior to
pregnancy
contraceptive containing ethinyl estradiol and norgestimate.
Monitor antiepileptic drug serum concentrations at the start of A review of her medication prole shows that she is taking
pregnancy and monthly thereafter carbamazepine extended-release 1200 mg/day. Her last rell
Adjust antiepileptic drug doses to maintain baseline serum for this prescription was 2 weeks ago. She reports that she
concentrations has not had a seizure for a year and that she just became
Administer supplemental vitamin K during the eighth month of engaged. She is planning to be married in 4 months.
pregnancy to women receiving enzyme-inducing antiepileptic
drugs Is there an interaction between carbamazepine and the
Monitor postpartum antiepileptic drug serum concentrations to oral contraceptive?
guide adjustments of drug doses
If so, what is the mechanism and clinical outcome of the
interaction?
If there is an interaction, how should it be managed?
What AEDs interact with hormonal contraceptives?
What are the clinical implications of these interactions?
advisable to start alternative AEDs, if appropriate, in How should they be managed?
women of child-bearing potential.
As noted above, many of the AEDs induce hepatic micro-
somal enzyme systems and thus reduce the effectiveness of Patient Care and Monitoring
hormonal contraceptives. Women taking AEDs that may
reduce the effectiveness of hormonal contraceptives should
be encouraged to also use other forms of birth control. Due
to induction or inhibition of sex hormone metabolism and 1. Monitor the patients seizure frequency and characteristics.
changes in binding of hormones to sex hormone binding The only objective measure ofefcacy of AEDs is a count
globulin, some AEDs may reduce fertility. For example, val- of seizure frequency. Ask patients to keep seizure calen-
proate has been associated with a drug-induced polycystic dars, noting the numbers and types of seizures that occur
and have them bring the calendars to clinic at every visit
ovarian syndrome. Women who experience difculties with
for analysis and documentation of seizure frequency.
fertility should seek the advice of health care professionals
2. Monitor for acute and chronic adverse effects of AEDs. Acute
with expertise in fertility.
adverse effects are best detected by a thorough neurologic
examination at clinic visits. Instruct patients to report seda-
tion, ataxia, rash, or other problems immediately. Monitor for
Outcome Evaluation
chronic adverse effects including a loss of bone mineral den-
sity, which should be measured every 2 years in patients tak-
Efcacy ing phenytoin, phenobarbital, carbamazepine, and valproate.
Seizure counts are the only reasonable and standard way to 3. Monitor for comorbid disease states at each clinic visit.
evaluate efcacy of treatment. Evaluate for depression at every clinic visit.
Encourage patients to keep a seizure calendar that notes the 4. Take measures to ensure compliance with medications and
time and day seizures occur and the type of seizure. access to care. Compliance with medication regimens is a
Comparisons can then be made on a monthly basis to deter- common problem for patients with epilepsy. Patients should
mine the level of seizure control. be asked at every visit how they are taking their medica-
tions and if they missed any doses. Identify barriers to care,
such as nancial issues or transportation problems.
Toxicity
5. Instruct patients, family members, and caregivers on rst aid
Monitor toxicity of AEDs at every clinic visit.
for seizures. First aid for seizures consists primarily of
Question patients about common adverse effects of the AEDs keeping the patients from hurting themselves. They should
they are receiving. Weigh the impact of acute adverse effects be placed on the oor, if possible, and their heads cush-
against the extent of seizure control achieved. If it is deter- ioned. First responders to a seizure should never attempt
mined that the adverse effects negatively impact a patient to restrain them or force an item into their mouth. If a
more than the extent of seizure control obtained benets the seizure lasts longer than 5 to 10 minutes, emergency
patient, adjust the therapeutic regimen. Continuously moni- medical assistance should be called.
tor chronic adverse effects of AEDs.
ABBREVIATIONS Armijo JA, Shushtarian M, Valdizan EM, et al. Ion channels and
epilepsy. Curr Pharm Des 2005;11:19752003.
AAN: American Academy of Neurology Blumenfeld H. Cellular and network mechanisms of spike-wave
AED: antiepileptic drug seizures. Epilepsia 2005;46(Suppl 9):2133.
CBC: complete blood cell count Crawford P. Best practice guidelines for the management of women
CNS: central nervous system with epilepsy. Epilepsia 2005;46(Suppl 9):117124.
CYP450: cytochrome P-450 isoenzymes French JA, Kanner AM, Bautista J, et al. Efcacy and tolerability of
EEG: electroencephalogram the new antiepileptic drugs I: treatment of new onset epilepsy,
GABA: -aminobutyric acid report of the Therapeutics and Technology Assessment
ILAE: International League Against Epilepsy Subcommittee and Quality Standards Subcommittee of the
JME: juvenile myoclonic epilepsy American Academy of Neurology and the American Epilepsy
LFT: liver function test Society. Neurology 2005;62:12521260.
LGS: Lennox-Gastaut syndrome French JA, Kanner AM, Bautista J, et al. Efcacy and tolerability of the
MRI: magnetic resonance imaging new antiepileptic drugs II: treatment of refractory epilepsy, report
MTLE: mesial temporal lobe epilepsy of the Therapeutics and Technology Assessment Subcommittee
PDS: paroxysmal depolarizing shift and Quality Standards Subcommittee of the American Academy
of Neurology and the American Epilepsy Society. Neurology
2005;62:12611273.
National Institute for Clinical Excellence. The Epilepsies: The
Diagnosis and Management of the Epilepsies in Children and
Adults in Primary and Secondary Care; http://www.nice.org.uk/
Log into the website: www.pharmacotherapyprinciples.com pdf/CG020NICEguideline.pdf. Accessed December 20, 2005.
for information on obtaining continuing education credit for Patsalos PN, Froscher W, Pisani F, van Rijn CM. The importance
this chapter. of drug interactions in epilepsy therapy. Epilepsia 2002;43:
365385.
KEY REFERENCES AND READINGS Perruca E. An introduction to antiepileptic drugs. Epilepsia 2005;
46(Suppl 4):3137.
American Epilepsy Society. Epilepsy Education Program. http:// Scottish Intercollegiate Guidelines Network. Diagnosis and Management
www.aesnet.org/Visitors/ProfessionalDevelopment/MedEd/ of Epilepsy in Adults; http://www.sign.ac.uk/pdf/sign70.pdf.
epilepsyedu.cfm. Accessed April 19, 2006. Accessed December 20, 2005.
28 STATUS EPILEPTICUS
Gretchen M. Brophy and Eljim P. Tesoro
LEARNING OBJECTIVES
1. Discuss the pathophysiology of status epilepticus.

2. Explain the urgency of diagnosis and treatment of status epilepticus.
3. Recognize the signs and symptoms of status epilepticus.
4. Identify the treatment options available for termination of status epilepticus.
5. Formulate an initial treatment strategy for a patient in generalized convulsive status epilepticus.
6. Compare the pharmacotherapeutic options for refractory status epilepticus.
7. Describe adverse drug events associated with the pharmacotherapy of status epilepticus.
8. Recommend monitoring parameters for a patient in status epilepticus.
KEY CONCEPTS Refractory status epilepticus is seizure activity that is not con-
trolled by rst-line and second-line therapies, including ben-
Status epilepticus is a neurologic emergency that can lead to zodiazepines and antiepileptic drugs.
permanent brain damage or death. Midazolam, propofol, and pentobarbital infusions can be
Status epilepticus can be dened as any seizure lasting more used for refractory status epilepticus but may require inten-
than 30 minutes, with or without a loss of consciousness; or sive monitoring and supportive care.
having recurrent seizures without regaining consciousness
Status epilepticus (SE) is a neurologic emergency that can
between seizure episodes. However, this denition does not
lead to permanent brain damage or death. SE can be dened as
provide any guidance for treatment strategies in the clinical
any seizure lasting more than 30 minutes, with or without a loss of
setting where interventions begin within a few minutes of
consciousness; or having recurrent seizures without regaining con-
seizure onset. A more practical denition to guide treatment
sciousness between seizure episodes.1 However, this denition does
would be continuous seizure activity lasting more than 5 min-
not provide any guidance for treatment strategies in the clinical set-
utes or two or more seizures without complete recovery of
ting where interventions begin within a few minutes of seizure
consciousness.
onset. A more practical denition to guide treatment would be
It is important to evaluate for possible etiologies of status continuous seizures lasting more than 5 minutes or two or more
epilepticus and treat any underlying causes in order to opti-
seizures without complete recovery of consciousness.2 Refractory
mize seizure control.
status epilepticus (RSE) can be dened as seizure activity that
The goal of therapy is to arrest physical and electroencephalo- does not respond to rst-line antiepileptic therapy.3
graphic evidence of seizures, prevent recurrence of seizures,
SE can present as non-convulsive status epilepticus (NCSE)
and minimize adverse drug events.
or generalized convulsive status epilepticus (GCSE). NCSE is
The rst-line treatment for status epilepticus is intravenous characterized by a persistent state of impaired consciousness
benzodiazepines. Diazepam, lorazepam, or midazolam may be
and/or motor or sensory seizures without impaired conscious-
used to rapidly control clinical signs of seizures. Lorazepam is
ness. For patients with NCSE, electroencephalography (EEG) is
currently considered the rst-line agent by most clinicians.
the key to diagnosis. GCSE is characterized by full body motor
Antiepileptic drugs are used to prevent the recurrence of seizures and involves the entire brain. This chapter will focus on
seizures. Intravenous phenytoin (or fosphenytoin) and phe-
GCSE, which is the most common type of SE and is associated
nobarbital are administered after benzodiazepines are given.
with the greatest risk of neurologic and physical damage.
461
inhibitory neurotransmitter, g-aminobutyric acid (GABA),

Patient Encounter, Part 1 opposes the excitatory response by stimulating GABAA recep-
tors. GABAA-receptor stimulation enhances the chloride
inhibitory currents, producing hyperpolarization and inhibition
CH, a 42-year-old man, comes into the emergency depart-
of the postsynaptic cell membrane. The inhibitory ability of
ment after his sister discovered him seizing at home. He has GABA is diminished as the duration of seizures increases. This
a history of hypertension, diabetes, epilepsy, and rheumatoid may be due to a mechanistic shift in the functional properties of
arthritis. His medications include hydrochlorothiazide, gly- the GABAA receptors which causes a decrease in response to
buride, phenytoin, and aspirin. He smokes one pack per GABA-receptor agonists.8,9 Seizure activity lasting more than
day, drinks heavily on the weekends, and has a history of 30 minutes can cause cerebral injury and neuronal loss in the
cocaine use. Upon further discussion with his sister, you dis- hippocampal, cortical, and thalamic regions. These neurologic
cover that he stopped taking his phenytoin 4 days ago due sequelae are related to the excessive electrical activity and alter-
to failure to obtain a rell from his doctor. He is currently ations in cerebral metabolic demand. The clinical impact of the
unarousable since his last seizure 10 minutes ago. GABAA-receptor changes on treatment response and the wors-
ening degree of neuronal injury with prolongation of seizure
What initial assessments should be performed?
What are some possible etiologies for his seizure?
activity highlights the urgency of rapid control of SE.
What interventions need to be performed at this time? There are several systemic changes that occur during the
course of SE. These changes can be divided into two phases.
Phase I occurs during the rst 30 minutes of seizure activity,
EPIDEMIOLOGY AND ETIOLOGY and phase II occurs after 30 minutes of seizure activity.10
There are an estimated 150,000 cases of SE each year in the Phase I

United States, with approximately 55,000 associated deaths, During phase I, each seizure causes a sharp increase in autonomic
and an estimated annual direct cost for inpatient admissions of activity with increases in epinephrine, norepinephrine, and
$4 billion.4,5 Status epilepticus occurs more frequently in African- steroid plasma concentrations, resulting in hypertension, tachy-
Americans, children, and the elderly. Additional attention should cardia, hyperglycemia, hyperthermia, sweating, and salivation.
be given to elderly individuals with SE, as other underlying dis- Cerebral blood ow is also increased to preserve the oxygen sup-
ease states may complicate therapy and worsen prognosis.6 ply to the brain during this period of high metabolic demand.
It is important to understand the underlying cause of SE, Increases in sympathetic and parasympathetic stimulation with
as this will guide the course of treatment, potentially shortening muscle hypoxia can lead to ventricular arrhythmias, severe aci-
the duration of SE and improve outcomes. The causes of SE can dosis, and rhabdomyolysis. These, in turn, could lead to hypoten-
be categorized as acute or chronic. Acute changes that cause SE sion, shock, hyperkalemia, and acute tubular necrosis.
include metabolic disturbances; central nervous system (CNS)
disorders, infections, or injuries; hypoxia; drug toxicity; or Phase II
acute illness. Chronic processes that cause SE include preexist-
After approximately 30 minutes of continuous seizure activity,
ing epilepsy, chronic alcohol abuse, CNS tumors, and strokes.3
the patient enters phase II and there is loss of cerebral autoregu-
In individuals diagnosed with epilepsy, the common causes of
lation, decreased cerebral blood ow, increased intracranial pres-
SE are anticonvulsant withdrawal or subtherapeutic anticon-
sure, and systemic hypotension. Metabolic demand is still high;
vulsant levels. Patients with SE due to chronic processes gener-
however, the body is no longer able to compensate. The systemic
ally respond well to antiepileptic drug (AED) therapy.
changes that may occur during this phase include hypoglycemia,
hyperthermia, respiratory failure, hypoxia, respiratory and meta-
PATHOPHYSIOLOGY bolic acidosis, hyperkalemia, hyponatremia, and uremia. It is
important to note that during prolonged seizure activity, motor
Status epilepticus occurs because the brain fails to stop an iso- activity may not be clinically noticeable, but the electrical seizures
lated seizure. The exact reason for this failure is unknown and may still persist. This is referred to as subclinical seizure activity
probably involves many mechanisms. A seizure is likely to and needs to be recognized and treated aggressively.
occur due to a mismatch of excitatory and inhibitory neuro-
transmitters in the brain. The primary excitatory neurotrans-
mitter in the brain is glutamate. Glutamate stimulates postsy- CLINICAL PRESENTATION AND DIAGNOSIS
naptic N-methyl-D-aspartate (NMDA) receptors in the brain,
causing an inux of calcium into the cells and depolarization History
of the neuron. Sustained depolarization may maintain SE and When a patient presents with seizures, a thorough history
eventually cause neuronal injury and death.7 The primary is needed to determine the type and duration of the seizure
CHAPTER 28 / STATUS EPILEPTICUS 463
Clinical Presentation of Status Epilepticus
General
The patient may present with or without clinically noticeable seizure activity.
Symptoms
Impaired consciousness ranging from lethargy to coma
Disorientation after cessation of GCSE
Pain from associated injuries (e.g., tongue lacerations, dislocated shoulder, head trauma,
facial trauma)
Signs
Phase I: Phase II (greater than 30 minutes of SE):
Generalized convulsions Respiratory failure with pulmonary
Hypertension, tachycardia edema
Fever and sweating Cardiac failure (arrhythmias, shock)
Muscle contractions, spasms Hypotension
Respiratory compromise Hyperthermia
Incontinence Rhabdomyolysis and multiorgan failure
Laboratory Tests
Hyperglycemia (phase I) and hypoglycemia (phase II) can occur
Hyponatremia, hypernatremia, hyperkalemia, hypocalcemia, hypomagnesemia, and
hypoglycemia can cause SE
The white blood cell (WBC) count may slightly increase
Abnormal arterial blood gases (ABGs) due to hypoxia and respiratory or metabolic acidosis
Elevated serum creatinine will be present in renal failure patients
Myoglobinuria can occur in patients with continuous seizures
Diagnostic Tests
Electroencephalography (EEG) will show seizure activity
activity. This will help guide therapy and identify which labora- be observed. When seizure activity is sustained for more than
tory and diagnostic testing need to be conducted urgently. A approximately 30 to 60 minutes, muscle contractions may no
diagnosis of status epilepticus will be made when a patient with longer be visible, but the patient remains in SE. Twitching of
a history of repeated seizures and impaired consciousness has a the face, hands, or feet may be seen in these comatose patients
seizure witnessed by a health care professional. with prolonged seizures.
Physical Examination Laboratory Parameters

Upon admission and control of seizure activity, a neurologic It is important to obtain a serum chemistry prole to help
exam should be conducted to evaluate level of consciousness identify the underlying cause of SE. Abnormalities that can
(coma, lethargy, and somnolence), motor function and cause seizures include hypoglycemia, hyponatremia, hyperna-
reexes (rhythmic contractions, rigidity, spasms, and postur- tremia, hypomagnesemia, hypocalcemia, and renal failure. In
ing), and pupillary response. A physical exam to identify sec- a febrile patient with an elevated WBC count, an active infec-
ondary injuries from the SE should also be conducted. tion should be ruled out or treated appropriately. Cultures
from the blood, cerebrospinal uid (CSF), respiratory tract,
and urine should be obtained once the seizures are controlled.
Clinical Symptoms
Computed tomography (CT) or magnetic resonance imaging
Patients with SE usually present with generalized, convulsive (MRI) can be done to rule out CNS abscesses, bleeding, or
tonic-clonic seizure activity that is unresponsive to initial tumors, all of which may be a source for seizure activity. A
AED treatment. They may also be hypertensive, tachycardic, blood alcohol level and urine toxicology screen for drugs of
febrile, and diaphoretic; however, these symptoms will resolve abuse should also be conducted to determine if a chronic alco-
soon after the seizure is terminated. A loss of bowel or bladder holic is having alcohol withdrawal seizures or if illicit drug use
function, respiratory compromise, and nystagmus may also or a drug overdose could be the underlying cause of SE. Also,
drug levels should be obtained in a drug overdose situation to status and determine if airway protection or supplemental
rule out toxicity as a cause of SE. Knowing the source of SE oxygen is needed. Metabolic acidosis typically corrects on its
will help to guide the initial antiepileptic therapy and increase own after seizure activity stops, so pharmacologic treatment
the probability of halting seizure activity. is not required.
In patients with a history of AED use, a baseline serum con-
centration may be useful to determine if the drug concentra- Diagnostic Tests
tion is below the desired range and if a loading dose is needed.
Albumin levels, renal function tests, and liver function tests The only way to determine if a comatose patient has SE is by
can also be helpful when assessing antiepileptic therapy. EEG. EEG monitoring should be used for patients who remain
Hypoxia and respiratory or metabolic acidosis are com- unconscious after initial antiepileptic treatment, and for those
mon in patients with SE. Therefore, pulse oximetry and ABG who received a long-acting paralytic agent or require prolonged
measurements are useful to assess the patients respiratory therapy for RSE. Treatment should never be delayed while
awaiting EEG results. An electrocardiogram (ECG) should be
obtained to rule out cardiac dysfunction when hypotension or
Patient Encounter, Part 2 an abnormal heart rate is observed.
TREATMENT
Physical exam and laboratory studies reveal the following
additional information about CH. Desired Outcomes
PE The goals of treatment of status epilepticus include the ces-
VS: blood pressure 148/87 mm Hg, pulse 115 beats per sation of any seizure activity, both clinical and subclinical, and the
minute, respiratory rate 23/minute, temperature 39.0C
prevention of further seizures. Ideally, this is accomplished through
(102.2F), Ht 180 cm (511), Wt 80 kg (176 lbs)
CNS: Unresponsive, unarousable
directed pharmacotherapy with minimization of any side effects or
CV: Sinus tachycardia; normal S1, S2; no murmurs, rubs, adverse reactions. Complications of SE should also be treated.
gallops
Pulm: Tachypneic; oxygen saturation 92% on room air; no General Approach
rhonchi, wheezes, rales
Abd: Firm, non-tender, non-distended; (+) bowel sounds; no The initial approach to SE involves rst removing the patient
hepatosplenomegaly from harmful surroundings and ensuring a safe airway to pre-
Exts: Rhythmic tonic-clonic movements of all extremities vent respiratory collapse or aspiration. Benzodiazepines are
GU: Incontinent of urine and stool the rst medications administered, as they are the drugs of
HEENT: Persistent upward gaze choice to stop acute seizure activity, followed by the initiation
Labs of an antiepileptic agent. Medications are typically given
Sodium 130 mEq/L (130 mmol/L), WBC 12 103/mm3 intravenously (IV) for immediate onset of action, but if no IV
(12 109/L) access is available, certain medications may be given intra-
Phenytoin 2.1 mcg/mL (8.3 mol/L), albumin 3.5 g/dL (35 g/L) muscularly (IM), rectally, buccally, or via an endotracheal
Potassium 3.5 mEq/L (3.5 mmol/L), hemoglobin 14 g/dL tube. Once the seizures stop, clinicians must identify and treat
(140 g/L or 8.7 mmol/L) the underlying cause of the seizures, such as toxins, hypo-
Chloride 100 mEq/L (100 mmol/L), hematocrit 42% glycemia, or trauma. Patients with known seizure disorders
(0.42 volume fraction) should be evaluated for abrupt cessation of their medications
Carbon dioxide 12 mEq/L (12 mmol/L), platelets 235 or for history of non-compliance.
103/mm3 (235 109/L)
Blood urea nitrogen 10 mg/dL (3.6 mmol/L), prothrombin Nonpharmacologic Treatment
time 12 seconds
Non-drug interventions may include administration of oxygen
Serum creatinine 0.9 mg/dL (80 mol/L), International
Normalized Ratio 1.1 or intubation for mechanical ventilation in cases of hypoxemia
or body cooling for febrile seizures. All patients should receive
Glucose 189 mg/dL (10.5 mmol/L), activated partial throm-
boplastin time 28 seconds glucose in case of hypoglycemia-induced SE. In patients with a
history of alcohol abuse, thiamine 100 mg should be given prior
What is your assessment of the cause of this patients to the administration of any glucose-containing solutions to
condition? prevent encephalopathy. Specialists in neurology or epileptology
Identify your goals of therapy for this patient. should be consulted as appropriate. Admission to an emergency
What therapies must be instituted next? department or intensive care unit (ICU) will allow appropriate
monitoring during the seizure and in the postictal period.
Pharmacologic Treatment frequently or administered as a continuous infusion. Midazolam

can be given at 0.2 mg/kg either intravenously or intramuscu-
Initial Treatment larly as a single dose.18 The liquid or injectable formulation can
be given buccally or intranasally (0.3 mg/kg) when IV access
Benzodiazepines cannot be secured. Nasal administration in SE can be hindered
Initial drug therapy begins with the administration of an by rapid breathing and increased nasal secretions.
intravenous benzodiazepine since they are most effective in
aborting seizure activity. Intravenous bolus doses of diazepam, Anticonvulsants
lorazepam, and midazolam have all been used in status epilepti- Once the rst dose of benzodiazepine is given, an
cus because of their rapid effects at inhibiting GABA receptors in antiepileptic drug must be started to prevent further seizures
the CNS. Diazepam and lorazepam have historically been the from occurring. AEDs must not be given as rst-line therapy
more commonly used agents; however, most clinicians currently since they must be infused relatively slowly to avoid adverse
use lorazepam as the rst-line agent. When treating patients effects, delaying their onset of action.
who are taking chronic benzodiazepines, clinicians should Once the loading dose of the AED is administered, it is
consider higher doses to overcome the effects of tolerance. important to remember to initiate maintenance doses to ensure
Diazepam and lorazepam should be diluted with normal that therapeutic levels are sustained. Chronic and idiosyncratic
saline in a 1:1 ratio before parenteral administration via side effects as well as potential drug interactions should be con-
peripheral veins to avoid venous irritation from the propylene sidered if the patient will continue AED therapy indenitely. All
glycol diluent in the formulation. drug therapy should be adjusted for any hepatic or renal disease
states. Table 281 summarizes the drug doses used in SE, and
Diazepam Being extremely lipophilic, diazepam penetrates Table 282 provides an example of an algorithm for the treat-
quickly into the CNS, but can rapidly redistribute into body ment of patients in SE. Published studies comparing these
fat and muscle. This results in a faster decline in CNS levels treatment strategies are summarized in Table 283.
and early recurrence of seizures. It is dosed at 5 to 10 mg (or
0.15 mg/kg) and infused no faster than 5 mg/minute. Phenytoin The most widely used antiepileptic agent is pheny-
Repeated doses can be given every 5 minutes until seizure toin, which is administered IV as a loading dose (for patients
activity stops or toxicities are seen (e.g., respiratory depres- previously not on phenytoin) of 15 to 20 mg/kg. The loading
sion). Diazepam can also be administered as a rectal supposi- dose must be modied in those patients who are taking pheny-
tory, making it possible for non-medical personnel to provide toin and have subtherapeutic levels in order to avoid toxic
rapid therapy for seizures that develop at home or in public serum concentrations. The loading dose is infused no faster
areas.11 The adult dose is 10 mg given rectally and this dose than 50 mg/minute due to potential risks of hypotension or
may be repeated once if necessary. Diazepam is erratically arrhythmias. Continuous monitoring of ECG and blood pressure
absorbed via the intramuscular route; therefore, IM adminis- is recommended. Maintenance dosing can be started 12 hours
tration is not recommended. after the loading dose. Phenytoin should not be infused with
other medications because of stability concerns (it is soluble in
Lorazepam Less lipophilic than diazepam, lorazepam has a propylene glycol and compatible only in 0.9% sodium chloride
longer redistribution half-life, resulting in longer duration of solutions). It should not be given via the IM route due to its
action and a decrease in the need for repeated doses. Both alkaline nature. Extravasation of the drug can cause local dis-
lorazepam and diazepam are effective in stopping seizures,12 coloration, edema, pain, and sometimes necrosis (purple glove
but lorazepam is currently the preferred agent due to its syndrome). Although phenytoin comes in a variety of enteral
longer duration of action. Lorazepam is given as a single IV preparations, oral loading is not recommended in SE due to
dose of 0.1 mg/kg (maximum dose is 4 mg) with a maximum the delay in absorption.
rate of infusion of 2 mg/minute. It can be re-dosed every 10 to
15 minutes (up to a maximum cumulative dose of 8 mg) until Fosphenytoin Fosphenytoin is a water-soluble, phospho-ester
seizure activity stops or side effects such as respiratory depres- prodrug of phenytoin that is rapidly converted to phenytoin
sion occur. It should not be given IM since it has slow and in the body. It is compatible with most IV solutions and is well
unpredictable absorption via the IM route. tolerated as an IM injection, even with the large volumes asso-
ciated with loading doses (20 to 30 mL).19 It is dosed in
Midazolam Midazolam is water-soluble and can be adminis- phenytoin equivalents (PE), and it can be infused three times
tered intravenously, intramuscularly,13 buccally,14,15 and as fast as phenytoin, up to 150 mg PE/minute. The loading
nasally.16,17 At physiologic pH, it becomes more lipophilic and dose for patients not taking phenytoin is 15 to 20 mg PE/kg. It
can diffuse into the CNS. Compared to diazepam and can be an advantage to use IM fosphenytoin when IV access
lorazepam, it has fewer effects on the respiratory and cardio- cannot be obtained immediately and in patients with poor
vascular systems. Its short half-life requires that it be re-dosed venous access. Although it has fewer cardiovascular side
TABLE 281. Parenteral Medications Used in Status Epilepticus in Adults
Drug Name
(Brand Name) Loading Dose Administration Rate Therapeutic Level Side Effects Comments
Diazepam 0.15 mg/kg 5 mg/minute (IVP) N/A Hypotension, respiratory Rapid redistribution
(Valium) depression rate; can be given rectally
Lorazepam 0.1 mg/kg 2 mg/minute (IVP) N/A Hypotension, respiratory May be longer-acting than
(Ativan) depression diazepam
Midazolam 0.2 mg/kg 2 mg/minute (IVP) N/A Sedation Can also be given IM,
(Versed) buccally, intranasally;
expensive
Phenytoin 1520 mg/kg Up to 50 mg/minute 1020 mcg/mL Arrhythmias, hypotension, Hypotension, especially in
(Dilantin) (39.679.2 mol/L) elderly
Fosphenytoin 1520 mg Up to 150 mg 1020 mcg/mL Paresthesias, hypotension Can be given IM; less CV
(Cerebyx) PE/kg PE/minute side effects than
phenytoin; expensive
Phenobarbital 20 mg/kg 50100 mg/minute 1540 mcg/mL Hypotension, sedation, Long-acting
(Luminal) (64.7172.4 respiratory depression
mol/L)
Valproate 1520 mg/kg 36 mg/kg per minute 50150 mcg/mL Less CV side effects than
sodium (up to (346.51039.5 phenytoin
(Depacon) 40 mg/kg) mol/L)
Propofol 12 mg/kg Approximately N/A (typically Hypotension, respiratory Requires mechanical
(Diprivan) 40 mg every titrated to EEG) depression intubation; high lipid
10 seconds load (increased calories);
propofol infusion
syndrome
Pentobarbital 1015 mg/kg Up to 50 mg/minute 1020 mcg/mL Hypotension, respiratory Requires mechanical
(Nembutal) (typically depression, cardiac intubation, pressors,
titrated to EEG) depression, infection, hemodynamic monitoring
ileus
CV, cardiovascular; EEG, electroencephalogram; IM, intramuscular; IVP, intravenous push; N/A, not applicable; PE, phenytoin equivalents.
effects than phenytoin, clinicians should still continuously Valproate Sodium Valproate sodium is an older AED that was
monitor blood pressure, ECG, and heart rate. Maintenance released as an intravenous preparation (Depacon) in 1996.
doses are begun 12 hours after the loading dose. A common Although it is not FDA-approved for SE, its use has been doc-
side effect is paresthesias, especially around the lips and in the umented in various types of SE including generalized tonic-
groin, which typically resolve within a few minutes and should clonic, myoclonic, and non-convulsive SE.22,23 Reports indicate
not necessitate stopping the infusion. If a post-load serum
level is desired, it should be obtained 2 hours after an IV load
or 4 hours after an IM load. Fosphenytoin is more expensive
than phenytoin, making it difcult to justify its use in many
institutions.20
Treatment Failure
Phenobarbital If phenytoin or fosphenytoin fails to prevent It has been forty-ve minutes since CHs arrival, and he has
seizure recurrence, phenobarbital can be administered. been given lorazepam 4 mg twice and loaded with 1500 mg
However, emerging evidence suggests that phenobarbital may of phenytoin. He received another 400 mg dose of phenytoin
not be effective if SE persists after giving benzodiazepines and 15 minutes ago, but is still unarousable. His jerking move-
phenytoin. This may be due to the progressive resistance of ments have slowed down, but his temperature is now 39.9C
the GABAA receptor, at which the barbiturates also act.21 It is (103.8F), and his blood pressure has dropped to 124/62
dosed as an IV load of 15 to 20 mg/kg with a maximum rate mm Hg. His oxygen saturation is 91% on 4 L oxygen via
nasal cannula. Bilateral crackles are heard upon auscultation
of administration of 100 mg/minute. Adverse reactions of
of his lungs. A CT scan of his head is obtained which shows
phenobarbital include sedation, hypotension, and respiratory no evidence of hemorrhage, tumor, or mass effect.
depression; therefore, patients who receive a rapid IV loading
dose of phenobarbital should have hemodynamic monitoring What is your assessment of this patients condition?
and be mechanically ventilated. Its long half-life makes it a What possible treatment options exist at this time?
popular agent for both acute treatment and chronic mainte- How would you optimize this patients outcome?
nance therapy.
TABLE 282. Algorithm for Status Epilepticus in Adults
Time (minutes) Assessment/Monitoring Treatment

0 Vital signs (HR, RR, BP, T) Assess airway Stabilize airway (intubate if
Monitor cardiac function (ECG) necessary)
Pulse oximeter Administer oxygen
Check blood glucose Secure IV access and start uids
Check laboratory tests: Give thiamine (100 mg) + glucose
complete blood count (50 mL of 50% solution) if
serum chemistries hypoglycemic
liver function tests
arterial blood gas
blood cultures
serum anticonvulsant levels
urine drug/alcohol screen
010 Vital signs Lorazepam 0.1 mg/kg (maximum
Physical exam 4 mg) IVP at 2 mg/minute (may
Patient history including repeat in 1015 minutes to
medications (prescription, maximum of 8 mg if no
OTC, and herbals) response)
If no IV access, can give:
diazepam 10 mg PR (may
repeat in 10 minutes if no
response); midazolam 0.2
mg/kg IM (may repeat in 10
minutes if no response)
1030 Vital signs Phenytoin 1520 mg/kg IV at a
Review laboratory results and correct maximum rate of 50 mg/minute
any underlying abnormalities (or fosphenytoin 1520 mg
CT scan (if seizures controlled) PE/kg IV at a maximum rate of
150 mg/minute)
If no IV access, can give
fosphenytoin IM
Treat for possible infection
3060 Vital signs If seizures continue:
Consult additional phenytoin bolus
neurologist/epileptologist 510 mg/kg
Consider admission to ICU (or fosphenytoin 510 mg
Consider EEG PE/kg) OR start phenobarbital
at 20 mg/kg IV at a maximum
rate of 100 mg/minute
Greater than 60 Vital signs If seizures continue:
refractory Transfer to ICU repeat boluses of phenobarbital
status Obtain EEG 10 mg/kg until seizures stop
epilepticus Consider MRI when controlled OR valproate sodium 20 mg/kg
at 6 mg/kg per minute max
followed by 14 mg/kg per
hour CI OR midazolam
2 mg/kg bolus followed by
0.052 mg/kg per hour CI or
propofol 1 mg/kg bolus followed
by 215 mg/kg per hour CI OR
pentobarbital 1015 mg/kg
bolus over 12 hours followed
by 0.54 mg/kg per hour;
Consider intubation and/or pressor
support if needed
BP, blood pressure; CI, continuous infusion; CT, computed tomography; ECG, electrocardiogram; EEG, electroencephalog-
raphy; HR, heart rate; ICU, intensive care unit; IV, intravenous; IVP, intravenous push; OTC, over the counter; MRI, mag-
netic resonance imaging; PE, phenytoin equivalents; PR, per rectum; RR, respiratory rate; T, temperature.
Adapted from Phelps SJ, Hovinga CA, Boucher BA. Status epilepticus. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.)
Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 1054, with permission.
TABLE 283. Randomized, Prospective Trials Comparing Treatments for Status Epilepticus in Adults
Study Treatment Outcome Adverse Events Comments

Leppik (1983)44 Seizure control Onset did not differ
Diazepam 10 mg 76% 12% between two groups
Lorazepam 4 mg 89% 13%
Shaner (1988)45 Time spent in SE Incidence of intubation, Unblinded study
Goal: Time to Diazepam + phenytoin 9 minutes hypotension, and
seizure control Phenobarbital +/ 5 minutes arrhythmias similar
phenytoin in both groups
Treiman (1998)46 Seizure control Resp/cardiac events Patients with subtle GCSE
Goal: Seizure control Diazepam 0.15 mg/kg + 55.8% 2.131.6% fared worse than patients
within 20 minutes phenytoin 18 mg/kg with overt GCSE
and no recurrence
within 60 minutes
Lorazepam 0.1 mg/kg 64.9% 7.225.8%
Phenobarbital 15 mg/kg 58.2% 3.334.1%
Phenytoin 18 mg/kg 43.6% 6.927%
Alldredge (2001)47 Seizure control Resp/cardiac events Higher doses used in
Goal: Seizure control on Lorazepam 2 mg 59.1% 10.6% hospital for SE
arrival to ED Diazepam 5 mg 42.6% 10.3%
Placebo 21.1% 22.5%
Misra (2006)48 Seizure control Resp/cardiac events As second line agent,
Goal: Seizure control Sodium valproate 30 mg/kg 66% 4%/0% valproate controlled
after infusion Phenytoin 18 mg/kg 42% 14%/14% more seizures than
phenytoin (79% vs 25%)
ED, emergency department; GCSE, generalized convulsive status epilepticus; SE, status epilepticus.
a good response rate (80%) and a relatively benign side-effect EEG monitoring is not immediately available or while waiting for
prole compared to phenytoin and phenobarbital. It can be results. Treatment of RSE consists of continuous intravenous
considered when the use of phenytoin and phenobarbital are infusions of benzodiazepines (midazolam), anesthetic agents
precluded due to allergies or intolerance. Valproate sodium (propofol), or barbiturates (pentobarbital) to suppress all clinical
can be loaded intravenously at 15 to 20 mg/kg and infused at and electrographic evidence of seizures.27 These agents are typically
a rate of up to 3 mg/kg per minute. Higher doses (up to 30 to titrated to achieve burst suppression on the EEG, although no
40 mg/kg) have also been used to attain serum levels of 100 to strong evidence exists to support this as the universal goal.28 Any
150 mcg/mL in less responsive cases of SE.24 AEDs that were started before treatment for RSE should be con-
tinued and their serum levels optimized in order to minimize any
Treatment of Refractory Status Epilepticus breakthrough or withdrawal seizures. Patients should be intu-
Seizure activity that does not respond to benzodiazepines bated and mechanically ventilated before initiating these treat-
(rst-line) and antiepileptics (second-line) or persists beyond 60 ment strategies for RSE. Consultation with a neurologist or
minutes in duration can be considered refractory status epilepti- epileptologist is highly recommended in these cases.
cus (RSE).25 It can occur in up to 30% of patients with SE and
has a mortality rate approaching 50%. Patients in RSE are Midazolam
unlikely to return to their baseline state, even if the seizures are A loading dose of 0.2 mg/kg (repeated up to a maximum of
eventually controlled. As RSE progresses, clinical signs may 2 mg/kg) followed by a continuous infusion of 0.05 to 2 mg/kg
become subtle, and in certain patients, an EEG is required to per hour is recommended in RSE.2931 The dose must be
detect ongoing seizure activity. Even patients without clinical adjusted during prolonged infusions, especially in patients with
signs of seizing are at risk for brain damage or even death. renal impairment, as the active metabolite can accumulate.32
The optimal therapy for RSE has not been determined. Breakthrough seizures are common with midazolam infusions
Clinicians must aggressively investigate and treat possible causes and usually respond to a bolus and a 20% increase in the rate.
including infection, tumors, drugs or toxins, metabolic disorders, Despite this, tachyphylaxis can occur and the patient should be
liver failure, or fever.26 In general, patients with RSE are managed switched to another agent if seizure activity continues.
in an ICU where hemodynamic and respiratory support are
available and frequent monitoring can be performed. Con- Propofol
tinuous EEG monitoring is desirable to document cessation of The anesthetic agent propofol can be started with loading
seizure activity, but treatment should not be delayed if continuous doses of 1 mg/kg repeated every 3 to 5 minutes until a clinical
response is achieved, after which the infusion can be initiated together with its complications when determining which agent
at 2 to 4 mg/kg per hour. Propofol can cause hypotension, to use. Patients who fail midazolam and/or propofol infusions
especially with loading doses. Long-term, high-dose (greater should be switched over to pentobarbital therapy.
than 5 mg/kg per hour) propofol infusions are associated with
rhabdomyolysis, acidosis, and cardiac arrhythmias (propofol Other Agents
infusion syndrome), especially in children.33 Propofol has a Ketamine,37 topiramate, and inhaled anesthetics are newer
very short serum half-life and should be tapered off slowly to modalities that have been used to treat RSE. Ketamine is an
avoid withdrawal seizures. High-dose propofol infusions can NMDA receptor antagonist that has been given orally38 and
also provide a considerable amount of calories (1 kcal/mL of intravenously39 for RSE in children. Topiramate is a newer oral
the 1% solution) over time, so other sources of nutrition may antiepileptic agent with multiple mechanisms of action that may
have to be adjusted accordingly. have some benet in RSE. The dose in adults ranges from 300 to
1600 mg/day.41 Children have also been administered topiramate
Pentobarbital at a starting dose of 2 to 3 mg/kg per day and titrated to a main-
Barbiturate infusions have been reported to be highly success- tenance dose of 5 to 6 mg/kg per day.41 The inhaled anesthetics,
ful in treating RSE,34 but their side effects are considerable. desurane and isourane,42 are normally delivered in an operat-
They can cause signicant hypotension, myocardial and res- ing room, and require special equipment for administration in
piratory depression, ileus, and infection (especially gram-pos- an ICU. Future studies will determine their place in therapy.
itive organisms). As a result, patients often require mechanical
ventilation, intravenous vasopressor therapy, invasive hemo- Special Populations
dynamic monitoring, and total parenteral nutrition while Certain patient populations require special considerations
undergoing barbiturate coma. On the other hand, barbitu- due to their altered metabolism, unique volume of distribu-
rates are benecial if elevated intracranial pressure (ICP) is tion, or increased risk for side effects.43 Although many of
present, as they are effective in decreasing ICP. these patients are excluded from clinical trials in SE, the stan-
Pentobarbital is commonly loaded at a dose of 10 to 15 mg/kg dard algorithm for SE still applies for these patients in terms
over 1 to 2 hours, followed by a continuous infusion of 0.5 to of immediate care, assessment, and drugs (see Table 282).
4 mg/kg per hour. Therapy can be tapered off after 12 to
24 hours of seizure control as evident on the EEG.35 One meta- Pediatrics
analysis reported a lower incidence of treatment failure with The treatment approach of SE in children is similar to that in
pentobarbital (3%) when compared to midazolam (21%) or adults with a few exceptions (Table 284). The doses are also
propofol (20%), although the risk of hypotension requiring weight-based but are typically higher than those used in
vasopressor therapy was higher when pentobarbital was used.36 adults due to higher clearance by the liver. It may be difcult
This relative efcacy for pentobarbital must be considered to rapidly obtain IV access in children, so alternate methods of
TABLE 284. Drugs Used in Pediatric Status Epilepticus
Drug Dose Comments

Diazepam (Valium injection, IV: 0.20.3 mg/kg over 25 minutes Maximum dose in children less than 5 y: 5 mg
Diastat rectal gel) Maximum dose in children greater than 5 y: 15 mg
PR: 25 years: 0.5 mg/kg A second rectal dose can be given 412 hours
611 years: 0.3 mg/kg after the rst dose if necessary
greater than 12 years: 0.2 mg/kg
Lorazepam (Ativan) 0.050.1 mg/kg IV over 24 minutes May redose twice in 1015 minutes if necessary
Midazolam (Versed) 0.2 mg/kg IV bolus followed by 0.050.6 mg/kg Bolus dose may also be given intranasally,
per hour continuous infusion buccally, or intramuscularly
Phenytoin (Dilantin) 1520 mg/kg IV at 13 mg/kg per minute max
Fosphenytoin (Cerebyx) 1520 mg PE/kg IV at 3 mg/kg per minute max Dose can be given intramuscularly
Phenobarbital (Luminal) 1520 mg/kg IV at 100 mg/minute max
Valproate sodium (Depacon) 1520 mg/kg IV at 1.53 mg/kg per minute May have fewer cardiovascular side
effects than other agents
Propofol (Diprivan) Not recommended due to adverse events (e.g.,
rhabdomyolysis)
Pentobarbital (Nembutal) 1015 mg/kg IV over 12 hours followed by Titrated to EEG
continuous infusion at 1 mg/kg per hour
PR, per rectum; EEG, electroencephalograph; IV, intravenous; PE phenytoin equivalent.
drug administration have been studied, including intranasal, with RSE on multiple AEDs, slowly decrease the dose of one
buccal, rectal, and IM. drug at a time while continuing to evaluate the patient for
seizure activity. Base the titration schedule on the half-life of the
Geriatrics drug and individual patient response. The optimal treatment
The elderly are prone to injury and toxicity from multiple con- regimen is one that uses the least medications to prevent seizure
comitant disease states and polypharmacy. Seizures in the eld- recurrence and does not cause adverse drug reactions.
erly can easily arise from metabolic disorders, drug interactions, Continue to monitor AED serum trough concentrations
or even incorrect dosing of medications in patients with approximately every 3 to 5 days until the AEDs have reached
impaired renal and hepatic function and decreased protein steady-state concentrations. Give additional loading doses or
binding. Clinicians treating elderly patients presenting with SE hold doses as needed to maintain trough concentrations in
should investigate drug- and disease stateinduced causes, since the patients therapeutic range. Be sure to evaluate the time
treating these etiologies alone may terminate seizures. Acute the sample was drawn to assure it is a trough level.
treatment with benzodiazepines and AEDs is no different in the Frequently monitor the patient for signs of drug toxicity
elderly, but elderly patients may have a more pronounced reac- and seizures until the patients drug concentrations have sta-
tion to these medications in terms of their sedative and car- bilized. Drug interactions are likely when patients are on more
diorespiratory side effects. Phenytoin and fosphenytoin loading than one AED; therefore, closely evaluate the patients entire
doses should be carefully calculated in the elderly, as their medication prole, and change medications or doses to mini-
weights may be overestimated, and they may not tolerate the mize the interaction, if possible.
commonly ordered 1-g dose. They should also be infused at
slower rates to minimize hypotension and arrhythmias.
Phenobarbital may cause respiratory depression earlier in the Patient Care and Monitoring
elderly, especially after benzodiazepines are administered.
Clinicians should consider using smaller doses and should eval-
uate these patients for renal and hepatic insufciency if 1. Obtain a seizure history from the patient or family mem-
repeated doses are to be given. bers, including precipitating factors and duration of
seizure activity.
Pregnancy
2. Identify the underlying cause of the seizures and correct
The main concern in the treatment of pregnant females in SE the cause, if possible. Does the patient have any labora-
is the safety of the fetus which is at risk of hypoxia during peri- tory abnormalities? Is there a positive toxicology screen
ods of prolonged seizures. Although many of the agents used for alcohol or drugs?
in SE are teratogenic, clinicians should still use them as acute 3. Obtain a thorough history of non-prescription, prescrip-
measures to stop the seizures and consider alternative agents as tion, and alternative or herbal drug use. Determine
maintenance therapy. The volume of distribution and clear- adherence with the medication regimen and whether
ance of many drugs are typically increased during pregnancy, barriers to care exist. Does the patient have the nancial
and this should be considered when calculating doses. ability and transportation to obtain their prescriptions?
4. Assess the AED serum concentration and adjust therapy
as needed for agents with a dened therapeutic range
OUTCOME EVALUATION (e.g., phenytoin, carbamazepine, valproic acid, and phe-
nobarbital). Drug levels can also be used to determine
The success of treatment is measured by the early termina- adherence to medication regimens for agents that do not
tion of seizures, without adverse drug effects or brain injury. have dened ranges.
Therefore, it is essential to start pharmacologic treatment as soon 5. Evaluate the patient for adverse drug reactions, IV site
as possible. First-line treatment for SE should halt seizure activity extravasation and allergic reactions. What alternative
within minutes of administration. In patients who are unarous- AEDs should be used if a drug allergy is identied?
able following treatment, an EEG should be done to rule out con- 6. Determine whether there are any drug interactions with the
tinued excessive electrical brain activity and conrm termination patients current or home medication regimens. Do you
of seizures. A physical exam and evaluation of the patients labo- need to adjust the dose of any medications for toxic or
ratory results can help determine if the cause or complications of subtherapeutic concentrations from the drug interaction?
seizure activity are being appropriately treated. 7. Maintain adequate cardiovascular support, nutrition, and
Once seizure activity has ceased and the patient has stabi- electrolyte and glucose serum concentrations to prevent
lized, review the patients therapeutic regimen. Evaluate and recurrence of seizure activity.
monitor the serum trough concentrations of AEDs with 8. Continue to evaluate the patient for seizure activity and
dened target ranges to determine patient-specic therapeutic adjust therapy as needed to control seizures and opti-
ranges. If there is a known cause of SE, simplify the treatment mize quality of life.
regimen once the underlying cause has been treated. In patients
ABG: arterial blood gas Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam,
AED: antiepileptic drug diazepam, and placebo for the treatment of out-of-hospital status
CNS: central nervous system epilepticus. N Engl J Med 2001;345:631637.
CSF: cerebrospinal uid Bleck TP. Refractory status epilepticus. Curr Opin Crit Care
CT: computerized tomography 2005;11:117120.
ECG: electrocardiogram Claassen J, Hirsch LJ, Emerson RG, et al. Treatment of refractory sta-
EEG: electroencephalography tus epilepticus with pentobarbital, propofol, or midazolam: a
GABA: -aminobutyric acid systemic review. Epilepsia 2002;43:146153.
GCSE: generalized convulsive status epilepticus Limdi NA, Shimpi AV, Faught E, et al. Efcacy of rapid IV adminis-
ICP: intracranial pressure tration of valproic acid for status epilepticus. Neurology
ICU: intensive care unit 2005;64:353355.
IM: intramuscular Lowenstein D, Bleck T, MacDonald RL. Its time to revise the de-
IV: intravenous nition of status epilepticus. Epilepsia 1999;40:120122.
MRI: magnetic resonance imaging Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med
NCSE: non-convulsive status epilepticus 1998;338:970976.
NMDA: N-methyl-D-aspartate Marik PE, Varon J. The management of status epilepticus. Chest
PE: phenytoin equivalent 2004;126:582591.
RSE: refractory status epilepticus Mayer SA, Claassen J, Lokin J, et al. Refractory status epilepticus.
SE: status epilepticus Arch Neurol 2002;59:205210.
WBC: white blood cell Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status
epilepticus: A pilot study. Neurology 2006; 67: 340342.
Reference lists and self-assessment questions and answers are Pryor FM, Gidal B, Ramsay RE, et al. Fosphenytoin: pharmacokinet-
available at www.ChisholmPharmacotherapy.com. ics and tolerance of intramuscular loading doses. Epilepsia
2001:42:245250.
Treiman DM, Meyers PD, Walton NY, et al. A comparison of four
treatments for generalized convulsive status epilepticus. N Engl
for information on obtaining continuing education credit for J Med 1998;339:792798.
this chapter.
29 PARKINSONS DISEASE
Mary L. Wagner
LEARNING OBJECTIVES
1. Explain the etiology of Parkinsons disease.

2. Explain the pathologic and biochemical changes in patients with Parkinsons disease.
3. Identify motor and non-motor symptoms of Parkinsons disease as well as symptoms that
indicate disease progression.
4. Explain the desired therapeutic goals for patients with Parkinsons disease.
5. Recommend lifestyle modications and pharmacotherapy interventions for treating motor
symptoms of patients with Parkinsons disease.
6. Recommend drug and non-drug interventions for treating the non-motor symptoms of
patients with Parkinsons disease.
7. Develop a monitoring plan to assess effectiveness and adverse effects of nonpharmacologic
therapy and pharmacotherapy for Parkinsons disease.
8. Educate patients about the disease state, appropriate lifestyle modications, and drug
therapy required for effective treatment.
KEY CONCEPTS The best time to initiate dopaminergic therapy is controversial

and patient-specic. Generally, medication is started when the
Patients with Parkinsons disease display both motor and non- patients physical impairment affects quality of life.
motor symptoms. The non-motor symptoms may precede the Medication schedules should be individualized. The doses are
motor symptoms. divided throughout the day to maximize on and minimize off
The most useful diagnostic tool is the clinical history, includ- periods.
ing both presenting symptoms and associated risk factors. The The treatment of non-motor symptoms should be based on
Unied Parkinsons Disease Rating Scale (UPDRS) is used to whether they are worse during an off state or if they could be
dene the degree of disability. related to other neurotransmitter dysfunction.
The goals of treatment are to maintain patient independence, As the disease progresses, most patients develop response uc-
activities of daily living (ADL), and quality of life (QOL) by tuations. Treatment is based on optimizing the pharmacoki-
alleviating the patients symptoms, minimizing the develop- netic and pharmacodynamic properties of Parkinsons disease
ment of response uctuations, and limiting medication-related medications.
adverse effects. Patient monitoring should involve a regular systematic evalu-
The treatment of Parkinsons disease is categorized into three ation of efcacy and adverse events, referral to appropriate
phases: specialists, and patient education.
Lifestyle changes, nutrition, and exercise
Parkinsons disease (PD) is a slow, progressive, neurodegenera-
Pharmacologic intervention, primarily with drugs that
tive disease of the extrapyramidal motor system. Dopamine
enhance dopamine concentrations
neurons in the substantia nigra are primarily affected, and
Surgical treatments for those who fail pharmacologic
degeneration of these neurons causes a disruption in the ability
interventions
473
dysfunction, increased concentrations of excitotoxic amino

Patient Encounter, Part 1 acids and inammatory cytokines, immune system disorders,
trophic factor deciency, signal-mediated apoptosis, and envi-
ronmental factors. Conditions that may promote oxidative
stress include increased monoamine oxidase B metabolism or
MW, a 65-year-old man with a 2-year history of mild depres-
sion comes for an initial visit to evaluate his symptoms of
decreased glutathione clearance of free radicals which can
tremor and slowness. The tremor started in his right hand promote cell dysfunction and death. Environmental toxins
about 6 months ago, and he does not remember how long include 1-methyl-4-phenyl-1-2-5-6-tetrahydropyridine (MPTP),
he has been slower at completing his tasks. His wife reports carbon monoxide, manganese, methanol, hydrogen sulde,
that for the last 4 months he has been slower and that he petrochemicals and pesticides, but they have never been
kicks her while they are sleeping. clearly proven as causative. Drugs that deplete central dopamine,
such as some antipsychotics, amoxapine, antinausea drugs (i.e.,
Identify the motor and non-motor symptoms of Parkinsons prochlorpromazine) and metoclopramide, worsen Parkinsons
disease. symptoms.1,2,3
What additional information would you collect before Pathology studies of patients with PD indicated that there
creating this patients treatment plan?
is a loss of pigmented cells in the substantia nigra that make
and store dopamine. When patients are diagnosed with PD,
they have lost 50% to 60% of their dopamine neurons in the
substantia nigra, and the remaining neurons may not function
to generate body movements. There is no cure for PD and well, as they have lost about 80% of their activity in the stria-
treatment is aimed at controlling symptoms and slowing dis- tum. There may be cortical Lewy bodies along with Lewy neu-
ease progression. rites seen in microscopic samples from the medial temporal,
limbic, and frontal areas of the brain, gastrointestinal tract,
and peripheral autonomic nervous system that may explain
EPIDEMIOLOGY AND ETIOLOGY some of the non-motor symptoms of PD.24
PD affects approximately one million Americans (1% of people

over 60 years of age). The average age of onset is 60 years of PATHOPHYSIOLOGY
age, and PD is fairly uncommon in those under age 40. The
etiology of PD is unknown, but genetic predisposition, The extrapyramidal motor system controls muscle move-
environmental factors, or combinations of these have been ment through a system of pathways and nerve tracts that
proposed to explain why nerve cells in the substantia nigra connect the cerebral cortex, basal ganglia, thalamus, cerebel-
deteriorate. About 15% of patients with PD have a rst-degree lum, reticular formation, and spinal neurons. Patients with
relative with the disease. The pathogenesis of cell death (neuron PD lose dopamine neurons in the substantia nigra, which is
degeneration) may be due to oxidative stress, mitochondrial located in the midbrain within the brain stem. The substantia
Clinical Presentation of Parkinsons O = Other miscellaneous symptoms (problems with nausea,

Disease fatigue, speech, pain, dysesthesias, vision, seborrhea)
A = Autonomic symptoms (drooling, constipation, sexual
dysfunction, urinary problems, sweating, orthostatic
Patients with PD display both motor and non-motor symp- hypotension, dysphagia)
toms. The non-motor symptoms may precede the motor P = Psychological symptoms (anxiety, psychosis, cognitive
symptoms. impairment, depression)
Motor Symptoms (TRAP)7 Response Fluctuations (MAD)
T = Tremor at rest (pill rolling) M = motor uctuations (delayed peak, wearing off, random
R = Rigidity (stiffness and cogwheel rigidity) off, freezing)
A = Akinesia or bradykinesia A = akathisia
P = Postural instability and gate abnormalities D = dyskinesias (chorea, dystonia, diphasic dyskinesia)
Non-motor Symptoms (SOAP)
S = Sleep disturbances (insomnia, rapid eye movement sleep
behavioral disorder, restless legs syndrome)
CHAPTER 29 / PARKINSONS DISEASE 475
FIGURE 291. Anatomy of the extrapyramidal system.

The extrapyramidal motor system controls muscle
movement through a system of pathways and nerve
tracts that connect the cerebral cortex, basal ganglia,
Thalmus
thalamus, cerebellum, reticular formation, and spinal
Corpus striatum neurons. Patients with Parkinsons disease have a loss
of dopamine neurons in the substantia nigra in the
Nigrostriatal fibers
brain stem that leads to depletion of dopamine in the
corpus striatum. The corpus striatum is made up of the
Amygdala caudate nucleus and the lentiform nuclei that are
made up of the putamen and the globus pallidus.
Spinal cord
Cross-section
of the
Substantia Nigra brainstem
nigra sends nerve bers up to the corpus striatum, which is Patients feel slowed down or trapped in their body unable to
part of the basal ganglia in the cerebrum. The corpus stria- move. The tremor of PD occurs during rest and disappears
tum is made up of the caudate nucleus and the lentiform with purposeful movement. Tremor usually affects the hands
nuclei that consist of the pallidum (globus pallidus) and puta- or feet, but may occur in other body parts such as in the lip
men (Fig. 291). As dopamine neurons die, dopamine-relayed and chin. The hand tremor can appear as if the patient is
messages cannot communicate to other motor centers of the rolling a pill between their ngers. Patients describe rigidity as
brain and patients develop motor symptoms. A variety of stiffness. Upon physical exam, it feels like uniform resistance
chemicals are active in the basal ganglia including acetyl- as the muscles seem to be in a constant state of increased tone.
choline, histamine, glutamate, serotonin, dopamine, norepi- It is dened as cogwheel rigidity when the examiner extends
nephrine, epinephrine, -aminobutyric acid (GABA), or exes the patients extremities and feels as if they are rhyth-
enkephalins, substance P, and adenosine. Some of these neu- mically hitting a series of teeth on the rim of a wheel, or a gear
rotransmitters also decrease in concentration as other brain that is meshing with another gear with teeth. Bradykinesia is
regions degenerate resulting in degeneration of norepineph- noted when there is hesitancy in movement initiation, slow-
rine neurons in the locus ceruleus and acetylcholine neurons ness in movement performance, or rapid fatiguing during
in the nucleus basalis as well as selected neurons of the dor- movement. Patients may have a decrease in automatic move-
sal motor nucleus of the vagus, spinal cord, and peripheral ments, such as blinking, a decrease in facial expressions (often
autonomic system. Decreases in these neurotransmitters may termed masked facies), or a decrease in arm swing while
explain some of the non-motor symptoms of PD.3 For exam- walking. Postural instability is a result of the loss of reexes
ple, loss of dopamine and norepinephrine neurons in the necessary to maintain balance when standing or ambulating.
limbic system has been associated with depression and anxi- Patients may report a feeling of unsteadiness. Gait abnor-
ety, and neuron loss in the hippocampus and amygdala of the malities may be evidenced by shufing, leg dragging, festina-
limbic system is associated with cognitive impairment.5,6 tion, propulsion, retropulsion, or freezing. Rigidity and
bradykinesia may make handwriting difcult as evidenced
by micrographia.2,8
Non-motor Symptoms
As the onset of PD is insidious, patients are likely to rational-
ize other causes for their symptoms. A thorough patient his- Non-motor symptoms are due to multiple neurotransmitter
tory including past and present medications, family history, abnormalities throughout the brain, and some symptoms may
environmental exposure, and a detailed description of symp- be aggravated by PD medications. Sleep disturbance can affect
tom onset is essential in making an accurate diagnosis. more than 70% of PD patients and includes insomnia, sleep
fragmentation, rapid eye movement sleep behavioral disorder levodopa is administered and the plasma concentrations are sup-
(RBD), vivid dreams, nightmares, night terrors, hallucinations, plemented by the brains supply of dopamine. Thus, although the
restless legs syndrome (RLS), and sleep walking. Speech prob- plasma half-life of levodopa is 1.5 to 2 hours, the therapeutic
lems may be exhibited as a decrease in normal volume, slur- effect lasts about 5 hours, and the patient experiences no
ring, monotone speech, rapid speech, or stammering. Visual dopamine side effects.As the disease progresses over time, the ther-
problems such as reading problems, double vision, perceptual apeutic window narrows because the brain can no longer supple-
changes, decreased blink, burning eyes, or itchy eyes are the ment each levodopa dose with additional dopamine. Thus, during
result of impaired function of the muscles that move the eye- advanced disease, each dose lasts 2 to 3 hours and patients
ball and decreased retinal dopamine.711 experience dopamine side effects in order to be in an on
As the autonomic system is disturbed in patients with PD, state.1516
orthostatic hypotension and gastrointestinal, urinary, sexual,
and dermatologic symptoms are common. Patients with ortho-
The most useful diagnostic tool is the clinical history,
including both presenting symptoms and associated risk factors.
static hypotension may experience dizziness, lightheadedness,
The UPDRS is used to dene the degree of disability in motor
or fainting upon standing. Gastrointestinal symptoms include
and some non-motor symptoms.
constipation and dysphagia due to a slowing of the automatic
pattern of contraction and relaxation of the throat muscles.
These swallowing difculties may lead to weight loss, sialor-
rhea, and aspiration. Genitourinary symptoms include urinary Patient Encounter, Part 2: The Medical
incontinence, urgency, and frequency related to overactivity of History, Physical Exam, and Diagnostic
the bladder emptying reex. Symptoms may be worse at night, Tests
causing nocturia. Sexual dysfunction includes decreased libido,
erectile dysfunction, and delayed ejaculation. Skin symptoms Chief Complaint
include sweating, and intolerance to heat and cold.7,8,11,12 MW complains of stiffness, slow movements, and mild
Psychological symptoms may be exaggerated during the tremor that worsens his handwriting
patients off periods and include psychosis, dementia, impaired PMH
cognitive function, depression, and anxiety. Psychosis can Depression for 2 years
occur in nearly 30% of PD patients and is exhibited as vivid SH
dreams, hallucinations (usually visual), paranoia, and delusions. After owning a dry cleaning store for 40 years, he is
Hallucinations may be more common when the patient is in thinking about retiring because he does not enjoy visiting
dim light, falling asleep, or awakening. Dementia occurs in 20% with the customers anymore; he does not smoke or drink
to 44% of patients, and is described as problems with cognitive alcohol
function. Depression occurs in 30% to 70% of PD patients and Meds
may appear as apathy, psychomotor slowing, memory problems, Fluoxetine 10 mg every morning for 2 years
irritability, or sadness. It may be associated with agitation and Gen: Pessimistic attitude, apathetic, looks older than stated
sleep disturbances. Some features of PD, such as the decreased age, slow movements, thin
facial expression and bradykinesia, may make the diagnosis of PE
depression more difcult. Anxiety may present as panic attacks, VS: Blood pressure: sitting 130/80 mm Hg, standing 110/80
phobia, or generalized anxiety and occurs in 30% of patients. mm Hg (with orthostatic symptoms); pulse 78 beats per
Anxiety was noted in 66% of patients with motor uctuations minute, respiratory rate 16/minute, Wt 65 kg (143 lbs)
and is often comorbid with depression.79,11,13,14 CV: RRR, normal S1, S2; no murmurs, rubs, gallops
Abd: Soft, non-tender, non-distended; (+) bowel sounds, no
Response Fluctuations hepatosplenomegaly
Skin: Scalp itchy, oily, and aky silverish scales
Response uctuations occur with disease progression as the Exts: Tremor in right hand and foot while sitting, cogwheel
patients dopamine reserves are depleted in the brain and as a rigidity in right elbow
complication of PD treatment. Motor uctuations include Neuro: Steady gait, sensory function intact, alert, normal
delayed peak response, early wearing off, random unpredictable mental status, UPDRS = 10 while on
on-off, and freezing. Dyskinesias include chorea, dystonia, Labs
and diphasic dyskinesia. Wearing off can be visualized by Within normal limits
imagining the therapeutic window of dopamine narrowing
over time. The therapeutic window is dened as the minimum Assess the patients condition.
effective concentration of dopamine required to control PD Identify treatment goals for the patient.
symptoms (on without dyskinesia) and the maximum concen- Describe nonpharmacologic and pharmacologic treatments
tration before experiencing side effects from too much that are available for the patient.
dopamine (on with dyskinesia). Early in the disease, a dose of
The patients degree of disability should be evaluated by and weight loss. Patients should eat a balanced diet and take a
using the UPDRS which has six parts. The scale combines daily multivitamin if they do not eat well. Nutritionists can
patient history and a physical examination that is performed help with meal selection, products to boost calories, and sug-
on both sides of the body, as symptoms may appear asymmet- gestions for arranging the proper protein content of meals so
ric in early disease. It evaluates mentation, behavior, and mood as not to interfere with medication absorption. Speech ther-
(Part 1); activities of daily living (ADL, Part 2); PD motor apy may improve swallowing, articulation, and the force of
symptoms (Part 3); complications of therapy (Part 4); modi- speech. The therapist can perform swallowing studies that
ed Hoehn and Yahr stage of disease (Part 5); and Schwab and assess the patients risk of aspiration.
England ADL (Part 6). The modied Hoehn and Yahr staging An exercise program and increased activity during the day
scale denes eight stages of PD ranging from no symptoms to should minimize daytime sleepiness, possibly improve sleep at
wheelchair or bed bound. A copy of the exam can be obtained night, and may be neuroprotective. Maintaining a daily routine
at http://www.mdvu.org/pdf/updrs.pdf.17 that allows patients to remain as independent as possible is of
psychological and physical importance. Stretching, strengthen-
ing, and balance training should be encouraged, as well as pro-
TREATMENT
grams that enhance cardiovascular tness. Therapists can teach
patients skills that would improve motion and reduce the risk of
Desired Outcomes
falling. Patients PD symptoms improve with physical therapy
The goals of treatment are to maintain patient indepen- and return to baseline when physical therapy is stopped.1,8,19
dence, ADL, and QOL by alleviating the patients symptoms, min- Occupational therapy may improve condence and ability
imizing the development of response uctuations, and limiting to stay active. Therapists can provide information about adap-
medication-related adverse effects. tive equipment for the home, specialized clothing, and per-
sonal training that can maximize a patients independence,
General Approach to Treatment safety, and ADLs. They can help improve handwriting and
train patients to use special computer programs that enhance
The treatment of PD is categorized into three phases:
communication.
Maintaining social interactions helps overall well being; thus,
Lifestyle changes, nutrition, and exercise
patients should resist the temptation to withdraw from activi-
Pharmacologic intervention, primarily with drugs that
ties. Maintaining good communication with a spouse regarding
enhance dopamine concentrations
sexual issues may prevent conicts, and clinicians should
Surgical treatments for those who fail pharmacologic interventions
remind patients of this. Social workers help patients and their
families cope with their condition and handle problems related
The initial therapeutic modality selected depends in part on
to disease progression. They can provide family counseling and
the patients age, risk of psychiatric adverse effects, and degree
help arrange for special community assistance programs.
of physical impairment. The current approach to treatment is
to delay medication therapy until the symptoms begin to inter-
fere with the patients ability to function or impact their QOL. Surgery
Surgical treatment is for patients with persistent and disabling
Nonpharmacologic Therapy motor uctuations despite maximizing medications. Patients
need an intact cognition as determined by neuropsychological
Lifestyle Modications testing. Surgical procedures include ablative lesioning such as
Lifestyle modications should be started early and continued pallidotomy or thalamotomy, and deep brain stimulation.
throughout treatment because they may improve ADL, gait, Pallidotomy helps mostly tremors and drug-induced dyskine-
balance, and mental health. The most common interventions sia, whereas thalamotomy is benecial to tremor only. Deep
include maintaining good nutrition, physical condition, and brain stimulation has become the surgery of choice, as it is less
social interactions. Patients should avoid medications that traumatic and may be individualized to treat patient-specic
block central dopamine, as they may worsen PD.1,18 A multi- symptoms. It involves the implantation of a high-frequency
disciplinary approach using the expertise of nutritionists, device that provides electrical stimulation of the globus pal-
speech therapists, physical therapists, occupational therapists, lidus and subthalamic nucleus. Patients can expect a 40% to
and social workers may optimize care but may not be covered 75% decrease in symptoms.2,20,21
by insurance. Patients should maintain regular visits with their
optometrist or ophthalmologist and their dentist. The dentist
should be informed that the patient has PD, as PD medications
that decrease saliva ow may increase the risk of dental caries. The best time to initiate dopaminergic therapy is contro-
Dietary modication can improve constipation, nausea, versial and patient-specic. Generally, medication is started
erratic drug absorption, and minimize the risk of aspiration when the patients physical impairment affects QOL.
Medication schedules should be individualized. The doses dopamine agonist in preference to levodopa/carbidopa may
should be divided throughout the day to maximize on and min- result in less motor benet and greater risk of hallucinations
imize off periods. or somnolence. Levodopa results in greater motor improve-
Pharmacologic options include anticholinergic drugs, ment and should be used as initial therapy in the elderly
amantadine, MAO inhibitors, dopamine agonists, levodopa/ (greater than 75 years of age) and in those with cognitive
carbidopa, and catechol-o-methyltransferase (COMT) inhibitors. impairment. There is no preference for using controlled-
Medications help relieve symptoms, improve QOL, and may release over immediate-release levodopa as initial therapy.
lengthen life expectancy, but they are not curative, as treated There are insufcient data to recommend initiating treatment
PD patients still die earlier than controls.1 Medications pri- with both levodopa and a dopamine agonist. Initiating treat-
marily work by enhancing the concentration of dopamine in ment with anticholinergic medications, amantadine, or selegi-
the brain. Knowing how dopamine is metabolized and how line are only for patients who have mild symptoms, as they are
drugs affect dopamine metabolism is important in under- not as effective as dopamine agonists.1,22,23
standing the pharmacology of PD medications (Fig. 292). Medications should be started at the lowest dose and increased
Which medication to select for initial therapy is also contro- gradually based on the patients symptoms (Table 291). When
versial, but the American Academy of Neurology and the interviewing patients, ask the following questions for each sched-
Movement Disorder Society determined that it is reasonable uled dose before adjusting the dose or timing of medications:
to start with levodopa or a dopamine agonist. Starting treat-
ment with a dopamine agonist rather than levodopa may help When did the dose start to work and how long did it last?
to delay the onset of dyskinesias and the on/off uctuations How did you feel just before the dose, and during the dosing
commonly seen with long-term levodopa use. The use of a period?
Gastro intestinal tract Plasma compartment Brain compartment
Gut Epithelium Blood brain barrier
Stomach
3OMD 3OMD
Gastric
emptying
COMT COMT
Levodopa Levodopa
Sinemet Other
absorbed DDC
DDC
Small intestine Carbidopa
Dopamine Dopamine
Key MAOB COMT

Sinemet Levodopa/Carbidopa DDC = dopadecarboxylase
3OMD = 3omethyldopa
Food COMT = catechol-o-methyl transferase HVA
MAOB = monoamine oxidase
Active transport mechanism HVA = homovanillic acid
FIGURE 292. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma
and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase,
and catechol-O-methyltransferase. Carbidopa does not cross the bloodbrain barrier. Large, neutral amino acids in food compete with
levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain
(plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in
the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes
before or 60 minutes after meals.
TABLE 291. Mechanism of Action and Dosing of Medications to Treat Parkinsons Disease1,2,16,25,29,31,36
Generic Name (Trade Name) Mechanism of Action and Receptor Specicity Dosing
Levodopa (Larodopa, Dopar) LD metabolized to DA Start with Sinemet 1/2 tab (100 mg LD, 25 mg CD) twice daily for 1 week,
Carbidopa (Lodosyn) CD blocks peripheral conversion of LD to DA then 1/2 tab three times daily; then, increase by 1/2 tab daily every week;
and increases LD CNS penetration usual MD is 3002000 mg daily; since the duration of LD is 2 to 3 hours,
patients may require doses every 2 hours
Levodopa/Carbidopa (Sinemet) Standard, immediate-release LD Sinemet CR: Start with 1 tab (100 mg LD, 25 mg CD) two or three times daily;
(ParcopaTM with phenylalanine) Rapid-dissolving LD as symptoms increase, use 200 mg LD tab 24 times daily; usual MD is
(Sinemet CR) Controlled-release LD 2002200 mg daily
Apomorphine (Apokyn) Activate postsynaptic D1 and D2 DA receptors Start an antiemetic for 3 days, then give apomorphine 2 mg SC injection (1 mg
if outpatient) while monitoring blood pressure; then increase by 1 to 2 mg
every 2 or more hours; usual MD is 26 mg 35 times daily for off periods
Pergolide (Permax) Activate postsynaptic D1 and D2 DA receptors Start with 0.05 mg daily and increase by 0.050.15 mg daily every few days
over several weeks to a usual MD of 0.51 mg three times daily (maximum
5 mg daily)
Bromocriptine (Parlodel) Activate postsynaptic D2 and blocks Start with 1.25 mg daily at bedtime, then 1.25 mg twice daily; on week 2,
D1 DA receptors increase to 2.5 mg twice daily, then increase by 2.5 mg daily every 24 weeks
up to 1545 mg daily divided 23 times daily
Pramipexole (Mirapex) Activate postsynaptic D2 DA receptors Start with 0.125 mg three times daily; increase about weekly by 0.3750.75
mg/day to a MD of 0.51.5 mg three times daily; dosage reduction needed in
patients with creatinine clearance less than 60 mL/minute
Ropinirole (Requip) Activate postsynaptic D2 DA receptors Start with 0.25 mg three times daily; increase about weekly by 0.751.5 mg
daily to a MD dose of 38 mg three times daily
Selegiline (Eldepryl) Blocks MAOB metabolism and presynaptic Start with 5 mg in the morning; if symptoms continue, add 5 mg at noon; 5 mg
reuptake of DA in the brain daily may be as clinically effective as 10 mg daily with fewer side effects
(Zelapar with phenylalanine) Rapid-dissolving selegiline Start with 1.25 mg every morning before breakfast; if symptoms continue after
6 weeks, increase dose to 2.5 mg every morning. Avoid food or liquid for
5 minutes before or after the dose
Rasagaline (Azilect) Blocks MAOB metabolism Start with 0.5 mg daily if symptoms continue, increase to 1 mg daily
Tolcapone (Tasmar) Peripherally blocks COMT metabolism of DA; Start with 100 mg with rst Sinemet dose once daily; if symptoms continue,
some central activity increase to 2 and then 3 times daily, then to 200 mg each dose; usual MD
is 100 three times daily to minimize risk of side-effects
Entacapone (Comtan) Peripherally blocks COMT metabolism of DA Take a 200-mg tab with each Sinemet dose up to 8 tabs daily; usual MD is
200 mg 34 times daily; decrease dose by 50% with hepatic impairment
CD/LD/Entacapone (Stalevo) See CD, LD, and entacapone Usual MD is 3001200 mg LD daily; the largest strength tab contains 150 mg
LD and 200 mg entacapone; patients requiring larger LD doses will need
additional LD medication; titrate as with LD
Amantadine (Symmetrel) NMDA-receptor antagonist that blocks glutamate Start with 100 mg daily at breakfast; after 1 week, add 100 mg daily in the
transmission, promotes DA release, and blocks Ach early afternoon; decrease dose as creatinine clearance decreases less than
Anticholinergics (various, including Block Ach, decrease Ach: DA ratio 80 mL/minute
trihexyphenidyl, benztropine)
Ach, acetylcholine; CNS, central nervous system; CD, carbidopa; COMT, catechol-O-methyltransferase; D1, a class of dopamine receptors which includes D1 and D5 subtypes; D2, a class
of dopamine receptors which includes D2, D3, and D4 subtypes; DA, dopamine; LD, levodopa; MAO, monoamine oxidase; MD, maintenance dose; NMDA, N-methyl-D-aspartate.
479
If the dose did not last long enough, consider adding another Side effects of selegiline include nausea, confusion, halluci-
dose each day, higher individual doses, an additional agent, or nations, headache, jitteriness, and orthostatic hypotension.
changing to a longer-acting dosage form. If the patient experi- Selegiline is metabolized to amphetamines which may cause
ences side effects related to excessive dopamine concentrations insomnia, and should not be dosed in the afternoon or evening.
(i.e., dyskinesia), consider decreasing the dose, increasing the time Doses are limited to 10 mg daily, as MAOB selectivity may be
interval between doses, or decreasing the use of concomitant lost at higher doses increasing the risk of adverse effects and
medications that augment dopamine concentrations. A sample drug interactions. Rasagaline is not metabolized to ampheta-
diary for monitoring symptoms can be found at www. mine; thus, there is less risk of insomnia, and it may be neuro-
sinemetcr.com/cross_site/DiaryChart.shtml. protective. Treatment-limiting side effects in clinical trials
included diarrhea, weight loss, hallucinations, and rash. The
Anticholinergics MAOB selectivity of rasagaline in humans and sensitivity to
Anticholinergics may minimize resting tremor and drooling, tyramine has not been well dened. Therefore, the manufac-
but they are not as good as other agents in controlling rigidity, turer recommends that patients restrict the intake of tyramine-
bradykinesia, and gait problems. Anticholinergics should be containing foods and medications that contain amines.
discontinued gradually to avoid withdrawal effects or worsen- Dyskinesias can be minimized by decreasing the levodopa dose
ing of PD symptoms. Side effects of anticholinergics include when adding either of these agents. Patients should avoid or use
dry mouth (decreased saliva), blurred vision, constipation, cog- these medications cautiously with narcotic analgesics, antide-
nitive impairment (forgetfulness, confusion, and hallucina- pressants, or sympathomimetic amines (cold and weight loss
tions), urinary retention, orthostatic hypotension, temperature products). Drugs that inhibit CYP1A2, such as ciprooxacin,
sensitivity, and sedation. They are usually avoided or used with will increase serum rasagaline concentrations.1,2,7,8,16,18,22,25
caution in patients older than 70 years of age because of an
increased risk of cognitive impairment. Use of anticholinergics Dopamine Agonists
is associated with an increased incidence of amyloid plaques Dopamine agonists are useful as initial therapy, as they can
and neurobrillary tangles in patients with PD that may trans- delay the need to start levodopa and can decrease the risk of
late to an increased risk of Alzheimers disease.1,2,7,8,2427 developing motor uctuations by two- to threefold during the
rst 4 to 5 years of treatment. After a few years, dopamine ago-
nists inadequately control the patients symptoms and levodopa
Amantadine
needs to be started. In advanced disease, dopamine agonists can
Amantadine improves PD symptoms in mildly affected patients
be added to levodopa because they have a longer duration of
and reduces motor uctuations in patients with more advanced
action, minimize uctuations in dopamine blood concentra-
disease. Amantadine may minimize or delay the development
tions, decrease off-time, improve wearing-off symptoms, allow
of motor complications, as levodopas pulsatile stimulation of
a reduction in levodopa dose, and improve ADLs.13,16,22,23,26
dopamine receptors is associated with N-methyl-D-aspartate
Dopamine agonists include the ergot derivatives (per-
receptor changes and resultant motor complications. Patients
golide, bromocriptine, and cabergoline) and the non-ergot
who develop tolerance to amantadines effects may benet from
derivatives (rotigotine, pramipexole, ropinirole, and apomor-
a drug holiday. Doses need to be reduced in patients with renal
phine). Rotigotine is an investigational once-daily skin patch.
impairment. When stopping amantadine, gradually discontinue
Generally, all are equally effective except bromocriptine,
the drug to minimize potential withdrawal effects. Side effects
which is the least effective. There are ve subtypes of
include nausea, dizziness, livedo reticularis (purple mottling of
dopamine receptors that are divided into two classes called D1
the skin), peripheral edema, orthostatic hypotension, halluci-
(D1 and D5 subtypes) and D2 (D2, D3, and D4 subtypes).
nations, restlessness, and anticholinergic effects (confusion and
Receptor selectivity may result in subtle differences between
sedation). Its stimulant action may worsen insomnia, so aman-
the products, as pramipexole is thought to have an antide-
tadine should not be dosed in the evening. It should be avoided
pressant effect because it has greater D3 receptor afnity.
in the elderly who cannot tolerate its anticholinergic effects. It
Ropinirole and pergolide may also have higher D3 specicity,
should be used cautiously with memantine, as there may be an
but less than pramipexole. Pergolide and apomorphine are
increased risk of psychosis.1,2,7,8,16,18,22,2426,28
also D1 agonists which may optimize their effect. Cabergoline,
a very long-acting agonist, is effective for PD, but it is
MAOB Inhibitors approved for hyperprolactinemia instead of PD. If patients fail
MAOB inhibitors include selegiline and rasagaline. They may one dopamine agonist, another can be tried. Although not
provide mild symptomatic benet for those patients who well established, it appears that bromocriptine 30 mg, ropini-
choose to delay dopaminergic medications. Combining selegi- role 15 mg, pramipexole 4.5 mg, and pergolide 3 mg are
line or rasagaline with levodopa in early treatment may delay equivalent and can be a guide when switching agents.16,25,29
motor complications. In patients with advanced disease, they Common side effects include nausea, vomiting, sedation
decrease off time and improve wearing-off symptoms in patients (highest with apomorphine), pedal edema, orthostatic
with motor uctuations. hypotension (highest with pramipexole and cabergoline), and
psychiatric effects that are greater than with levodopa (night- started 3 days prior to starting apomorphine and continued
mares, confusion, and hallucinations). Obsessive-compulsive for 2 months or until tolerance to the nausea develops. It
behaviors such as pathologically excessive gambling, shopping, should be used with caution in patients receiving antihyper-
sexual desire, or eating may occur. Reducing or eliminating the tensives or drugs that increase the QT interval. Patients who
agonist will usually resolve the problem.26,30,31 Ergot side effects are allergic to sultes may be allergic to apomorphine.36
are uncommon but include painful reddish discoloration of
the skin over the shins and pleuropulmonary, retroperitoneal, Levodopa/Carbidopa
and cardiac brosis.1,16,25 Levodopa, a dopamine precursor, is the most effective agent for
In addition, pergolide, and possibly other ergot dopamine ago- PD. Patients experience a 40% to 50% improvement in motor
nists, may cause a thickening and restriction in cardiac valves in function. It is absorbed in the small intestine and peaks in the
33% of patients. As of March 2007, the manufacturers of pergolide plasma in 30 to 120 minutes. A stomach with excess acid, food, or
voluntarily withdrew their drug from the market because of this anticholinergic medications will delay gastric emptying time and
risk. It may remain available under an Investigational New Drug decrease the amount of levodopa absorbed. Antacids decrease
Application. It is hypothesized that ergot derivatives stimulate stomach acidity and improve levodopa absorption. Levodopa
5-HT2B serotonin receptors that promote brotic lesions. While requires active transport by a large, neutral amino acid trans-
there are no specic guidelines, many specialists obtain a baseline porter protein from the small intestine into the plasma and
echocardiogram when starting pergolide, or get one as soon as from the plasma across the bloodbrain barrier into the brain
possible if the patient is already receiving pergolide. If there are (Fig. 292). Levodopa competes with other amino acids, such as
no specic abnormalities of concern, the echocardiogram should those contained in food, for this transport mechanism. Thus, in
be repeated yearly while the patient receives pergolide. If valvular advanced disease, adjusting the timing of protein-rich meals in
regurgitation is detected, and determined to be signicant by the relationship to levodopa doses may be helpful. Levodopa also
cardiologist, pergolide should be discontinued. The risk is greater binds to iron supplements and administration of these should be
in patients receiving doses higher than 5 mg/day.1,2,29,32 spaced by at least 2 hours from the levodopa dose.1,8,16,25
Excessive daytime sleepiness occurs in 15% to 20% of PD The controlled-release (CR) formulation is more slowly
patients and can be aggravated by all dopaminergic drugs. absorbed and longer acting than immediate-release tablets.
Sleep attacks without warning may occur in up to 6% of Patients need to increase the total daily dose by 30%, as it is not
patients. Patients at greatest risk of sleep attacks are those with as bioavailable as the immediate-release levodopa/carbidopa.
an Epworth Sleepiness Scale score more than 10 The CR formulation has a delayed onset (45 to 60 minutes)
(http://jama.amaassn.org/cgi/content/full/287/4/455/ compared to the standard formulation (15 to 30 minutes).
TABLEJOC10367T1), long duration of PD, and those taking Thus, patients may also need to take immediate-release tablets
dopamine agonists with levodopa. Sleepiness may also be due or even a liquid formulation when they want a quicker onset of
to the pathology of PD or co-existing conditions such as sleep effect, such as with the rst morning dose.1,8,25
disturbances or depression.10,11,3234 Adding modanil (100 to Carbidopa, a dopa-decarboxylase inhibitor, is added to the
200 mg twice daily) or possibly selegiline can improve alert- levodopa in order to decrease the peripheral conversion of lev-
ness.35 Patients who are still driving need to be aware of this odopa to dopamine. It does not cross the bloodbrain barrier
potentially dangerous effect. Occupational therapists can evalu- and does not interfere with levodopa conversion in the brain.
ate the patients driving ability by using a simulated drivers test. Concomitant administration of carbidopa and levodopa allows
All dopamine agonists are metabolized by the liver except for lower levodopa doses and minimizes levodopa peripheral side
pramipexole, which is eliminated unchanged in the urine by effects such as nausea, vomiting, anorexia, and hypotension. For
active tubular secretion and requires dose reduction in renal most patients, at least 75 to 100 mg daily of carbidopa is required
insufciency (creatinine clearance less than 60 mL/minute). to adequately block dopamine decarboxylase in the peripheral
Drug interactions may occur if it is given concurrently with other metabolism of levodopa in most patients. Taking extra carbidopa
agents that are eliminated by active tubular secretion, such as may reduce nausea related to initiating levodopa.8,16
procainamide, trimethoprim, and cimetidine. Ropinirole is Side effects include dyskinesias, orthostatic hypotension,
metabolized by cytochrome P-450 oxidation in the liver and sub- dizziness, nausea, insomnia, sleep attacks, pathologic gam-
ject to drug-drug interactions with drugs that induce or inhibit bling, discoloration of urine/sweat, and psychiatric effects
CYP1A2 such as ciprooxacin, uvoxamine, and mexiletine.31 (confusion, hallucinations, nightmares, and altered behavior).
Apomorphine is approved for acute off episodes in patients Dyskinesias caused by adding other PD drugs to levodopa may
with advanced stages of PD. The onset of effect is within 10 to be improved by decreasing the levodopa dose. Motor compli-
20 minutes and the duration of effect is about 60 minutes. It cations occur in about 40% of patients within 4 to 6 years of
requires premedication with an antiemetic because it causes starting levodopa.1,8,24,25,37
nausea and vomiting. Antiemetics that block central dopamine Patients with severe dyskinesias and off periods may achieve
worsen the symptoms of PD, and 5-HT3 antagonists, such as more constant blood concentrations (lower peak and higher
ondansetron, can aggravate PD-related hypotension. trough concentrations) by taking a liquid formulation of levodopa
Trimethobenzamide (300 mg three times daily) should be with carbidopa. Each day patients make a 1 mg/mL levodopa
solution made with water and ascorbic acid or with a carbonated may be associated with an increased risk of vascular disease,
beverage, which allows patients to take a precisely adjusted dementia, and depression. Administering levodopa with a
dose every 30 to 90 minutes.25,38 COMT inhibitor may minimize the increase in homocysteine.
Vitamin B is involved in maintaining normal homocysteine
COMT Inhibitors concentrations; thus, PD patients may have a greater require-
Catechol-O-methyltransferase inhibitors are used in conjunc- ment of B vitamins than patients not receiving levodopa.
tion with levodopa/carbidopa. They minimize peak and trough Eating foods rich in B vitamins (i.e., wheat germ, beans, and
levodopa uctuations by prolonging the half-life and area under whole grains) and taking a multivitamin should be sufcient;
the curve of levodopa. They may allow for a decrease in daily however, B vitamin supplements may be warranted in patients
levodopa doses while increasing on time, decreasing wearing off, with elevated homocysteine concentrations. Excess pyridox-
and improving ADLs in patients with motor uctuations. Some ine (vitamin B6) may decrease the effect of levodopa, so limit
clinicians believe that a COMT inhibitor should be added when doses to less than 50 mg per day.8,40,41
levodopa is rst introduced in an effort to promote more con- Coenzyme Q10 is an antioxidant essential for mitochon-
tinuous dopamine stimulation, potentially minimizing long- drial function. A dose of 1200 mg daily was associated with a
term complications associated with the more pulsatile effect of slower decline in UPDRS scores than patients not receiving
intermittent levodopa administration. However, starting multi- coenzyme Q10. Lower doses were no better than placebo, but
ple drugs at the same time increases the risk of side effects. Side the drug continues to be studied in doses up to 2400 mg daily.
effects include diarrhea, nausea, vomiting, anorexia, dyskinesias, Many formulations contain vitamin E, and patients should
urine discoloration, daytime sleepiness, sleep attacks, orthostatic not exceed recommended daily allowances of this vitamin, as
hypotension, and hallucinations. Dyskinesias should improve bleeding times may be prolonged.42,43
with a decrease in the levodopa dose.24,25,29
Tolcapone has been associated with several cases of severe liver Treatment of Non-motor Symptoms
failure, including fatalities, and has been removed from the mar- The treatment of nonmotor symptoms should be based on
ket in some countries. Thus, it should only be used in patients whether they are worse during an off state or if they could be
who cannot take or do not respond to entacapone. Serum alanine related to other neurotransmitter dysfunction.
aminotransferase and aspartate aminotransferase concentrations The treatment of non-motor symptoms, such as psycholog-
should be monitored at baseline, then every 2 to 4 weeks for ical conditions, sleep disorders, and autonomic dysfunction,
6 months, and then periodically for the remainder of therapy. should include both pharmacologic and nonpharmacologic
Patients who fail to show symptomatic benet after 3 weeks approaches. Patients should be given suggestions for main-
should discontinue tolcapone. Entacapone has not been asso- taining ADLs, a positive self-image, family communication,
ciated with liver damage, so monitoring of liver enzymes is and a safe environment.
not currently recommended.24,25,29
Psychological Symptoms
Herbs and Supplements Patients should report vivid dreams or nightmares, as these
Clinicians should ask patients if they take any herbs and sup- may herald psychosis. Neuropsychometric testing may be a
plements, as they may not volunteer this information. The helpful diagnostic tool. Other potential causes of psychosis,
most common herbs and supplements that patients ask about dementia, or depression, such as infections, metabolic changes,
are vitamins, melatonin, valerian, and coenzyme Q10. There is or toxic exposures should be ruled out. Psychological symp-
very little support for using creatinine, gingko, ginseng, green toms may be alleviated by the presence of a night light or cor-
tea, ginger, yohimbine, and St Johns wort in patients with PD. rection of vision and hearing decits. PD therapy should be
Patients should be cautioned that supplements and herbs are adjusted to decrease off periods when depression and anxiety
not well controlled by the FDA and may not contain the may be more likely to occur. Low-efcacy PD medications
amounts indicated on the label. Melatonin and valerian may should be gradually decreased and stopped in patients with
improve insomnia, but they are not commonly used because psychosis. Patients should be encouraged to participate in tasks
there is insufcient information in PD patients.39 that improve cognition, such as puzzles or reading. Some
There is usually no need to supplement with specic vita- patients and their families may benet from professional coun-
mins. Patients should be encouraged to eat a well balanced seling. Some antidepressants may be used for anxiety, panic, or
diet and should also take a multivitamin and mineral supple- depression. Low-dose quetiapine (12.5 to 200 mg) or clozapine
ment. Some clinicians recommend vitamins C and E for their (6.25 to 150 mg) at bedtime can improve psychosis
antioxidant properties; however, no signicant improvements although clozapine requires at least monthly blood moni-
have been shown compared to placebo. Encourage patients to toring for agranulocytosis. Dementia symptoms may
eat a diet rich in vitamin C and E (i.e., bright colored fruits improve with acetylcholinesterase inhibitor or memantine.
and vegetables, nuts, and whole grains). Metabolism of lev- Electroconvulsive therapy can be considered in patients who
odopa may cause elevated homocysteine concentrations that fail medications.2,79,11,13,14,44,45
Sleep Problems Treatment of Response Fluctuations

Sleep problems and fatigue are common in PD and may be due As the disease progresses, most patients develop response uc-
to medications, uncontrolled PD symptoms, or many other tuations. Management of these is based on optimizing the phar-
medical and psychological causes. The patients bed partner can macokinetic and pharmacodynamic properties of PD medications.
provide useful information on the patients quality of sleep. Treatment includes adjusting or adding medications to
Patients may benet from instruction on good sleep hygiene, maximize the patients on time, minimize the time on with
adjustment of therapy to control nighttime PD symptoms, or dyskinesia, and minimize off time (Table 292). Use various
cognitive behavioral therapy. Referral to a sleep specialist may be
necessary. Amantadine and selegiline may worsen insomnia,
TABLE 292. Management of Motor Complications in
selegiline and tricyclic antidepressants may worsen RBD, and
Advanced Disease2,15,16,4446
some antidepressants and antipsychotics may worsen RLS.
Short-acting benzodiazepines and sedating antidepressants I. Motor Fluctuations
are used for short periods to help insomnia. Ramelteon may A. Suboptimal or delayed peak response
prove benecial in patients with circadian sleep disorders. 1. Take Sinemet on an empty stomach
2. Use rapid-dissolving tablet (ParcopaTM), crush Sinemet, or
Pramipexole, melatonin, and clonazepam are recommended
make liquid Sinemet
for RBD. In addition to dopaminergic medications, iron, 3. Decrease dietary protein around the dose that is delayed
gabapentin, and opioids are recommended for RLS. A nighttime 4. Substitute standard Sinemet for some of the Sinemet CR
dose of a COMT inhibitor may also help RLS. Benzodiazepines B. Optimal peak but early wearing off
may increase the risk of falling. Iron may decrease the absorp- 1. Decrease dose and increase frequency of standard Sinemet
2. Substitute Sinemet CR for some of the standard Sinemet
tion of levodopa and increase constipation.2,10,11,44,45 3. Add other PD medications (dopamine agonist, selegiline,
amantadine, or COMT inhibitor)
C. Optimal peak but unpredictable offs
Autonomic and Other Problems 1. Adjust time with meals and avoid high-protein meals or
Drooling may be accompanied by speech problems and dyspha- redistribute the protein in meals
gia. Anticholinergics, botulinum toxin injections, and sublingual 2. Substitute or add rapid-dissolving tablet form or liquid form
atropine can decrease drooling. A speech therapist can perform of Sinemet
3. Rescue with a dopamine agonist (apomorphine) given with
a swallowing study to assess the risk of aspiration, and a nutri-
domperidone or trimethobenzamide
tionist can help optimize diet. Patients at high risk of aspiration 4. Sinemet via intraduodenal tube
or poor nutrition may require placement of a percutaneous 5. Deep brain stimulation procedure
endoscopic gastrostomy tube. Nausea can be improved by having D. Freezing
patients take their PD medications with meals or pharmacologic 1. Gait modications (use visual cues such as walk over lines,
tapping, rhythmic commands, rocking; use rolling walker)
therapy (domperidone from Canada or trimethobenzamide). 2. Difcult to treat so adjust current medication up or down
Sexual dysfunction or urinary problems may need a urologic based on other PD symptoms
evaluation. Improvement of PD therapy to increase on time, 3. Treat anxiety with benzodiazepine
removal of drugs that decrease sexual response, and pharmaco- II. Dyskinesias
A. Peak dose chorea
logic therapy (sildenal or yohimbine) may be helpful to treat
1. Decrease risk by lowering Sinemet dose when adding
sexual dysfunction. Patients with urinary frequency may nd a other PD medications
bedside urinal along with a decrease in evening uids helpful. 2. Smaller doses more frequently (liquid Sinemet)
Improvement in PD control can also benet, but worsening 3. Decrease Sinemet dose and add dopamine agonist
symptoms may require catheterization or pharmacologic meas- 4. Amantadine
5. Add propranolol, uoxetine, buspirone, or clozapine
ures (oxybutynin, tolterodine, propantheline, imipramine, 6. Deep brain stimulation
hyoscyamine, or nocturnal intranasal desmopressin). Anti- B. Off period dystonia in the early morning (i.e., foot cramping)
cholinergic drugs could cause urinary retention as well as con- 1. Add Sinemet CR or dopamine agonist at bedtime if having
stipation. Constipation can be helped with increased uid and nighttime offs
2. Morning Sinemet dose should be immediate-release with
ber-rich diet intake and physical activity. Patients should or without CR
avoid cathartic laxatives and use stool softeners, osmotic or 3. Selective denervation with botulinum toxin
bulk-forming laxatives, glycerin suppositories, or enemas. C. Diphasic dyskinesia
Dyskinesia-related sweating may respond to PD therapy 1. Avoid controlled-release preparations; consider liquid Sinemet
adjustment or -blockers. Orthostasis may respond to removal 2. Add dopamine agonist, amantadine, or COMT inhibitor
3. Deep brain stimulation
of offending drugs (tricyclic antidepressants, PD medications, III. Akathisia
alcohol, and antihypertensives) increasing carbidopa doses, or 1. Benzodiazepine
addition of salt or uids to the diet, compression stockings, 2. Propranolol
udrocortisone, indomethacin, or mitodrine. Seborrhea usually 3. Dopamine agonists
4. Gabapentin
responds to over-the-counter dandruff shampoos or topical
steroids.2,7,8,11,12,44,45 COMT, catechol-O-methyltransferase.
Patient Encounter, Part 3: Creating a Patient Care and Monitoring

Care Plan
Create a care plan for MW that includes: Patient monitoring should involve a regular systematic
evaluation of efcacy and adverse events, referral to appro-
The goals of therapy. priate specialists, and patient education.
A list of problems and how well each is controlled.
A therapeutic plan that includes non-drug and drug 1. Determine type of symptoms, frequency, and exacerbat-
therapy. ing factors. Does the patient have any PD treatment-
A protocol for monitoring efcacy and adverse related complications? Assess the patients symptoms
effects. to determine if therapy should be adjusted or main-
A denition of your outcome variables. tained, or if referral for more extensive evaluation is
needed.
2. Review any available diagnostic data to determine
status, motor ability, dyskinesias, and non-motor
dosage plans to minimize suboptimal or delayed peak lev- symptoms.
odopa concentrations by adding longer-acting medications to 3. Obtain a thorough history of prescription, non-prescription,
minimize wearing off periods, adding or adjusting medica- and complementary/alternative medication use. Determine
tions to stop an unpredicted off period, and providing treat- what treatments have been helpful to the patient in the
ments that decrease freezing episodes. It also involves adjust- past. Is the patient taking any medications that may
ing or adding medications to decrease chorea, dystonia, increase PD symptoms?
diphasic dyskinesias, or akathisia. Patients should schedule 4. Educate the patient about lifestyle modications that
activities when they are on. Patients can also keep an extra will improve symptoms and sustain independence.
dose of medication with them when they are away from home 5. Is the patient taking the appropriate dose of PD med-
in case their medication wears off.2,15,16,4446 ication to maximize on time and minimize adverse
effects? If not, why?
OUTCOME EVALUATION 6. Determine if polytherapy treatment is necessary and/or
adequate.
Evaluate the clinical outcomes of treatment by using the 7. Assess improvement in QOL measures.
UPDRS. In addition, periodically ask patients to record the 8. Evaluate the patient for the presence of drug adverse
amount of on and off time they have with and without dyski- reactions, allergies, and interactions.
nesias in a diary. There are a variety of scales that can be used to 9. Recommend a therapeutic regimen that is easy for the
assess QOL, depression, anxiety, and sleep disorders. Patients patient to follow. Educate the patient on how to use
with PD cannot be cured; but treatment can delay the progres- medications, and allow the patient to adjust medica-
sion of symptoms and improve QOL. Delaying the patients tions for uctuations in response.
admission into a nursing home is a good outcome. 10. Educate patients regarding PD, including lifestyle modi-
cations and drug therapy, including:
When and how to take medications.
The potential adverse effects that may occur.
Patient Encounter, Part 4: Evaluation of Which drugs may interact with therapy (give patients
the Outcomes a list).
Warning signs to report to the physician.
Where they can obtain further information such as
At the last visit, MWs uoxetine was changed to bupropion, books and Web sites (e.g., http://www.apdaparkinson.org;
pergolide was started and gradually increased to 0.25 mg three http://www.parkinson.org)
times daily, and a dandruff shampoo was started. Since that
time his skin condition, attitude, apathy, stiffness, rigidity, 11. Refer patients to a local PD support group where they can
handwriting, tremor, slowness, and kicking have improved. obtain educational materials as well as empathy and social
The UPDRs score is 5 while on. support from fellow PD patients. Support groups that
include patients with advanced disease may upset patients
Do you agree with this therapeutic plan? with early disease; therefore, the advantages and disadvan-
Have therapeutic goals been achieved? tages of attending should be explained to the patient.
What additional questions would you ask the patient?
ABBREVIATIONS Acknowledgment: Deborah L. Caupto, APRN and BC Margery

H Mark, MD for editorial review
ADL: activities of daily living
COMT: catechol-O-methyltransferase
CR: controlled-release
GABA: -aminobutyric acid
MAO: monoamine oxidase
MPTP: 1-methyl-4-phenyl-1-2-5-6-tetrahydropyridine Ahlskog JE. The Parkinsons disease treatment book. Partnering with
NMDA: N-methyl-D-aspartate your doctor to get the most from your medications. New York:
PD: Parkinsons disease Oxford University Press, 2005.
RBD: rapid eye movement sleep behavioral disorder Anonymous. Treatment Guidelines from the Medical Letter. Drugs
RLS: restless legs syndrome for Parkinsons disease. Med Lett 2004;2: 4146.
UPDRS: Unied Parkinsons Disease Rating Scale Duvoisin RC, Sage J. Parkinsons disease. A Guide for Patient and
Family. 5th ed. Philadelphia: Lippincott Williams & Wilkins,
2001:1195.
Nutt JG, Wooten GF. Diagnosis and initial management of Parkinsons
available at www.ChisholmPharmacotherapy.com. disease. N Engl J Med 2005;353: 10211027.
Samii A, Nutt JG, Ransom BR. Parkinsons disease. Lancet 2004;363:
Log into the website: www.pharmacotherapyprinciples.com 17831793.
for information on obtaining continuing education credit for Siderowf A, Stern M. Update on Parkinsons disease. Ann Intern Med
this chapter. 2003;138:651658.
30 PAIN MANAGEMENT
Christine K. ONeil
LEARNING OBJECTIVES
1. Identify characteristics of the types of pain: nociceptive, inammatory, neuropathic, and

functional.
2. Explain the mechanisms involved in pain transmission.
3. Select an appropriate method of pain assessment.
4. Recommend an appropriate choice of analgesic, dose, and monitoring plan for a patient
based on type and severity of pain and other patient-specic parameters.
5. Perform calculations involving equianalgesic doses, conversion of one opioid to another,
rescue doses, and conversion to a continuous infusion.
6. Educate patients and caregivers about effective pain management, dealing with chronic
pain, and the use of nonpharmacologic measures.
KEY CONCEPTS activities of daily living. Since there are no reliable objective
markers for pain, the patients are the only ones to describe the
Pain is an unpleasant subjective experience that is the net intensity and quality of their pain.
effect of a complex interaction of the ascending and descend- Pain is the most common symptom prompting patients to
ing nervous systems involving biochemical, physiologic, psy- seek medical attention and is reported by more than 80% of
chological, and neocortical processes. individuals who visit their primary care provider.1 Despite the
Following initial assessment of pain, reassessment should be frequency of pain symptoms, individuals often do not obtain
done as needed based on medication choice and the clinical satisfactory relief of pain. This has led to recent initiatives in
situation. health care to make pain the fth vital sign, thus making pain
Effective treatment involves an evaluation of the cause, dura- assessment equally important as obtaining a patients temper-
tion, and intensity of the pain and selection of an appropriate ature, pulse, blood pressure, and respiratory rate.
treatment modality for the pain situation.
Whenever possible, the least potent oral analgesic should be
selected.
Equianalgesic doses should be used when converting from one EPIDEMIOLOGY AND ETIOLOGY
opioid to another.
Prevalence of Pain
Pain is dened by the International Association for the Study of Most people experience pain at some time in their lives, and
Pain (IASP) as an unpleasant sensory and emotional experience pain is a symptom of a variety of diseases. For some, pain may
associated with actual or potential tissue damage, or described in be mild to moderate, intermittent, easily managed, and has
terms of such damage.1 Pain is an unpleasant subjective expe- minimal effect on daily activities. For others, pain may be
rience that is the net effect of a complex interaction of the ascending chronic, severe or disabling, all consuming, and be treatment
and descending nervous systems involving biochemical, physio- resistant. Thus, identifying the exact prevalence of pain is a
logic, psychological, and neocortical processes. Pain can affect all difcult task. According to the American Pain Foundation,
areas of a persons life including sleep, thought, emotion, and more than 50 million people in the United States suffer from
487
chronic pain, and an additional 25 million experience acute available pain management strategies, including pharmacologic,
pain from injury or surgery.2 About 20% of adults, mostly nonpharmacologic, and alternative therapy options, also often
women and the elderly, experience chronic pain such as back leads to suboptimal pain management. In one survey, approxi-
pain, headache, and joint pain. mately three-fourths of physicians cited low competence in pain
Prevalence rates for a variety of different types of pain have assessment as the major barrier to effective pain management.16
been described. The annual incidence of moderate-intensity Concerns about opiate misuse, abuse, and diversion also con-
back pain is 10% to 15% in the adult population with a point tribute to less than optimal pain management and cause
prevalence of 15% to 30%.3 Migraine affects more than 25 mil- providers to exercise caution when prescribing opiates for pain.
lion Americans, and 90% of Americans report some other Misunderstandings about the terms addiction, physical depend-
types of headaches (e.g., tension or sinus) each year.4 Pain ence, tolerance, and pseudoaddiction are additional obstacles to
resulting from bromyalgia affects 4 million Americans.5 optimal pain management.
Cancer is commonly associated with both acute and chronic Patients may present barriers to pain management by not
pain, and about 70% of those diagnosed with cancer will expe- reporting pain symptoms because of fear of becoming
rience signicant pain.6 addicted or because of cultural beliefs. Elderly patients may
The prevalence of neuropathic pain is unknown because of not report pain for a variety of reasons including belief that
the lack of epidemiologic studies. Current estimates suggest that pain is something they must live with, fear of consequences
approximately 1.5% of the population in the United States may (e.g., hospitalization or loss of independence), or fear that the
be affected by neuropathic pain.7 However, this gure is probably pain may be forecasting impending illness, inability to under-
an underestimate and will likely increase due to the increase in stand terminology used by health care providers, or a belief
disorders associated with neuropathic pain in the ever-growing that showing pain is unacceptable behavior.
older population. Approximately 25% to 50% of all pain clinic
visits are related to neuropathic pain.8 Central neuropathic pain
is estimated to occur in 2% to 8% of all stroke patients.9 PATHOPHYSIOLOGY
The elderly, dened as people 65 years of age and over, bear
a signicant burden of pain, and pain continues to be under- Types of Pain
recognized and undertreated in this population. The preva- Several distinct types of pain have been described: nociceptive,
lence of pain in people over the 60 years of age is twice that in inammatory, neuropathic, and functional.17 Nociceptive
those younger than 60 years of age.10 Studies suggest that 25% pain is a transient pain in response to a noxious stimulus at
to 50% of community-dwelling elderly suffer pain. Pain is nociceptors that are located in cutaneous tissue, bone, muscle,
quite common among nursing home residents. It is estimated connective tissue, vessels, and viscera. Nociceptors may be clas-
that pain in 45% to 80% of nursing home patients contributes sied as thermal, chemical, or mechanical. The nociceptive sys-
to functional impairment and a decreased quality of life.11 tem extends from the receptors in the periphery to the spinal
The nancial impact of pain is considered to be signicant. cord, brain stem, and to the cerebral cortex where pain sensa-
The National Institute for Occupational Safety and Health tion is perceived. This system is a key physiologic function that
(NIOSH) estimated that the cost of low back pain alone was prevents further tissue damage due to the bodys autonomic
between $50 billion and $100 billion per year.12 The American withdrawal reex. When tissue damage occurs despite the
Productivity Audit of the United States workforce, conducted nociceptive defense system, inammatory pain ensues. The
from 2001 to 2002, revealed that the cost of lost productivity body now changes focus from protecting against painful stimuli
due to arthritis, back pain, headache, and other musculoskeletal to protecting the injured tissue. The inammatory response
pain was approximately $ 80 billion per year.13 contributes to pain hypersensitivity that serves to prevent con-
tact or movement of the injured part until healing is complete,
The Undertreatment of Pain
thus reducing further damage.
Despite the growing emphasis on pain management, pain Neuropathic pain is dened as spontaneous pain and hyper-
often remains undertreated and continues to be a problem in sensitivity to pain associated with damage to or pathologic
hospitals, long-term care facilities, and the community. In one changes in the peripheral nervous system as in painful diabetic
series of reports, 50% of seriously ill hospitalized patients peripheral neuropathy (DPN), acquired immunodeciency
reported pain; however, 15% were dissatised with pain con- syndrome (AIDS), polyneuropathy, post-herpetic neuralgia
trol, and some remained in pain after hospitalization.14,15 (PHN); or pain originating in the central nervous system (CNS),
Misconceptions about pain management, both from that which occurs with spinal cord injury, multiple sclerosis, and
patients and health care providers, are among the most com- stroke. Functional pain, a relatively newer concept, is pain sensi-
mon causes of analgesic failure. Some clinicians may be hesi- tivity due to an abnormal processing or function of the central
tant to treat pain because they do not believe the patients nervous system in response to normal stimuli. Several conditions
reports of pain or feel the patient is exaggerating symptoms in considered to have this abnormal sensitivity or hyperresponsive-
order to obtain medications. Inadequate clinical knowledge of ness include bromyalgia and irritable bowel syndrome.
CHAPTER 30 / PAIN MANAGEMENT 489
Mechanisms of Pain in these settings may occur spontaneously without any stimulus
or may be evoked by a stimulus. Evoked pain may arise from a
Pain Transmission stimulus that normally does not cause pain (allodynia) such as
The mechanisms of nociceptive pain are well-dened and pro- a light touch in neuropathic pain. Hyperalgesia, an exaggerated
vide a foundation for the understanding of other types of pain.18 and/or prolonged pain response to a stimulus that normally
Following nociceptor stimulation, tissue injury causes the causes pain, can also occur as a result of increased sensitivity in
release of substances (bradykinin, serotonin, potassium, hista- the CNS.
mine, prostaglandins, and substance P) that may further sensi- During normal pain transmission, the AMPA receptors are
tize and/or activate nociceptors. Nociceptor activation produces activated, but the N-methyl-D-aspartate (NMDA) receptor is
action potentials (transduction) that are transmitted along blocked by magnesium.16 Repeated nerve depolarization causes
myelinated A- bers and unmyelinated C bers to the spinal release of the magnesium block allowing the inux of calcium
cord. The A- bers are responsible for rst, fast, sharp pain and and sodium and results in excessive excitability and amplica-
release excitatory amino acids that activate -amino-3-hydroxy- tion of signals. Continued input from C bers and subsequent
5-methylisoxazole-4-propionic acid (AMPA) receptors in the increases in substance P and glutamate causes the activation of
dorsal horn. The C bers produce secondary pain which is the NMDA receptor, a process referred to as wind-up. Wind-up
described as dull, aching, burning, and diffuse. These nerve increases the number and responsiveness of neurons in the
bers synapse in the dorsal horn of the spinal cord, where sev- dorsal horn irrespective of the input from the periphery.
eral neurotransmitters are released including glutamate, sub- Recruitment of neurons not normally involved in pain trans-
stance P, and calcitonin gene-related peptide. Transmission of mission or spread occurs leading to allodynia, hyperalgesia, and
pain signals continues along the spinal cord to the thalamus, spread to uninjured tissues.20 The wind-up phenomenon sup-
which serves as the pain relay center, and eventually to the corti- ports the observation that untreated acute pain can lead to
cal regions of the brain where pain is perceived. chronic pain and the belief that pain processes are plastic and
not static.
Pain Modulation
Modulation of pain (inhibition of nociceptive impulses) can
occur by a number of processes. Based on the gate control the- CLINICAL PRESENTATION AND DIAGNOSIS
ory, pain modulation may occur at the level of the dorsal
horn.19 Since the brain can process only a limited number of Classication of Pain
signals at one time, other sensory stimuli at nociceptors may Pain has always been described as a symptom. However, recent
alter pain perception. This theory supports the effectiveness of advances in the understanding of neural mechanisms have
counterirritants and transcutaneous electrical nerve stimula- demonstrated that unrelieved pain may lead to changes in the
tion (TENS) in pain management. Pain modulation may result nervous system known as neural plasticity. Since these changes
through several other complex processes. The endogenous opi- reect a process that inuences a physiologic response, pain, par-
ate system consists of endorphins (enkephalins, dynorphins, ticularly chronic pain, may be considered a disease unto itself.
and -endorphins) that interact with , , and receptors Pain can be divided into two broad categories: acute and
throughout the CNS to inhibit pain impulses and alter percep- chronic or persistent pain. Acute pain is also referred to as
tion. The CNS also includes inhibitory descending pathways adaptive pain since it serves to protect the individual from fur-
from the brain that can attenuate pain transmission in the ther injury or promote healing.17 However, chronic pain has
dorsal horn. Neurotransmitters involved in this descending been called maladaptive, a pathologic function of the nervous
system include endogenous opioids, serotonin, norepinephrine, system or pain as a disease.
-aminobutyric acid (GABA) and neurotensin. The perception
of pain involves not only nociceptive stimulation but physio- Acute Pain
logic and emotional input that contributes to the perception of Acute pain is pain that occurs as a result of injury or surgery
pain. Consequently, cognitive behavioral treatments such as and is usually self-limited, subsiding when the injury heals.
distraction, relaxation, and guided imagery can reduce pain Untreated acute pain can produce physiologic symptoms
perception by altering pain processing in the cortex. including tachypnea, tachycardia, and increased sympathetic
nervous system activity, such as pallor, diaphoresis, and pupil
Peripheral Sensitization, Central Sensitization, and dilation. Furthermore, poorly treated pain can cause psycho-
Wind-Up logical stress and compromise the immune system due to the
Under normal conditions, a balance generally exists between release of endogenous corticosteroids. This situation accompa-
excitatory and inhibitory neurotransmission. Changes in this nied by decreased range of motion and decreased lung capac-
balance can occur both peripherally and centrally resulting in ity can delay recovery from the initial injury. Somatic acute
exaggerated responses and sensitization such as that observed pain arises from injury to skin, bone, joint, muscle, and con-
in inammatory, neuropathic, or functional chronic pain. Pain nective tissue, and it is generally localized to the site of injury.
Visceral pain involves injury to nerves on internal organs (e.g., nervous systems. Neuropathic pain may be broadly categorized
intestines or liver) and can present as diffuse, poorly differen- as peripheral or central in nature. Examples of neuropathic
tiated, and often referred pain. Acute pain should be treated pain include PHN, which is pain associated with acute herpetic
aggressively, even before the diagnosis is established, except in neuralgia or an acute shingles outbreak. Peripheral or polyneu-
conditions of head or abdominal injury where pain may assist ropathic pain is associated with the distal polyneuropathies of
in the differential diagnosis. diabetes, human immunodeciency virus (HIV), and chemother-
apeutic agents. Types of central pain include central stroke pain,
Chronic Pain trigeminal neuralgia, and a complex of syndromes known as
Chronic pain persists beyond the expected normal time for complex regional pain syndrome (CRPS). Complex regional
healing and serves no useful physiologic purpose. Chronic pain pain syndrome includes both reex sympathetic dystrophy and
may be nociceptive, inammatory, neuropathic, or functional causalgia, both of which are neuropathic pain associated with
in origin; however, all forms share some common characteris- abnormal functioning of the autonomic nervous system. One of
tics. Chronic pain can be episodic or continuous, or both. the newest categories of neuropathic pain is neuropathic low
Physiologic responses observed in acute pain are often absent in back pain.
chronic pain; however, other symptoms may predominate. The symptoms of neuropathic pain are characterized as
There are four main effects of chronic pain, and these include: tingling, burning, shooting, stabbing, electric shocklike qual-
1) effects on physical function, 2) psychological changes, 3) social ity, or radiating pain. The patient may describe either a con-
consequences, and 4) societal consequences. Effects of chronic stant dull throbbing or burning pain, or an intermittent pain
pain on physical function include impaired activities of daily that is stabbing or shooting. Frequent damage to the periph-
living and sleep disturbances. Psychological components of eral nerves may be referred to the body region innervated by
chronic pain may include depression, anxiety, anger, and loss of those nerves.
self-esteem. As a result of physical and psychological changes, Traditionally neuropathic pain has been difcult to treat and
social consequences may ensue such as changes in relationships involves a variety of therapeutic modalities. Rational choice of
with friends and family, intimacy, and isolation. On a societal treatment options may be accomplished through evaluation of
level, chronic pain contributes to increased health care costs, the neuropathy and its relationship to peripheral or central nerve
disability, and lost productivity. Management of chronic pain damage. Targeting the mechanistic points in the pain pathway is
should be multimodal and may involve cognitive interventions, another rationale for treating neuropathic pain. For example, cer-
physical manipulations, pharmacologic agents, surgical inter- tain opioids, such as methadone, are characterized by NMDA
vention, and regional or spinal anesthesia. receptor antagonist activity and are effective in treating pain.
Anticonvulsant drugs are able to block sodium channels in the
Chronic Malignant Pain peripheral afferent nerve bers. Agents such as tricyclic antide-
Chronic malignant pain is associated with a progressive disease pressants, bupropion, and venlafaxine block the release of
that is usually life-threatening such as cancer, AIDS, progressive monoamines targeting dorsal horn inhibitory mechanisms.
neurologic diseases, end-stage organ failure, and dementia.21
The goal is pain alleviation and prevention, often through a sys-
tematic and stepwise approach. Tolerance, dependence, and Clinical Presentation of Pain
addiction are often not a concern due to the terminal nature of
the illness.
Chronic Non-malignant Pain General

Pain not associated with a life-threatening disease and lasting Patients may be in acute distress (acute pain) or have no
longer than 6 months beyond the healing period is referred to signs or symptoms of suffering (chronic pain).
as chronic non-malignant pain. Pain associated with low back Symptoms
pain, osteoarthritis, previous bone fractures, peripheral vascu- Pain is described based on the following characteristics:
lar disease, genitourinary infection, rheumatoid arthritis, and onset, duration, location, quality, severity, and intensity.
coronary heart disease is considered non-malignant. The Other symptoms may include anxiety, depression, fatigue,
numerous causes of this type of chronic pain make treatment anger, fear, and insomnia.
complex and involves a multidisciplinary approach. Treatment Signs
is initially conservative but may involve the use of more Acute pain may cause hypertension, tachycardia, diaphore-
potent analgesics including opiates in psychologically healthy sis, mydriasis, and pallor.
patients.22 Diagnosis
The patient is the only person who can describe the inten-
Neuropathic Pain sity and quality of their pain. There are no laboratory tests
Neuropathic pain may be considered to be a type of chronic non- that can diagnose pain.
malignant pain involving disease of the central and peripheral
Pain Assessment Simple Descriptive Pain Intensity Scale1

Effective pain management begins with a thorough and accu-
rate assessment of the patient. Even though pain is a common No Mild Moderate Severe Very Worst
pain pain pain pain severe possible
presenting complaint, lack of regular assessment and reassess- pain pain
ment of pain remains a problem and contributes to the under-
treatment of pain.23 010 Numeric Pain Intensity Scale1
Pain Assessment Guidelines and Regulations for Specic 0 1 2 3 4 5 6 7 8 9 10

Practice Settings No Moderate Worst
pain pain possible
Screening for pain should be a part of a routine assessment, pain
and this has led several organizations such as the Veterans
Health Administration (VHA) and the American Pain Society Visual Analog Scale (VAS)2
(APS) to declare pain the fth vital sign. Many states have
adopted a bill of rights for patients in pain. In 2001, the Joint No Pain as bad
pain as it could
Commission on Accreditation of Healthcare Organizations possibly be
(JCAHO) incorporated pain as the fth vital sign in its accred- 1If used as a graphic rating scale, a 10 cm baseline is recommended.
itation standards. 24 According to the JCAHO, patients have a 2A 10-cm baseline is recommended for VAS scales.
right to appropriate assessment and management of their pain

and education regarding their pain. Following initial assess- FIGURE 301. Pain rating scales.27
ment of pain, reassessment should be done as needed based on
medication choice and the clinical situation. Rating scales provide a simple way to classify the intensity of
Methods of Pain Assessment pain, and should be selected based on the patients ability to
A patient-oriented approach to pain is essential, and methods communicate (Fig. 301).27 Numeric scales are widely used and
do not differ greatly from those used in other medical condi- ask patients to rate their pain on a scale of 0 to 10, with 0 indi-
tions. A comprehensive history (medical, family, and psycho- cating no pain and 10 being the worst pain possible. Using this
logical) and physical exam are necessary to evaluate underlying type of scale, 1 to 3 is considered mild pain, 4 to 6 is moderate
disease processes for the source of pain and other factors con- pain, and 8 to 10 is severe pain. The visual analog scale (VAS) is
tributing to the pain.20 A thorough assessment of the character- similar to the numerical scale in that it requires patients to place
istics of the pain should be completed including questions a mark on a 10-cm line where one end is no pain, and the worst
about the pain (onset, duration, location, quality, severity, and possible pain is on the other end. For patients who have dif-
intensity), pain relief efforts, and efcacy and side effects of cur- culty assigning a number to their pain, a categorical scale may
rent and past treatments for pain. A common mnemonic for be an option to communicate the intensity of the pain experi-
pain assessment is PQRST (Palliative/Provocative, Quality, ence. Examples of this include a simple descriptive list of words
Radiation, Severity, and Temporal).25 Some clinicians have sug- and the Wong-Baker FACES of Pain Rating Scale.28
gested the addition of U (you) to this mnemonic.26 During the Multidimensional assessment tools obtain information
pain interview, the impact of the pain on the patients func- about the pain and impact on quality of life, but are often more
tional status, behavior, and psychological states should also be time-consuming to complete. Examples of these types of tools
assessed. Evaluation of psychological status is especially impor- include the Initial Pain Assessment Tool, Brief Pain Inventory,
tant in patients with chronic pain since depression and affective McGill Pain Questionnaire, the Neuropathic Pain Scale, and
disorders may be common comorbid conditions. A history of the Oswestry Disability Index.2933
drug and alcohol use should be elicited due to the potential for
addiction in patients who may require opiates or other pain Pain Assessment in Challenging Populations
medications with a potential for abuse. Other conditions such
as renal or hepatic dysfunction, diabetes, and conditions that Children Pain interviews may be conducted with children as
affect bowel function can inuence therapy choices and goals. young as 3 or 4 years of age; however, communication may be
A discussion of the patients expectations and goals with respect limited by vocabulary.34 Terms familiar to children such as
to pain management (level of pain relief, functional status, and hurt, owie, or boo boo may be used to describe pain. The
quality of life) should also be part of any pain interview. VAS is best used with children older than 7 years of age. Other
scales based on numbers of objects (e.g., poker chips), increasing
Pain Assessment Tools color intensity, or faces of pain may be helpful for children
Pain, particularly acute pain, may be accompanied by physio- between 4 and 7 years of age. In children younger than 3 to
logic signs and symptoms, and there are no reliable objective 4 years of age, behavioral or physiologic measures, such as pulse
markers for pain. Many tools have been designed for assessing or respiratory rate, may be more appropriate. Pain assessment
the severity of pain including rating scales and multidimen- in newborns and infants relies on behavioral observation for
sional pain assessment tools. such clues as vocalizations (crying and fussing), facial expressions,
body movements (ailing of limbs and pulling legs in), with-

drawal, and change in eating and sleeping habits.35 Preschool Patient Encounter, Part 1
children experiencing pain may become clingy, lose motor and
verbal skills, and start to deny pain because treatment may be
linked to discomfort or punishment. School-age children may
HPI
exhibit aggressiveness, nightmares, anxiety, and withdrawal when BA is a 58-year-old male recently diagnosed with lung cancer.
in pain, while adolescents may respond to pain with opposi- Following surgery he was placed on morphine patient-
tional behavior and depression. controlled analgesia (PCA). He has been using 120 mg of
morphine/24 hours with adequate pain control.
Elderly Most of the previously discussed pain scales can be used
PMH
in older persons that are cognitively intact or with mild dementia. Hypertension 18 years
The pain thermometer and FACES of pain have been studied in
FH
older persons. In persons with moderate to severe dementia or
Non-contributory
those who are nonverbal, observation of pain behaviors, such as
guarding or grimacing, provides an alternative for pain assess- SH
Lives with wife; has four grown children; smoked 2 packs
ment. The Pain Assessment in Advanced Dementia (PAINAD)
of cigarettes per day 40 years (quit with diagnosis of lung
tool may be used to quantify signs of pain and involves observing cancer)
the older adult for 15 minutes for breathing, negative vocaliza-
Meds
tions, facial expression, body language, and consolability.36
Hydrochlorothiazide 25 mg every day
Regardless of which pain assessment tool is used, the practitioner
should rst determine if the patient understands the concept of Pain assessment: Patient rates pain as 8 on a scale of 1 to 10.
the scale to ensure reliability of the instrument.
The physician would like to convert him to a combination
preparation of oxycodone and acetaminophen. What dos-
ing regimen would you suggest?
TREATMENT Six months later, BAs pain is controlled with the escalat-
ing doses of the combination product; however, he has
General Approach to Treatment reached the maximum dose of acetaminophen. What
would you suggest at this time?
Effective treatment involves an evaluation of the cause,
duration, and intensity of the pain and selection of an appropriate
treatment modality for the pain situation. Depending on the guidelines can be useful for initial therapy, the clinical situation
type of pain, treatment may involve pharmacologic or non- (type of pain); cost and pharmacokinetic prole of available
pharmacologic therapy or both. General principles for the drugs; and patient-specic factors (age, concomitant illnesses,
pharmacologic management of pain are listed in the section previous response, and other medications) must also be con-
on patient care and monitoring. Two common approaches to sidered. Pain medications may also be used in the absence of
the selection of treatment are based on severity of pain and pain in anticipation of a painful event such as surgery to min-
the mechanism responsible for the pain (Fig. 302). Clinical imize peripheral and central sensitization.
practice guidelines for pain management are available from
the APS, the Agency for Healthcare Research and Quality
(AHRQ), the American Geriatrics Society (AGS), and the Mechanistic Approach to Therapy
American Society of Anesthesiologists (ASA). Current analgesic therapy is aimed at controlling or blunting
pain symptoms. However, diverse mechanisms contributing to
the various types of pain continue to be further elucidated. An
Selection of Agent Based on Severity of Pain understanding of these new mechanisms of pain transmission
Whenever possible, the least potent oral analgesic should may lead to improvement in pain management, as pharmaco-
be selected. logic management of pain becomes more mechanism-specic.
Guidelines for the selection of therapeutic agents based on Use of NSAIDs for inammatory types of pain is an example of
pain intensity are derived from the World Health Organization a mechanistic approach. Since several mechanisms of pain often
(WHO) analgesic ladder for the management of cancer pain co-exist, a polypharmacy approach seems rational to target each
(Table 301). 37 Mild to moderate pain is generally treated with mechanism.
non-opioid analgesics. Combinations of medium-potency Two current foci in pain management are to identify the
opioids and acetaminophen or non-steroidal anti-inamma- mechanisms that are responsible for pain hypersensitivity and
tory drugs (NSAIDs) are often used for moderate pain. Potent to prevent this initial hypersensitivity. Therefore, the goal of
opioids are recommended for severe pain. Throughout this pain therapy is to reduce peripheral sensitization and subse-
progression adjuvant medications are added as needed to quent central stimulation and amplication associated with
manage side effects and to augment analgesia. While these wind-up, spread, and central sensitization.17
Pain
Acute Chronic
Mild/Moderate Severe Visceral Neuropathic Inflammatory Functional
NSAIDs or Opioids for APAP or TCA or

Opioids Peripheral Central
APAP Severe NSAIDs Tramadol
Long-acting Opioids SSRI/SNRI

Add Add Adjuvants
Opioids NSAIDs or APAP (e.g., AED, TCA) TCA or AED (e.g., MS Contin,
Oxycontin) Pregabalin
Clonidine or
Lidocaine
Baclofen
SSRI or SNRI
Long-acting
Opioid
FIGURE 302. Pain algorithm. AED, antiepileptic drug; APAP, acetaminophen; NSAID, non-steroidal antiin-
ammatory drug; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake
inhibitor; TCA, tricyclic antidepressant.
groups, and spiritual counseling. Biofeedback teaches patients
Nonpharmacologic therapies (psychological interventions to control physiologic responses to pain and has been effective
and physical therapy) may be used in both acute and chronic in headache and chronic low back pain. Cognitive therapy
pain. Psychological interventions can reduce pain as well as encourages patients to monitor their perceptions of pain,
the anxiety, depression, fear, and anger associated with pain. reducing stress and negativism. Psychotherapy is very useful
Psychological interventions helpful in management of acute for patients with chronic pain, and it can also assist in treat-
pain are imagery (picturing oneself in a safe, peaceful place) ment of psychiatric comorbidities and help patients to deal
and distraction (listening to music or focusing on breathing). with terminal illnesses.38 The patient should be educated
Chronic pain patients may benet from relaxation, biofeed- about what to expect regarding pain and its treatment
back, cognitive-behavioral therapy, psychotherapy, support whether pain is acute (i.e., preoperative explanations of
TABLE 301. Selection of Analgesics Based on Intensity of Pain37
Corresponding WHO Therapeutic Examples of Initial

Pain Intensity Numerical Rating Recommendations Therapy Comments
Mild 13/10 Non-opioid analgesic; regular Acetaminophen 1000 mg Consider adding an
scheduled dosing every 6 hours; Ibuprofen adjunct or using
600 mg every 6 hours an alternate regimen
if pain is not reduced
in 12 days
Moderate 46/10 Add an opioid to the Acetaminophen 325 mg + Consider step-up therapy
non-opioid for moderate codeine 60 mg every if pain is not relieved
pain; regular scheduled 4 hours; Acetaminophen by greater than or
dosing 325 mg + oxycodone equal to 2 or more
5 mg every 4 hours different drugs
Severe 710/10 Switch to a high-potency Morphine 10 mg every
opioid; regular scheduled 4 hours; Hydromorphone
dosing 4 mg every 4 hours
WHO, World Health Organization.

expected postsurgical pain) or chronic (patient and family arthritis and osteoarthritis, menstrual cramps, and postsurgical
education in hospice care). pain) and in the management of pain from bone metastasis, but
Physical therapy is an essential part of many types of pain sit- they are of minimal use in neuropathic pain.
uations. Treatment modalities include heat, cold, water, ultra- Aspirin is effective for mild to moderate pain; however, the
sound therapy, TENS, massage, and therapeutic exercise. Heat risk of gastrointestinal irritation and bleeding limits frequent
and cold therapy are utilized in a variety of musculoskeletal use of this drug for pain management. Direct effects of aspirin
conditions (muscle spasms, low back pain, bromyalgia, sprains, on the gastrointestinal mucosa and irreversible platelet inhi-
and strains). Heating modalities include local hot packs, paraf- bition contribute to this risk which can occur even at low doses.
n wrap, hydrotherapy, and deep-heating methods (ultra- Hypersensitivity reactions are also possible and may occur in
sound). Cold treatments may be delivered via cold packs, ice 25% of patients with co-exsiting asthma, nasal polyps, or
massage, cold water immersion, or coolant sprays. TENS ther- chronic urticaria. Of additional concern is the potential for
apy is based on the theory that electrical stimulation of a nerve cross-sensitivity of other NSAIDs in this group of patients.
in a particular area can block pain impulses originating from Non-acetylated salicylates (choline magnesium salicylate and
that area. TENS is also believed to release endogenous endor- sodium salicylate) have a reduced risk of gastrointestinal effects
phins and enkephalins. Massage therapy is used to relieve mus- and platelet inhibition and may be used in aspirin-sensitive
cle tension and stiffness and is also felt to increase endogenous patients. Diunisal, a salicylic acid derivative, is associated with
endorphins. Therapeutic exercise improves not only strength, fewer gastrointestinal (GI) complaints compared to aspirin, but
endurance, and range of motion, but also provides cardiovascu- platelet inhibition does increase the risk of GI bleeding.
lar, psychological, and other health benets.
Non-steroidal Anti-Inammatory Drugs
Pharmacologic Therapy NSAIDs provide analgesia equal to or better than that of aspirin
or acetaminophen combined with codeine, and they are very
Non-opioid Analgesics effective for inammatory pain and pain associated with bone
metastasis.18 These agents may be classied by their chemical
Acetaminophen structures (fenamates, acetic acids, propionic acids, pyranocar-
Acetaminophen, an analgesic and antipyretic, is often selected boxylic acids, pyrrolizine carboxylic acids, and COX-2 inhibitors).
as initial therapy for mild to moderate pain and is considered While only some members of this class have approval for treat-
rst-line in several pain situations such as low back pain and ment of pain, it is likely that all of them have similar analgesic
osteoarthritis.39 Mechanistically, acetaminophen is believed to effects. All members of this class appear to be equally effective,
inhibit prostaglandin synthesis in the CNS and block pain but there is great intrapatient variability in response. After an
impulses in the periphery. Acetaminophen is well-tolerated at adequate trial of 2 to 3 weeks with a particular agent, it is rea-
usual doses and has few clinically signicant drug interactions sonable to switch to another member of the class. NSAIDs
except causing increased hypoprothrombinemic response to demonstrate a at dose-response curve, with higher doses pro-
warfarin in patients receiving acetaminophen doses of more ducing no greater efcacy than moderate doses, but resulting in
than 2000 mg per day. The maximum recommended dose for an increased incidence of adverse effects (gastrointestinal irrita-
patients with normal renal and hepatic function is 4000 mg per tion, hepatic dysfunction, renal insufciency, platelet inhibition,
day. Hepatotoxicity has been reported with excessive use and sodium retention, and CNS dysfunction).
overdose and the risk of this adverse effect increases in those Patients at increased risk of NSAID-induced gastrointesti-
with hepatitis or chronic alcohol use, as well as those who nal adverse effects (e.g., dyspepsia, peptic ulcer formation, and
binge drink or are in a fasting state. Regular chronic use of bleeding) include the elderly, those with peptic ulcer disease,
acetaminophen has been associated with chronic renal failure, coagulopathy, and patients receiving high doses of concurrent
but reports are conicting. For these reasons, the maximum corticosteroids. Nephrotoxicity is more common in the elderly,
dose should be reduced by 50% to 75% in patients with renal patients with creatinine clearance values less than 50 mL/minute,
dysfunction or hepatic disease and in those who engage in and those with volume depletion or on diuretic therapy. NSAIDs
excessive alcohol use. should be used with caution in patients with reduced cardiac
output due to sodium retention and in patients receiving
Aspirin and Other Salicylates antihypertensives, warfarin, and lithium.
Aspirin, non-acetylated salicylates, and other NSAIDs have anal- NSAIDs are classied as non-selective (they inhibit COX-1
gesic, antipyretic, and anti-inammatory actions. These agents and COX-2) or selective (they inhibit only COX-2) based on
inhibit cyclooxygenase (COX-1 and COX-2) enzymes, thereby degree of cyclooxygenase inhibition. COX-2 inhibition is
preventing prostaglandin synthesis, which results in reduced responsible for anti-inammatory effects, while COX-1 inhibi-
nociceptor sensitization and an increased pain threshold. tion contributes to increased GI and renal toxicity associated
NSAIDs are the preferred agents for mild to moderate pain in with non-selective agents. Since the antiplatelet effect of non-
situations that are mediated by prostaglandins (e.g., rheumatoid selective NSAIDs is reversible, concurrent use may reduce the
cardioprotective effect of aspirin due to competitive inhibition with cancer.45 For chronic pain, their use was once highly con-
of COX-1. For this reason, administration of aspirin prior to the troversial; however, use of opioids in chronic pain is now gain-
NSAID is recommended.40 The cardiovascular safety of the ing acceptance.46 Opioids may be classied by their activity at
COX-2 inhibitors has been questioned due to increased risk of the receptor site, usual pain intensity treated, and duration of
myocardial infarction and stroke seen in several trials.4143 The action (short- versus long-acting).
Food and Drug Administration (FDA) Committees on Arthritis
and Drug Safety and Risk Management convened in February Selection and Dosing
2005 to evaluate the published studies and manufacturer infor- The opioids exert their analgesic efcacy by stimulating opi-
mation about the cardiovascular adverse events associated with oid receptors (, , and ) in the CNS. There is a wide variety
COX-2 inhibitors.44 As a follow-up to the committees recom- of potencies among the opioids, with some used for moderate
mendations, the FDA took regulatory action in April 2005, pain (codeine, hydrocodone, tramadol, and partial agonists)
announcing that the increased risk of cardiovascular events was and others reserved for severe pain (morphine and hydro-
likely a class effect of NSAIDs. A boxed warning highlighting the morphone). Pure agonists (morphine) bind to receptors to
potential for increased risk of cardiovascular events and GI produce analgesia that increases with dose without a ceiling
bleeding is now required for all prescription non-selective effect. Pure agonists are divided into three chemical classes:
NSAIDs and celecoxib. Stronger warnings about these adverse phenanthrenes or morphine-like, phenylpiperidine or
events are also required on non-prescription NSAIDs. As a meperidine-like, and diphenylheptane or methadone-like.
result of the data and subsequent events, two members of this Partial agonists/antagonists (butorphanol, pentazocine, and
class, rofecoxib and valdecoxib, have been withdrawn from the nalbuphine) partially stimulate the receptor and antagonize
market. Future COX-2 inhibitors and non-selective NSAIDs the receptors. This activity results in reduced analgesic ef-
will likely have to undergo cardiovascular safety studies before cacy with a ceiling dose, reduced side effects at the receptor,
receiving FDA approval. When an NSAID is needed in a psychotomimetic side effects due to antagonism, and possi-
patient with cardiovascular risk, the benets of therapy must ble withdrawal symptoms in patients who are dependent on
outweigh the risk and the lowest effective dose of NSAID is pure agonists.
recommended. Selection of the agent and route depend on individual
patient-related factors including severity of pain, individual
Opioid Analgesics
perceptions, weight, age, opioid tolerance, and concomitant
Opioids are considered the agents of choice for the treatment
disease (renal or hepatic dysfunction). Since pure agonists are
of severe acute pain and moderate to severe pain associated
pharmacologically similar, choice of agent may also be guided
by pharmacokinetic parameters and other drug characteristics.
Hepatic impairment can decrease the metabolism of most
Patient Encounter, Part 2: Converting opioids, particularly methadone, meperidine, pentazocine,
to Different Drugs and Adjusting
Doses
Two years following his diagnosis of lung cancer, BA has TABLE 302. Equianalgesic Doses of Selected Opioids26,45,49,51
been diagnosed as having bone metastases. Pain has been
controlled with the following medications: hydromorphone Dose Equianalgesic to 10 mg
(Dilaudid) 10 mg IV every hour and levorphanol of Parenteral Morphine (mg)
(Levodromoran) 10 mg orally every 4 hours. He is currently Opioid Parenteral (mg) Oral (mg)
receiving hydrochlorothiazide 25 mg daily, senna two
Mild-Moderate Pain
tablets twice daily, and docusate sodium 100 mg twice
Codeine 120 200
daily. As the home care pharmacist, you are asked to con- Hydrocodone N/A 30
vert this patient to a morphine infusion. Oxycodone N/A 20
Morphine equivalents (based on 10 mg parenteral mor- Meperidine (Demerol) 100 400
phine) (Table 302): Propoxyphene (Darvon) N/A 65130
Hydromorphone 1.5 mg is equivalent to 10 mg of morphine. Moderate-Severe Pain
Levorphanol 4 mg is equivalent to 10 mg of morphine. Morphine 10 30
Hydromorphone (Dilaudid) 1.5 7.5
Based on BAs opioid requirement, recommend an initial Oxymorphone 1 N/A
infusion rate (in milligrams per hour) of parenteral Levorphanol 2 4
Fentanyl (Duragesic) 0.10.2 N/Aa
morphine.
Methadone (Dolophine) 10b 35b
Which adjuvant therapy could be considered for BA?
a
Recommend a monitoring plan for this patient. Transdermal: 100 mcg/hour = 24 mg/hour of IV morphine.
b
Dosage calculations when converting from morphine to methadone are
How would you assess pain response? not linear. The equianalgesic dose of methadone will decrease progres-
sively as the morphine equivalents increase (Table 30-4).
and propoxyphene. Furthermore, the clearance of meperidine, for chronic pain. The long half-life of methadone (30 hours)
propoxyphene, and morphine and their metabolites is reduced permits extended dosing intervals; however, the potential for
in renal dysfunction. accumulation with repeated dosing often results in challenging
Table 303 provides a summary of opiate side effects, but sev- dose conversions. Tramadol is a synthetic opioid with a dual
eral drugs warrant further discussion. Normeperidine, the active mechanism of action ( agonist and inhibition of serotonin and
metabolite of meperidine, can produce tremors, myoclonus, norepinephrine reuptake), and efcacy and safety similar to that
delirium, and seizures. Due to the potential for accumulation of of equianalgesic doses of codeine plus acetaminophen.
normeperidine, meperidine should not be used in the elderly, Tramadol has been evaluated in several types of neuropathic
those with renal impairment, in patients using patient-controlled pain and may have a place in the treatment of chronic pain.
analgesia devices, or for more than 1 to 2 days of continuous Tramadol is associated with an increased risk of seizures in
dosing with intermittent dosing. Propoxyphene also has an patients with a seizure disorder, those at risk for seizures, and
increased risk of seizures and cardiac conduction abnormalities those taking medications that can lower the seizure threshold.
and should be avoided in the elderly. Despite its popularity, Doses greater than 500 mg have also been associated with
propoxyphene has proven to be no more effective than aceta- seizures. Use of tramadol with other serotonergic drugs [e.g.,
minophen, aspirin, or codeine alone.18 Methadone is unique selective serotonin reuptake inhibitors (SSRIs)] may precipitate
among the opiates since it has several mechanisms ( agonist, serotonin syndrome. While originally thought to be non-habit
NMDA receptor antagonist, and inhibition of reuptake of sero- forming, dependence may occur with tramadol.
tonin and norepinephrine) that makes it an interesting choice About 70% of individuals will experience signicant
analgesia from 10 mg/70 kg (154 lbs) of body weight of
intravenous morphine or its equivalent.18 For severe pain in
opiate-nave patients, a usual starting dose is 5 to 10 mg of
TABLE 303. Managing Opioid Side Effects27,45,49
morphine every 4 hours. In the initial stages of severe pain,
Adverse Effects Drug Treatment/Management medication should be given around the clock. Rescue doses
should be made available in doses equivalent to 10% to 20%
Excessive sedation Reduce dose by 25% or
increase dosing interval of the total daily opioid requirement and administered
Constipation Casanthranol-docusate 1 cap at every 2 to 6 hours if needed. Alternatively one-sixth of the
bedtime or twice daily; senna total daily dose or one-third of the 12-hourly dose may be
12 tabs at bedtime or twice used. Doses should be titrated based on the degree of pain.
daily; bisacodyl 510 mg daily + One method involves adjustment of the maintenance dose
docusate 100 mg twice daily
Nausea and vomiting Prevention: hydroxyzine 25100 mg based on the total 24-hour rescue dose requirement.
(PO/IM) every 46 hours as Utilizing dose escalation, doses should be increased by 50%
needed; diphenhydramine 2550 mg to 100% or 30% to 50% of the current dose, for those in
(PO/IM) every 6 hours as needed; severe and moderate pain, respectively. Once pain relief is
ondansetron 4 mg IV or 16 mg PO achieved, and if treatment is necessary for more than a few
Treatment: prochlorperazine 510 mg
(PO/IM) every 34 hours as days, conversion to a controlled-release or long-acting opi-
needed or 25 mg per rectum twice oid should be made with an equal amount of agent. Several
daily; ondansetron 48 mg IV every sustained-release products are available containing mor-
8 hours as needed phine, oxycodone, and fentanyl. Some clinicians will reduce
Gastroparesis Metoclopramide 10 mg (PO/IV) every the total daily dose of the long-acting dosage form by 25%
68 hours
Vertigo Meclizine 12.525 mg PO every 6 hours when initiating a sustained-release product to reduce the
as needed likelihood of oversedation. The dose of a pure agonist is lim-
Urticaria/itching Hydroxyzine 25100 mg (PO/IM) every ited only by tolerability to side effects. Tolerance may
46 hours as needed; develop to analgesic effects necessitating increasing doses to
diphenhydramine 2550 mg (PO/IM) achieve the same level of pain relief. Physical dependence
every 6 hours as needed
Respiratory depression Mild: Reduce dose by 25% will also occur with long-term use of opioids. However,
Moderate-severe: naloxone 0.42 mg addiction or psychological dependence is unlikely in legiti-
IV every 23 minutes (up to 10 mg) mate pain patients unless there are predisposing risk factors.
for complete reversal; 0.10.2 mg Pain patients who are undertreated may appear to be drug-
IV every 23 minutes until desired seeking (pseudoaddiction); however, effective pain manage-
reversal for partial reversal; may need
to repeat in 12 hours depending ment resolves the behaviors. When opioids are used for
on narcotic half-life chronic pain, use of informed consent for chronic opioid
CNS irritability Discontinue opioid; treat with therapy and medication management agreements or pain
benzodiazepine contracts may be appropriate to monitor the use (prescrib-
CNS, central nervous system; IM, intramuscular; IV, intravenous; PO, orally. ing and dispensing) of controlled substances.
Opioids may be administered in a variety of routes includ- an agent in another chemical class. For the purpose of drug
ing oral (tablet and liquid), sublingual, rectal, transdermal, selection in patients with allergies, mixed antagonists should
transmucosal, intravenous, subcutaneous, and intraspinal. be treated as morphine-like agents.
While the oral and transdermal routes are most common, the
method of administration is based on patient needs (severity of Tapering of Opioids
pain) and characteristics (swallowing difculty and preference). Tapering of opioids may be necessary once the painful situation
Oral opioids have an onset of effect of 45 minutes, so has resolved in patients receiving doses greater than 160 mg/day
intravenous or subcutaneous administration may be preferred of oral morphine (or the equivalent) or in those with prolonged
if more rapid relief is desired. Intramuscular injections are opioid use. In these situations the dose should be reduced by
not recommended because of pain at the injection site and 15% to 20% each day to avoid withdrawal symptoms.
wide uctuations in drug absorption and peak plasma con-
Managing Opioid Side Effects and Drug Interactions
centrations achieved. More invasive routes of administration
Side effects common to all opioids include sedation, hallucina-
such as PCA and intraspinal (epidural and intrathecal) are
tions, constipation, nausea and vomiting, urinary retention,
primarily used postoperatively, but may also be used in refrac-
myoclonus, and respiratory depression. In terms of medication
tory chronic pain situations. PCA delivers a self-administered
management, the most frequent are sedation, nausea, and
dose via an infusion pump with a preprogrammed dose, min-
constipation. Sedation and nausea are common when initiat-
imum dosing interval, and maximum hourly dose. Morphine,
ing therapy and when increasing doses. Nausea can be pre-
fentanyl, and hydromorphone are commonly administered
vented with a centrally-acting antiemetic (Table 203).
via PCA pumps by the intravenous route, but less frequently
Sedation usually improves with continued therapy but may
by the subcutaneous or epidural route.
become intractable at high doses, and stimulants may be
Epidural analgesia is frequently used for lower extremity
needed. Respiratory depression is a serious adverse effect, and
procedures and pain (e.g., knee surgery, labor pain, and some
usually occurs after acute administration in opioid-nave
abdominal procedures). Intermittent bolus or continuous
patients. Tolerance to respiratory depression develops rapidly
infusion of preservative-free opioids (morphine, hydromor-
with repeated doses and is rarely a clinically signicant prob-
phone, or fentanyl) and local anesthetics (bupivacaine) may be
lem in pain patients, even those with respiratory impairment.
used for epidural analgesia. Opiates given by this route may
Constipation is a signicant adverse effect to which tolerance
cause pruritus that is relieved by naloxone. Adverse effects
does not develop, and prophylaxis with stimulant laxatives
including respiratory depression, hypotension, and urinary
(e.g., senna or bisacodyl) and stool softeners, such as docusate,
retention may occur. When epidural routes are used in narcotic-
is recommended.
dependent patients, systemic analgesics must also be used to
Codeine, hydrocodone, morphine, methadone, and oxy-
prevent withdrawal since the opioid is not absorbed and
codone are substrates of the cytochrome P-450 isoenzyme
remains in the epidural space. Doses of opioids used in epidural
CYP2D6.47 Inhibition of CYP2D6 results in decreased analge-
analgesia are 10 times less than intravenous doses, and intrathe-
sia of codeine and hydrocodone due to decreased conversion to
cal doses are 10 times less than epidural doses (i.e., 10 mg of
the active metabolites (e.g., morphine and hydromorphone,
IV morphine is equivalent to 1 mg epidural morphine and
respectively) and increased effects of morphine, methadone,
0.1 mg of intrathecally administered morphine).45
and oxycodone. Methadone is also a substrate of CYP3A4, and
its metabolism is increased by phenytoin and decreased by
Combination Analgesics
cimetidine. CNS depressants may potentiate the sedative
Combinations of opioids and non-opioids often result in
effects of opiates.
enhanced analgesia and lower dose of each. Combination
analgesics are frequently used in moderate pain. However, in Opioid Rotation
severe pain, the non-opioid component reaches maximum Opioid rotation is the switch from one opioid to another to
dosage, and thus, the usefulness of non-opioids in this situa- achieve a better balance between analgesia and treatment-
tion is limited. Additionally, the combination products are limiting adverse effects. This practice is often used when esca-
short-acting and often not suitable for chronic therapy. lating doses (greater than 1 g of morphine per day) become
Single agents offer greater dosing exibility than combina- ineffective. In some settings opioid rotation is utilized rou-
tion products. tinely to prevent the development of analgesic tolerance.48
Opioid Allergy Equianalgesic Dosing of Opioid Analgesics

True narcotic allergies are rare and should not be confused Conversion from one dosage form to another or from one opi-
with pruritus associated with opiate use. Cross-sensitivity oid to another may be necessary in situations such as ineffective
between morphine-like, meperidine-like, and methadone-like pain control, emergence of side effects, change in patient status,
agents is unlikely. Therefore, when an individual is allergic to and in formulary restrictions. Equianalgesic doses should be
one drug in a chemical class of opioids, it is reasonable to select used when converting from one opioid to another. Clinicians
should be familiar with the equianalgesic dosing and conver- for chronic pain, particularly neuropathic pain, is warranted.
sion strategies to avoid analgesic failure. Equianalgesic tables Adjuvant analgesics are drugs that have indications other
serve as a guide for selection of the dosage of the new opioid, than pain but are useful as monotherapy or in combination
but have limitations, as they are often based on single-dose with non-opioids and opioids. Common adjuvants include
studies and clinical observations.32 Opioid potency is compared antiepileptic drugs (AEDs), antidepressants, antiarrhythmic
using a reference standard of 10 mg of parenteral morphine. drugs, local anesthetics, topical agents (e.g., capsaicin), and a
Switching from one dosage form to another of the same opioid variety of miscellaneous drugs (e.g., NMDA antagonists,
(i.e., IV to PO) is relatively simple. The current total daily dose clonidine, and muscle relaxants).
is calculated and the total of the new dosage form is determined There is little consensus as to the optimal management of
using a ratio of the equianalgesic doses. This result is then neuropathic pain, because much of the evidence for treatment
adjusted based on the usual dosing frequency of the new form. effectiveness consists of anecdotal reports or poorly designed
When converting to a sustained-release form of the same opioid, trials. Published guidelines have been suggested for the general
dosage may be reduced by 25% to avoid initial sedation; how- management of neuropathic pain.54 Suggestions for rst-line
ever, the specic product literature should also be consulted. therapy include gabapentin, lidocaine patch, or tricyclic antide-
The rst step in an opioid rotation is to calculate the pressants (TCAs) (Table 305).5458 Newer antidepressants, such
patients total daily dose of opioid based on the regularly as the SSRIs, have fewer side effects but appear to be less effec-
scheduled dose and the total amount of rescue dose needed in tive than the TCAs for neuropathic pain. However, serotonin-
24 hours. This total is then converted to morphine dosing norepinephrine reuptake inhibitors (SNRIs) (e.g., duloxetine
equivalents using equianalgesic doses (Table 302). The total and venlafaxine) have been used successfully for painful DPN.
daily morphine dose is then used to calculate the daily dose of
the new opioid using dosing equivalents from an equianalgesic
table. Since cross-tolerance may not be complete between opi-
oids, some references suggest that the calculated equianalgesic TABLE 305. Selected Adjuvant Analgesics and Suggested
Dosing5458
dose be reduced by 25% to 50%.49 If the opioid switch is due to
uncontrolled pain, a dosage reduction may not be needed. The FDA-Approved
equianalgesic dose may need to be reduced more in the med- Agent Dosing Guidelines Indication
ically frail and when converting to methadone.50 Using the Amitriptyline 1025 mg at bedtime with
commonly cited equianalgesic dose of morphine to methadone (Elavil) weekly increments to a
(10 mg morphine/10 mg methadone), methadone doses target dose of 25150 mg
should be reduced by 75% to 80%. However, this ratio is not of amitriptyline or an
applicable even in patients tolerant to low doses of morphine.51 equivalent dose of another
TCA
Methadone appears to be much more potent than once Duloxetine 60 mg daily DPN
believed, and morphine/methadone ratios vary according to (Cymbalta)
the total dose of morphine taken at the time of making the Gabapentin Initially, 300 mg three times PHN
conversion to methadone (Table 304).52,53 Conversion to (Neurontin) daily up to a maximum
methadone is a complex process, and several different strate- of 3600 mg daily, in
divided dosesa
gies have been proposed including a switch of the entire dose Pregabalin DPN: Initially, 50 mg three DPN
in one day or a gradual conversion over 3 days. (Lyrica) times daily; may be and PHN
increased to 100 mg
Adjuvant Agents for Chronic Pain three times daily within
The role of NSAIDs and opioids in chronic non-malignant 1 week based on efcacy
pain has been discussed; however, a review of adjuvant agents and tolerabilitya
PHN: Initially 75 mg twice
daily or 50 mg three times
TABLE 304. Methadone Dose Conversions53 daily; may be increased
to 100 mg three times
Total Daily Dose Morphine: daily within 1 week based
Oral Morphine Methadone Factor on efcacy and tolerabilitya
Lidocaine 5% Up to three patches may be PHN
Less than 100 mg 3:1 (Lidoderm applied directly over the
3 mg morphine: 1 mg methadone patch) painful site once daily;
101300 mg 5:1 patches are applied using
301600 mg 10:1 a regimen of 12 hours on
601800 mg 12:1 and 12 hours off
8011,000 mg 15:1
a
Greater than 1,000 mg 20:1 Dosing for creatinine clearance of 60 mL/minute or greater.
DPN, diabetic peripheral neuropathy; PHN, post-herpetic neuralgia;
Data from reference 53 with permission. TCA, tricyclic antidepressant.
A stepwise approach is suggested for managing the patient with

neuropathic pain, beginning with the least invasive effective Patient Care and Monitoring
therapeutic choice and proceeding to the rational use of multi-
ple drug regimens. To guide the choice of pharmacologic
agents, patients may be identied as candidates for AEDs,
1. Identify the source of pain.
TCAs, or opioids based on the presence of peripheral or central
nerve pain and description of symptoms (Fig. 302). Choice of 2. Assess the level of pain using a pain intensity scale.
agent may also depend on dosing frequency and comorbidities. 3. Base the initial choice of analgesic on the severity and
Data on combination therapy are lacking, and the use of com- type of pain, as well as on the patients medical condi-
bined treatment is empirical based on additive therapeutic ben- tion and concurrent medications.
et. Scheduled medication regimens instead of as needed 4. Use the least potent oral analgesic that provides ade-
dosing should be employed when treating chronic pain, and quate pain relief and causes the fewest side effects.
the effectiveness of therapy should be reassessed regularly. If 5. Titrate the dose to one that achieves an adequate level
patients are managed on a multiple drug regimen and changes of pain control.
are indicated, changing only one drug at a time is suggested. 6. Use a dosing schedule versus as-needed dosing.
Topical agents (e.g., capsaicin) may be added to a regimen to 7. Assess the patient for analgesic effectiveness and for
reduce the oral medication load, particularly if adverse effects side effects at each visit or more frequently, depending
are a problem or if pain is not relieved. on the acuity of the patients condition.
8. Avoid excessive sedation.
Complementary and Alternative Medicine 9. Adjust the route of administration if the patient is
Complementary and alternative medicine (CAM) is a term unable to take oral medications.
used to encompass a variety of therapies (e.g., acupuncture,
10. Use equianalgesic doses as a guide when switching
chiropractic, botanical and non-botanical dietary supple- opioids.
ments, and homeopathy) not typically taught in medical and
allied health schools. Painful conditions are among the most
common reasons individuals seek relief from CAM. In a
recent survey, neck pain, joint pain, arthritis, and headache
were among the top ten reasons for use of CAM, and low back ABBREVIATIONS
pain ranked the number one reason for CAM therapies. A
variety of dietary supplements have been suggested for painful AED: Antiepileptic drug
AGS: American Geriatrics Society
conditions, such as S-adenosylmethionine (SAM-e), ginger,
AHRQ: Agency for Healthcare Research and Quality
sh oil, feverfew, -linoleic acid, glucosamine, and chon- AIDS: acquired immunodeciency syndrome
droitin. Of these, glucosamine and chondroitin are the most AMPA: -amino-3-hydroxy-5-methylisoxazole-4-propionic
popular and have the most evidence of efcacy. Glucosamine acid
in doses of 1500 mg/day is effective in reducing pain of APAP: acetaminophen
osteoarthritis by repair of cartilage and is recommended by APS: American Pain Society
the American Pain Society. ASA: American Society of Anesthesiologists
CAM: complementary and alternative therapy
CNS: central nervous system
OUTCOME EVALUATION COX: cyclooxygenase
CRPS: complex regional pain syndrome
Individualize treatment goals at the beginning of treatment. CYP: cytochrome P-450 isoenzyme
Utilize information obtained during the pain interview to cre- DPN: diabetic peripheral neuropathy
ate goals that are consistent with the patients expectations. FDA: Food and Drug Administration
Prevention, reduction, or elimination of pain are important GABA: -aminobutyric acid
goals for treatment of acute pain. With chronic pain, elimi- GI: gastrointestinal
nation of pain may not be possible, and goals may focus on HIV: human immunodeciency virus
improvement or maintenance of functional capacity and IASP: International Association for the Study of Pain
IM: intramuscular
quality of life. Thus, for example, pain goals may include
IV: intravenous
pain scale less than 3, be able to play a game with grand- JCAHO: Joint Commission on Accreditation of Healthcare
children, or be able to knit again. Assess patients periodi- Organizations
cally, depending on the method of analgesia and pain condition, NIOSH: National Institute for Occupational Safety and Health
for achievement of pain goals. Evaluate the patient for the NMDA: N-methyl-D-aspartate
presence of adverse drug reactions, drug allergies, and drug NSAID: non-steroidal anti-inammatory drug
interactions. PAINAD: Pain Assessment in Advanced Dementia (tool)
PCA: patient-controlled analgesia American Pain Society. Principles of Analgesic Use in the Treatment
PHN: postherpetic neuralgia of Acute Pain and Cancer Pain. 5th ed. Glenview, IL: American
PO: oral Pain Society, 2003: 1341.
PQRST: Palliative/precipitating, Quality, Radiation, Severity, and Time Clinical Practice Guideline, Cancer Pain Management. United States
SAM-e: S-adenosylmethionine Department of Health and Human Services, Agency for Health
SNRI: serotonin-norepinephrine reuptake inhibitor Care Policy and Research. AHCPR Pub. Rockville, MD: 1994.
SSRI: selective serotonin reuptake inhibitor Available at: http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/
TCA: tricyclic antidepressant hstat6/f37_capcf4.gif.Accessed January 10, 2006.
TENS: transcutaneous electrical nerve stimulation Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neu-
VAS: visual analog scale ropathic pain: diagnosis, mechanisms, and treatment recom-
VHA: Veterans Health Administration mendations. Arch Neurol 2003;60:15241534.
WHO: World Health Organization Joint Commission on Accreditation of Healthcare Organizations.
Pain Assessment and Management: an Organizational Approach.
Reference lists and self-assessment questions and answers are Oakbrook Terrace, IL: JCAHO,2000:16.
available at www.ChisholmPharmacotherapy.com. Woolf CJ. Pain: moving from symptom control toward mechanism-
specic pharmacologic management. Ann Intern Med 2004;140:
Log into the website: www.pharmacotherapyprinciples.com 441451.
this chapter.
American Geriatrics Society Panel on Persistent Pain in Older

Persons. The management of persistent pain in older persons. J
Am Geriatr Soc 2002;50:120.
31 HEADACHE
Leigh Ann Ross and Brendan S. Ross
LEARNING OBJECTIVES
1. Differentiate among types of headaches based on symptoms and signs.

2. List underlying causes and precipitating factors of different types of headache disorders.
3. Recommend appropriate nonpharmacologic measures for headache treatment and
prevention.
4. Based on patient-specic data, determine when pharmacologic therapy is indicated for
headache.
5. Propose individualized pharmacologic treatment regimens for the acute and chronic
management of headache syndromes.
6. Construct therapeutic and adverse-effect monitoring plans for patients with headache.
7. Discuss pertinent patient education points for patients with headache disorders.
KEY CONCEPTS causally related to an underlying medical disorder. Primary

headaches are more common and will be the focus of this chap-
Headache may be a primary, or a secondary disorder due to an ter. Patients may seek evaluation of headache from a variety of
underlying medical condition. health care providers. Therefore, all clinicians must be familiar
Primary headaches are classied as migraine, tension-type, or with the types of headache, their diagnostic criteria, red ags
cluster and other trigeminal autonomic cephalalgias. indicating need for urgent intervention or specialist referral,
The pain experienced with headache is likely due to overactiv- and nonpharmacologic and pharmacologic options for treat-
ity in the trigeminovascular system of the brain. ment. The International Headache Society (IHS) classies pri-
Migraine is further classied as migraine with aura and mary headaches as migraine, tension-type, or cluster and other
migraine without aura. trigeminal autonomic cephalalgias.1 Tension-type headaches
The short-term goal of headache therapy is pain relief and a appear to be more common than migraine, and both are more
return to normal activities. common in women than in men. Cluster is a less common
The long-term goal of therapy is the prevention of headache chronic headache syndrome that affects predominantly men.
recurrence.
Pharmacologic treatment of acute headache should be started
early to improve the response to therapy. EPIDEMIOLOGY OF HEADACHE DISORDERS
Prophylaxis is indicated if headaches are frequent or severe,
lead to signicant disability, or require the use of pain-relieving Migraine Headache
medications two or more times per week.
Regimens for headache disorders should be individualized Migraine is a primary headache disorder that is estimated to
based on the pattern of occurrence, response to therapy, med- affect 10% to 15% of adults in the United States.2 Less than
ication tolerability, and comorbid medical conditions. one-half of headaches meeting the diagnostic criteria for
migraine are appropriately diagnosed. Migraine prevalence
Headaches are common and have a signicant impact on depends on age and gender. In children less than 12 years of
quality of life. They can be classied as primary or secondary, age, migraines are more prevalent in males. After age 12, this
501
prevalence shifts markedly to women. The evolution in this gender

difference is brought on by the hormonal changes of menarche.3 Patient Encounter, Part 1
Onset typically occurs between the ages of 10 and 30 years, but
the prevalence is highest in the age range of 35 to 45 years.4
Migraines signicantly impact patient function, with over one-
GC, a 28-year-old woman, complains of a terrible headache
half of sufferers reporting severe disability requiring bed rest dur- that wont go away. She describes the pain as on one side
ing an attack. The economic burden of migraine due to direct and throbbing. The pain began yesterday morning and
and indirect costs is substantial. Migraines are the leading cause caused her to leave work. She reports a history of similar
of employee absenteeism and decreased workplace productivity.5 headaches since the age of 16, but none that lasted this
long. In the past, her headaches were relieved with the use
of over-the-counter non-steroidal anti-inammatory drugs
Tension-Type Headache (NSAIDs). She often has to take analgesics multiple times
Tension-type headache (TTH) is the most common primary per week.
headache disorder. It is often underrepresented in clinical
practice, as many patients do not present for care.6 The term What type of headache is the patient most likely experiencing?
What characteristics of the headache support this diagnosis?
tension-type headache is used to describe all headache syn-
What are possible causes or triggers of headache in this
dromes in which muscle contraction is the most signicant patient?
factor in the pathogenesis of pain. The 1-year prevalence of What additional information is needed to formulate a
TTH in the population ranges from 30% to 90%.6 It is more treatment plan?
common in adult females. Environmental factors, as opposed to
genetic predisposition, play a more central role in their devel-
opment. Tension-type headaches can be further divided into
theories exist: tissue pain generated by vascular reactivity or
episodic or chronic; the mean frequency of attacks is 3 days
neuronal imbalance accompanied by trigeminovascular sys-
per month in episodic disorders, and chronic TTH is dened
tem overactivity.10 The vascular hypothesis suggests that
as 15 or more attacks in a 1-month period.7 The estimated
intracerebral vasoconstriction leads to neural ischemia and is
prevalence of chronic TTH is less than 5%.6 Some researchers
followed by reex extracranial vasodilation and pain. Recent
believe that chronic TTHs represent a continuum of headache
neuroimaging evidence and the effectiveness of medications
severity with migraine headache.8 When severe headaches are
with no vascular properties do not support this theory, and
difcult to differentiate clinically, treatment should initially
ischemia alone is no longer accepted as the primary cause of
target TTH.
migraine distress.6 A neuronal etiology has emerged as the
leading mechanism of the development of migraine.11
Cluster Headache and Other Trigeminal Depressed neuronal electrical activity spreads across the
Autonomic Cephalalgias brain, which produces transitory neural dysfunction.12 The
pain experienced with headache is likely due to compensatory
Cluster headache disorders are the most uncommon and
overactivity in the trigeminovascular system of the brain.
severe primary headache syndromes.9 The estimated point
Activation of trigeminal sensory nerves leads to the release of
prevalence is less than 1%. Unlike migraine and TTH, cluster
vasoactive peptides [e.g., calcitonin gene-related peptide
headaches occur more frequently in men. Onset commonly
(CGRP), neurokinin A, and substance P] that produce a sterile
occurs prior to age 30.6 A genetic predisposition seems appar-
inammatory response around vascular structures in the
ent, although affected individuals often provide a history of
meninges of the brain, which leads to pain.11 Continued sensi-
tobacco use and alcohol abuse.6 Attacks consist of debilitating,
tization of central nervous system sensory neurons can poten-
unilateral head pains that occur in series lasting up to months
tiate and intensify headache pain as an attack progresses.12
at a time, but that remit over months to years between occur-
Bioamine pathways projecting from the brain stem regulate
rences. In rare instances, cluster headache can be a chronic
activity within the trigeminovascular system. Thus, the patho-
disorder without remissions.4
genesis of migraine may be due to an imbalance in the mod-
ulation of nociceptors and blood vessel tone by serotonin and
norepinephrine neurons.13
ETIOLOGY AND PATHOPHYSIOLOGY OF
HEADACHE DISORDERS Tension-Type Headaches
The pathophysiologic mechanisms of TTH are not clearly
Migraine Headache
understood. The pain is thought to originate in the myofas-
The mechanism by which headache pain occurs in cial tissues of the head, but central brain processing is
migraineurs is not conrmed, but competing pathoetiologic believed to be an important modulator of pain perception.14
CHAPTER 31 / HEADACHE 503
Chronic TTH syndromes may evolve from recurrent episodic CLINICAL PRESENTATION OF HEADACHES
headaches as central nociception becomes sensitized.15
Migraine Headache
Cluster Headache and Other Trigeminal Migraine presents as a recurrent headache that is severe enough
Autonomic Cephalalgias to interfere with daily functioning. Migraine headaches are
Cluster headache is one of a group of disorders referred to as classied as migraine with aura and migraine without aura.6 The
trigeminal autonomic cephalalgias.16 The autonomic dysfunc- correlating terms of classic and common migraine are no
tion is characterized by sympathetic underactivity and parasym- longer employed. Aura is dened as a transient focal neurologic
pathetic activation. Similar to migraine, the pain of a cluster symptom, which can be positive or negative, and can occur
headache is believed to be the result of vasoactive peptide release prior to or during an attack.18 Examples of positive symptoms
and neurogenic inammation. The exact cause of trigeminal include the visual perception of ickering lights, spots, or wavy
activation is not clear.9 A leading hypothesis is that hypothala- lines; whereas a partial loss of vision is a classic negative symp-
mic dysfunction, occasioned by diurnal or seasonal changes in tom of an aura. The International Classication of Headache
neurohumoral balance, are responsible for headache periodic- Disorders (ICHD) outlines diagnostic criteria that differentiate
ity.6 Serotonin affects neuronal activity in the hypothalamus and migraine with and without aura.6 The pain of a migraine
trigeminal system and may play a role in the pathophysiology of headache is typically described as moderate to severe, throb-
cluster headache. The precipitation of cluster headache by high bing, unilateral, and retro-orbital in location. The pain is
altitude exposure also implicates hypoxemia in the pathogenesis accompanied by nausea, sensitivity to light and sound, and dif-
of trigeminal autonomic cephalalgias.17 culty concentrating.19 Untreated migraines can last from 4 to
Patient Encounter: Part 2: Medical Naproxen sodium 220 mg, 2 PO twice daily prn
History, Physical Exam and Diagnostic for headache
Tests
Review of Systems
Headache, severe in intensity
Further evaluation of GC reveals the following:
Sensitivity to light
Past Medical History No chest pain or palpitations
Mild persistent asthma No shortness of breath or wheezing
Gastroesophageal reux disease (GERD) Nauseated, anorectic
Generalized anxiety disorder Dizzy, difculty concentrating
Family History Physical Exam
Father living, age 58 years; hypertension, diabetes mellitus, VS: Blood pressure 138/82 mm Hg, pulse 88 beats per
dyslipidemia minute, respiratory rate 16/minute, temperature 37.0C
Mother living, age 57 years; chronic daily sick (98.6F), oral
headaches HEENT: No papilledema, no neck stiffness
No siblings CV: RRR, normal S1, S2, no murmur, rub, or gallop
Paternal grandparents died at ages 58 and 65 years, both of Chest: CTA
ischemic stroke Abdomen: Benign, bowel sounds positive
Maternal grandparents, living, ages 73 and 84; hyperten- Neurologic: Non-focal
sion, osteoarthritis
Labs
Social History
CBC and chemistry panel within normal limits
Married
Employed as an account ofcer in a local bank
What is your assessment of this patients condition?
No tobacco use, social alcohol intake (1 to 2 glasses of wine
What medical comorbidities or drug therapies may be con-
on weekends), drinks 3 to 4 caffeinated beverages per day
tributing to her distress?
Medication Prole Identify treatment goals for this patient.
Advair 250/50 mg, 1 inhalation twice daily What nonpharmacologic options are needed at present, and
Albuterol 2 inhalations prn for bronchospasm what options are appropriate in the long term for this patient?
Omeprazole 20 mg PO daily What pharmacologic therapy would you recommend for
Sertraline 150 mg PO daily this patient in the acute setting?
Combination ethinyl estradiol/norgestimate oral Does this patient require long-term pharmacologic prophy-
contraceptive laxis against recurrent headaches?
72 hours. Migraines occurring 15 days per month or for

3 months or longer, without the overuse of analgesic medica- Clinical Presentation and Diagnosis of
tions, are classied as chronic migraines.6 Severe and debilitating Migraine with Aura
migraine pain lasting greater than 72 hours is termed status
migrainosus.19 Even in the absence of neurologic focality, brain
Patients experiencing migraine with aura may display the fol-
imaging is mandated in patients with frequent, severe, and pro- lowing headache symptoms and characteristics:
longed attacks or headaches that are atypical for a migraineurs One or more of the following present with no motor
stereotyped presentation.20 weakness:
Tension-Type Headache 1. Visual symptoms (positive and/or negative; reversible)

2. Sensory symptoms (positive and/or negative; reversible)
Tension-type headache pain differs from migraine pain in that 3. Dysphasic speech (reversible)
it is usually reported to be mild to moderate, non-pulsating, 4. Moderate or severe pain intensity
and bilateral.6 The pain is described by sufferers as a bandlike
tightness or pressure around the head. No transient neurologic Two or more of the following present:
decits are noted, and systemic symptoms are rare.4 Tension-
type headaches infrequently disrupt normal activity. Muscle 1. Homonymous visual symptoms and/or unilateral sensory
palpation in the fronto-temporal and parieto-occipital may symptoms
identify localized tender points.4 Neuroimaging and labora- 2. One aura symptom develops at least 5 minutes prior
and/or a second aura symptom develops 5 minutes or
tory testing are unrevealing, and they are unnecessary if the
more after headache
presentation and clinical history are classic for TTHs. 3. Duration of each symptom 4 to 60 minutes
Cluster Headache Criteria for diagnosis: Two or more attacks fullling the
Pain associated with cluster headache differs from migraine and above criteria are necessary for diagnosis
TTH in that it is severe, intermittent, and short in duration.6
Headaches typically occur at night, but attacks may occur mul-
tiple times per day.9 The pain is usually unilateral, but unlike
and pain intensity peaks early after onset and may persist for
migraine it is not described as pulsatile.6 Aura is not a feature,
hours.6 The headache is described as explosive and excruciating.
A constellation of features ascribed to parasympathetic overac-
tivity can be seen, such as ipsilateral conjunctival injection,
Clinical Presentation and Diagnosis of
Migraine without Aura lacrimation, rhinorrhea, and sweating.9 Unlike migraineurs,
cluster headache disorder patients tend to become excited and
restless during attacks, rather than seeking quiet and solitude.16
Patients experiencing migraine without aura display the fol-
lowing headache symptoms and characteristics:
Two or more of the following present: Clinical Presentation and Diagnosis of
1. Pain interrupts or worsens with physical activity Tension-Type Headache
2. Unilateral pain
3. Pulsating pain
4. Moderate to severe pain intensity Patients experiencing tension-type headache may display the
following headache symptoms and characteristics:
Two or more of the following present during headache: Two or more of the following present:
1. Nausea 1. Bilateral pain

2. Vomiting 2. Non-pulsating pain
3. Photophobia 3. Mild or moderate pain intensity
4. Phonophobia
5. Osmophobia Both of the following present:
Duration: 4 to 72 hours (treated or not treated) 1. No nausea or vomiting (anorexia possible)

Criteria for diagnosis: Five or more attacks fullling the 2. Either photophobia or phonophobia (not both)
above criteria are necessary for diagnosis
Laboratory assessments that may be helpful in excluding Duration: 30 minutes to 7 days
medical comorbidities: Complete blood cell count (CBC), Criteria for diagnosis: Ten or more attacks fullling the
chemistry panel, thyroid function tests, erythrocyte above criteria occurring on average less than 1 day per
sedimentation rate (ESR) month are necessary for diagnosis
TABLE 311. Headache Red Flags That, if Present, Warrant

Clinical Presentation and Diagnosis of Urgent Further Evaluation
Cluster Headache
New onset, sudden, and/or severe
Onset after 40 years of age
Patients experiencing cluster headache may display the fol- Stereotyped pattern worsens
lowing headache symptoms and characteristics: Systemic signs (e.g., fever, weight loss, accelerated hypertension)
Focal neurologic symptoms (i.e., other than typical visual or
sensory aura)
1. Unilateral pain Papilledema
2. Orbital, supraorbital, or temporal pain Cough-, exertion-, or Valsalva-triggered headache
3. Sharp and stabbing pain Pregnancy or postpartum
Patients with cancer, human immunodeciency virus, and other
One or more of the following present: infectious and immunodeciency disorders
Seizures
1. Conjunctival injection and/or lacrimation
2. Nasal congestion and/or rhinorrhea
3. Eyelid edema Nonpharmacologic Therapy
Patient education is key to the successful management of
Duration of pain: 2 seconds to 10 minutes
Frequency of attacks: One or more per day more than half
headache disorders. Recording headache frequency, duration,
of the time and severity in a headache diary provides useful information
Criteria for diagnosis: Twenty or more attacks fullling the for the patient regarding headache precipitants and insight for
above criteria are necessary for diagnosis the clinician in selecting appropriate management strategies.27
To prevent future occurrences, exposure to headache triggers
(Table 312) should be limited. In the acute setting, environ-
TREATMENT OF HEADACHE DISORDERS mental control may be able to abort a migraine attack. Many
patients benet from resting in a dark, quiet area.28 Behavioral
Desired Outcomes interventions, such as biofeedback, relaxation training, and
cognitive-behavioral therapy, are effective and can be recom-
The primary short-term goal of migraine treatment is to mended for headache prevention.17 Tension-type headaches
achieve rapid pain relief that allows the patient to resume nor- may also be managed through stress management training.17
mal activities.21 The long-term goal of therapy is prevention Acupuncture has yielded inconsistent benets in clinical trials.22
of headache recurrence and diminution of headache severity. Cluster headache patients should be advised to moderate alco-
Similarly, the goal of TTH is to lessen headache pain, while the hol use and curtail tobacco abuse.23 Emotional distress may
long-term goal is to avoid analgesic dependence.22 The short- compound headache pain through the outward displacement of
term goal in cluster headache therapy is to achieve rapid pain inner conicts into somatization. Psychological interventions are
relief. Prophylactic therapy may be necessary to obtain the urged in such instances, and they should be considered in all
intermediate-term outcome of reducing the frequency and headache sufferers resistant to standard medication treatments.29
severity of headaches within a periodic cluster series, as well as All such non-prescription therapies may be useful in augment-
to achieve the long-term goal of delaying or eliminating recur- ing pharmacologic response.
rent periods.23
The most important goal of acute headache management is pain Migraine
relief. The primary pharmacologic agents used in the acute setting Analgesics such as NSAIDs and opioids are the initial phar-
include analgesics and serotonin receptor agonists (triptans).24 macologic option for the acute management of migraine
Despite available pharmacologic therapy, most headache headache. If these prove to be ineffective, then migraine-
patients are not treated adequately and rely on over-the-counter specic medications, such as triptans, are administered.30
products for pain relief.25 Pharmacologic treatment of acute Early, abortive treatment should be the rule. If orally admin-
headache should be started early to abort the intensication of pain istered medications are selected, then appropriate larger doses
and to improve symptomatic response to therapy. The long-term than otherwise needed to produce pain relief are provided due
management of headache syndromes focuses on lifestyle modi- to the enteric stasis and poor drug absorption accompanying
cation and other nonpharmacologic therapeutic options, but if migraine attacks.20 Intranasal, parenteral, and rectal adminis-
the headaches are severe and frequent, then prophylactic phar- tration can circumvent this complication.
macologic therapy is needed.26 Several so-called red ags have Clinical trial evidence supports many NSAID medications
been identied that, if present, warrant urgent physician referral in the acute treatment of migraines with and without aura.30
and further diagnostic evaluation (Table 311). The currently marketed cyclooxygenase-2 (COX-2) selective
TABLE 312. Migraine Triggers dosage forms. The marketed agents differ in their dosing and
pharmacokinetic properties, but all are effective treatments to
Behavioral
abort or diminish migraine headache pain (Table 313).35
Fatigue
Menstruation or menopause Patient response can be variable. If a patient does not respond
Sleep excess or decit to one agent, then another is selected before labeling a patient
Stress triptan-unresponsive.36 The initial severity of pain correlates
Vigorous physical activity with response, thus, administration should be prompt. Relief is
Environmental usually experienced within 2 to 4 hours. Treatment delay may
Flickering lights lead to decreased analgesia through the development of refrac-
High altitude
Loud noises
tory central pain sensitization. Efcacy tends to be dose-
Strong smells related, though adverse effects are less so.37 The most common
Tobacco smoke side effects are a sensation of warmth, dizziness, chest fullness,
Weather changes and nausea. Rarely, ischemic vascular events may be precipi-
Food tated by the vasoconstrictive nature of these drugs.34 An initial
Alcohol dose under direct practitioner supervision is indicated for
Caffeine intake or withdrawal
patients presumed at cardiovascular risk. Triptans are avoided
Chocolate
Citrus fruits, bananas, gs, raisins in patients experiencing migraine associated with neurologic
Dairy products focality, previous stroke, poorly controlled hypertension, or
Fermented or pickled products unstable angina. Triptans are relatively contraindicated for
Food containing: routine use in pregnancy.30 Triptans should not be used with
Monosodium glutamate (Asian food, seasoned salt)
concurrent ergotamine administration.34
Nitrites (processed meats)
Saccharin or aspartame (diet soda or diet food) Ergotamine derivatives produce salutary effects on sero-
Sultes (shrimp) tonin receptors similarly to triptans. They also impact adren-
Tyramine (cheese, wine, organ meats) ergic and dopaminergic receptors. Ergotamine tartrate and
Yeast (breads) dihydroergotamine are the most commonly employed
Medications agents.20 The latter is not available in an oral dosage form.
Cimetidine Analgesic onset is within 4 hours, though additional dosing is
Estrogen or oral contraceptives
Indomethacin
required if an acceptable response is not appreciated. When
Nifedipine dosed parenterally, these drugs are usually provided with an
Nitrates antiemetic, due to their potential to worsen the nausea associ-
Reserpine ated with migraine. Metoclopramide and chlorpromazine are
Theophylline the drugs of choice. Intranasal dihydroergotamine can be self-
Withdrawal due to overuse of analgesics, benzodiazepines,
decongestants, or ergotamines
administered to abort an attack.20 The outpatient use of sub-
cutaneous ergotamines is limited by the lack of a prelled
drugs are not clearly supported for migraine use, but are likely syringe form. The same cautions as those for triptans apply to
acceptable. Acetaminophen alone, or in proprietary combina- ergot use in patients at risk for vascular events.
tions with aspirin, opioids, caffeine, or the barbiturate butal- The choice of initial therapy for acute migraine attacks is a
bital are also effective.28 Although deemed to have a benign subject of debate among specialists.38 Some believe that non-
adverse-effect prole on gastric mucosal integrity and renal specic analgesics should be used rst-line, while others believe
blood ow, overwhelming clinical experience supports the migraine-specic drugs should be the choice for patients with
observation that the overuse of acetaminophen may lead to tol- severe pain or a history of signicant disability. A stepped-care
erance or dependence clinically manifested as acute withdrawal approach within attacks from less to more specic drugs is usu-
headaches.31 These so-called rebound headaches are the result ally recommended.39 Once a history of headache refractory to
of poor attention to prevention therapies, and thus chronic use common analgesics is established, triptans should be utilized as
of daily analgesics.32 initial therapy. In patients who present to the hospital with
The triptans are considered specic therapies in that they intractable pain, intravenous metoclopramide supplemented
target the pathophysiology underlying migraine.33 They abort with dihydroergotamine may be needed. Oral medications in
headache through benecial effects on neuronal imbalances.11 this setting are not utilized, as nausea and vomiting limit their
Triptans inhibit neurotransmission in the trigeminal complex bioavailability. Migraineurs with frequent and severe attacks are
and activate serotonin 1b/1d pathways that modulate nocicep- candidates for prophylactic treatment.
tion in the brain stem. They also decrease the release of vasoac-
tive peptides leading to vascular reactivity and pain.34 Triptans Tension-Type Headache
are a welcome addition to the therapeutic armamentarium in Most individuals who experience episodic TTHs will not seek
that they are available in intranasal, subcutaneous, and oral medical attention.22 Instead, they will nd relief with the use of
TABLE 313. Comparison of Serotonin Receptor Agonists (Triptans)5965
Medication Strength Usual Dosage May Potential Drug

(Brand Name) Dosage Forms (mg) (mg) Repeat In Interactions
Almotriptan Oral tablets 6.25, 12.5 6.2512.5 Ergot derivatives
(Axert)
Eletriptan Oral tablets 20, 40 2040 Substrate: CYP3A4,
(Relpax) CYP2D6; ergot
derivatives
Frovatriptan Oral tablets 2.5 25 2 hours Substrate:
(Frova) CYP1A2; ergot
derivatives
Naratriptan Oral tablets 1, 2.5 2.5 4 hours Substrate: CYP450
(Amerge) (various); ergot
derivatives
Rizatriptan Oral tablets, 5, 10 510 2 hours Ergot derivatives;
(Maxalt and disintegrating MAOA inhibitors
Maxalt MLT) tablets
Sumatriptan Subcutaneous 6 6 1 hour Ergot derivatives;
(Imitrex) injection MAOA inhibitors
Oral tablets 25, 50, 100 50 2 hours
Nasal spray 5, 20 520 2 hours
Zolmitriptan Oral tablets, 2.5, 5 2.5 2 hours Substrate:
(Zomig and disintegrating CYP1A2; ergot
Zomig-ZMT) tablets derivatives;
Nasal spray 5 5 2 hours MAOA inhibitors
CYP, cytochrome P-450 isoenzyme; MAO, monoamine oxidase.

Data from references 5965.
widely available over-the-counter analgesics. Acetaminophen are useful as adjunctive therapy. They are also used when sup-
products and NSAIDs are commonly utilized. An individual plemental oxygen is not readily available. The triptan class
patient may benet from topical analgesics (e.g., ice packs) or agents are safe and effective. Intranasal or subcutaneous sum-
physical manipulation (e.g., massage) during an acute attack, itriptan has demonstrated efcacy in decreasing cluster
but the evidence supporting nonpharmacologic therapies is headache pain.43 Oral triptans are also effective, but their
inconsistent.6 Relaxation techniques can often reduce headache delayed onset of action may limit their applicability in acute
frequency and severity. When pain is unrelieved, prescription- cluster headache treatment.44 Cluster headache pain is rapid in
strength NSAID use is required or the combination of aceta- onset, achieves peak intensity quickly, and is of short duration.
minophen with an opioid analgesic may be necessary. The fre- Oral agents may have utility in limiting the recurrence of clus-
quency of use of these more potent analgesics should be lim- ter attacks. Intranasal, intramuscular, or intravenous ergota-
ited to prevent dependency. Use for more than 2 days per week mine agents are an alternative to triptan use.6 Repeated dosing
suggests the need for prophylactic therapy.40 In those sufferers may break a cluster series. For those patients in whom triptans
who do not seek expedient medical attention, but rely instead and ergotamine derivatives are contraindicated due to
on the frequent use of unprescribed analgesics, medication- ischemic vascular disease, octreotide may be helpful to relieve
overuse headache may supervene. This chronic daily headache pain.45 Octreotide is a somatostatin analogue that has a shorter
syndrome requires physician referral to desensitize patient- half-life, and it is available for subcutaneous administration.
initiated analgesic tolerance and dependence.41 Unlike the other abortive agents, it has no vasoconstrictive
effects. The most prominent treatment emergent adverse effect
Cluster Headache with octreotide use is gastrointestinal upset. Glucocorticoids,
Cluster headache responds to many of the same treatment provided intravenously and later tapered orally, are also an
modalities used in acute migraine; however, initial prophylactic effective option when cluster headache attacks are not satisfac-
therapy is required to limit the frequency of recurrent headaches torily controlled.9
within a periodic series. A novel therapy specic to cluster
headaches is the administration of high-ow-rate oxygen: 100%
Pharmacologic Therapy for Headache Prophylaxis
at 5 to 10 L/minute by non-rebreather facemask for approxi-
mately 15 minutes.42 If pain is not aborted, then retreatment is Prophylaxis for headache disorders is indicated if signi-
indicated. No side effects are seen with short-term oxygen use. cant disability occurs or pain-relieving medications are used two
If oxygen therapy is not wholly effective, then pharmaceuticals or more times per week.
Migraine Prophylaxis impact aura as well as pain. The different calcium channel
Migraine headaches that are severe, frequent, or lead to signi- blockers are variably effective, and none carries an FDA indica-
cant disability will require long-term medication therapy. tion. Moreover, even in responsive patients, tachyphylaxis may
Prophylactic therapy is also recommended for migraines associ- develop. Recently, renin-angiotensin antagonists have been
ated with neurologic focality, as it may prevent permanent noted to decrease headache frequency and severity in migraine
sequelae. Although multiple medication classes have garnered sufferers.47 Consensus recommendations for hypertension treat-
Food and Drug Administration (FDA)-labeling for migraine ment often advocate multidrug regimens to achieve tight blood
prevention, there is no consensus on the best initial therapy pressure control48; combination therapy with the agents noted
(Table 314). The choice of pharmacologic agent should be above are ideal for migraineurs with comorbid hypertension.
individually tailored to patient tolerability and medical Low-dose amitriptyline or other tricyclic antidepressants
comorbidities. (TCAs) are also of proven efcacy in migraine prevention.27
The -blockers propranolol and timolol are FDA-approved Due to sedation, these medications are commonly adminis-
for migraine prophylaxis, but other drugs in the class are also tered at night. The use of later-generation tricyclic medica-
as effective.46 Cautious dosage titration is advised for those tions (e.g., nortriptyline) or heterocyclic compounds (e.g.,
patients who do not have other indications for -blocker use. trazodone) decreases the dose-limiting adverse effects of
Rizatriptan interacts with propranolol and thus dosages must TCAs, especially those attributable to their anticholinergic
be titrated downward, or another triptan chosen for abortive properties (e.g., dry mouth, constipation, and urinary reten-
therapy.36 Comorbid reactive airway disease is a relative con- tion). Whether the various selective serotonin reuptake
traindication to -blocker prophylaxis, and patients with car- inhibitors (SSRIs) can yield consistent efcacy in the majority
diac conduction disturbances should be closely monitored. of migraineurs is questionable.21 Although they affect sero-
Calcium channel antagonists are often used when patients tonin balance in the brain, their utility may derive from their
cannot tolerate -blockers. They are purported to benecially benecial impact on mood and anxiety, rather than through
serotonergic effects on migraine generation. Concurrent TCA
TABLE 314. Medications for Prophylaxis of Migraines6668 and triptan administration may rarely precipitate the sero-
tonin syndrome, which presents clinically with confusion, gas-
Medication Usual Dosage Main
trointestinal upset, symptomatic blood pressure changes, and
(Brand Name) (mg per day) Adverse Effects
muscle rigidity.20
Antiepileptics The antiepileptics valproic acid and topiramate are
Gabapentin (Neurontin) 12002400 Paresthesias,
Lamotrigine (Lamictal) 50200 dizziness,
approved for migraine prophylaxis. Gabapentin and lamo-
a
Topiramate (Topamax) 50200 fatigue, nausea trigine are anecdotally reported to be efcacious as well. In
Valproic acid (Depakene) 5001500 patients whose migraine headaches are believed to be related
a
Divalproex sodium 5001500 to trigeminal neuralgia, carbamazepine is employed as pre-
(Depakote) vention for both disorders. The precise mechanism of benet
b-Blockers of these agents is unclear, but enhancement of -aminobutyric
Atenolol (Tenormin) 50200 Fatigue, exercise
Metoprolol (Lopressor) 50200 intolerance
acid (GABA) neuroinhibition and modulation of the neu-
Nadolol (Corgard) 20160 roexcitatory amino acid glutamate is likely.49 Divalproex
a
Propranolol (Inderal) 80240 sodium doses are gradually titrated to 1000 mg per day; topi-
a
Timolol (Blocadren) 2030 ramate is titrated to a maximum of 100 mg twice per day. At
Calcium Channel Blockers these doses, serum drug level monitoring is infrequently
Amlodipine (Norvasc) 2.510 Constipation needed. These medications are as effective as propranolol at
Verapamil (Calan) 120320
reducing the frequency and severity of migraines and are pre-
Tricyclic Antidepressants ferred for prevention in patients intolerant to -blockers.50
Amitriptyline (Elavil) 10150 Weight gain, dry
Nortriptyline (Pamelor) 10150 mouth, sedation Topiramate is especially useful in metabolic syndrome, dia-
Ergot Alkaloids
betes, and dyslipidemic patients, as it is unlikely to lead to the
Ergotamine tartrate 1 weight gain often seen with valproic acid use. Patients pre-
(Cafergot) scribed topiramate should be advised to stay well hydrated to
Methysergide (Sansert) 26 prevent dysgeusia, disordered taste, and more seriously,
Others hyperthermia.
Hormones (various) Varies per Methysergide is an ergotamine derivative that impacts cen-
agent
Muscle Relaxants Varies per
tral serotonin balance.51 It is reserved for use in migraineurs
(various) agent refractory to other agents, due to its signicant adverse-
Trazodone (Desyrel) 25150 effect prole. As an ergot compound, it is a vasoconstrictor
a
FDA-approved for migraine prophylaxis. that may worsen vascular dilatory reserves and precipitate
Data from references 6668. cardiovascular events or ischemic stroke in those with
underlying atherosclerotic disease. Inammatory brosis is

a rare, but potentially serious, adverse reaction associated Patient Encounter, Part 3: Creating a
with prolonged use of methysergide. Retroperitoneal bro- Care Plan
sis, pulmonary brosis, or brosis in cardiac tissue can
occur. Drug withdrawal usually reverses the condition, so Based on the information presented, create a care plan for
treatment should be interrupted for at least a 3-week inter- the acute and chronic management of this patients headache.
val every 6 months. On occasion, cardiac valvular damage Your plan should include: (1) a statement of drug-related
can be irreversible. needs and/or problems, (2) goals of therapy, (3) a patient-
specic detailed therapeutic plan, and (4) a plan for clinical
Tension-Type Headache Prophylaxis follow-up to determine whether goals have been achieved
The prevention of chronic TTHs employs the same pharma- and adverse effects avoided.
cologic strategies as for migraine prophylaxis. Tricyclic antide-
pressants are a mainstay of chronic therapy. The efcacy of
serotonergic agents remains in question. Although there is lit-
tle need for muscle relaxants (e.g., methocarbamol) in the SPECIAL POPULATIONS
treatment of acute TTH, they are often provided as a preven-
tive intervention.6 Combination prophylactic therapies may Migraine Headache in Children and Adolescents
be needed to wean patients from daily analgesic abuse. Stress
Migraine headaches are common in children, and their preva-
reduction techniques augmenting pharmacologic therapies
lence increases in the adolescent years.2,3 The diagnosis and
may be particularly effective in this setting. The injection of
evaluation of headaches is especially difcult in children,
botulinum toxin into cranial muscles has demonstrated pro-
given their decreased ability to articulate symptoms.
phylactic efcacy for severe TTHs.41
Treatment presents another challenge to the practitioner,
because medications used for headache management in adults
Cluster Headache Prophylaxis
have not been fully evaluated for efcacy and safety in chil-
The calcium channel blocker verapamil is the mainstay of clus-
dren. Consensus panel recommendations identify ibuprofen
ter attack prevention and chronic prophylaxis.6 Within an
as effective and acetaminophen as probably effective in the
attack period, it is dosed at 240 to 360 mg per day. Higher doses
acute treatment of headache in patients over the age of 6.26
may be necessary to stave off recurrent cluster periods.
Aspirin use is avoided due to the risk of precipitating Reyes
Benecial effects may be appreciated after 1 week of treatment,
syndrome. Antiemetic therapy can be used alone or in com-
but 4 to 6 weeks is usually needed to fully assess response.
bination with analgesics; promethazine is usually prescribed,
Adverse effects include smooth muscle relaxation with the sub-
as it is less prone to cause extrapyramidal reactions than
sequent exacerbation of gastroesophageal reux and the devel-
other antiemetics. For adolescents over the age of 12, triptans
opment of constipation. Caution should be exercised in patients
are effective and are benecial for abortive migraine therapy.26
with myocardial disease, as verapamil is an inotropic and
Medication prophylaxis for migraines in children and adoles-
chronotropic cardiac depressant. Pharmacokinetic drug-drug
cents is understudied. The data are conicting, and no con-
interactions must be considered, as verapamil is a potent
sensus recommendation for the use of preventive drug therapy
inhibitor of oxidative metabolism through cytochrome P-450
exists.26 Nonpharmacologic interventions and trigger identi-
(CYP) enzyme 3A4. Eletriptan is a CYP3A4 substrate and
cation and avoidance are advised.
should not be concurrently administered.36 Lithium is another
effective therapy to reduce headache frequency in a cluster
Pregnancy
series and to limit recurrences.9 The dose administered should
be individualized to achieve a low-serum concentration (0.4 to Headaches are more common in women than in men.
0.8 mEq/L or mmol/L). Dose adjustments in the setting of renal Fluctuation in estrogen levels is believed to account for this gen-
disease and congestive heart failure are required.6 Lithium is der discrepancy.52 Hence, headaches are common in pregnancy.
contraindicated in patients concurrently prescribed thiazide Tension-type headaches predominate; migraine attacks may
diuretics and angiotensin-converting enzyme inhibitors and increase in frequency, but more usually decrease in frequency
angiotensin receptor blockers. Patient persistence with long- during pregnancy.53 Recommendations for headache care dur-
term lithium therapy may be hindered by the emergence of ing pregnancy are based on an insufcient evidence base and are
tremor, gastrointestinal distress, and lethargy. Verapamil and largely anecdotal. As headaches are not associated with fetal
lithium doses can be lowered when used in combination with harm, reexive pharmacologic therapy should be avoided and
ergotamine. If possible, bedtime dosing of these therapies is drug treatment choices considered carefully. Standard non-
recommended, given the nocturnal predilection of cluster pharmacologic therapies are often sufcient. Acetaminophen is
headache attacks.16 Methysergide can shorten the course of safe for the pregnant woman and her fetus.54 NSAIDs are avoided
cluster attacks, but long-term use should be avoided. late in the third trimester to prevent detrimental prostaglandin
alterations leading to premature ductus arteriosus closure. Serotonin receptor agonists (triptans): Monitor patients
Opioids are second-line agents. They are not to be used chroni- for ushing, palpitations, chest pain, and shortness of breath.
cally, as they can lead to dependence in the mother and acute Recommend electrocardiography if symptoms persist.
withdrawal in the baby after birth. Centrally-acting antiemetic Ergotamine derivatives: Monitor cardiovascular compli-
agents are safe and may be useful as adjunctive agents. cations as for serotonergic agents.
Corticosteroids may be needed for intractable headache relief. If prophylactic medications are required, monitor patients
Prednisone and methylprednisolone are preferred, as they are for short- and long-term adverse effects:
metabolized in the placenta and do not expose the fetus. In preg- Antiepileptics: Monitor patients for dizziness, fatigue,
nant women with migraine, vasoconstrictive agents such as trip- nausea, and paresthesias. Assess changes in weight at quar-
tans are relatively contraindicated, even though maternal reg- terly intervals.
istry data reveal little teratogenicity.55 Ergot compounds are -Blockers: Monitor patients for bradycardia (heart rate
strictly avoided, as they may precipitate uterine contractions and less than 60 bpm), symptomatic hypotension (blood pres-
consequent ischemia leading to hypoxemia in the fetus. sure less than 90/60 mm Hg), and easy fatigability.
Migraine prophylaxis is considered cautiously, as -blockers and Calcium channel blockers: Monitor for cardiovascular
calcium channel antagonists may lead to maternal hypotension effects similarly to -blockers. If dihydropyridine calcium
and diminished placental blood ow or fetal bradycardia. channel blockers are employed, assess for dependent
Antiepileptic drug use in this setting has not been sufciently edema. Consider withdrawal if GERD or constipation
studied to allow denitive recommendations. responds poorly to therapy.
Some headache disorders are specic to the pregnant state. Tricyclic antidepressants: Monitor for change in vision,
These include postprocedure headaches and those associated sedation, dry mouth, gastrointestinal upset, and orthosta-
with preeclampsia. The former are the result of dural puncture tic dizziness.
with cerebrospinal uid leakage after spinal anesthesia.56
Puncture headache generally responds to bed rest in the supine
position, though analgesics may be needed as well. The latter are Patient Care and Monitoring
seen in the third trimester accompanied by the clinical triad of
hypertension, edema, and proteinuria. Preeclamptic headache
pain is believed to result from alterations in cerebral blood
ow.57 Headaches experienced in preeclamptic women herald Regimens for headache disorders should be individualized
eclampsia, and urgent delivery is indicated. Antihypertensives based on headache type, pattern of occurrence, response
are administered to prevent intracranial thrombosis or hemor- to therapy, medication tolerability, and comorbid medical
rhage and prophylactic anticonvulsants are provided to prevent conditions.
eclamptic seizures.
1. Assess the patient complaint to yield a detailed descrip-
tion of headache: precipitating factors; presence or
absence of prodromal symptoms; location, intensity,
OUTCOME EVALUATION and duration of pain; changes in sensory acuity; and
neurologic alterations.
Monitor patients for the relief of headache pain and the lack
2. Determine if immediate referral for emergency or spe-
of headache recurrence. Assure that full patient functionality cialist care is necessary.
is restored. Note environmental and behavioral triggers; the
3. Obtain a thorough history of non-prescription and pre-
onset, character, and duration of pain; and associated symp-
scription drug use and complementary and alternative ther-
toms and physical ndings. apies utilized, as well as identifying medication allergies.
Assess frequency and severity of headaches to determine the
4. Identify the presence of drug-drug interactions that
need for prophylactic therapy.
may guide therapeutic decision making in regard to
Monitor patients for adverse effects of abortive therapies selecting acute and prophylactic headache treatments.
used for headache pain relief:
5. Obtain a complete medical and social history, identify-
Acetaminophen: Monitor patients for analgesic overuse,
ing any potential drug-disease interactions or social fac-
which may lead to dependence and the precipitation of tors that may inuence treatment choices.
withdrawal headaches.
6. Obtain a family medical history, focusing on headache
NSAIDs: Monitor patients for gastrointestinal distress,
or mental health disorders in rst-degree relatives.
signs or symptoms of gastrointestinal bleeding, and hyper-
7. Complete a review of systems and physical examina-
tension and edema that may reect renal dysfunction.
tion to identify causes or complications of headache.
Monitor CBC and serum creatinine as clinically indicated.
Opiates: Monitor patients for sedation and depressed cog-
(Continued)
nition. Address constipation with use of stimulant laxatives.
IHS: International Headache Society

8. Determine the type of headache disorder and rule out MAOA: Monoamine oxidase type A
acute complications. NSAID: non-steroidal anti-inammatory drug
9. Recommend appropriate pharmacologic therapy to SSRI: selective serotonin reuptake inhibitors
abort headache based on type, patient characteristics, TCA: tricyclic antidepressant
current medication prole, and comorbid conditions. TTH: tension-type headache
10. Educate the patient on administration, maximum
dosage, and anticipated adverse effects of the pre-
scribed medication.
11. Recommend appropriate nonpharmacologic therapy to Log into the website: www.pharmacotherapyprinciples.com
abort headache and to prevent future headaches. for information on obtaining continuing education credit for
12. Determine if the patient is a candidate for prophylactic this chapter.
pharmacologic therapy.
13. Recommend appropriate pharmacologic treatment for
prevention of future headaches.
14. Assess response to therapy indicated by the absence of
pain and a return to normal activities. Assess response Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin
to prophylactic therapy by improvements in headache 5-HT1B/1D agonists) in acute migraine treatment: A meta-analysis
frequency and severity. of 53 trials. Lancet 2001;358:15581575.
15. Instruct the patient to keep a headache diary to identify Goadsby PJ, Lipton RB, Ferrari MD. Migrainecurrent understand-
potential causes of headaches and responses to therapy. ing and treatment. N Engl J Med 2002;346:257270.
16. Provide the patient specic information regarding actions Headache Classication Committee of the International Headache
to take if therapy is ineffective or adverse effects develop. Society. The International Classication of Headache Disorders,
2nd ed. Cephalalgia 2004; 24(Suppl 1):1160.
17. Educate the patient on the importance of adherence to
Lewis D, Ashwal S, Hershey A, et al. Practice parameter:
the individualized pharmacologic regimen to prevent
Pharmacological treatment of migraine headache in children
headache and to diminish pain upon recurrence.
and adolescents. Report of the American Academy of Neurology
18. Educate the patient on the warning symptoms and signs Quality Standards Subcommittee and the Practice Committee
of headache complications, and when to seek emer- of the Child Neurology Society. Neurology 2004;63:22152224.
gency medical attention. Lipton RB, Bigal ME, Steiner MB, et al. Classication of primary
headaches. Neurology 2004;63:427435.
Ruoff G, Urban G. Treatment of primary headache: episodic tension-
ABBREVIATIONS type headache. In: Standards of care for headache diagnosis
and treatment. Chicago: National Headache Foundation, 2004:
CBC: complete blood cell count 5358.
CGRP: calcitonin gene-related peptide Silberstein SD, Lipton RB, Dalessio DJ. Overview, diagnosis, and clas-
COX-2: cyclooxygenase-2 sication of headache. In: Silberstein SD, Lipton RB, Dalessio
CTA: clear to auscultation DJ, eds. Wolff s Headache and Other Head Pain. 7th ed. New
CYP: cytochrome P-450 isoenzyme system York: Oxford University Press, 2001:626.
ESR: erythrocyte sedimentation rate Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice.
FDA: Food and Drug Administration London: Martin Dunitz, 2002:2133, 69128.
GABA: -aminobutyric acid Snow V, Weiss K, Wall EM, Mottur-Pilson C. Pharmacologic man-
GERD: gastroesophageal reux disease agement of acute attacks of migraine and prevention of
ICHD: International Classication of Headache Disorders migraine headache. Ann Intern Med 2002;137:840849.
Section 6. Psychiatric Disorders
32 ALZHEIMERS DISEASE
Gary M. Levin, Toya M. Bowles, and Megan J. Ehret
90 LEARNING OBJECTIVES
80
70
1. Describe the epidemiology of Alzheimers disease and its effects on society.

2. Describe the pathophysiology including genetic and environmental factors that may be
associated with the disease.
3. Detail the clinical presentation of the typical patient with Alzheimers disease.
4. Describe the clinical course of the disease and typical patient outcomes.
5. Describe how nonpharmacologic therapy is combined with pharmacologic therapy for
patients with Alzheimers disease.
6. Recognize and recommend treatment options for disease-specic symptoms as well as
behavioral/non-cognitive symptoms associated with the disease.
7. Develop an alternative treatment plan for patients with Alzheimers disease.
8. Educate patients and/or caregivers about the expected outcomes for patients with
Alzheimers disease, and provide contact information for support/advocacy agencies.
KEY CONCEPTS Treatment of behavioral symptoms should begin with non-

pharmacologic treatments, but may also include antipsychotic
Alzheimers disease is characterized by progressive cognitive agents and/or antidepressants.
decline including memory loss, disorientation, and impaired Delaying disease progression through pharmacotherapy can
judgment and learning. reduce the total cost of treating AD and delay nursing home
Pathologic hallmarks of the disease in the brain include placement.
neurobrillary tangles and neuritic plaques (senile plaques)
made up of various proteins, which result in a shortage of the Alzheimers disease (AD) is a non-reversible, progressive
neurotransmitter acetylcholine. dementia manifested by gradual deterioration in cognition and
A diagnosis can be made only at autopsy; therefore the diag- behavioral disturbances. AD is primarily diagnosed by exclu-
nosis is established following an extensive history and physical sion of other dementias. There is no single symptom unique to
examination, and by ruling out other potential causes of AD; therefore diagnosis relies on a thorough patient history.
dementia. The exact pathophysiologic mechanism underlying AD is not
Treatment is focused on delaying disease progression and entirely known, although certain genetic and environmental
preservation of functioning as long as possible. factors may be associated with the disease. There is currently
The current gold standard of treatment for cognitive symptoms no cure for AD; however, drug treatment can slow symptom
includes pharmacologic management with a cholinesterase progression over time.
inhibitor and/or an N-methyl-D-aspartate (NMDA) antagonist. Family members of AD patients are also profoundly affected
The general approach to treatment of cognitive symptoms by the increased dependence of their loved one as the disease pro-
includes both pharmacologic and nonpharmacologic gresses. Early education and social support of both the patient
management. and family is also important treatment. The Alzheimers
513
514 SECTION 6 / PSYCHIATRIC DISORDERS
TABLE 321. Ten Warning Signs of Alzheimers Disease TABLE 322. Classication of Dementia
1. Memory loss: more than typical forgetfulness without remember- Dementia of the Alzheimers type (early- or late-onset)
ing later With or without behavioral symptoms
2. Difculty performing familiar everyday tasks (e.g., preparing a Vascular dementia
meal and grooming) Uncomplicated, with delirium, with delusions, and with
3. Problems with language: forgetting simple words or substitut- depressed mood
ing unusual words Dementia due to HIV disease
4. Disorientation to time and place: may forget where they are Dementia due to head trauma
and/or how they got there Dementia due to Parkinsons disease
5. Poor or decreased judgment: dress without regard to weather Dementia due to Huntingtons disease
or falling prey to scam artists Dementia due to Picks disease
6. Problems with abstract thinking: not just difculty balancing a Dementia due to Creutzfeldt-Jakob disease
checkbook, but forgetting what the numbers represent Dementia due to a specic general medical condition (specify)
7. Misplacing things in unusual places: such as placing an iron in Dementia that is substance-induced
a freezer Dementia due to multiple etiologies
8. Changes in mood or behavior: rapid mood swings with no Dementia not otherwise specied
apparent reason why
9. Changes in personality: extreme confusion, suspicion, or HIV, human immunodeciency virus.
Data from reference 3 with permission.
fearfulness
10. Loss of initiative: passivity and loss of interest in usual activities
Data from reference 1 with permission.

were between 75 and 84 years of age, and 40% were persons over
85 years of age.2 It is projected that by the year 2050 there will be a
Association has developed a checklist of common symptoms three-fold increase in prevalence yielding potentially 13.4 million
(Table 321).1 AD patients due to a population increase in persons over 65 years
of age. Additionally, the cost to society due to rising Medicare
spending for AD is projected to increase from $62 billion in 2000
EPIDEMIOLOGY AND ETIOLOGY to over $1 trillion in 2050. Furthermore, the costs associated
with nursing home care alone are projected to increase from
AD is the most common type of dementia, affecting approxi- $19 billion in 2000 to $118 billion in 2050 (Fig. 321).4,5 The
mately 4.5 million Americans in the year 2000.2 Table 322 severity of AD also correlates with increasing age and is classied
lists the different classications of dementia.3 This chapter
will address only dementia of the Alzheimers type.
The prevalence of AD increases with age and it is most preva- 90
lent in persons age 65 years and older. In the year 2000, it was 1000
80
estimated that there were 4.5 million people in the United States
with AD. Of those affected, 7% were 65 to 74 years of age, 53% 70
800
Population in millions
Dollars in billions
60
Patient Encounter, Part 1 50 600
40
400
30
A woman arrives at the clinic with her 80-year-old mother,
LB, complaining that her mother is becoming increasingly 20
200
forgetful and confused with old age. The woman complains
10
that her mother sometimes takes her diabetes and hyperten-
sion medications at a frequency greater than that prescribed. 0 0
This has become more frequent in the last 6 months and the 2000 2025 2050
mother has been getting very agitated when her daughter US Population over age 65 (millions)
confronts her. The woman asks you for a pill organizer and
US Population with AD (millions)
if any of the over-the-counter drugs claiming to help with
Medicare nursing home spending for AD (Billions)
memory would help her mother.
Total medicare spending for AD (Billions)
What information is suggestive of AD? FIGURE 321. Projected increases in the population of patients
Does the mother have any risk factors for AD? with Alzheimers disease, Medicare nursing home spending,
How would you approach and address the daughters and total Medicare spending. (Based on data from references 4
question? and 5.)
CHAPTER 32 / ALZHEIMERS DISEASE 515
as mild, moderate, or severe. Other risk factors associated with resulting in cell damage, and their presence has been correlated
AD besides age include family history, female gender, vascular with the severity of dementia.12 Unfortunately, these tangles
risk factors such as diabetes, hypertension, heart disease, and are insoluble even after the cell dies, and they cannot be
current smoking.6,7 However, it is unknown how other factors removed once established. The neurons that provide most of
such as environment contribute and interact with the genetic the cholinergic innervation to the cortex are most prominently
predisposition for AD. affected.13 Therefore, prevention is the key to targeted therapy
The mean survival time of persons with AD is reported to of these tangles.
be approximately 6 years from the onset of symptoms until
death. However, age at diagnosis, severity of AD, and other
Plaques
medical conditions affect survival time.8 Although AD does
not directly cause death, it is associated with an increase in var- Neuritic or senile plaques are extracellular protein deposits of
ious risk factors which often contribute to death such as senil- brils and amorphous aggregates of -amyloid protein.11 This
ity, sepsis, stroke, pneumonia, dehydration, and decubitus formed protein is central to the pathogenesis of AD. The
ulcers. -amyloid protein is present in a non-toxic, soluble form in
The exact etiology of AD is unknown; however, it has been human brains. In AD, conformational changes occur that render
suggested that genetic factors may contribute to errors in pro- it insoluble and cause it to deposit into amorphous diffuse
tein synthesis resulting in formation of abnormal proteins plaques associated with dystrophic neuritis.14 Over time, these
involved in the pathogenesis of AD.9 Early onset, which is deposits become compacted into plaques and the -amyloid
dened as AD prior to age 60, accounts for approximately 1% protein becomes brillar and neurotoxic. Inammation
of all AD. This type is usually familial and follows an autosomal occurs secondary to clusters of astrocytes and microglia sur-
dominant pattern in approximately 50% of cases of early-onset rounding these plaques.
AD. Mutations in three genes, presenilin 1 on chromosome 21,
amyloid precursor protein (APP) on chromosome 21, and pre-
Acetylcholine
senilin 2 on chromosome 1, lead to an increase in -A4 pep-
tide fragments of APP which forms neuritic plaques that are The neurotransmitter acetylcholine (Ach) is responsible for
the pathologic hallmark of AD.10 transmitting messages between certain nerve cells in the
The genetic basis for the more common late-onset AD brain. In AD, the plaques and tangles damage these pathways,
appears more complex. Genetic susceptibility is more spo- leading to a shortage of Ach, resulting in learning and memory
radic and it may be more dependent on environmental impairment.15 The loss of Ach activity correlates with the
factors.9 The apolipoprotein E (apo E) gene on chromosome severity of AD. The basis of pharmacologic treatment of AD
19 has been identied as a strong risk factor for late-onset AD. has been to improve cholinergic neurotransmission in the
There are three variants of apo E; however, carriers of two or brain. Acetylcholinesterase is the enzyme that degrades Ach
more of the apo E4 allele have an earlier onset of AD (approx- in the synaptic cleft. Blocking this enzyme leads to an increased
imately 6 years earlier) compared with non-carriers.9 Only level of Ach with a goal of stabilizing neurotransmission.16 In
50% of AD patients have the apo E4 allele, thus indicating it is the United States, the four cholinesterase inhibitors
only a susceptibility marker. approved for the treatment of AD are tacrine, donepezil,
rivastigmine, and galantamine.
PATHOPHYSIOLOGY Glutamate
Glutamate is the primary excitatory neurotransmitter in the
The pathologic hallmarks of the disease in the brain central nervous system (CNS) involved in memory, learning,
include neurobrillary tangles and neuritic plaques made up of
and neuronal plasticity. It acts by providing information from
various proteins, which result in a shortage of the neurotransmitter
one brain area to another and affects cognition through facil-
acetylcholine. These are primarily located in brain regions
itation of connections with cholinergic neurons in the cere-
involved in learning, memory, and emotional behaviors such
bral cortex and basal forebrain.17 In AD, one type of glutamate
as the cerebral cortex, hippocampus, basal forebrain, and
receptor, N-methyl-D-aspartate (NMDA), is less prevalent
amygdala.11
than normal. There also appears to be overactivation of
unregulated glutamate signaling. This results in a rise in cal-
cium ions that induces secondary cascades which lead to neu-
Tangles
ronal death and an increased production of APP.16 The
Neurobrillary tangles are intracellular and consist of abnor- increased production of APP is associated with higher rates
mally phosphorylated tau protein which is involved in micro- of plaque development and hyperphosphorylation of tau
tubule assembly. Tangles interfere with neuronal function protein.18 The drug memantine is a non-competitive NMDA
antagonist which targets this pathophysiologic mechanism.19 Health Initiative Memory Study reported that hormone
Memantine is presently the only agent in this class that is replacement with either estrogen alone or estrogen plus
approved for the treatment of AD. medroxyprogesterone resulted in negative effects on memory.22
Cholesterol
Increased cholesterol concentrations have been associated
with AD. The cholesterol increases -amyloid protein synthe- Diagnosing AD relies on a thorough medical and psy-
sis which can lead to plaque formation.16 Also, the apo E4 chological history, mental status testing, and laboratory data to
allele is thought to be involved in cholesterol metabolism and exclude other possible causes. There are no biological markers
is associated with higher cholesterol levels.16 other than those pathophysiologic changes found at autopsy
that can conrm AD. The American Academy of Neurology
Estrogen has adopted practice guidelines for the diagnosis and man-
agement of AD.23 The diagnostic criteria are based on the
Estrogen appears to have properties that protect against mem- Diagnostic and Statistical Manual of Mental Disorders,
ory loss associated with normal aging. It has been suggested Fourth Edition, Text Revision (DSM-IV-TR) (Table 323)24
that estrogen may block -amyloid protein production and or the National Institute of Neurological and Communicative
even trigger nerve growth in cholinergic nerve terminals.20,21 Diseases and Stroke/Alzheimers Disease and Related Disorders
Estrogen is also an antioxidant and helps prevent oxidative cell Association (NINCDS-ADRDA). These diagnostic criteria are
damage.20 It is important to note, however, that the Womens 85% to 90% accurate in diagnosing AD.24
AD is a progressive disease, which over time affects multi-
ple areas of cognition. The symptoms of AD can be divided
into cognitive symptoms, non-cognitive symptoms (i.e.,
Clinical Presentation of Alzheimers behavioral), and functional symptoms for assessment and
Disease treatment purposes. Table 324 describes the stages of cogni-
tive decline.25,26
General
The diagnosis of AD relies on thorough mental status testing
TABLE 323. Diagnostic Criteria for Alzheimers Disease
and neuropsychological tests, medical and psychiatric his-
Based on DSM-IV-TR
tory, neurologic exam, interview of caregivers and family
members, and laboratory and imaging data to support the Dementia of the Alzheimers type
diagnosis and exclude other causes. A. The development of multiple cognitive decits manifested by both
Signs and Symptoms (1) memory impairment (impaired ability to learn new
information or to recall previously learned information)
Cognitive: memory loss, problems with language, disorien-
(2) one or more of the following cognitive disturbances:
tation to time and place, poor or decreased judgment, prob- (a) aphasia (language disturbance)
lems with learning and abstract thinking, misplacing things (b) apraxia (impaired ability to carry out motor activities
Non-cognitive: changes in mood or behavior, changes in despite intact motor function)
personality, or loss of initiative (c) agnosia (failure to recognize or identify objects despite
Functional: difculty performing familiar tasks intact sensory function)
(d) disturbance in executive functioning (i.e., planning,
Laboratory Tests organizing, sequencing, abstracting)
Magnetic resonance imaging (MRI) or computed tomogra- B. The cognitive decits in criteria A1 and A2 each cause signi-
phy (CT) is used to measure changes in brain size and vol- cant impairment in social or occupational functioning and rep-
ume and rule out stroke, brain tumor, or a cerebral edema. resent a signicant decline from a previous level of functioning.
Tests to exclude possible causes of dementia include a C. The course is characterized by gradual onset and continuing
depression screen, vitamin B12 deciency, thyroid func- cognitive decline.
tion tests [thyroid-stimulating hormone (TSH) and free tri- D. The cognitive decits in criteria A1 and A2 are not due to any
iodothyronine and thyroxine], complete blood cell count, of the following:
and chemistry panel.21 (1) other central nervous system conditions that cause
progressive decits in memory and cognition
Other diagnostic tests to consider for differential diagnosis:
(2) systemic conditions that are known to cause dementia
erythrocyte sedimentation rate, urinalysis, toxicology, chest (3) substance-induced conditions
x-ray, heavy metal screen, HIV testing, cerebrospinal uid E. The decits do not occur exclusively during the course of delirium.
(CSF) examination, electroencephalography, and neuro- F. The disturbance is not better accounted for by another Axis I
psychological tests such as the Folstein Mini Mental Status disorder.
Exam.
Data from American Psychiatric Association with permission.3
TABLE 324. Stages of Cognitive Decline
Stage Clinical Attribute Pathology and Clinical Picture

Stage 1 No cognitive impairment No memory problems and no impairment is evident to a health care professional.
Stage 2 Very mild decline Lapses of memory; forgetting familiar names or locations of personal objects (e.g.,
keys or glasses); problems not evident to friends, family, coworkers, or health care
professionals.
Stage 3 Mild cognitive decline Friends, family, and coworkers begin to notice deciencies; problems with names or
words become evident; performance issues become evident; retention of reading
material declines; losing valuable objects; decline in planning and organizational
abilities.
Stage 4 Moderate cognitive decline Medical interview detects clear-cut deciencies; decreased knowledge of current
(mild or early-stage AD) events; impaired ability to perform difcult mathematical problems (e.g., serial 7s);
decreased ability to perform complex tasks (managing nances); decreased recall of
personal history; individuals may become withdrawn and subdued.
Stage 5 Moderately severe cognitive Major gaps in memory appear and assistance with day-to-day activities is necessary;
decline (moderate AD) inability to recall details such as current address and telephone number may
begin; difculty with orientation to place and time; less challenging mathematical
problems may become difcult (e.g., serial 4s or 2s); can still recall their own name
and those of spouse and children.
Stage 6 Severe cognitive decline Signicant personality and behavioral symptoms may emerge (delusions, suspiciousness,
(moderately severe AD) hallucinations, compulsions) and extensive help with ADLs become necessary (e.g.,
toileting); loss of awareness of recent experiences and surroundings; may still recall
their own name, but recall of other personal history is decreasing; need help in
getting dressed properly; disruptions of sleep/wake cycle occur; increase in urinary
and fecal incontinence; wandering and getting lost becomes common.
Stage 7 Very severe cognitive Final stage of illness; loss of ability to respond to surroundings; inability to speak and
decline (severe AD) control movement; help is required for eating, walking, and toileting; movements
become abnormal and rigid and swallowing is impaired.
AD, Alzheimers disease; ADLs, activities of daily living.

Data from Alzheimers Association25 and Reisberg B with permission.26
TREATMENT patient. Treatment options, legal and nancial decisions, and

course of the illness need to be discussed with the patient and
Desired and Expected Outcomes family members. In this regard, the clinicians emphasis should
be on helping to maintain a therapeutic living environment
Although there are currently ve agents approved for the while minimizing the burden of care resulting from the disease.
treatment of Alzheimers disease, none of these agents are cur-
ative or are known to directly reverse the disease process.
Consequently, the primary outcome of treatment of Alzheimers
disease is to symptomatically treat the cognitive symptoms of the Treatment of Alzheimers disease involves both pharmacologic
patient and preserve the patients functioning for as long as pos- and nonpharmacologic methods, because this disease can be dev-
sible. Secondary goals include treating psychiatric and behav- astating to both the patient and the family. Upon the initial
ioral symptoms that may occur during the course of the disease. diagnosis, the patient and family should be counseled on the
course of the illness, prognosis, available treatments, legal
decisions, and quality-of-life issues. The life of a patient with
Alzheimers disease must become progressively more simple
The current gold standard of treatment for cognitive symp- and structured as the disease progresses, and the caregiver
toms includes pharmacologic management with a cholinesterase must learn to keep requests and demands on the patient sim-
(ChE) inhibitor and/or an NMDA antagonist. There are currently ple. The family of the patient will need to be prepared to face
four ChE inhibitors available on the United States market: tacrine, changes in life that will occur as the disease becomes worse.
rivastigmine, galantamine, and donepezil. The use of tacrine is Basic principles in the treatment of patients with AD include:
limited due to its propensity for hepatotoxicity and difcult titra-
tion schedule. Psychiatric and behavioral symptoms that occur Using a gentle, calm approach to the patient
during the course of the disease should be treated as they occur. Giving reassurance when needed
Essential elements in the treatment of AD include education, Empathizing with the patients concerns
communication, and planning with the family/caregiver of the Using distraction and redirection
Conventional Pharmacologic Treatment for

Patient Encounter, Part 2: The Medical Cognitive Symptoms
History, Physical Exam, and Diagnostic
Tests Cholinesterase Inhibitors (Donepezil, Rivastigmine,
and Galantamine)
HPI
LB has seen a neurologist to address her cognitive decline The ChE inhibitors all have the indication for the treatment
and behavioral issues and is at the clinic for follow-up after of mild to moderate dementia of the Alzheimers type. Guidelines
obtaining her assessments and labs. for the treatment of AD were written before the approval of
PMH memantine and recommend the use of ChE inhibitors as a
Diabetes mellitus since age 55; it was well controlled valuable treatment for AD.2729 None of the ChE inhibitors
until last year when it worsened because of increased have been compared in head-to-head studies, so the decision
confusion of when to take her medication to use one over another is based on differences in mechanisms
Hypertension treated for 20 years and well controlled; of action, adverse reactions, and titration schedules.
has been hypotensive on a few occasions recently during
Treatment should begin as early as possible in patients with
physicals
Insomnia which is getting worse
a diagnosis of AD.30 Figure 322 provides a recommended
treatment algorithm for AD.31 Patients should be switched to
FH
Father died of myocardial infarction at age 76; mother died
another ChE inhibitor from their initial ChE inhibitor if they
of breast cancer at age 79 show an initial lack of efcacy; initially respond to treatment,
but lose clinical benet; or experience safety/tolerability
SH
Lives alone; denies drinking alcohol or smoking issues. This switch should not be attempted until the patient
has been on a maximally tolerated dose for a period of 3 to
Meds
Hydrochlorothiazide 25 mg PO once daily 6 months. The switch should also be based on realistic expecta-
Losartan 50 mg PO twice daily tions of the patient and/or caregiver.32 ChE inhibitor therapy
Metformin 1000 mg PO twice daily should be discontinued in patients who experience poor tol-
Lorazepam 1 mg PO at bedtime erance or compliance, who show a lack of clinical improvement
ROS after 3 to 6 months at optimal dosing, who continue to dete-
(+)weight loss of 12 lb (5.5 kg); () N/V/D, change in appetite, riorate at the pretreatment rate, or who demonstrate dramatic
heartburn, chest pain, or shortness of breath clinical deterioration following initiation of treatment.33
PE
VS: blood pressure 128/62 mm Hg supine, pulse 77 beats per
Donepezil
minute, respiratory rate 15/minutes, temperature 37C (98.6F)
Gen: Poorly-groomed, thin woman looks stated age Donepezil is a piperidine cholinesterase inhibitor, which
Neuro: Folstein Mini Mental Status Exam score 16/30; dis- reversibly and non-competitively inhibits centrally active acetyl-
oriented to month, date, and day of week, clinic name and cholinesterase.34 This specicity is claimed to result in fewer
oor; poor registration with impaired attention and short- peripheral side effects as compared to the other ChE inhibitors.
term memory; recalled 0 out of 3 items; good language Donepezil is approved for the treatment of mild to moderate
skills but problems with commands dementia of the Alzheimers type at a dose of 5 mg/day. This
CT Scan: Mild to moderate generalized cerebral atrophy
dose should be increased to 10 mg/day if needed after 4 to 6 weeks.
Based on the new information, what is your assessment
Table 325 describes the dosing strategies for all of the approved
of the patient? agents for Alzheimers disease.3438
What nonpharmacologic and pharmacologic interven- Adverse reactions with donepezil include nausea, vomiting,
tions could be recommended? and diarrhea. These are typical cholinergic side effects to expect
What are the short-term and long-term treatment goals? with all of the cholinesterase inhibitors. Table 326 compares
the major side effects for all of the approved agents for
Alzheimers disease.3438
Maintaining daily routines Only a small number of drug interactions have been
Providing a safe environment reported with donepezil. In vitro studies show a low rate of
Providing daytime activities binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6.
Avoiding overstimulation Whether or not donepezil has the potential for enzyme induc-
Using familiar decorative items in the living area tion is not known. No interactions with theophylline, cimeti-
Bringing abrupt declines in function and the appearance of dine, warfarin, digoxin, or ketoconazole have been docu-
new symptoms to professional attention mented. In vitro studies show that inhibitors of CYP3A4 and
2D6 have the potential to inhibit the metabolism of donepezil.
Preparation in the early stages of the illness will lessen care- The clinical relevance of this is unknown. However, monitor-
giver stress as the disease progresses. ing for possible increased peripheral side effects is advised
when adding a CYP2D6 or 3A3/4 inhibitor to donepezil treat-

Cognitive Treatment ment. Also, inducers of CYP2D6 and 3A4 could increase the
A Patient diagnosed rate of elimination of donepezil.34
with AD according to NINCDS-ADRDA criteria
Rivastigmine
Assess all comorbid medical disorders and drug Rivastigmine has central activity for both the acetylcholinesterase
therapies that may affect cognition
and butyrylcholinesterase enzymes.36 Acetylcholinesterase is found
in two forms: globular 4 and globular 1. In postmortem stud-
Rule out comorbid depression ies, globular 4 is signicantly depleted, while globular 1 is still
abundant. Thus, blocking metabolism of globular 1 may lead
Evaluate for pharmacotherapy based
to higher concentrations of acetylcholine. Rivastigmine has
on illness stage higher activity at globular 1 than at globular 4. Theoretically
this may be advantageous, as rivastigmine prevents the degra-
ModerateSevere AD Mild AD dation of acetylcholine via the acetylcholinesterase globular 1
over the course of the disease as compared to the other ChE
Cholinesterase inhibitor, Cholinesterase
memantine, or combination inhibitor
inhibitors.
cholinesterase inhibitor or memantine The dual inhibition of acetylcholinesterase and butyryl-
and memantine + cholinesterase may lead to broader efcacy. As acetyl-
+ Vitamin E
Vitamin E cholinesterase activity decreases with disease progression, the
acetylcholinesterase-selective agents may lose their effect, while
Deteriorating MMSE the dual inhibitors may still be effective due to the added inhi-
Stable MMSE
(greater than or equal to 4 point
(less than 4 point decline over
decline over 1 year) bition of butyrylcholinesterase. However, this has not been
1 year) Continue regimen
above
Alternate from above + demonstrated clinically.
Vitamin E
Rivastigmine is approved for the treatment of mild to
moderate dementia of AD at an initial dose of 1.5 mg twice
Concomitant Psychiatric or Behavioral Symptoms
daily; if this dose is tolerated for at least 2 weeks, then the dose
B Psychiatric assessment can be increased to 3 mg twice daily. Increases to 4.5 mg twice
Address medical comorbidities
Address concomitant drug therapy for potential side effects
daily and 6 mg twice daily should be attempted only after at
least 2 weeks at the previous dose. Tolerability and absorption
Environmental and psychosocial interventions
are improved when the dose is given with food.
Cholinergic side effects (nausea, vomiting, and diarrhea)
are common with rivastigmine, but are usually well tolerated
Depression Psychosis Other agitation
if the recommended dosing schedule is followed. If side effects
cause intolerance, several doses can be held, then dosing can
Citalopram or Olanzapine or Olanzapine or be restarted at the same or next lower dose. There are no phar-
sertraline risperidone risperidone
macokinetic drug interactions with drugs metabolized via
Alternate option Alternate option Alternate option from CYP1A2, 2D6, 3A4/5, 2E1, 2C9, 2C8, or 2C19 expected. Drugs
from above from above above that induce or inhibit CYP450 metabolism are not expected to
alter the metabolism of rivastigmine.36
Fluoxetine, Citalopram or
Quetiapine
paroxetine carbamazepine
venlafaxine, Galantamine
or
mirtazapine Haloperidol
Oxazepam, buspirone,
trazodone, or selegiline
Galantamine is a ChE inhibitor, which elevates acetyl-
Studies in patients with dementia sementics have revealed a higher rate of cerebrovascular choline in the cerebral cortex by slowing the degradation of
adverse events, some resulting in fatalities in the active treatment group. acetylcholine.37 It also modulates the nicotinic acetylcholine
receptors to increase acetylcholine from surviving presynaptic
FIGURE 322. Treatment algorithm for Alzheimers disease. A. nerve terminals. In addition, it may increase glutamate and
Cognitive treatment. B. Treatment of psychiatric or behavioral serotonin levels. The clinical benet of action of these addi-
symptoms. AD, Alzheimers disease; MMSE, Mini Mental Status tional neurotransmitters is unknown.
Examination; NINCDS-ADRDA National Institute of Galantamine is approved for the treatment of mild to
Neurological and Communicative Disorders and
moderate dementia of Alzheimers disease. It can be dosed
Stroke/Alzheimers Disease and Related Disorders Association.
(From Faulkner JD, Bartlett J, Hicks P. Alzheimers disease. In: once or twice daily (if using the immediate-release tablet
DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A or extended-release capsule). The initial dose is 8 mg daily
Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; (or 4 mg twice daily) for 4 weeks. If tolerated the dose can be
2005: 1164, with permission.) increased if needed to 16 mg daily (or 8 mg twice daily) for at
TABLE 325. Dosing Strategies for Cognitive Agents
Tacrine Donepezil Rivastigmine Galantamine Memantine

Starting dose 10 mg four 5 mg daily 1.5 mg twice daily 4 mg twice daily or 8 mg 5 mg daily
times daily daily
Maintenance 2040 mg four 510 mg daily 36 mg twice daily 812 mg twice daily 10 mg twice daily
dose times daily or 1624 mg daily
Time between 46 weeks 46 weeks 2 weeks 4 weeks 1 week
dose
adjustments
Data from product Information for tacrine, donepezil, rivastigmine, galantamine, and memantine.3438
least 4 weeks. Again, if this dose is tolerated, the dose can be throughout the brain by controlling the amount of calcium
increased if needed to 24 mg daily (or 12 mg twice daily). that enters the nerve cell, a process essential for establishing an
The adverse reactions associated with galantamine are sim- environment required for information storage. Overstimulation
ilar to that observed with the ChE inhibitors (e.g., nausea, of the NMDA receptor by excessive glutamate allows too
vomiting, and diarrhea). much calcium into the cell, disrupting information process-
CYP3A4 and 2D6 are the major enzymes involved in the ing. Blocking NMDA receptors with memantine may protect
metabolism of galantamine. Pharmacokinetic studies with neurons from the effects of excessive glutamate without dis-
inhibitors of this system have resulted in increased galantamine rupting normal neurotransmission.38
concentrations or reductions in clearance. Similarly to donepezil, Memantine is indicated for the treatment of moderate-
if inhibitors are given concurrently with galantamine, to-severe dementia of the Alzheimers type. The initial dose
monitoring for increased cholinergic side effects should be is 5 mg/day with increases to 20 mg/day if needed, with a min-
done. Studies with inducers of these enzymes have not been imum of 1 week between dosage increases. Doses greater than
completed.37 5 mg/day should be given in two divided doses. A suggested
titration is: 5 mg/day for at least 1 week; 5 mg twice daily for at
NMDA Receptor Antagonist least 1 week; 15 mg/day (5 mg in the morning and 10 mg in the
evening) for at least 1 week; then 10 mg twice daily. If the
Memantine patient has a creatinine clearance of 5 to 29 mL/minute, then
Memantine is a non-competitive antagonist of the N-methyl- the target dose should be 5 mg twice daily. It is likely to be
D-aspartate (NMDA) type of glutamate receptors, which are given as monotherapy, but can be given in combination with
located ubiquitously throughout the brain. It regulates activity ChE inhibitors.
TABLE 326. Comparative Common Adverse Effects of AD Medications from Clinical Trial Dataa
Tacrine Donepezil Rivastigmine Galantamine Memantine

Adverse Event (n = 634) (n = 747) (n = 1189) (n = 1040) (n = 940)
Elevated liver function tests 29% NR NR NR NR
Nausea or vomiting 28% NR NR NR NR
Nausea NR 11% 47% 24% NR
Vomiting NR 5% 31% 13% 3%
Diarrhea 16% 10% 19% 9% NR
Headache 11% 10% 17% 8% 6%
Dizziness 12% 8% 21% 9% 7%
Muscle cramps 9% 6% NR NR NR
Insomnia 6% 9% 9% 5% NR
Fatigue 4% 5% 9% 5% 2%
Anorexia 9% 4% 17% 9% NR
Depression 4% 3% 6% 7% NR
Abnormal dreams NR 3% NR NR NR
Weight decrease 3% 3% 3% 7% NR
Abdominal pain 8% NR 13% 5% NR
Agitation 7% NR NR NR NR
Rhinitis 8% NR 4% 4% NR
a
Caution is urged in making comparisons between drugs based on these data, as different clinical trials often collect adverse event
data using different methodologies.
NR, not reported.
Data from Product Information tacrine, donepezil, galantamine, memantine, and rivastigmine.3438
Adverse reactions associated with memantine include: aggression) of Alzheimers disease. Double-blind, con-
constipation, confusion, dizziness, headache, coughing, and trolled trials support the efcacy of risperidone and olanza-
hypertension. These adverse effects are similar to those expe- pine in reducing the rate of psychosis and agitation.4547
rienced with ChE inhibitors. Extra monitoring should be Risperidone should be initiated at 0.25 mg/day and titrated in
done if memantine is given concurrently with a ChE inhibitor. 0.25 to 0.5 mg/day increments to 1 mg/day, with a maximum
In vitro studies have shown that memantine produces min- dose of 2 mg/day.45,46,48 Olanzapine has been studied with
imal inhibition of CYP450 enzymes CYP1A2, 2A6, 2C9, 2D6, modest results at doses of 5 to 10 mg/day, and 15 mg/day has
2E1, and 3A4. These data indicate that no pharmacokinetic not shown to be any better than placebo.47
interactions with drugs metabolized by these enzymes should In April 2005, the Food and Drug Administration (FDA)
be expected.38 issued a statement requesting black-box warnings on all atyp-
ical antipsychotics stating that elderly people with dementia-
related psychosis treated with an atypical antipsychotic are at
Non-conventional Pharmacologic Treatment an increased risk of death compared to those treated with
placebo. Of a total of 17 placebo-controlled trials investigating
Many other non-conventional treatments have been used as
olanzapine, aripiprazole, quetiapine, and risperidone in eld-
adjunctive treatments during the course of Alzheimers disease.
erly demented patients with behavioral disorders, 15 showed a
Vitamin E has often been recommended for use as an adjunc-
numerical increase in mortality in the drug-treated group
tive treatment because of its antioxidant properties.39 It has
compared to the placebo-treated groups (1.6 to 1.7 times
potential effectiveness, a favorable side-effect prole, and low
increased risk of death). Specic causes for these deaths were
cost. The maintenance dose of vitamin E should be titrated to
heart-related events (heart failure and sudden death) and
1000 International Units twice daily. However, a recent meta-
infections (mostly pneumonia). The atypical antipsychotics
analysis suggests that high doses (greater than 400 International
are not currently approved for the treatment of elderly
Units per day) of vitamin E should be avoided due to an
patients with dementia-related psychosis.
increased all-cause mortality.40 Estrogen has been investi-
Differentiating between depression and dementia can be
gated for use in AD, but as mentioned previously, was asso-
difcult, so symptoms of depression should be documented
ciated with an increased risk of dementia. Non-steroidal
for several weeks prior to initiating therapy for the treatment
anti-inammatory drugs (NSAIDs) have also been investi-
of depression with AD. Citalopram and sertraline are recom-
gated for their place in the therapy of Alzheimers disease.
mended as rst-line agents because of their efcacy in
There is a lack of convincing data and signicant adverse
placebo-controlled trials.49 Indications for the use of antide-
effects (gastritis and gastrointestinal bleeds) associated
pressants include depression characterized by poor appetite,
with their use, so they are not recommended for general use
insomnia, hopelessness, anhedonia, withdrawal, suicidal
in the treatment or prevention of AD at this time.41 Statins
thoughts, and agitation.
(3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) should
Other miscellaneous therapies for AD include benzodi-
be reserved for those patients who have other indications for
azepines for anxiety, agitation, and aggression. However, their
their use.42 Ginkgo biloba has also been studied for its potential
routine use is not advised.28 Additionally, benzodiazepines
use in AD. Until this product has more standardized manufac-
have been associated with an increase in falls leading to the
turing and long-term use is investigated, it should be recom-
potential for hip fractures in the elderly.50 Buspirone has
mended with caution.43
shown benet in treating agitation and aggression in a limited
number of patients with minimal adverse effects.51,52 In open-
Treatment for Behavioral Symptoms label and controlled studies, selegiline decreased anxiety,
depression, and agitation.53,54 Finally, trazodone has been
Treatment of behavioral symptoms should begin with shown to decrease insomnia, agitation, and dysphoria, and
nonpharmacologic treatments, but may also include antipsy- has been used to treat sundowning in Alzheimers patients.
chotic agents and/or antidepressants. Nonpharmacologic rec- Figure 322 also provides a treatment algorithm for the
ommendations for treatment include:44 behavioral symptoms of Alzheimers disease.31
Music
Videotapes of family members PHARMACOECONOMIC CONSIDERATIONS
Audio tapes of the voices of caregivers
Walking and light exercise Delaying disease progression through pharmacotherapy
Sensory stimulation and relaxation can reduce the total cost of treating AD and delay nursing home
placement. Studies with donepezil, rivastigmine, and galanta-
The atypical antipsychotics are the preferred agents for mine have predicted decreases in total costs of AD therapy and
the treatment of psychosis (hallucinations, delusions, and delayed nursing home placement.5558 A placebo-controlled
suspiciousness) and the disruptive behaviors (agitation and trial with memantine also reported cost savings and a lower
incidence of institutionalization than in the placebo group.59

Although these studies show a reduced cost of treating AD, the Patient Care and Monitoring
true cost-effectiveness of these therapies has yet to be estab-
lished. Further prospective pharmacoeconomic trials of
longer duration and more comprehensive cost analysis are
1. Assess the frequency and duration of the patients cogni-
needed to determine the position of pharmacotherapy in the tive and non-cognitive symptoms.
treatment of Alzheimers disease. Could the patient be depressed?
2. Review any available diagnostic data from the medical
and psychiatric history including interviews from family,
OUTCOME EVALUATION
neuropsychological testing, and other labs.
The success of therapy is measured by the degree to which 3. Obtain a thorough history of prescription, non-prescription,
and natural drug product use. Is the patient taking any
the care plan decreases the pretreatment deterioration rate,
medications that could contribute to cognitive changes
preserves the patients functioning, and treats psychiatric
in the elderly?
and behavioral symptoms. The primary outcome measure is
4. Educate both the patient and caregivers about lifestyle
thus subjective information from the patient and the care-
modication and refer them to support when needed.
giver, although the MMSE can be a helpful tool for monitor-
ing changes in the severity of illness. There are no physical 5. Monitor pharmacotherapy initiation. Is it titrated correctly?
examination or laboratory parameters that are used to eval- 6. Develop a plan to monitor cognitive response to treat-
uate the success of therapy. ment over time.
Once a tolerated agent is found, continue that therapy until 7. Routinely assess medication compliance.
poor tolerance or compliance occurs, no clinical improve- 8. Educate patient and caregivers on what to expect from
ment is seen with 3 to 6 months of optimal dosing, or the pharmacotherapy.
pretreatment deterioration rate continues. Inform the 9. Regularly evaluate the patient for the presence of
patient and the caregiver that the treatments available for adverse drug reactions, drug allergies, and drug-drug
Alzheimers disease are not curative, but may slow the dete- and drug-disease interactions.
rioration rate of the patient. 10. Be a resource and give continuous support to the patient
Treat behavioral and psychiatric issues as they arise. and caregivers throughout the long course of the disease.
Consider the patients choices of nonpharmacologic and
pharmacologic options before recommending a treatment.
Discontinue the pharmacologic treatments periodically to
Alzheimers Association stands out as the organization that can
re-evaluate the need for continued treatment.
provide many resources as well as facilitate contacts with other
Develop a plan to assess the effectiveness of the cholinesterase
organizations. Contact the association at:
inhibitor in slowing the deterioration of the patient after an
Alzheimers Association
appropriate interval (3 to 6 months). Assess improvement in
Contact Center: 1.800.272.3900
quality-of-life measures such as ability to function inde-
TDD Access: 1.312.335.8882
pendently and for slowing of memory deterioration.
Web site: www.alz.org
Evaluate the patient for the presence of adverse drug reac-
E-mail: [email protected]
tions, drug allergies, and drug interactions at appropriate
National Ofce: 225 N. Michigan Ave., Fl. 17
intervals. Continue to be a resource for the patient and care-
Chicago, IL 606017633
giver throughout the long course of the disease.
TABLE 327. Living with Alzheimers Disease: Ten Quick Tips

SUMMARY
1. Carry with you a book of important notes and photos.
Alzheimers disease is a progressive deterioration of cognitive abil- 2. Enroll in Alzheimers Association Safe Return.
ities, and patients are likely to have behavioral disturbances and 3. Be open to accepting help from others.
personality changes in the later stages of the disease. Additionally, 4. Keep doing the things you most enjoy.
5. Talk to others who have Alzheimers.
the disease can be extremely taxing on the patient and caregiver 6. Find ways to laugh as often as you can.
and be very costly to both the family members and society. In an 7. Maintain your physical health.
effort to help prepare patients and their caregivers for the 8. Take steps to make your home safe.
inevitable, the Alzheimers Association has developed ten 9. Extend the time you can live safely in your home with help
quick tips on Living with Alzheimers disease (Table 327).60 from your family and friends.
10. Put plans in place now for your future.
Although there are many resources available for patients, care-
givers affected by AD, and health care professionals, the Data from the Alzheimers Association with permission.60
Ach: acetylcholine American Psychiatric Association. Diagnostic and Statistical Manual of

AD: Alzheimers disease Mental Disorders, Fourth Edition, Text Revision. Washington,
Apo E: apolipoprotein E DC: American Psychiatric Association, 2000:147154.
APP: amyloid precursor protein Cummings J. Drug therapy: Alzheimers disease. N Engl J Med 2004;
ChE: cholinesterase 351:5667.
CNS: Central Nervous System Cummings JL. Use of cholinesterase inhibitors in clinical practice:
CSF: cerebrospinal uid evidence-based recommendations. Am J Geriatr Psych 2003;11:
CT: computed tomography 131145.
CYP: cytochrome P-450 Doody RS, Stevens JC, Beck C, et al. Practice parameter: management
DSM-IV-TR: Diagnostic and Statistical Manual of of dementia (an evidence-based review). Neurology 2001;56:
Mental Disorders, Fourth Edition, Text 11541166.
Revision Ganguli M, Dodge HH, Shen C, et al. Alzheimer disease and mortal-
FDA: Food and Drug Administration ity. Arch Neurol 2005;62:779784.
HIV: human immunodeciency virus Gauthier S. Advances in the pharmacotherapy of Alzheimers disease.
MMSE: Mini Mental Status Examination Can Med Assoc J 2002;166:616623.
MRI: magnetic resonance imaging Gauthier S, Emre M, Farlow MR, et al. Strategies for continued suc-
NINCDS-ADRDA: National Institute of Neurological and cessful treatment of Alzheimers disease: switching cholinesterase
Communicative Disorders and Stroke/ inhibitors. Curr Med Res Opin 2003;19:707714.
Alzheimers Disease and Related Disorders Hebert LE, Scherr PA, Bienias JL, et al. Alzheimer disease in the US
Association population: prevalence estimates using the 2000 census. Arch
NMDA: N-methyl-D-aspartate Neurol 2003;60:11191122.
NSAID: non-steroidal anti-inammatory drug Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter:
TSH: thyroid-stimulating hormone diagnosis of dementia (an evidence-based review). Report of
the quality standards subcommittee of the American Academy
Reference lists and self-assessment questions and answers are of Neurology. Neurology 2001;56:11431153.
available at www.ChisholmPharmacotherapy.com. Mattson MP. Pathways towards and away from Alzheimers disease.
Nature 2004;430:631639.
this chapter.
33 SUBSTANCE-RELATED DISORDERS
Sally K. Guthrie, Kirk J. Brower, and Maher Karam-Hage
LEARNING OBJECTIVES
1. Identify the extent of abuse of and dependence on commonly used drugs in different
segments of the United States population.
2. Explain the commonalities of action of abused substances on the reward system in the brain.
3. Identify the typical signs and symptoms of intoxication associated with the use of alcohol,
opioids, cocaine/amphetamines, and cannabis, and determine the appropriate treatment
measures to produce a desired outcome following episodes of intoxication.
4. Determine when a patient meets criteria for substance dependence.
5. Describe the different approaches to treating drug withdrawal, and identify the
circumstances in which each of these different approaches would be most appropriate.
6. Recognize when long-term maintenance therapy is indicated for an opioid addict, and
describe how to choose and initiate a maintenance regimen.
7. Determine which nonpharmacologic therapies should be used, either alone or in
combination with pharmacologic treatments, to foster a recovery from addiction.
8. Recommend a comprehensive treatment and monitoring program to establish lifestyle
changes that help maintain sobriety and prevent relapse.
KEY CONCEPTS The treatment goals for withdrawal from ethanol, cocaine/
amphetamines, and opioids include: (1) a determination if
Virtually all abused substances appear to activate the same pharmacologic treatment of withdrawal symptoms is neces-
brain reward pathway. sary, (2) management of medical manifestations of with-
While activation of the reward pathways explains the pleasur- drawal such as hypertension, seizures, arthralgias, and nausea,
able sensations associated with acute substance use, chronic and (3) referral to the appropriate program for substance
use of abused substances resulting in both addiction and with- abuse treatment.
drawal may be related to neuroadaptive effects occurring To facilitate recovery from addiction it is necessary to utilize a
within the brain. comprehensive biopsychosocial assessment that includes the
Individuals with a pattern of chronic use of commonly abused motivation for change. Pharmacologic treatments are always
substances should be assessed to determine if they meet adjunctive to psychosocial therapy.
Diagnostic and Statistical Manual of Mental Disorders, Fourth While pharmacologic agents may help prevent relapse, psy-
Edition, Text Revision (DSM-IV-TR) criteria for substance chotherapy should be the core therapeutic intervention.
dependence (addiction). Motivational enhancement therapy (MET), cognitive-behavioral
The treatment goals for acute intoxication of ethanol, therapy (CBT), 12-step facilitation (TSF), behavioral couples
cocaine/amphetamines, and opioids include (1) management therapy (BCT), community reinforcement approaches, and
of psychological manifestations of intoxication, such as aggres- contingency management are the best-studied forms of psy-
sion, hostility, or psychosis, and (2) management of medical chotherapy in this group of patients.
manifestations of intoxication such as respiratory depression, Certain pharmacologic agents have been helpful in the treat-
hyperthermia, hypertension, cardiac arrhythmias, or stroke. ment of withdrawal and in drug maintenance programs.
525
A major component of successful treatment of addiction is 80

to continue monitoring the use of medications such as disul- Twelfth Grade
ram, naltrexone, or acamprosate, which are designed to Tenth Grade
decrease craving or to block the hedonic effects of abused Eighth Grade
substances. Also, it is important to identify a mechanism for 60
long-term support of sobriety that might be appropriate for
a specic individual such as Alcoholics Anonymous, a spiri-
Percentage
tual group, or professional recovery programs for profes-
sionals such as doctors, nurses, and police ofcers. 40
Substance abuse and dependence are highly prevalent prob-

lems in the United States and in the world. In the United
States the use of all substances of abuse has undergone a series 20
of periodic cycles of societal tolerance or condemnation. As an
example, cocaine was rst isolated from coca leaves in 1860 by
a chemistry graduate student in Germany. Its use was advo-
0
cated by many in the medical establishment until around the '76 '78 '80 '82 '84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04
mid-1890s when it became evident that chronic use of cocaine Year
might be addictive in some individuals and could be associ-
ated with deleterious physiologic effects. Its use decreased fol- FIGURE 331. Trends in illicit drug use in eighth, tenth, and
twelfth graders from the Monitoring the Future Survey. Data
lowing restriction of prescribing and dispensing of cocaine in
from reference 2.
the early twentieth century. Cocaine continued to be abused by
a small segment of the population, but by and large, much of
the medical community seemed to forget the earlier cocaine
epidemic. By the late 1970s, at least one pharmacology text- While initiation of the use of substances is often in middle
book indicated that cocaine was not addictive. Unfortunately, and high school, chronic use may be established in young
in the 1980s a smokeable formulation of cocaine (crack) adulthood. The National Alcohol Epidemiologic Survey
became available, and cocaine use again became an epidemic. reported that 16.2% of its 18- to 29-year-old sample met cri-
The cyclic nature of substance abuse is common to many teria for alcohol abuse or dependence.3
drugs, including heroin and marijuana, in addition to cocaine. The association of substance abuse with emergency
The abused substances covered in this chapter include: department (ED) visits in 21 different metropolitan areas in
nicotine, alcohol, cocaine, amphetamines, cannabis, and opi- the United States is reported by the Drug Abuse Warning
oids. While many more substances can be and have been Network (DAWN). This survey tracks ED visits that are due to
abused, these drugs are among the most popular. a condition induced by or related to drug use. Included in the
data are ED visits associated with alcohol, alone and in com-
bination with other substances of abuse, including cocaine,
EPIDEMIOLOGY
heroin, marijuana, and major stimulants. Figure 332 indi-
cates the number of ED visits that are associated with illicit
In the United States the federal government annually conducts
the National Survey on Drug Use and Health, using a sample of
persons who are 12 years of age or older to determine the preva-
60
ED visits per 100,000 population
lence of licit and illicit drug use.1 In 2004, 7.9% of the American
population (12 years of age and older) had used an illicit drug 50
within the previous month. Fifty percent of the population cur-
40 44
rently used alcohol, and 6.9% were heavy users. Tobacco use has
declined in recent years from a high of 42% in 1965 to a rate of 30
29.2% in 2004. Unfortunately, use in the younger age groups 28
20
remains high. In 2004 39.5% of Americans in the 18- to 25-year-
old range reported using cigarettes within the previous month. 16 15
10
The trends in prevalence of use for eighth, tenth, and twelfth
graders are shown in Fig. 331. The use of any illicit drug and of 0
Cocaine Marijuana Heroin Stimulants
marijuana have both decreased since 1999, and this decrease
seems to be correlated with an increase in the perceived risk for FIGURE 332. Emergency department visits associated with
illicit drugs for the third and fourth quarters of 2003. Data
using marijuana, cigarettes, heroin, and alcohol among 8th from reference 4.
graders.2
CHAPTER 33 / SUBSTANCE-RELATED DISORDERS 527
drugs per 100,000 people in the population. Abuse of alcohol

in combination with other substances ranged from 69 to 75
per 100,000 in each 4-year age subpopulation range from the
ages of 18 to 44. The rate dropped to 59 per 100,000 for the
45- to 54-year-old group, and down to 15 for those 55 to 64,
and further to 3 per 100,000 population for the 65 and over
age group.4
The results of these surveys indicate that substance abuse is
wide ranging, begins early, and is associated with a consider-
able number of medical emergencies.
PATHOPHYSIOLOGY
Reward Pathway FIGURE 334. Where different abused substances interact with
Abused drugs generally produce pleasant effects that are desired the reward system in the brain. Data from reference 5. (From:
by the user. However, while most individuals will experience http://www.drugabuse.gov/pubs/Teaching/)
these pleasant effects, not everyone abuses these drugs, and not
everyone who abuses them becomes dependent on them. Why
some persons abuse drugs while most people do not is a com- indicate that ablation of DA neurons in the NA results in
plex area of research. It appears that genetic, environmental, and decreases in cocaine self-administration. Although many
cultural factors may all interact to predispose some individuals other neurotransmitters can be involved in activation of the
to substance abuse and subsequent dependence. The initial reward system, DA appears to be the nal common neuro-
hedonic experiences secondary to use of drugs appear to be pri- transmitter of this pathway.6
marily due to their ability to activate the primary reward circuits Cocaine and stimulants, such as amphetamines, probably
in the brain. These same reward circuits operate under normal cause euphoria by blocking the DA reuptake transporter.
circumstances to reinforce certain activities that promote sur- Additionally, amphetamines also cause the reverse transport of
vival, such as food, social afliation, or sexual activity. DA into the extracellular space.6 Although opioids eventually uti-
lize the same circuitry as stimulants, initially they activate opi-
Virtually all abused substances appear to activate the same oid receptors, in the NA or VTA, which ultimately results in an
brain reward pathway. Key components of the reward pathway increase of DA release in the NA. However, reinforcement of opi-
are the dopamine (DA) mesocorticolimbic system that pro- oid use may derive from two mechanisms because in animal
jects from the ventral tegmental area (VTA) and the nucleus studies, when the DA bers are destroyed, the reinforcing effects
accumbens (NA) to the prefrontal cortex, the amygdala, and of opioids remain.6 Ethanol probably produces its effects
the olfactory tubercle (Figs. 333 and 334).5 Animal studies through multiple neurotransmitter pathways. Antagonists of
-aminobutyric acid (GABA) reverse some of the behavioral
effects of ethanol, suggesting that there may be cross-reactivity
between benzodiazepines and alcohol, and that alcohol may
somehow modulate GABA receptors. Ethanol may activate the
DA system indirectly by facilitating the activity of GABA neurons
in the pars reticulata, ultimately disinhibiting the VTA DA neu-
rons, resulting in an increase in DA in the NA.6 There also may be
an interaction between serotonin (5-HT) and the reinforcing
effects of ethanol, because both 5-HT reuptake inhibitors and
5-HT2C receptor antagonists decrease ethanol intake in animals.
However, studies of these drugs that have been conducted in
alcohol-dependent humans have not been very promising.
Animal studies have indicated that when opioid antagonists are
administered to the central nucleus of the amygdala that oral
ethanol self-administration will decrease. Studies in humans
have noted a modest decrease in alcohol consumption in alco-
FIGURE 333. Location of the dopamine neural tracts associ- holics who took a long-acting opioid antagonist (naltrexone)
ated with the reward system in the brain. Data from reference 5.
(From http://www.drugabuse.gov/pubs/Teaching/)
following detoxication. Finally, small doses of ethanol inhibit
N-methyl-D-aspartate (NMDA) glutamate receptors, and animals
will substitute glutamate receptor antagonists for ethanol, sug- With regard to relapse, multiple factors are associated with an
gesting that they nd the effects of the two drugs to be similar. increased risk including the availability of the abused drug, an
Nicotine also affects the reward pathways by more than one mech- increase in psychological stressors, and a triggering of condi-
anism. In animal studies, either DA antagonists or destruction of tioning factors (cues) such as seeing a white powder or going to
DA neurons in the NA decrease nicotine self-administration. a location where drugs were often previously used or obtained.
Nicotine also interacts with the opioid pathway, because opioid These factors may be acting to trigger residual adaptational
antagonists can precipitate nicotine withdrawal in animals. changes that occurred in the brain during the period of drug
Finally, marijuanas main active component, tetrahydrocannabi- addiction.
nol (THC), binds to cannabinoid-1 (CB1) receptors resulting in
activation of DA neurons in the mesocorticolimbic system. THC
also increases the release of DA into the shell of the NA.6 OVERALL THEORY OF USE OF
PHARMACOLOGIC AGENTS TO TREAT
SUBSTANCE ABUSE
Neuronal Adaptation
While activation of the reward pathways explains the pleas- Unfortunately, unlike some medical diseases, substance depend-
urable sensations associated with acute substance use, chronic use ence cannot be cured with medications alone. However, we can
of abused substances resulting in both addiction and withdrawal sometimes alleviate the effects of drug intoxication, attenuate
may be related to neuroadaptive effects occurring within the brain. the adverse effects of withdrawal, or use agents that may some-
Chronic use of drugs of abuse appears to cause a generalized what decrease craving for, and relapse to, abused substances.
decrease in DA neurotransmission, probably in response to The intoxicating effects of opioids appear to be due to their
the intermittent increases in DA induced by the frequent use action as agonists on mu () receptors of the opioid neuro-
of these drugs. Additionally, with chronic drug use, release of transmitter system. Competitive opioid antagonists such as
corticotropin-releasing factor (CRF) is increased, indicating an naloxone and naltrexone acutely reverse many of the adverse
activation of central stress pathways. In vivo microdialysis stud- effects of opioids. To date we do not have specic antagonists
ies in rats withdrawing from ethanol, cocaine, or THC all for most other abused substances, so rapid pharmacologic
showed an increase in extracellular CRF. Also, microinjections of reversal of intoxication is usually not possible.
a CRF antagonist into the amygdala reversed some of the anxio- Similarly, reversal of withdrawal syndromes caused by abused
genic behaviors seen during withdrawal.7 substances is not always possible. One pharmacologic solution
Two neuroadaptive models have been used to explain how for reversing a drug withdrawal syndrome, most commonly
changes in reward function are associated with the development employed by dependent individuals, is to re-administer the drug
of substance dependence: sensitization and counteradaptation. 7 that caused the physiologic dependence. The more commonly
Sensitization refers to the increased response following repeated used clinical method is to administer a medication that has
intermittent administration of a drug. This is in contrast to the some cross-dependence with the abused drug, but also has fewer
tolerance to drug effects that occurs secondary to continuous of the reinforcing effects and a more predictable pharmacoki-
exposure to the drug. Sensitization may be akin to the increase netic prole. A good example is the use of benzodiazepines for
in craving a drug after repeated intermittent use of the drug and the withdrawal of ethanol. While benzodiazepines can cause
would facilitate transition from occasional use to compulsive dependence, they are rated as less desirable than ethanol by sub-
use. Counteradaptation postulates that the initial positive stance abusers, they cause fewer of the long-term adverse health
rewarding feelings are followed by the opposing development of effects of ethanol, and they are easier to manage medically.
tolerance. Since tolerance takes longer to dissipate than the pos- In the case of heroin addiction, maintaining the addict on a
itive rewarding effects, a cycle of escalating drug use ensues. regimen of medically managed, orally administered opioids
Ultimately, chronic activation of the reward system may result in may be preferred over rapidly detoxifying the patient who has
a depletion of neurotransmitter systems that are overactivated in a high likelihood of returning to heroin use when extensive
an effort to maintain response to drugs of abuse. During with- strategies for rehabilitation have not been put in place. In order
drawal, microdialysis experiments have documented decreases to allow time for psychosocial strategies to help the addicted
in dopaminergic and serotonergic transmission in the NA. Also individual change his or her overall lifestyle, a period of opioid
seen during alcohol withdrawal are an increase in opioid recep- agonist treatment may be indicated. This strategy has been
tor sensitivity combined with decreased GABAergic and used to maintain addicts on either orally administered opi-
increased NMDA glutamatergic transmission in the accumbens- oid agonists such as methadone, or partial agonists such as
amygdala pathway. The increase in CRF and concomitant buprenorphine.
decrease in neuropeptide Y during withdrawal are associated No matter which method has been used to facilitate detoxi-
with increases in anxiety and an activation of norepinephrine cation from the abused substance, addicts have a high risk for re-
(NE) pathways, which in turn also activates more CRF release, using substances and manifesting their dependence again. In the
possibly resulting in an amplication of arousal and stress and long term, the most effective mechanisms for maintaining sobri-
maybe even neurotoxic effects if these effects are long-lasting.7 ety are psychosocial strategies rather than pharmacologic ones.
(b) the same (or a closely related) substance is taken to

Patient Encounter 1 relieve or avoid withdrawal symptoms
(3) the substance is often taken in larger amounts or over a
longer period than was intended
(4) there is a persistent desire or unsuccessful efforts to cut
BB, a 48-year-old man with a history of hypertension, pre-
down or control substance use
sents to your clinic for follow-up evaluation of his hyperten-
sion. You notice that he admits to drinking from one-half to (5) a great deal of time is spent in activities necessary to
one pint (237473 mL) of whiskey daily. He says he drinks obtain the substance (e.g., visiting multiple doctors or
more on the weekends, but he drinks every day. When you driving long distances), use of the substance (e.g., chain-
question him about his drinking he says that he doesnt think smoking), or recover from its effects
that its a problem but admits that his wife has told him he (6) important social, occupational, or recreational activities
needs to cut down. He doesnt believe that he is alcohol are given up or reduced because of substance use
dependent because on workdays he never drinks before 5 P.M. (7) the substance use is continued despite knowledge of having a
He admits to having had occasional blackouts. persistent or recurrent physical or psychological problem that
is likely to have been caused or exacerbated by the substance
What information would suggest that this gentleman
(e.g., current cocaine use despite recognition of cocaine-
might be alcohol dependent?
induced depression, or continued drinking despite recogni-
What additional information would you need to deter-
mine if he meets the criteria for alcohol dependence? tion that an ulcer was made worse by alcohol consumption)
specify if:
With Physiological Dependence: evidence of tolerance or
withdrawal (i.e., either item 1 or 2 is present); or
Without Physiological Dependence: no evidence of tolerance
Individuals with a pattern of chronic use of commonly or withdrawal (i.e., neither item 1 nor 2 is present)
abused substances should be assessed to determine if they meet the
(Reprinted from the Diagnostic and Statistical Manual of
Diagnostic and Statistical Manual of Mental Disorders, Fourth
Mental Disorders, Copyright 2000, American Psychiatric
Edition, Text Revision (DSM-IV-TR) criteria for substance
Association, with permission.)
dependence (addiction).8 Criteria are not dened for each sepa-
rate abused substance; rather, a pattern of behavior common to
Intoxication Signs and Symptoms
the abuse or dependence of all drugs of abuse is established.
The criteria for abuse indicate an established pattern of Euphoria is the one symptom that most drugs of abuse (with
using a substance that has resulted in undesirable family, job, the exception of tobacco) have in common. Other signs and
or legal consequences, such as recurrent instances of neglect- symptoms are specic to the particular drug or class of drugs
ing school, work, or family responsibilities, or being arrested involved. Table 331 lists the psychological/behavioral and
for driving under the inuence. However, abuse becomes
dependence when tolerance to the drug, withdrawal from the
drug, or an inability to discontinue use of the drug is appar- Patient Encounter 2
ent or there is a loss of control over its use or the use has
become compulsive. The criteria for substance dependence
from the DSM-IV-TR are listed below.
KI, a 27-year-old woman, was admitted to the cardiology
Criteria for Diagnosis of Substance Dependence unit from the emergency department after she called 911
claiming that she had severe chest pain. Upon arrival in
A maladaptive pattern of substance use, leading to clinically the ED it was noted that her blood pressure was slightly
signicant impairment or distress, as manifested by three elevated at 143/92 mm Hg, and that she was diaphoretic. She
(or more) of the following, occurring at any time in the was in otherwise good physical condition, with no previous
same 12-month period: cardiac history. After a urine toxicology screen was positive
for cocaine she admitted that she had smoked several rocks
(1) tolerance, as dened by either of the following: of crack an hour prior to having the chest pain. She said she
almost never uses crack, but shes currently really depressed
(a) a need for markedly increased amounts of the sub-
because she has lost her job.
stance to achieve intoxication or desired effect
(b) markedly diminished effect with continued use of the What are the possible physical signs and symptoms of
same amount of the substance cocaine use?
(2) withdrawal, as manifested by either of the following: What are the possible psychiatric symptoms associated
(a) the characteristic withdrawal syndrome for the with cocaine use?
substance
TABLE 331. Signs and Symptoms of Drug Intoxication
Drug Behavioral Effects Physiologic Effects

Ethanol Mood lability, inappropriate aggressive or sexual behavior, At blood levels of 0.02 g%0.09 g% (4.34 to
giddiness or verbally loud, impaired judgment; possibly 19.5 mmol/L): may see some prolonged
progressing to somnolence and coma as the blood reaction time and muscular incoordination
level increases At blood levels from 0.1 g%0.2g% (21.7 to
43.4 mmol/L): may see obvious prolonged
reaction time, obvious incoordination and
ataxia, and mental impairment
At blood levels from 0.2 g% to 0.3g% (43.4 to
65.1 mmol/L): marked ataxia, some dysarthria,
and possible nausea and vomiting
At blood levels from 0.3 g% to 0.4g% (61.5 to
86.8 mmol/L): severe dysarthria, amnesia, and
hypothermia
At blood levels from 0.4g%0.6g% (86.8 to
130.2 mmol/L): alcoholic coma often occurs,
accompanied by decreased respiration, blood
pressure, and body temperature
Blood levels between 0.6 g% and 0.8 g% (130.2
to 173.6 mmol/L): are often fatal resulting
from respiratory arrest, aspiration of gastric
contents, or airway obstruction due to
accid tongue
Cocaine/ Initially, most prominent effect is elated mood, although depression Neurologic: papillary dilation, headache, tremor,
stimulants may occur; hypervigilance and anxiety that may progress to hyperreexia, muscle twitching, ushing,
panic; with high doses or chronic use, may see impairment of hyperthermia or cold sweats, seizures,
judgment, violence to others or self, paranoia or psychosis coma, possible cerebral hemorrhage
with delusions and hallucinations (hallucinations are generally Cardiovascular: increased pulse and blood
tactile or auditory, rarely visual); an increase in motor activity is pressure, peripheral vasoconstriction,
common; compulsive or stereotyped behavior (e.g., skin picking) arrhythmias, myocardial infarction
may be seen; severe intoxication may result in a self-limited Gastrointestinal: nausea and vomiting
delirium Renal: possible incontinence or renal failure
Neuromuscular: rhabdomyolysis, possibly
resulting in renal failure
Opioids Euphoria and sedation are the most prominent effects; analgesia is Nausea and vomiting; respiratory depression
also prominent; slurred speech, and impaired memory and that is dose-related and may progress to coma;
attention can be seen along with psychomotor retardation constipation is very common in chronic
users, itching, miosis (pinpoint pupils)
Cannabis Euphoria or giddiness and increase in appetite may occur; depending Ocular effects include conjunctival reddening, a
on the social setting and the amount ingested, may see panic, slight miosis, and decreased intraocular pressure
paranoia, hallucinations, depersonalization or delirium Cardiovascular: tachycardia and vasodilation
combined with orthostatic hypotension in
high doses
Neuromuscular: decreased muscular
coordination may be seen;
Gastrointestinal/genitourinary: dry mouth is common
and urinary retention may occur in some
persons
Data from references 9, 10, and 11.
physiologic effects of intoxication with ethanol, cocaine and withdrawal symptoms seen upon abstinence from drug
amphetamines, opioids, and cannabis.911 use.912
Withdrawal Signs and Symptoms

TREATMENT OF INTOXICATION SYNDROMES
Though most abused drugs can cause some degree of phys-
iologic dependence, the severity of withdrawal varies con- The treatment goals for acute intoxication due to ethanol,
siderably among these drugs. Table 332 lists the common cocaine/amphetamines, and opioids include: (1) management of
TABLE 332. Signs and Symptoms of Drug Withdrawal
Drug Duration Symptoms

Ethanol As ethanol level decreases Vivid dreams, insomnia
Within 624 hours Tremor, nausea and vomiting,
tachycardia (greater than
110 bpm), hypertension
(greater than 140/90 mm Hg)
648 hours Convulsions (usually 12 grand
maltype, but they can be
more numerous and possibly
fatal)
Days 35 Delirium tremens
Onset at any time Hallucinations, usually visual
Cocaine/ Immediately following binge Stimulant craving, accompanied
amphetamine by intense dysphoria,
depression, anxiety, agitation
Within 14 hours Desire for sleep, dysphoria
continues
Days 34 Hypersomnia, increased appetite,
craving may dissipate slightly,
but returns strongly later
Opioids For shorter-acting opioids (e.g., Gastrointestinal: nausea and
heroin, morphine, vomiting, diarrhea, and
hydrocodone, oxycodone) dehydration
withdrawal may begin Neurologic/psychologic:
within 624 hours following irritability, restlessness, yawning,
the last dose and last for tremulousness, and twitching
about 1 week; with Cardiovascular: increase in heart
longer-action opioids rate, blood pressure
(e.g., methadone) it may Musculoskeletal: chills, increased
take up to 24 days for body temperature,
withdrawal to emerge, and piloerection, rhinorrhea
it will last longer Ocular: lacrimation and dilated
pupils
Nicotine Within 24 hours of cessation The severity of symptoms reects
of use the degree and duration of
nicotine use; symptoms
include anxiety, irritability,
frustration, anger, craving,
difculty concentrating,
decreased heart rate, and
increased appetite
Cannabis Withdrawal is not usually Symptoms are generally mild and
noticeable, except in heavy, reect the degree and duration
chronic marijuana users; of dependence; symptoms
withdrawal occurs within include irritability, insomnia,
24 hours, peaks in 24 days restlessness, anorexia,
and resolves in 12 weeks diaphoresis, diarrhea, and
muscle twitches; mild
increases in heart rate and
blood pressure may also occur
Data from references 9, 10, 11, and 12.
psychological manifestations of intoxication, such as aggression, Alcohol Intoxication

hostility, or psychosis, and (2) management of medical manifes-
Most cases of mild to moderate intoxication with alcohol, as well
tations of intoxication such as respiratory depression, hyper-
as cases in which blood alcohol levels (BALs) are at the lower
thermia, hypertension, cardiac arrhythmias, or stroke. In all
limits of legal intoxication (80 to 100 mg%, 0.08 to 0.1% or 17.4
cases of intoxication associated with a substance use disorder
to 21.7 mmol/L), do not require formal treatment. Such intoxi-
(abuse or dependence), referral to and participation in sub-
cations are characterized by mood lability, loud or inappropriate
stance abuse treatment following acute treatment for intoxi-
behavior, slurred speech, incoordination, or unsteady gait.
cation is desirable.
Providing a safe environment and supportive reassurance until reversing the poor judgment and motor incoordination that
the effects of alcohol have worn off is sufcient in most cases. At are vital for complex tasks such as driving. Thus, stimulants
more severe levels of intoxication, confusion, stupor, coma, and are neither indicated nor a viable option to make driving safe.
death may be observed. In nontolerant individuals, confusion, Flumazenil (Romazicon) reverses the effects of benzodi-
depressed consciousness, and vomiting are observed at BALs of azepine agonists at GABA receptors, which mediate some of
200 to 300 mg% (0.2 to 0.3%, or 43.4 to 65.1 mmol/L); stupor alcohols effects, but alcohol also acts on many other neuro-
and coma are seen with BALs exceeding 300 to 400 mg% (0.3 to transmitter systems making umazenil generally ineffective in
0.4%, or 65.1 to 86.8 mmol/L). Death may occur at levels of reversing alcohol intoxication.
400 mg% (0.4% or 86.8 mmol/L) or higher from cardiac
arrhythmias or respiratory depression. Thus, the most impor- Stimulant Intoxication (Cocaine and Amphetamines)
tant physiologic goal of treating high levels of intoxication is
The desired outcomes of the treatment of stimulant intoxication
maintaining cardiopulmonary functioning, including the pre-
are appropriate management of medical and psychiatric prob-
vention of aspiration. Accordingly, vital signs must be monitored
lems. Medical problems include hyperthermia, hypertension,
regularly. Serial BALs at least hourly are strongly recommended,
cardiac arrhythmias, stroke, and seizures. Some medical prob-
and patients should not be allowed to leave the treatment setting
lems are related to route of administration such as nosebleeds
on their own while legally intoxicated (greater than or equal to
with intranasal administration and infections with intravenous
80 mg% [0.8% or 17.4 mmol/L]). Initially, BALs may continue
administration. Psychiatric effects include anxiety, irritability,
to rise if gastrointestinal absorption is still occurring. Otherwise,
aggression, and psychosis. Psychosis may take the form of tactile
the BAL generally decreases at a rate of 15 to 20 mg% (0.015 to
hallucinations (such as the sensation of bugs crawling under
0.02% or 3.3 to 4.34 mmol/L) per hour. Although more tolerant
ones skin, aka formication), visual hallucinations (usually sim-
individuals may not show the same level of symptoms for a
ple geometric shapes), and most commonly auditory hallucina-
given BAL as non-tolerant individuals, behavioral tolerance and
tions, as well as paranoia or delusions of grandeur. Cocaine is
tolerance for vital physiologic functions may differ. Thus, alco-
short-acting, and a single dose of a benzodiazepine sedative-
holic patients who are awake and alert at a BAL greater than or
hypnotic may be sufcient treatment for anxiety reactions.
equal to 400 mg% (0.4% or 86.8 mmol/L) may still be at risk for
Depending on the half-life of the benzodiazepine, one or more
cardiopulmonary instability and collapse.
sequential doses may be required for amphetamine intoxication.
Other causes of confusion, stupor, or coma must be ruled out,
Because stimulants are commonly used in combination with
because alcohol-intoxicated individuals commonly combine
alcohol or opioids, benzodiazepines could increase their seda-
alcohol with other substances, sustain head and other injuries,
tive and respiratory depressant effects, so a comprehensive drug
and have vitamin deciencies and electrolyte abnormalities. If
history and urine drug screen should be obtained. In a small
consciousness is impaired, then thiamine should be given intra-
percentage of patients, benzodiazepines can cause paradoxical
venously or intramuscularly at 100 mg daily for at least 3 days.
activation and aggression. Thus, antipsychotics may be needed.
Patients may also develop adverse interactions between alcohol
Antipsychotics are denitely indicated when psychosis is pres-
and medications that have been prescribed, including disulram.
ent, and the psychosis usually responds quite rapidly in the
See Table 333 for a listing of drug-drug interactions.1315 If
absence of other co-occurring psychiatric disorders.
hypoglycemia is suspected, then thiamine administration should
precede administration of glucose-containing uids to prevent
Opioid Intoxication
precipitation of an acute Wernickes syndrome.
Behaviorally, patients may insist on driving, become phys- The word opioid is used to refer to the overall class including
ically aggressive and agitated, or otherwise become a danger to the semi- and fully-synthetic agents, but the word opiate
self or others. Indeed, most suicidal behaviors among alcohol- only refers to the naturally occurring opioids such as heroin,
dependent individuals occur while intoxicated. In such cases, opium, and morphine.
the desired outcomes are appropriate management of medical Patients who are acutely intoxicated with an opioid usually
problems, prevention of harmful behaviors, and stabilization present with miosis, euphoria, slow breathing and slow heart
of mood. Less commonly, agitation may require treatment rate, low blood pressure, and constipation. Seizures may occur
with haloperidol such as 5 to 10 mg by mouth every 2 to 4 hours, with certain agents such as meperidine (Demerol). It is criti-
or 5 mg either intravenously (IV) or intramuscularly (IM) every cally important to monitor patients carefully to avoid cardiac/
1 to 2 hours. Antipsychotics, however, may lower the seizure respiratory depression and death from an excessive dose of
threshold and are best avoided. Sedation with benzodiazepines opioids. One strategy is to reverse the intoxication by utilizing
has been used in some cases, but the risk of respiratory depres- naloxone (Narcan) 0.4 to 2 mg IV every 2 to 3 minutes up to
sion when mixed with the alcohol already in the patients system 10 mg. Alternatively, the IM/SC route may be used if IV access is
can be dangerous if not fatal. not available. Because naloxone is shorter-acting than most
There are no available medications that can fully reverse the abused opioids, it may need to be readministered at periodic
effects of alcohol intoxication. Caffeine and other stimulants intervals; otherwise the patient could lapse into cardio-
can induce arousal and alertness, but they are less effective at pulmonary arrest after a symptom-free interval of reversed
TABLE 333. Drug Interactions with Abused Drugs or Drugs Used to Treat Drug Abuse
Drug Interacting Drug Type of Interaction and Appropriate Action

Amphetamine Monoamine oxidase inhibitors (phenelzine, Pharmacodynamic interaction resulting in an increase in blood
tranylcypromine, possibly linezolid) pressure; possibly resulting in a hypertensive emergency or
stroke; avoid this combination.
Sodium bicarbonate Sodium bicarbonate increases renal tubular reabsorption of
amphetamine, resulting in a prolonged amphetamine
elimination half-life; be aware of this combination.
Buprenorphine There are currently no reported drug interactions Theoretically buprenorphine metabolism could be inhibited
with buprenorphine; however, buprenorphine by itraconazole, ketoconazole, grapefruit juice, and
is metabolized primarily by CYP3A4 erythromycin or any other CYP3A4 inhibitor; the effects
may be greater than expected for the dose of buprenorphine
being given; may need to decrease buprenorphine dose.
Conversely buprenorphine metabolism could by increased by
carbamazepine, phenytoin, St. Johns wort, efavirenz, and
nevirapine, or any other CYP3A4 inducer; the effects may
be less than expected; may need to increase buprenorphine
dose.
Cigarette smoking Clozapine Cigarette smoking induces CYP1A2; increasing the metabolism
of clozapine; may need to increase usual clozapine dose
when a patient begins to smoke, or decrease clozapine
dose if smoking is stopped or nicotine replacement is used
instead of smoking.
Olanzapine Similar interactions as clozapine; may need to increase the
usual olanzapine dose when a patient begins to smoke, or
decrease olanzapine dose if smoking is stopped or nicotine
replacement is used instead of smoking.
Theophylline Theophylline is also a CYP1A2 substrate; may need to increase
the usual theophylline dose when a patient begins to
smoke, or decrease the theophylline dose if smoking is
stopped or nicotine replacement is used instead of smoking.
Clonidine Amitriptyline, imipramine, desipramine (also Pharmacodynamic interaction; clonidine acts as an agonist at
likely with nortriptyline, doxepin, 2-receptors, and these TCAs block this receptor to varying
protriptyline, and trimipramine) degrees; the result is an increase in blood pressure; either
avoid this interaction by choosing another antidepressant or
increase the dose of clonidine.
Cyclosporine Clonidine may increase cyclosporine blood levels; although
only a single case report supports this, it would be prudent
to monitor cyclosporine blood levels in a patient receiving
clonidine.
Mirtazapine This interaction is the same as the one when clonidine is
combined with TCAs; however, mirtazapine is a more
potent 2-receptor blocker than the TCAs; avoid this
interaction and choose an alternative antidepressant
without 2-blocking effects.
Disulram Benzodiazepines (including alprazolam, Disulram inhibits CYP enzymes 1A2, 2C9, and 3A4; many
chlordiazepoxide, diazepam, urazepam, benzodiazepines are metabolized via these pathways;
halzepam, prazepam, triazolam) lorazepam, temazepam, and oxazepam are NOT
metabolized via the CYP450 system and are reasonable
alternatives.
Otherwise, if benzodiazepines are combined with disulram
the pharmacologic effect may be greater than expected, and
the dose of benzodiazepine may need to be lowered.
Cocaine Disulram decreases the clearance of cocaine from the body;
may see increased or prolonged cocaine effects with this
combination.
Isoniazid The addition of disulram to isoniazid therapy has resulted in
changes in affect and behavior and decreased coordination;
avoid the combination if possible; if they must be given
concomitantly, monitor closely.
(Continued )
TABLE 333. Drug Interactions with Abused Drugs or Drugs Used to Treat Drug Abuse (Continued )

Phenytoin Disulram decreases the metabolism of phenytoin, resulting in
higher phenytoin levels; the dose of phenytoin will need to be
reduced; since phenytoin undergoes nonlinear metabolism
it is difcult to predict the magnitude of increase in blood
levels that could be seen; it is best to avoid this interaction if
possible; otherwise, closely monitor phenytoin blood levels.
Theophylline Disulram inhibits CYP1A2, resulting in an increase in
theophylline blood levels; monitor theophylline blood
concentration; may need to decrease theophylline dose.
Warfarin Disulram inhibits several of the enzymes responsible for
warfarin metabolism; increased PT/INR have been noted; if
disulram is added to warfarin therapy, carefully monitor
PT/INR; the warfarin dose will probably have to be decreased.
Ethanol Acetaminophen Chronic ethanol use increases the risk of hepatotoxicity when
acetaminophen is used in high doses; however, acute
ingestion of alcohol along with an acetaminophen overdose
decreases the toxicity of acetaminophen.
Cefamandole, A disulram-type reaction may occur when these anti-infectives
cefoperazone, cefotetan, are combined with alcohol; the reaction includes ushing,
and moxalactam, metronidazole diaphoresis, tachycardia, headache, and increases in blood
pressure; avoid alcohol if these drugs are used.
Isoniazid Hepatotoxicity is a higher risk when isoniazid is given to those
who chronically drink large amounts of alcohol; avoid
isoniazid in this group if possible, otherwise monitor LFTs.
Methotrexate Hepatotoxicity is a higher risk when methotrexate is given to
those who chronically drink large amounts of alcohol; avoid
methotrexate in this group if possible; otherwise monitor LFTs.
Monoamine oxidase inhibitors Ethanol DOES NOT interact with MAOIs; however, tyramine
may be a component of some aged alcoholic drinks, such
as red wines or tap beers; if a reaction occurs, hypertension
and a pounding headache are the most likely symptoms;
usually white wine is ne (in moderation) and most widely
available domestic canned beers do not contain signicant
amounts of tyramine.
Methadone Carbamazepine Carbamazepine is an inducer of CYP3A4 and methadone is
primarily metabolized via CYP3A4; if carbamazepine is
added to a drug regimen containing methadone, the
methadone dose will probably need to be adjusted upward
to avoid withdrawal.
Efavirenz This HIV drug is a CYP3A4 inducer; efavirenz decreases
methadone blood levels and has precipitated withdrawal in
opioid-dependent individuals; may need to increase
methadone dose.
Fluconazole Fluconazole is an antifungal agent that moderately inhibits
CYP3A4; when added to a drug regimen containing
methadone, higher blood levels have been noted;
adjustment of methadone dose should be based on clinical
judgment, but a decrease of dose may be necessary. NOTE:
Both itraconazole and ketoconazole are more potent
inhibitors of CYP3A4, although interactions have not yet
been reported, theoretically, they are very likely to occur,
resulting in elevated methadone concentrations.
Nevirapine Nervirapine is an HIV drug that is a CYP3A4 inducer; in a
small sample, nevirapine caused a 50% reduction in
methadone blood levels, resulting in complaints of methadone
withdrawal symptoms in patients receiving methadone main-
tenance; may need to increase methadone dose in patients
who have nevirapine added to their drug regimen.
Phenobarbital An inducer of many CYP450 enzymes; may result in
complaints of withdrawal symptoms in methadone
maintenance patients when added to their drug regimen;
may need to increase methadone dose.
TABLE 333. Drug Interactions with Abused Drugs or Drugs Used to Treat Drug Abuse (Continued )

Phenytoin Similar to phenobarbital; may need to increase methadone dose when
phenytoin is added to a methadone maintenance drug regimen
to avoid withdrawal symptoms.
St. Johns wort This herbal remedy may induce CYP3A4; the certainty of an interaction
probably rests on the specic preparation being used, but caution
would dictate that this herbal product should be avoided in those
receiving methadone treatment; withdrawal symptoms have been
noted in patients taking methadone maintenance who have added
St. Johns wort to their drug regimen.
CYP. cytochrome P450 isoenzyme; HIV, human immunodeciency virus; INR, International Normalized Ratio; LFTs, liver function tests; MAOI,
monoamine oxidase inhibitor; PT, prothrombin time; TCA, tricyclic antidepressant.
Data from references 13, 14, and 15.
intoxication. In addition, naloxone can induce withdrawal or hallucinosis. Symptoms are typically rated using a validated
symptoms in opioid-dependent patients, so patients may scale such as the Clinical Institute Withdrawal Assessment for
awaken feeling quite distressed and agitated. It is also critical to Alcohol-Revised (CIWA-Ar; Table 334).16 The recommended
secure the airway and ensure breathing. In some cases intubation CIWA-Ar threshold score for treating uncomplicated alcohol
and manual/ mechanical ventilation may be required. This is a withdrawal with medications on an outpatient basis is between
necessary measure to avoid oxygen desaturation leading to brain 8 and 10. For patients that score greater than or equal to 15,
hypoxia or anoxia that may cause brain damage or death. inpatient treatment should be strongly considered. Patients who
Overall, intoxication with any of the substances discussed score 20 or higher on the CIWA-Ar should always be treated
above is evidence of substance abuse and is strongly suggestive with medications. The risks of not treating high-scoring patients
of substance dependence. In all cases it is important to with medications are seizures and DTs, and those with a prior
strongly emphasize to the patient that this is an issue that history of seizures or DTs have an increased risk for subsequent
needs to be addressed, and that entry into a treatment pro- episodes. Therefore, when a history of seizures or DTs is positive,
gram could be very benecial. the lower threshold of 8 is recommended, and hospitalization is
safer than outpatient detoxication. There is some evidence for
kindling during successive episodes of alcohol withdrawal,
TREATMENT OF WITHDRAWAL SYNDROMES
such that symptom severity and complications increase with
additional withdrawal episodes. Thus, some authors recom-
The treatment goals for withdrawal from ethanol, mend routinely using medications when the CIWA-Ar score is
cocaine/amphetamines, and opioids include: (1) a determination
in the 8 to 10 range.
if pharmacologic treatment of withdrawal symptoms is necessary,
Benzodiazepines are the evidence-based treatment of choice
(2) management of medical manifestations of withdrawal such
for uncomplicated alcohol withdrawal.17 Barbiturates are not
as hypertension, seizures, arthralgias, and nausea, and (3) refer-
recommended because of their low therapeutic index due to
ral to the appropriate program for substance abuse treatment.
respiratory depression. Some of the anticonvulsants have also
The desired outcomes in the treatment of withdrawal syn-
been used to treat uncomplicated withdrawal (particularly car-
dromes are to ensure patient safety, comfort, and successful
bamazepine and sodium valproate). Although anticonvulsants
transition from treatment of withdrawal to treatment of
provide an alternative to benzodiazepines, they are not as well
dependence. Referral to specialized treatment for substance
studied and are less commonly used. The most commonly
dependence is strongly recommended following treatment for
employed benzodiazepines are chlordiazepoxide, diazepam,
withdrawal syndromes, because treatment of withdrawal is
lorazepam, and oxazepam. They differ in three major ways:
not sufcient to prevent relapse to problematic substance use.
(1) their pharmacokinetic properties, (2) the available routes
Achieving a drug-free state by detoxication and then rehabil-
for their administration, and (3) the rapidity of their onset of
itation with a focus on total abstinence is the ideal outcome.
action due to the rate of gastrointestinal absorption and rate of
crossing the bloodbrain barrier.
Alcohol Withdrawal
Benzodiazepines can be administered using a symptom-
There are four different alcohol withdrawal syndromes, which triggered approach when withdrawal signs and symptoms are
differ in terms of their pharmacologic treatment and need for already present.18 In this approach, medication is administered
hospitalization. every hour when the CIWA-Ar is greater than or equal to 8. For
the shorter-acting agents, oxazepam (15 to 60 mg orally) or
Uncomplicated Alcohol Withdrawal lorazepam (1 to 4 mg orally) is given, and the CIWA-Ar is
This is the most commonly observed syndrome, and as the name repeated hourly after each administration during the rst
denotes, is not complicated by seizures, delirium tremens (DTs), 24 hours until the patient is comfortably sedated. Because of
TABLE 334. Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar)
Patient Name _______________________ 0 None

Date: _____ Time: __________ 1 Very mild itching, pins & needles, burning or numbness
2 Mild itching, pins & needles, burning or numbness
Pulse: _____ BP: _____ 3 Moderate itching, pins & needles, burning or numbness
NAUSEA & VOMITING: Ask Do you feel sick to your stomach? 4 Moderately severe hallucinations
Have you vomited? Observation. 5 Severe hallucinations
0 No nausea and no vomiting 6 Extremely severe hallucinations
1 Mild nausea with no vomiting 7 Continuous hallucinations
2 AUDITORY DISTURBANCES: Ask Are you more aware of sounds
3 around you? Are they harsh? Do they frighten you? Are you
4 Intermittent nausea with dry heaves hearing anything that is disturbing to you? Are you hearing
5 things you know are not there? Observation.
6 0 Not present
7 Constant nausea, frequent dry heaves and vomiting 1 Very mild harshness or ability to frighten
TREMOR: Arms extended and ngers spread apart. 2 Mild harshness or ability to frighten
Observation. 3 Moderate harshness or ability to frighten
0 No tremor 4 Moderately severe hallucinations
1 Not visible, but can be felt ngertip to ngertip 5 Severe hallucinations
2 6 Extremely severe hallucinations
3 7 Continuous hallucinations
4 Moderate, with patients arms extended VISUAL DISTURBANCES: Ask, Does the light appear to be too
5 bright? Is the color different? Does it hurt your eyes? Are you
6 seeing anything that is disturbing to you? Are you seeing things
7 Severe, even with arms not extended you know are not there? Observation.
PAROXYSMAL SWEATS: Observation. 0 Not present
0 No sweat visible 1 Very mild sensitivity
1 Barely perceptible sweating, palms moist 2 Mild sensitivity
2 3 Moderate sensitivity
3 4 Moderately severe hallucinations
4 Beads of sweat obvious on forehead 5 Severe hallucinations
5 6 Extremely severe hallucinations
6 7 Continuous hallucinations
7 Drenching sweats HEADACHE, FULLNESS IN HEAD: Ask Does your head feel
ANXIETY: Ask, Do you feel nervous? Observation. different? Does it feel like there is a band around your head?
Do not rate dizziness or lightheadedness. Otherwise, rate
0 No anxiety, at ease
severity.
1 Mildly anxious
2 0 Not present
3 1 Very mild
4 Moderately anxious or guarded, so anxiety is inferred. 2 Mild
5 3 Moderate
6 4 Moderately severe
7 Equivalent to acute panic states, as seen in severe delirium or 5 Severe
acute schizophrenic reactions 6 Very severe
7 Extremely severe
AGITATION: Observation.
ORIENTATION AND CLOUDING OF SENSORIUM: Ask, What
0 Normal activity
day is this? Where are you? Who am I? Observation.
1 Somewhat more than normal activity
2 0 Oriented and can do serial additions
3 1 Cannot do serial additions or is uncertain about date
4 Moderately dgety and restless 2 Disoriented for date by no more than 2 calendar days
5 3 Disoriented for date by more than 2 calendar days
6 4 Disoriented for place and/or person
7 Paces back and forth during most of the interview, or constantly Total Score: _____
thrashes about Rater: __________
TACTILE DISTURBANCES: Ask Have you any itching, pins & Maximum Possible Score: 67
needles sensations, any burning, any numbness, or do you feel
bugs crawling on or under your skin? Observation.
their short half-life, dosing on subsequent days may be needed, Benzodiazepines are the treatment of choice. Intravenous (IV)
and the risk of seizures may possibly (although not denitively diazepam 5 to 10 mg is preferred to terminate a seizure in
proven) be higher. For the longer-acting agents, chlordiazepoxide progress if IV access is available. The dose may be repeated in
and diazepam, the symptom-triggered approach is used in com- 5 minutes if seizures persist. Alternatively, lorazepam 4 mg
bination with another technique known as loading. With the may be given IM, followed by insertion of an IV line when
loading technique, chlordiazepoxide at doses of 50 to 100 mg or convulsive movements have subsided. In the event of a recur-
diazepam (10 to 20 mg) is administered orally at 1-hour inter- rent seizure, lorazepam 2 mg IV may be administered if the
vals during the rst 24 hours until the patient is comfortably patient already received IM lorazepam. Intramuscular use of
sedated and the CIWA-Ar score is lower than 4. Due to differ- diazepam or chlordiazepoxide should be avoided because of
ences in disposition and metabolism, the absolute amount of erratic absorption that complicates the timing of subsequent
benzodiazepine required in the rst 24 hours will vary, but the doses and can result in delayed oversedation. IV benzodi-
majority of patients will respond to about 400 mg of chlor- azepines may depress respiration, so they should be adminis-
diazepoxide or 60 mg of diazepam. Some may require higher tered only when and where advanced cardiopulmonary support
dosages, but it is important to monitor closely for respiratory is readily available. When the patient becomes conscious enough
depression or excessive sedation. Then loading is stopped, and to take medication orally, then treatment may continue using
for the next 24 hours the benzodiazepine is used as needed only the loading procedure for diazepam or the symptom-triggered
if the CIWA-Ar score is greater than or equal to 8, although the technique for lorazepam as described above. Electrolyte imbal-
long half-lives of these drugs and their active metabolites usually ances can contribute to seizures and should be corrected if they
provides a natural taper without further drug administration. exist. IV magnesium sulfate should be given in addition to ben-
The loading technique is especially useful in the hospital, where zodiazepine treatment. Hypomagnesemia can be corrected with
patients can be medically monitored throughout the day. If vital magnesium sulfate 1 g every 6 hours IV for the rst day of with-
signs are elevated in the absence of high CIWA-Ar scores, then drawal, assuming renal function is intact. Oral replenishment of
anti-adrenergic drugs like clonidine or propanolol may be used magnesium may be difcult to accomplish due to resultant diar-
if there are no contraindications (see Chapter 2, Hypertension). rhea. As with alcohol intoxication, thiamine should be given IV
In contrast to chlordiazepoxide and diazepam, lorazepam or IM at 100 mg daily for at least 3 days to prevent precipitation
and oxazepam are not metabolized into active compounds in of an acute Wernickes encephalopathy, although some guide-
the liver. Instead, they are excreted by the kidneys following lines recommend higher doses (250 mg daily parenterally for
glucuronidation. This is important because many alcohol- 3 to 5 days) for patients with signs of malnutrition or a history
dependent patients have compromised liver function. Therefore, of not eating properly.19 Still higher doses of thiamine (500 mg
when treatment is initiated before the results of blood tests for three times daily parenterally for at least 2 days followed by
liver function are known, as is often the case in outpatient clin- 250 mg IM or IV daily for 5 days) have been recommended to
ics, lorazepam and oxazepam may be preferred. Patients with treat suspected or diagnosed cases of Wernickes encephalopathy
liver disease may still be treated with diazepam and chlor- and to prevent the development of Korsakoffs syndrome.19 In
diazepoxide, but at lower doses. This can be accommodated with addition, thiamine administration should always precede
the loading technique, although hourly dosing with 5 mg of administration of any dextrose-containing IV uids.
diazepam or 25 mg of chlordiazepoxide may be sufcient.
Oxazepam is available in oral form only, so it is useful only Alcohol Withdrawal Delirium (Delirium Tremens or DTs)
for uncomplicated withdrawal. Other benzodiazepines are Deterium tremens is another medical emergency that requires
available in injectable form and will be further described hospitalization in order to prevent mortality. Parenterally
below. Diazepam and lorazepam are more lipophilic than administered benzodiazepines are the treatment of choice.20 A
chlordiazepoxide and oxazepam, resulting in quicker gas- sample regimen consists of diazepam 5 mg IV (at 2.5 mg/minute)
trointestinal absorption and passage across the bloodbrain every 5 to 10 minutes until light somnolence is achieved, refer-
barrier, which makes them valuable in an inpatient setting, ring to a tendency to fall asleep without stimulation or a light
especially to treat or prevent seizures. However, their faster stage of sleep from which the patient is easily awakened. If the
onset of action may be associated with feeling high, which can rst two doses of diazepam are not effective, then 10 mg IV every
be a disadvantage of their use. 5 to 10 minutes can be administered for the third and fourth
doses. If still not effective, then up to 20 mg IV may be used
Alcohol Withdrawal Seizures thereafter. Once a state of light somnolence is induced, then
Alcohol withdrawal seizures (AWS) are a medical emergency it should be maintained with diazepam 5 to 20 mg IV every
and should be treated in an inpatient setting. Withdrawal 1 hour as needed. Similarly, lorazepam 1 to 4 mg IV every 5 to
seizures are usually few in number and generalized. The 10 minutes or lorazepam 1 to 4 mg IM every 30 to 60 minutes
occurrence of focal seizures or status epilepticus may suggest may be given to achieve light somnolence, which is then main-
another etiology. Management consists of keeping the airway tained by similar doses every hour as needed. The antipsy-
open and preventing self-injury during convulsions. chotic haloperidol is given only for severe agitation that is
unresponsive to benzodiazepine therapy. The evidence does not underlying medical problems should be evaluated for possible
support the use of an antipsychotic as a single agent.20 triage to an inpatient detoxication program, to be followed
Haloperidol may be given as 0.5 to 5 mg IV or IM every 30 to up with substance abuse treatment on either the inpatient or
60 minutes as needed or 0.5 to 5 mg orally every 4 hours as outpatient level. Rapid referral to substance abuse treatment
needed. The newer-generation antipsychotic agents have not will help seize the moment and introduce patients to the
been studied yet for the treatment of DTs. Thiamine should be concept of recovery while they still vividly remember the neg-
given according to the same guidelines described above for AWS. ative consequences from abusing substances. Withdrawal from
opioids is commonly described by patients as resembling a
Alcohol Hallucinosis bad case of the u and symptoms include nausea, vomiting,
Alcohol hallucinosis refers to auditory hallucinations that diarrhea, anxiety, headaches, mydriasis, rhinorrhea, lacrima-
occur during a clear sensorium, which distinguishes it from tion, muscle/bone/joint pain, piloerection, yawning, fever,
DTs, during which hallucinations are associated with a increased heart rate, and hypertension. The use of clinical
reduced clarity of awareness of the environment. Alcohol hal- withdrawal scales such as Clinical Opiate Withdrawal Scale
lucinosis is generally treated with oral antipsychotics at usual (COWS),21 provides high interrater reliability and clinical util-
therapeutic dosages for psychosis. ity since it is an objective measurement of withdrawal severity.
See Table 335 for a copy of the COWS instrument. The base-
line score helps to make the decision to treat pharmacologically
Stimulant Withdrawal (Cocaine Withdrawal and
or to observe. A score of less than or equal to 5 is considered
Amphetamine Withdrawal)
very mild, and these patients usually do not require pharma-
Cocaine and amphetamine withdrawal are grouped together cologic intervention, although they benet from supportive
because their symptom proles as described in DSM-IV-TR8 environment and observation. A score of 5 to 12 is considered
are identical, and the physiologic basis of their withdrawal mild and 13 to 24 is moderate. Patients with scores in these
syndromes involves the DA neurotransmitter system. ranges should be managed with a symptom-based approach
Stimulants of this group also include methylphenidate, but not (Table 336) or initiation of buprenorphine induction/
nicotine and caffeine, which have different neurophysiologic detoxication. A score of 25 to 36 is moderately severe, and
mechanisms of action. Although neurophysiologic alterations greater than 36 is considered severe withdrawal. In severe with-
underlie the syndrome of stimulant withdrawal, its symptoms drawal either buprenorphine or a full agonist is recommended
are manifested psychologically for the most part as a depressed for detoxication. Methadone is the most commonly used full
or dysphoric mood. Consequently, the major adverse compli- agonist, but under current United States law, methadone detox-
cation of stimulant withdrawal is profound depression with ication requires referral to a federally approved methadone
suicidal thoughts, and the major goal of treatment is to prevent detoxication program. The two possible options for the treat-
suicide. Other symptoms that are commonly associated with ment of opioid withdrawal in regular clinical settings are symp-
the mood disturbance include fatigue, sleep disturbance, tomatic treatment and opioid agonists.
increased appetite, psychomotor retardation or agitation, Symptomatic treatment focuses on minimizing the with-
and/or vivid dreaming, although these symptoms are neither drawal symptoms to help patients be as comfortable as possible
life-threatening nor require pharmacologic treatment. (Tables 336 through 338). This is combined with the use of
Therefore, unless suicidality warrants hospitalization, stimu- methadone or buprenorphine (Suboxone or Subutex) to
lant withdrawal can be treated on an outpatient basis with psy- suppress the withdrawal symptoms by providing a opioid
chological support and reassurance. full or partial agonist in a tapering dose schedule within a
A number of medications have been studied to alleviate controlled environment.
symptoms of stimulant withdrawal and the intense craving that Treatment with a opioid agonist is accomplished with
may accompany it, but inconsistent results across controlled either buprenorphine or methadone. Buprenorphine is a partial
trials preclude any recommendations for their routine use. agonist at the opioid receptors that can be used sublingually. It
Patients with stimulant use disorders should be referred to sub- is available in three formulations, two of which are indicated for
stance abuse treatment because of the high risk for continued use the treatment of addiction. Buprenorphine plus naloxone
either during or immediately following stimulant withdrawal. (Suboxone) in ratio of 4:1 (2 mg/0.5 mg or 8 mg:2 mg) is the
recommended formulation unless the patient is pregnant or
hypersensitive to naloxone, in which case buprenorphine with-
Opioid Withdrawal
out naloxone (Subutex) is recommended. Naloxone was added
Almost no one dies from opioid withdrawal per se; however, to the Suboxone formulation to secure Food and Drug
underlying medical complications (e.g., hypertension or recent Administration (FDA) approval in the United States. Since
myocardial infarction) increase the risk of death. Therefore, it naloxone is poorly absorbed when used sublingually but blocks
is important to manage and stabilize any medical issues (i.e., opioid receptors if injected, this combination is designed to
uncontrolled blood pressure or diabetes, among others), and minimize diversion of the drug to the street for intravenous use.
then determine if hospitalization is appropriate. Patients with Only 10% of buprenorphine is bioavailable if it is swallowed, but
TABLE 335. Clinical Opiate Withdrawal Scale (COWS)
Patients Name:____________________________ Date and Time __/__/____:____

Reason for assessment:_________________________________________
Resting Pulse Rate: _____beats/minute GI Upset: over last _hour
Measured after patient is sitting or lying for 0 no GI symptoms
one minute 1 stomach cramps
0 pulse rate 80 or below 2 nausea or loose stool
1 pulse rate 81100 3 vomiting or diarrhea
2 pulse rate 101120 5 multiple episodes of diarrhea or vomiting
4 pulse rate greater than 120
Sweating: over past_hour not accounted for by Tremor: observation of outstretched hands
room temperature or patient activity 0 no tremor
0 no report of chills or ushing 1 tremor can be felt, but not observed
1 subjective report of chills or ushing 2 slight tremor observable
2 ushed or observable moistness on face 4 gross tremor or muscle twitching
3 beads of sweat on brow or face
4 sweat streaming off face
Restlessness: observation during assessment Yawning: observation during assessment
0 able to sit still 0 no yawning
1 reports difculty sitting still, but is able to do so 1 yawning once or twice during assessment
3 frequent shifting or extraneous movements of 2 yawning three or more times during
legs/arms assessment
5 unable to sit still for more than a few seconds 4 yawning several times/minute
Pupil size Anxiety or irritability
0 pupils pinned or normal size for room light 0 none
1 pupils possibly larger than normal for room light 1 patient reports increasing irritability or
2 pupils moderately dilated anxiousness
5 pupils so dilated that only the rim of the iris is 2 patient obviously irritable or anxious
visible 4 patient so irritable or anxious that
participation in the assessment is difcult
Bone or joint aches: if patient was having pain. Gooseesh skin
Previously, only the additional component 0 skin is smooth
attributed to opiates withdrawal is scored 3 piloerection of skin can be felt or hairs
0 not present standing up on arms
1 mild diffuse discomfort 5 prominent piloerection
2 patient reports severe diffuse aching of
joints/muscles
4 patient is rubbing joints or muscles and is
unable to sit still because of discomfort
Runny nose or tearing Not accounted for by Total Score:_____
cold symptoms or allergies The total score is the sum of all 11 items
0 not present
1 nasal stufness or unusually moist eyes Initials of person
2 nose running or tearing
4 nose constantly running or tears streaming completing assessment: _______________
down cheeks
50% is bioavailable via the sublingual route. An IM/IV prepara- of the particular opioid (the longer the half-life, the longer a clini-
tion of buprenorphine is available in the United States cian should wait before initiating buprenorphine induction).
(Buprenex), and its bioavailability reaches 80% if used IM The score on the COWS should be greater than or equal to 5,
and100% if used IV. The Buprenex formulation is indicated otherwise buprenorphine likely will induce withdrawal since
only for anesthesia and operative pain use, but not detoxication it has high afnity for receptors and it will displace any other
or maintenance of opioid dependence, due to the high risk for opioid agonist that is present. Also, buprenorphine should
abuse and diversion. not be used in those taking greater than 60 to 80 mg/day of
To initiate a buprenorphine induction, a patient has to be methadone because buprenorphine would have low efcacy;
suffering moderate or severe withdrawal, and the last opioid use the methadone dose should be decreased below this amount
should be at least 12 to 24 hours earlier, depending on the half-life prior to induction of buprenorphine detoxication. Once
TABLE 336. A Symptoms-Based Treatment Approach for TABLE 338. Sample Regimen of Clonidine for Withdrawal
Opioid Withdrawal from Methadone (Up to 2030 mg/day) or
Equivalent Fentanyl (Duragesic) Patches
This approach includes the use of any single or a combination of
two or more of the following agents, depending on the Day Clonidine Oral Dosage
symptoms reported:
1 0.1 mg four times daily
a) Clonidine (Catapres) 0.10.2 mg every 68 hours blocks the 2 0.1 mg four times daily to 0.2 mg three times daily
peripheral response and reduces anxiety (shaking, sweating, and 3 0.1 mg four times daily to 0.2 mg four times daily
piloerection). Patients may be given as-needed doses, maximum 410 Maintain on day 3 dose
dosage not to exceed 1.2 mg in 24 hours. BP should be moni- 11+ Decrease by 0.2 mg/day; reduce nighttime dose last
tored prior to each clonidine dose in the clinic. Hold if systolic
blood pressure is below 85 or diastolic is below 55 mm Hg. Developed by K. Brower and M. Karam-Hage.
Advantages and Limitations: Clonidine is a non-narcotic agent

that effectively reduces opioid withdrawal. However, lethargy,
craving, insomnia, and muscle pains are not as well treated as
other withdrawal symptoms, and supplemental medications are
is tapered down gradually to zero within 1 to 2 weeks (a 25%
often necessary. Patients with low blood pressure may require reduction per day is a general rule of thumb). Methadone, can
inpatient treatment. Avoid in pregnant patients; they can be also be used for opioid detoxication; however, in the United
treated with buprenorphine (Subutex, NOT Suboxone) or States this can be done only at a federally approved
methadone in a government-licensed program. methadone clinic. Methadone detoxication regimens will
b) Dicyclomine (Bentyl) at 20 mg orally every 812 hours up to
80 mg per 24 hours as needed for abdominal cramps.
not be covered here. The reader is referred to the literature for
c) Loperamide (Imodium) 2-mg capsules; use 2 capsules by additional information.22
mouth initially, then 1 capsule by mouth as needed for diarrhea
(max dose 4 capsules/day). General Patient Guidelines for Outpatient Opioid
d) Trimethobenzamide (Tigan) suppository 200 mg; one per rectum Detoxication
daily as needed for nausea or vomiting to help with stomach con-
tractions and cramping.
When treating opioid withdrawal with pharmacologic agents,
e) Non-steroidal anti-inammatory or analgesic medications patient safety is the highest priority. The rst step is to educate
(acetaminophen 500 mg1 g by mouth every 6 hours or patients about the course of withdrawal. Symptoms peak at
ibuprofen 600 mg by mouth every 8 hours or naproxen 600 mg around 5 to 7 days and may last up to 2 weeks. Patients also
by mouth) for general pain. need to be advised regarding the side effects of the drugs used
f) Benzodiazepines such as lorazepam (Ativan) by mouth 1 mg
every 68 hours or oxazepam (Serax) 1530 mg every 68
to treat detoxication. For instance, clonidine causes dizziness
hours to help with anxiety and sleep. from low blood pressure, sedation (which may impair driving
or operating heavy machinery), and dry mouth. There is also
Developed by K. Brower and M. Karam-Hage.
an overdose potential if clonidine is mixed with opioids or
other central nervous system (CNS) sedatives or antihyper-
withdrawal is established, buprenorphine can be started at 2 to tensives. The risk of these adverse events needs to be balanced
4 mg every 2 hours with a maximum recommended dose of 8 mg with potential benets. The side effects of buprenorphine
the rst day (Table 339). The next day, if the patient is still in include constipation (most commonly), sedation, and
withdrawal, the rst buprenorphine dose should be the total headaches. It should also be noted that there is a potential
amount required in the previous 24-hour period. Then the for serious overdose when buprenorphine is mixed with
dose can be increased gradually every 2 hours up to a maximum benzodiazepines or other sedative-hypnotics. The risk of
of 16 mg. By the third day the dose can be increased up to 32 mg
per day to achieve maximum relief of withdrawal symptoms
TABLE 339. Sample Regimena for Buprenorphine Induction
(see Table 339 for a typical induction regimen). Then the dose
Treatment of Opioid Withdrawal
Day Buprenorphine Oral Dosage

TABLE 337. Sample Regimen of Clonidine for Withdrawal
from All Opioids Except Methadone and 1 2 mg every 2 hours (max 8 mg on rst day)
Fentanyl (Duragesic) Patches 2 Start by total dose of day 1, with additional 2 mg every
2 hours (max 16 mg)
Day Clonidine Oral Dosage 3 Start by total dose of day 2, with additional 4 mg every
2 hours (max 32 mg)
1 0.1 mg four times daily 45 Maintain on dose required to alleviate withdrawal
2 0.1 mg four times daily to 0.2 mg three times daily symptoms
35 Maintain day 2 dose as tolerated 6+ Decrease dose by 25% each day (or less if patient does
6+ Decrease dose by 0.10.2 mg/day; reduce nighttime not tolerate 25%)
dose last
a
For withdrawal from any opioid including fentanyl (Duragesic) patches.
Developed by K. Brower and M. Karam-Hage. Data from reference 21.
developing physiologic tolerance to buprenorphine is high if are affected by nicotine including DA, NE, 5-HT, glutamate,
it is used for prolonged periods. In this case buprenorphine GABA, and endogenous opioid peptides. In the brain, nicotine
should be slowly tapered to discontinuation. However, with- activates nicotinic acetylcholine (nAch) receptors, which are
drawal from buprenorphine is easier and less severe than part of the neurotransmitter-gated ion channel family and have
withdrawal from a pure agonist such as methadone. crucial neuromodulatory roles in the CNS.26 Nicotine depend-
Successful transition from treatment of withdrawal to treat- ence is assessed using the Fagerstrm Test for Nicotine
ment of opioid dependence in a rehabilitation setting is the most Dependence, and a score of greater than or equal to 4 is indica-
important challenge for a clinician. Patients often think that all tive of physical dependence on nicotine.27 Nicotine withdrawal
they need is detoxication, but this is not the case because a suc- can be measured using any of the available scales (e.g., the
cessful outcome is tied to successful rehabilitation and acquiring Wisconsin Scale for Nicotine Withdrawal). In the United States,
recovery skills after detoxication. This goal can be accom- the FDA does not have the authority to regulate tobacco prod-
plished by either achieving detoxication on site during rehabil- ucts; however, it does regulate all NRT formulations. Some of
itation or by quick and seamless transition of the patient from the NRTs are prescription only (Rx), and some are available
detoxication to a rehabilitation program. The more time that over the counter (OTC); others are available in both forms. The
elapses between the two, the greater the likelihood of failure and FDA has approved the following NRTs: polacrilex gum (OTC);
return to drug use. This transition is especially important for patches (16- or 24-hour) (Rx and OTC); nasal spray (Rx); buc-
patients who have engaged in ultra-rapid opioid detoxication cal inhaler (puffer) (Rx); avored gum (OTC); and lozenges
using naltrexone or naloxone under conscious sedation. These (OTC). Table 3310 shows NRT and other smoking cessation
opioid detoxication regimens are experimental and controver- products. Non-nicotine medications that are thought to be
sial and they are currently considered to be risky procedures due helpful for craving and maybe even withdrawal from nicotine
to several reported deaths mainly due to pulmonary edema.23 include sustained-release bupropion (Zyban or Wellbutrin-
SR), nortriptyline (Pamelor), clonidine (Catapres). The
sustained-release form of the antidepressant bupropion was
Nicotine Withdrawal
approved by the FDA with a new name (Zyban) for the treat-
Smoking cessation counseling should be provided to all smok- ment of tobacco dependence. It is started 1 to 2 weeks before
ers, and those interested should be directed and assisted to the quit date. It is begun at 150 mg per day for 3 to 7 days and
achieve cessation. Furthermore, it is now a standard of practice then increased to 300 mg/day (150 mg twice daily). Bupropion
for clinicians to screen for smoking and provide all smokers with blocks reuptake of DA and NE. Additionally, it acts as a non-
brief advice and assistance with appropriate medications to quit competitive antagonist on a high-afnity nAch receptor. It
or provide referral to specialized services when needed.24 reduces nicotine reinforcement, withdrawal, and craving.28
Symptomatic detoxication from nicotine is achieved with Doubling up the NRTs (i.e., double patch or adding NRTs to
any of the currently available nicotine replacement therapies each other) is a more effective strategy for certain refractory
(NRTs) or a combination thereof.25 Several CNS neurotransmitters smokers than either strategy used alone.29 Studies have also
TABLE 3310. Pharmacotherapies for Smoking Cessation
Medication Dose Range and Use

Nicotine patch 722 mg/day (started at 21 mg per day 2 weeks then
Transdermal 14 mg per day 2 weeks then 7 mg/day)
Nicotine gum 2040 mg/day; 2 or 4 mg/piece; one piece every 2 hours up to
Buccal 10 times/day
Nicotine lozenge 2040 mg/day; 24 mg/lozenge; one lozenge every 2 hours,
Buccal up to 10 times/day
Nicotine nasal spray 1632 mg/day; 12 mg/spray, one in each nostril up to 16 times/day
Intranasal
Nicotine vapor inhaler 616 mg/day; continuous pufng up to 10 puffs per cartridge
Buccal maximum of 12 cartridges daily (approx. 120 puffs)
Bupropion Begin at 150 mg/day 37 days then 300 mg/day in twice-per-
Oral tablets day dosing
Clonidine 0.61.2 mg/day, 23 times/day
Oral tablets
Tricyclic antidepressants Given by mouth once daily or in two divided doses
Nortriptyline 75150 mg/day
Doxepin 150250 mg/day

suggested that NRTs are safe in certain high-risk patients and the 6-month efcacy ranges between 20% and 25%. Not
such as those with cardiac diseases (i.e., postmyocardial every smoker requires the same amount of intervention.
infarction) and pregnant smokers, as long as the risk/benet One of the possible future directions in smoking cessation
ratio is favorable. is the controversial notion of substituting smokeless tobacco
Second-line pharmacotherapies include nortriptyline and for cigarettes. The idea is based on the premise that the expo-
clonidine. Clonidine exhibits modest efcacy in smoking sure to most carcinogens in tobacco is a result of formation by
cessation trials, and two meta-analyses that included a total pyrolysis during the combustion of tobacco. This approach
of 13 placebo-controlled clinical trials indicate that it is has not been embraced widely by public health and anti-
superior to placebo, with odds ratios of 2.4 (1.7 to 32.8) and tobacco advocates because certain diseases are more prevalent
2.0 (1.3 to 3.0).30 Several tricyclic antidepressants (TCAs), in users of smokeless tobacco such as gum disease (i.e., gin-
that inhibit the reuptake of NE and 5-HT, such as nortripty- givitis), and oral (mouth and lip) cancers. Among the differ-
line, might facilitate smoking cessation, either alone or in ent types of smokeless tobacco some products may be safer
combination with behavioral treatment. However, TCAs than others, such as the Swedish Snus (widely available in
have signicant disadvantages, including a signicant anti- Sweden and available OTC in some states in the United States).
cholinergic burden, cardiac side effects, and possible lethality These contain air dried and processed tobacco that eliminates
in overdose.31 most nitrosamines that are produced by bacterial fermentation
of tobacco and constitute a major group of carcinogenic sub-
Nonpharmacologic Treatments stances present in tobacco. Other potentially promising devel-
for Tobacco Cessation opments in different phases of testing25 include:
Behavioral treatment delivered by a variety of clinicians (e.g., Cannabinoid receptor CB1-blockers, such as rimonabant
physician, psychologist, nurse, pharmacist, and dentist) (under FDA review)
increases abstinence rates. The ve As should be applied by all A combination of the nicotine antagonist mecamylamine
clinicians:24 and bupropion (Quitpack)
A nicotine partial agonist (Chantix by Pzer)
Ask if they smoke Nicotine vaccine
Advise to quit
Assess motivation for change
Assist if willing to change
Arrange for follow-up GENERAL APPROACH TO THE TREATMENT OF
SUBSTANCE DEPENDENCE
The Department of Health and Human Services, in con-
cert with other public health and federal government agen- The overall goals in recovery from addiction are the same for
cies, has provided general guidelines for smoking cessation24 all substances and they consist of:
(Table 3311).
There are in excess of 100 studies validating the use of mul- Developing coping skills: establish a balanced lifestyle
timodal behavioral therapies for smoking cessation, either between stressors and positive healthy rewards
alone or in combination with pharmacologic therapies. Developing a sober social network: this can be through
Multimodal behavioral therapies without pharmacologic 12-step programs or other mutual self-help resources
agents achieve double the quit rates compared with controls, Relapse prevention skills and strategies: the recovering
addict should develop a menu of options, a toolbox of cop-
TABLE 3311. General Guidelines on How To Assist if a ing skills
Patient Wants to Quit Smoking Addressing and beginning to process prior histories of inter-
personal problems, conicts, and abuse
Start bupropion-SR (Zyban or Wellbutrin SR) 12 weeks before Searching for a spiritual meaning for ones life
quit date.
Help patient set a quit date (one of the most important strategies).
Remove all tobacco products the night before the quit date. All of the above correlate with better long-term outcomes.
Follow-up with patient on the quit date or next day to support
self-efcacy.
To facilitate recovery from addiction it is necessary to utilize
Provide nicotine replacement: patch, nasal spray or mouth inhaler, a comprehensive biopsychosocial assessment that includes the
gum, or lozenge. motivation for change. Pharmacologic treatments are always
Identify and help educate a support person (best if ex-smoker). adjunctive to psychosocial therapy. It is important to remember
Educate about the high risk for relapse and how to cope with it: that mere treatment of withdrawal is not sufcient treatment of
dont quit quitting.
DSM-IV-TR dependence (addiction), and that medications are
Data from reference 24. always adjunctive to psychosocial therapy. Comorbid psychiatric
conditions such as anxiety, depression, insomnia, pain, and con- shame and guilt; minimizing isolation; and providing peer
tinued smoking should be addressed. All of these conditions acceptance and role modeling, realistic feedback, and opti-
increase the risk of relapse to use of drugs. Special precautions mism and hope for the future. The disadvantages are a lack of
are needed when treating dual diagnosis and chronic pain focus on a particular persons problem, the discussion is not
patients with controlled substances. always pertinent to every member, and scheduling times are
inexible. It is also less successful in small communities where
people might know each other prior to formation of the
group, and/or for people with certain personality disorders
While pharmacologic agents may help prevent relapse, such as borderline, schizoid, avoidant, or paranoid.32
psychotherapy should be the core therapeutic intervention.
Motivational enhancement therapy, cognitive-behavioral ther-
apy, 12-step facilitation, and contingency management are the
best-studied forms of psychotherapy in this group of patients.
Maintenance Treatment
Certain pharmacologic agents have been helpful in the
Individual Therapy
treatment of withdrawal and in drug maintenance programs.
Traditional psychodynamic therapy in the treatment of addic-
Remaining sober following the treatment of withdrawal is
tion often fails; however, the principles of psychodynamic
extremely difcult. This is probably related to a complex inter-
therapy are still valuable and important for a clinician in order
action of biological factors (craving), social factors (lack of
to understand the patient and help him or her work through
employment or lack of a sober social network), and psycholog-
his or her mechanisms of defense, attachment difculties,
ical factors (lack of the ability to cope with negative emotions
processing grief, and coping with internal and external
without resorting to drug use). Long-term use of medications
drives.32 Among the validated and thoroughly studied
to help achieve a reduction in drug craving or to maintain a
approaches are the following:
steady state of legally supervised and predictable drug use may
have a better long-term outcome than immediate abstinence.
Enhancing motivation, known as motivational interviewing
The ultimate goal is always abstinence, but these strategies
or motivational enhancement therapy, is designed to engage
may allow time to develop new behavioral strategies and a
patients with basic principles like expressing empathy, high-
social network within which the patient will be more likely to
lighting the discrepancy between patients ideals and their
achieve long-term sobriety.
current behavior, and working within the framework of a
specic patients defenses.
Alcohol Dependence
The development of coping skills is designed to help patients
Currently the three FDA-approved medications that are indi-
cope with life events, daily stressors, and managing painful
cated to treat alcohol dependence are disulram, naltrexone, and
affects.
acamprosate. Both disulram and acamprosate are indicated in
Cognitive-behavioral therapy (CBT) has the specic goal of
patients who have already achieved initial abstinence. Only nal-
learning relapse prevention techniques such as having a ready
trexone may be initiated without regard to abstinence status.
toolbox to deal with cravings and avoidance of triggers that
have led to relapses in the past. Disulram
Contingency management consists of providing positive Disulram works by irreversibly blocking the enzyme aldehyde
rewards for desirable behavior and setting limits and conse- dehydrogenase, a step in the metabolism of alcohol, resulting in
quences for undesirable behavior. increased blood levels of the toxic metabolite acetaldehyde. As
Improving interpersonal functioning and enhancing social levels of acetaldehyde increase, the patient experiences decreased
supports can be accomplished through 12-step facilitation blood pressure, increased heart rate, chest pain, palpitations,
(TSF), or any other mechanism for developing a sober social dizziness, ushing, sweating, weakness, nausea and vomiting,
network. headache, shortness of breath, blurred vision, and syncope.
Finally, engaging the spouse or signicant other, as well as the These effects are commonly referred to as the disulram-ethanol
nuclear family, is a very important aspect in the initial stages, reaction. Their severity increases with the amount of alcohol
as well as in consolidating recovery. that is consumed, and they may warrant emergency treatment.
Disulram is contraindicated in patients who have cardiovascu-
Group Therapy lar or cerebrovascular disease, because the hypotensive effects of
Group therapy for substance abuse/dependence includes the disulram-alcohol reaction could be fatal in such patients or
more than three people (ideally 8 to 10) who interact in the in combination with antihypertensive medications. Disulram
same room for 90 to 120 minutes. Group therapy provides is relatively contraindicated in patients with diabetes, hypothy-
patients with the opportunity to bond with others; and the roidism, epilepsy, liver disease, and kidney disease as well as
advantages of this can be mutual identication; dealing with impulsively suicidal patients.
Psychologically, disulram works through negative reinforce- should be warned accordingly. See Table 333 for additional
ment, and drinking is avoided to prevent the aversive disulram- drug-drug interactions with disulram.
ethanol reaction. The classic study by Fuller and colleagues
demonstrated that the efcacy of disulram was compromised Naltrexone
by non-compliance.33 Although that randomized controlled trial Naltrexone is a competitive opioid antagonist, especially at
is widely cited as a negative study, because no difference between opioid receptors, that decreases alcohol intake in both animals
the three groups (disulram 250 mg daily, disulram 1 mg daily, and humans. There is evidence that it works by decreasing both
and a no disulram condition) was found for continuous absti- craving for alcohol and alcohol-induced euphoria. The large
nence rates over a 1-year follow-up period, the 250-mg group majority of over 15 double-blind randomized controlled trials
drank on signicantly fewer days (49 days) during that 1-year of naltrexone versus placebo demonstrate its moderate efcacy
period than the other groups (75.4 and 86.5 days for the 1-mg for decreasing relapse to heavy drinking,36 but not for increas-
disulram and no disulram groups, respectively). Other con- ing rates of total continuous abstinence. The usual therapeutic
trolled trials have demonstrated that disulram can be highly dose of naltrexone is 50 mg orally per day, with a range from 25
effective when procedures for enhancing compliance are to 100 mg. The 25-mg dose is commonly given initially as a test
employed, such as supervised administration.34 This may be dose to minimize side effects, especially nausea, and then
particularly true when supervised administration is coupled increased to 50 mg daily as tolerated. An alternative dosing
with receiving incentives, such as described above for contin- regimen is 100 mg on Mondays, 100 mg on Wednesdays, and
gency management techniques, behavioral couples therapy 150 mg on Fridays, which is most conducive for patients taking
(BCT), and the community reinforcement approach. naltrexone under conditions of supervised observation.
The usual starting dose of disulram is 250 mg orally per Because naltrexone can precipitate withdrawal in patients
day, and the range is 125 to 500 mg daily. Compared to 250 mg dependent on opioids, the rst dose should be withheld for 7 to
daily, the larger dose is recommended in the absence of a 10 days following the last use of opioids and only when the urine
disulram-ethanol reaction, and the smaller dose is given drug screen for opioids is negative. Also, naltrexone can be hepa-
when intolerable side effects are experienced. Dosing begins totoxic, albeit not typically at doses less than 250 mg daily.
only after the BAL is zero (usually 12 to 24 hours after the last Nevertheless, the same guidelines for monitoring liver function
drink) and after the patient understands the consequences of tests as with disulram (described above) are recommended. The
the disulram-ethanol reaction. The most common side most common side effects are nausea, headache, fatigue, and
effects are rash, drowsiness, metallic or garliclike taste, and nervousness. It is important for patients to carry a pocket warn-
headache. If drowsiness occurs, the dose may be lowered or ing card or wear a warning bracelet in the event that emergency
given at night. Other adverse effects include optic neuritis and treatment is needed, because they will be insensitive to opioid
peripheral neuropathy. Because of potential hepatotoxicity analgesia unless toxic doses are administered. Patients need to be
with disulram including rare cases of fulminant liver failure, warned of the potential for an opioid overdose under two dif-
estimated at 1 in 25,000 treated patients,34 baseline liver func- ferent conditions. First, dosing with opioids to reverse opioid
tion tests (LFTs) and periodic monitoring are recommended. insensitivity (i.e., naltrexones competitive blockade of opioid
If serum levels of alanine aminotransferase (ALT) or aspartate receptors) requires very high doses of opioids that can cause res-
aminotransferase (AST) are greater than three times normal piratory depression and death. Second, chronic antagonist
values, then disulram should be withheld and the tests therapy with naltrexone may cause patients to become hyper-
repeated every 1 to 2 weeks until they are normal. Once LFTs sensitive to opioid drugs after stopping naltrexone, thereby facil-
are within prescribing range, they may be repeated every 1 to itating respiratory depression and death when opioids are used.
6 months. Although elevated LFTs may signal disulram- Reported predictors of naltrexone efcacy include a family
induced hepatotoxicity, the more likely cause in clinical prac- history of alcoholism, early age at onset of drinking problems,
tice is non-compliance and ethanol-induced hepatotoxicity. high levels of the active metabolite -naltrexol, and medica-
Alcohol-dependent patients are also at high risk for viral hep- tion adherence.37 Combining naltrexone with disulram had
atitis. Another uncommon side effect of disulram is psy- no advantage over either medication alone in one study of
chosis, which has been reported in doses exceeding 500 mg alcohol-dependent patients with comorbid psychiatric disor-
daily, especially in predisposed patients. Nevertheless, alcohol- ders.35 Combining naltrexone with acamprosate is discussed
dependent patients with schizophrenia and other co-occurring below in the section on acamprosate. Combining naltrexone
mental disorders have received disulram at usual therapeutic with CBT possibly may have an advantage over combining
doses without difculties.35 naltrexone with other psychotherapies.38 Long-acting intra-
The disulram-ethanol interaction is described above. muscular forms of naltrexone designed for once-monthly
Depending on the dose of disulram, sensitivity to disulram, administration have been efcacious on some measures of
amount of alcohol consumed, and metabolism, patients may drinking in randomized controlled trials.39
be at risk to have an adverse interaction with alcohol for 2 to Naltrexone can theoretically increase the risk of hepato-
14 days after stopping disulram (5 days on average) and toxicity if combined with disulram, although in practice this
was not demonstrated.35 As mentioned above, it can reverse Finally, a recent meta-analysis of antidepressants to treat alco-
the effects of opioid receptor agonists, rendering them ther- hol dependence with or without comorbid depression con-
apeutically ineffective. Finally, somnolence and lethargy cluded that any benecial effects were modest at best.44
have been reported in combination with the antipsychotic
thioridazine. Stimulant Dependence
There are no proven pharmacotherapies for treatment of
Acamprosate cocaine or amphetamine dependence. Disulram, however,
Acamprosate is an NMDA receptor antagonist that was shows some promise in randomized controlled trials for treat-
approved by the FDA in 2004, but it has been available in ing cocaine dependence at doses of 250 mg daily, especially in
Europe for nearly 20 years. Alcohol use acutely inhibits combination with CBT.45 Its mechanism of action for treating
NMDA receptors and chronically causes upregulation of cocaine dependence is not known, but may be due to its inhi-
NMDA receptors. During alcohol withdrawal and postacute bition of the dopamine -hydroxylase enzyme that converts
alcohol withdrawal, increased activity of the NMDA system is DA to NE in the brain. The resulting increase in DA levels may
caused by upregulation of receptors and the absence of alcohol- counter the DA-decient state that is believed to underlie
related inhibition. Acamprosate is believed to modulate and cocaine withdrawal and craving.
normalize the NMDA receptor system, although it is ineffec-
tive in diminishing acute withdrawal symptoms. It may also Opioid Dependence
have some GABA-enhancing activity. In certain patients who have failed one or more abstinence-
The efcacy of acamprosate has been extensively reviewed.40 based treatments for opioid dependence, maintenance treat-
In contrast to both disulram and naltrexone, acamprosate ment might be the best possible option.
increases continuous abstinence rates in alcohol-dependent After the conclusion of withdrawal, some patients still
patients for periods of 3 to 12 months.40 Preliminary evidence dont feel their usual selves for a long time and may relapse to
suggests that combining acamprosate and naltrexone may be using drugs again, just to feel normal. Long-term use of opi-
more effective than using either one alone, and a large-scale oids results in changes in the brain and the brain might not
randomized controlled trial to confirm the efcacy of the com- readily return to its prior homeostasis. Since the goal of treat-
bination was recently completed and will be published soon.41 ment is to encourage stability, both in the body and in the
Project COMBINE also compared medical management alone patients life, if an individual is not successful in tapering off
to medical management in combination with a combined of opioids because of a re-emergence of severe withdrawal or
behavior intervention (consisting of elements from CBT, a return to opioid use, then maintenance treatment should be
MET, and TSF). Combining acamprosate with disulram may considered.
also increase its efcacy.42
The therapeutic dose of acamprosate is 666 mg orally three Opioid Agonists
times daily, and it is supplied as a 333 mg tablet. It can be The time-honored opioid agonist treatment for opioid depend-
started at the full dose in most patients without titration. It dif- ence is methadone maintenance, which is beyond the scope of
fers from disulram and naltrexone in that it is excreted by the this chapter. In the United States methadone maintenance can-
kidneys without liver metabolism. Consequently, it is contraindi- not be provided except in ofcially designated and approved
cated in patients with severe renal impairment (creatinine clear- methadone clinics. The more recent development of the Ofce-
ance less than or equal to 30 mL/minute), and dose reduction Based Opioid Treatment (OBOT) exclusively utilizes buprenor-
is necessary when the creatinine clearance is between 30 and phine, a partial agonist.21 The effective maintenance dose of
50 mL/minute. The most common side effects are gastroin- buprenorphine (Suboxone) is usually between 8 and 16 mg per
testinal and include nausea and diarrhea. Rates of suicidal day, with maximum reported efcacy at 64 mg per day. Patients
thoughts were also increased in patients treated for 1 year with receiving buprenorphine maintenance should sign a treatment
acamprosate (2.4%) versus placebo (0.8%). If necessary the contract requiring full compliance, nancial responsibility for
total daily dose may be decreased by 1 to 3 tablets (333999 mg) treatment, adherence to ofce policies, respectful behavior to
per day to alleviate side effects. staff, agreement to provide random urine samples for drug
Naltrexone can increase blood levels of acamprosate by screens, and patients should bring their bottles for pill counts at
increasing its absorption, but the clinical signicance of this is every visit. In the event of failure of OBOT, the alternative to
not known. buprenorphine maintenance is a referral to an approved
methadone clinic where methadone is used at minimal effective
Other Agents doses of 80 mg per day or higher. Under the provisions of the
Anticonvulsants, especially topiramate, and serotonergic drugs, OBOT law physicians may prescribe buprenorphine (Suboxone
especially ondansetron, show promise in initial, but well- or Subutex) in their ofce if they meet requirements of expert-
designed, randomized controlled trials.43 Further studies are ise in the area of substance abuse or if they receive 8 hours of
needed. Buspirone is well studied, but results are inconsistent. approved training.21 In either case a registration with the Drug
respirations, and body temperature as well as mental state.

Patient Encounter 3 Choose from a number of validated and standardized rating
scales to monitor the responsiveness of withdrawal syn-
dromes to medical treatment. To determine the overall effec-
tiveness of your health system for the treatment of substance
PC, a 19-year-old man, has undergone detoxication of his
abuse and dependence, you could monitor outcomes using
3-bags-per-day addiction to heroin. The detoxication regi-
men began when he had been heroin-free for 24 hours and sentinel events such as the rates of cardiopulmonary arrest,
was undergoing some mild withdrawal symptoms. He was seizures, discharges against medical advice, patient violence,
begun on 8 mg daily of sublingual buprenorphine, and the and use of physical restraints. The ultimate goal should be to
dose of buprenorphine was slowly tapered off during the enable the transition of patients to formal substance abuse
next 4 weeks. He had begun snorting heroin at about 15 treatment when indicated, because this is the optimal out-
years of age and eventually had progressed to injecting his come of treatment for substance-induced intoxications and
daily heroin. He dropped out of high school at 17 years of withdrawals.
age, prior to graduation, and has never worked, except A major component of successful treatment of addiction is to
once in a fast food restaurant for a 2-week period. Since continue monitoring the use of medications such as disulram,
achieving abstinence he has come to realize that he has no
naltrexone, or acamprosate designed to decrease craving or to
legal means of earning a living and he is reluctant to return
block the hedonic effects of abused substances. Also, it is impor-
home to his parents since they have recently divorced. He
feels he is worthless and has wasted his life up to now. tant to identify a mechanism for long-term support of sobriety
that might be appropriate for a specic individual such as
What are the most immediate concerns regarding this Alcoholics Anonymous, a spiritual group, or professional recov-
young mans newly achieved abstinence? ery programs for professionals such as doctors, nurses, and
How can he be helped to maintain abstinence? police ofcers.
What are the long-term treatment goals for this young man? Important outcome indicators to evaluate postintoxication
and/or postwithdrawal treatment of substance abuse and
dependence can be divided into three major groups:
Enforcement Administration (DEA) to obtain a specially desig- decreased consumption of substances, decreased problems
nated DEA number is needed after receiving a waiver. associated with substance use, and increased psychosocial
functioning. Although it is less commonly employed, a
Opioid Antagonists quality-of-life scale can help determine how substance
Naloxone, naltrexone, and nalmefene (not available yet in the abuse/dependence treatment has affected your patients
United States for clinical use) can be used to reinforce absti- lives. If you are involved in the cost-justication of serv-
nence. The long-acting naltrexone is especially ideal for health ices, a cost-benet analysis could also become important,
professionals or others who are highly motivated or face although this is more often used at the administrative level,
major consequences if they do not maintain their abstinence. rather than the patient care level. In the cases in whom
It is important not to initiate an antagonist until the with- complete abstinence has not been achieved, quantify the
drawal period is over and after 7 to 12 days from the last use consumption of substances using: quantity-frequency
of opioid agonists. This is necessary to avoid precipitating measures; rates of abstinence; and time to rst relapse as
more severe withdrawal due to hypersensitive or up-regulated determined by interviews and self-report, and by biologi-
opioid receptors as a result of prior long-term or heavy use of cal markers such as urine and blood tests. One example of
opioid agonists. Naloxone can be used 0.2 to 0.4 mg subcuta- an instrument to measure alcohol-related problems is The
neously (naloxone challenge) to test if an individual is indeed Drinker Inventory of Consequences.46 Another scale that
abstinent and to make sure it does not induce withdrawal before you could use to determine the severity of alcohol-related
giving the longer-acting oral naltrexone, although this technique problems is the Addiction Severity Index, which measures
is rarely used in actual practice. Most opioid-dependent patients problems associated with any type of substance depend-
will be honest about how recently they have used when (1) they ence across a variety of dimensions, including legal, fam-
understand that severe withdrawal is a consequence of prema- ily, psychiatric, medical, and social.47 If you are concerned
ture naltrexone administration, and (2) a urine test is obtained. about the effects of substance abuse or dependence on
cognitive abilities in an older adult, the Mini-Mental State
Exam is a commonly used scale. Scores of 26 and higher
OUTCOME EVALUATION are generally considered to indicate acceptable cognitive
ability with regard to everyday functioning.48 Quantify
To determine immediate treatment outcomes for intoxica- overall psychosocial functioning using the Global
tion and withdrawal syndromes at the individual patient Assessment of Functioning Scale which is readily accessi-
level, evaluate parameters such as blood pressure, heart rate, ble in DSM-IV-TR.8
Patient Care and Monitoring the severity of withdrawal. A score greater than or equal
to 15 merits strong consideration of inpatient treatment
combined with medications. Those with a score of 20 or
greater should always be treated in an inpatient setting
1. By evaluating the patients history and symptoms, deter- with medications.
mine if substance intoxication or withdrawal are likely. Always treat AWS or DTs in the inpatient setting. The
drug of choice for both is a benzodiazepine.
2. If drug intoxication is a likely scenario:
Withdrawal from opioids is uncomfortable but unlikely
Conduct a physical exam and measure blood pressure,
to be fatal unless the patient has underlying medical
pulse, respiratory rate, and body temperature.
problems. Administer the COWS to determine the severity
In most cases, management of intoxication is supportive.
of withdrawal. Those with a score of 5 or less require no
The most important goal is to maintain cardiopulmonary
pharmacologic intervention, while those with scores
function. If consciousness is impaired, obtain blood
from 6 to 24 are likely to benet from either a symptoms-
chemistries and administer intravenous glucose and
based approach or the initiation of buprenorphine. Those
thiamine (100 to 250 mg).
with scores greater than 25 should receive either
Cocaine or stimulant intoxication may require adminis-
buprenorphine or an alternative full agonist.
tration of a small dose of a short-acting benzodiazepine
(e.g., lorazepam 1 to 2 mg) for agitation or severe anxiety. 4. Withdrawal from nicotine is treated in the outpatient set-
Antipsychotics (e.g., haloperidol 2 to 5 mg) should be ting. Symptomatic detoxication from nicotine is achieved
used only if psychosis is present. If hyperthermia is with any single or combination of NRTs. Additional non-
present, initiate cooling measures. nicotine medications such as bupropion, nortriptyline, and
Observe the patient until the intoxication has resolved [if clonidine may be helpful to reduce craving and various
alcohol, the BAL should be less than 80 mg% (0.08% or other withdrawal symptoms. Including a behavioral therapy
17.4 mmol/L)]. Encourage the patient to consider treat- component increases abstinence rates when combined
ment for substance abuse, especially if this is not the with pharmacologic treatment.
rst episode of intoxication. 5. The overall goals in recovery from addiction are the same
3. If substance withdrawal is the likely scenario: for all substances and include improved coping skills and
Determine from which substance or substances the patient relapse prevention. Methods for accomplishing long-term
is withdrawing. sobriety include both nonpharmacologic and pharmaco-
Conduct a physical exam to determine if medical logic means.
problems are present. Consider initiation of buprenorphine or methadone
If withdrawal is from alcohol, administer the CIWA-Ar to maintenance treatment for opioid dependence. In the
determine withdrawal severity. A score of 8 to 10 United States buprenorphine is easier to arrange since
denotes relatively mild withdrawal, and the patient can physicians can be approved to prescribe buprenorphine
be treated as an outpatient with supportive care only. A following a short course of federally-approved training.
score from 11 to 14 can be treated on either an outpa- Disulram (250 mg per day) can be used to promote
tient or inpatient basis, with either supportive care or abstinence from alcohol. Acamprosate and naltrexone can
with benzodiazepines, depending on the presence of be used to decrease craving for alcohol, but they are not
underlying medical problems and the prior history of likely to result in complete abstinence from alcohol use.
ABBREVIATIONS DEA: Drug Enforcement Administration

DSM-IV-TR: Diagnostic and Statistical Manual of Mental
ALT: alanine aminotransferase Disorders, Fourth Edition, Text Revision
AST: aspartate aminotransferase DTs: delirium tremens
AWS: alcohol withdrawal seizures ED: emergency department
BAL: blood alcohol level FDA: Food and Drug Administration
BCT: behavioral couples therapy GABA: -aminobutyric acid
CB1: cannabinoid-1 receptor 5-HT: serotonin
CBT: cognitive-behavioral therapy IM: intramuscular
CIWA-Ar: Clinical Institute Withdrawal Assessment for IV: intravenous
Alcohol-Revised LFT: liver function test
CNS: central nervous system MET: motivational enhancement therapy
COWS: Clinical Opiate Withdrawal Scale NA: nucleus accumbens
CRF: corticotropin-releasing factor nAch: nicotinic acetylcholine receptor
DA: dopamine NE: norepinephrine
DAWN: Drug Abuse Warning Network NMDA: N-methyl-D-aspartate
NRT: nicotine replacement therapy Chao J, Nestler EJ. Molecular neurobiology of drug addiction. Annu
OBOT: Ofce-Based Opioid Treatment Rev Med 2004;55:113132.
OTC: over the counter Galanter M, Kleber HD. Textbook of Substance Abuse Treatment.
Rx: prescription medication 3rd ed. Washington, DC: American Psychiatric Publishing,
SC: subcutaneous 2004.
TCA: tricyclic antidepressant George TP, OMalley SS. Current pharmacological treatments for
THC: tetrahydrocannabinol nicotine dependence. Trends Pharmacol Sci 2004;25:4248.
TSF: 12-step facilitation Hodgson R. Family interventions for alcohol problems. Alcohol and
VTA: ventral tegmental area Alcoholism 2004;39:8687.
Lowinson JH, Ruiz P, Millman RB, Langrod JG. Substance Abuse: a
Reference lists and self-assessment questions and answers are Comprehensive Textbook. 4th ed. Baltimore: Lippincott Williams &
available at www.ChisholmPharmacotherapy.com. Wilkins, 2005.
OConnor PG, Fiellin DA. Pharmacologic treatment of heroin-
dependent patients. Ann Intern Med 2000;133:4054.
Miller WR, Tonigan JS, Longabaugh R. The Drinker Inventory of
for information on obtaining continuing education credit for Consequences (DrInc): an instrument for assessing adverse conse-
this chapter. quences of alcohol abuse. National Institute on Alcohol Abuse and
Alcoholism Project MATCH Monograph Series, Vol. 4. Rockville,
MD: National Institutes of Health (Publication No. 953911),
KEY REFERENCES AND READINGS 1995.
The Tobacco Use and Dependence Clinical Practice Guidelines Panel,
American Psychiatric Association. Diagnostic and Statistical Manual Staff, and Consortium Representatives. A clinical practice
of Mental Disorders, Fourth Edition, Text Revision. Washington, guideline for treating tobacco use and dependence. A US Public
DC: American Psychiatric Association, 2000. Health Service report. JAMA 2000;283:32443254.
34 SCHIZOPHRENIA
Deanna L. Kelly and Elaine Weiner
LEARNING OBJECTIVES
1. Explain the pathophysiologic mechanisms that are thought to underlie schizophrenia.

2. Recognize the signs and symptoms of schizophrenia and be able to distinguish among
positive, negative, and cognitive symptoms of the illness.
3. Identify the treatment goals for a patient with schizophrenia.
4. Recommend appropriate antipsychotic medications based on patient-specic data.
5. Compare the side-effect proles of individual antipsychotics.
6. Describe the components of a monitoring plan to assess the effectiveness and safety of
antipsychotic medications.
7. Educate patients and families about schizophrenia, treatments, and the importance of
adherence to antipsychotic treatment.
KEY CONCEPTS the development of glucose and lipid abnormalities; therefore

careful monitoring is essential.
Patients presenting with odd behaviors, illogical thought Education of the patient and family regarding the benets and
processes, bizarre beliefs, and hallucinations should be assessed risks of antipsychotic medications and the importance of
for schizophrenia. adherence to their therapeutic regimens must be integrated
A diagnosis of schizophrenia is made clinically, as there are no into pharmacologic management.
psychological assessments, brain imaging, or laboratory
examinations that conrm the diagnosis. In most cases schizophrenia is a chronically debilitating disorder
The goals of treatment are to reduce symptomatology, and is likely one of the most devastating of chronic medical ill-
decrease psychotic relapses, and improve patient functioning nesses. Conceptually, schizophrenia might better be thought of
and social outcomes. as a clinical syndrome, comprising several disease entities that
The cornerstone of treatment is antipsychotic medications. manifest with psychotic symptoms, including hallucinations,
Because most patients with schizophrenia relapse when not delusions, and disordered thinking. Commonly, these more a-
medicated, long-term treatment is usually necessary. grant symptoms are accompanied by more insidious ones, includ-
Psychosocial support is needed to help improve functional ing cognitive impairment (abnormalities in thinking, reasoning,
outcomes. attention, memory, and perception), impaired insight and judg-
Compared to the older antipsychotics (rst-generation anti- ment, loss of motivation (avolition), loss of emotional range
psychotics), the more recently developed second-generation (restricted affect), and a decrease in spontaneous speech
antipsychotics are associated with a lower risk of motor side (poverty of speech). The later three symptoms are termed nega-
effects (tremor, stiffness, restlessness, and dyskinesia); may tive symptoms, and when taken together, are frequently called
offer greater benets for affective, negative, and cognitive the decit syndrome. Cognitive impairments and negative
symptoms; and may prolong the time to psychotic relapse. symptoms account for much of the poor social and functional
Second-generation antipsychotics as a class are heterogeneous outcomes observed in schizophrenia. Schizophrenia is the
with regard to side-effect proles. Many second-generation fourth leading cause of disability among adults and is associated
antipsychotics carry an increased risk for weight gain and for with substantially lower rates of employment, marriage, and
549
illness if the other twin has schizophrenia is about 50%. Many

Patient Encounter, Part 1 genes have been weakly associated with the development of
schizophrenia; however, no clear association exists for any one
gene. There is probably no single schizophrenic gene. Recent
data, however, suggest that genes encoding dopamine recep-
AG is a 28-year-old single African-American male with an approxi-
tors, serotonin receptors, and the enzyme that metabolizes
mately 3-year history of paranoia, increasing use of marijuana and
cocaine, and poor work performance. His symptoms seemed to dopamine, catechol-O-methyltransferase (COMT), may be
intensify around his being caught taking money from his girlfriends implicated in the etiology of schizophrenia.2 Environmental
bank account to buy cocaine. Since then he has become suspicious stimuli or triggers along with genetic liability may contribute to
that the police were watching his movements and that people on the expression of the illness. Some data suggest that intrauter-
the street knew personal information about him. He has left several ine exposure to viral or bacterial infections may be a risk factor;
jobs one after another due to his belief that other employees were however, more research is needed in this area.
sabotaging him and that people were talking behind his back. He
occasionally hears his father speaking to him but has not seen him
in 10 years. He is sad and hopeless about the state of his life and
very guilty about his substance abuse and stealing from his girl- PATHOPHYSIOLOGY
friend. Though supportive of him, the patients girlfriend is feeling
somewhat frustrated by the patients withdrawal from her and reluc- The oldest theory associated with the pathophysiology of
tance to socialize to the extent that they had in the past. schizophrenia is the dopamine hypothesis, which proposes
that psychosis is due to excessive dopamine in the brain. This
What diagnoses are suggested by this presentation? hypothesis was formed in the late 1950s, following the discov-
What additional information would help to clarify the ery that chlorpromazine, the rst antipsychotic drug, acted as
diagnosis?
a postsynaptic dopamine antagonist. There is evidence from
many pharmacologic challenge studies that drugs that lead to
an increase in dopamine (e.g., cocaine and amphetamines)
increase psychotic symptoms, while drugs that decrease
independent living compared to population norms. Approximately dopamine (as do all current antipsychotic medications)
10% of people with schizophrenia die by suicide.1 However, ear- decrease psychotic symptoms. A wide array of scientic work
lier diagnosis and treatment, as well as advances in research over the last several decades, including functional magnetic
and newer treatment developments, have led to better out- resonance imaging (MRI), positron emission tomography
comes for people who suffer from this complex and challenging (PET), computed tomography (CT), and studies of dopamine
illness. metabolites have revealed a more complicated picture with
both hyperdopaminergic, as well as hypodopaminergic brain
regions. Hypodopaminergic activity observed in the prefrontal
EPIDEMIOLOGY AND ETIOLOGY lobe is thought to relate to the core negative symptoms associ-
ated with schizophrenia. Thus, a more modern reworking of
One percent of the worlds population suffers from schizophre- the dopamine hypothesis is the dysregulation hypothesis
nia and symptoms usually rst present in late adolescence or which takes these ndings into account.3 It is possible, how-
early adulthood.1 While equally prevalent between genders, ever, that the dopamine abnormalities hypothesized to under-
symptoms generally appear earlier in males, and males have a lie the etiology of schizophrenia may represent compensatory
younger age at rst hospitalization (15 to 24 years) compared to changes that occur secondary to other pathophysiologic
females (25 to 34 years). This earlier age of onset leads to a greater abnormalities intrinsic to the illness. Despite the accumula-
disruption in the successful completion of developmental mile- tion of knowledge surrounding dopamines etiologic relation-
stones, which may account for the poorer functional outcomes ship to schizophrenia, other neurotransmitter systems have
seen in males compared to females. Men are more likely to be been implicated. Some investigators have suggested that a
treated in the hospital settings and generally account for 60% to combined dysfunction of the dopamine and glutamate trans-
70% of the total inpatient population with this illness. There does mitter systems may better explain the disorder.4 There has also
not appear to be signicant differences in the incidence or preva- been a great deal of speculation regarding a role for serotonin
lence across cultures or among racial or ethnic groups. receptor antagonism in antipsychotic efcacy,5 as many second-
The etiology of schizophrenia remains largely unknown, generation antipsychotics (SGAs) are active at serotonin
though the evidence strongly supports a genetic basis for the receptors. Serotonin receptor binding may be important to
disorder. First-degree relatives of patients with schizophrenia drug action, possibly by modulating dopamine activity in
carry a 10% risk of developing the disorder. When both par- mesocortical pathways. However, a compelling pathophysio-
ents have the diagnosis, the risk to their offspring is 40%. For logic theory relating to dopamine and serotonin receptor
monozygotic twins, the likelihood of one twin developing the afnities does not yet exist. It is important to note that to date,
CHAPTER 34 / SCHIZOPHRENIA 551
Clinical Presentation of Schizophrenia
General
Schizophrenia is a chronic disorder of thought and affect, causing a signicant distur-
bance in the individuals ability to function vocationally and interpersonally. The onset of
symptoms in most cases is insidious, usually preceded by a prodromal phase characterized
by gradual social withdrawal, diminished interests, changes in appearance and hygiene,
changes in cognition, and bizarre or odd behaviors. Despite the tendency of the media to
portray a stereotype, the clinical presentation of a person with schizophrenia is extremely
varied. Hallmark symptoms include psychotic symptoms, negative symptoms, and cognitive
impairments that last for at least 6 months.
Symptoms
Psychotic symptoms: These symptoms are sometimes called positive symptoms, as they are
added on to a persons normal experience. They may include hallucinations (distortions or
exaggeration of perception), delusions (xed false beliefs), and thought disorder (illogical
thought and speech). Hallucinations, most frequently auditory, can also be visual, olfactory,
gustatory, and tactile. Auditory hallucinations may be experienced as voices or as thoughts
that feel distinct from the persons own thoughts. The content of the hallucinations is vari-
able but often they are threatening or commanding (i.e., commanding the person to per-
form a particular action). Patients may feel compelled to perform the commanded task or
may experience much anxiety when they do not. Delusions frequently involve xed false
beliefs despite invalidating evidence, and may be bizarre in nature. Often they have para-
noid themes, which may make the patient suspicious of others. The characteristic thought
disorder of schizophrenia includes loosening of associations, tangentiality, thought blocking,
concreteness, circumstantiality, and perseveration. Thinking and speech may be incompre-
hensible and illogical. Subtle disturbances in associative thinking may develop years before
disorganized thinking (formal thought disorder).
Negative symptoms: So called because they are qualities taken away from the per-
sonality, include impoverished speech and thinking, lack of social drive, atness of
emotional expression, and apathy. Though quite ubiquitous, these symptoms are dif-
cult to evaluate because they occur in a continuum with normality, and can be due to
secondary causes, including medication side effects, mood disorder, environmental
understimulation, or demoralization. When due to schizophrenia itself, they are termed
primary negative symptoms or decit symptoms. The best strategy for differentiating pri-
mary from secondary negative symptoms is to observe for their persistence over time,
despite efforts at resolving the other causes. Approximately 10% to 15% of people with
schizophrenia may present primarily with negative symptoms; these people may be
referred to as having a decit syndrome.
Cognitive symptoms: Neuropsychological research shows that patients with schizophre-
nia show abnormalities in the areas of attention, processing speed, verbal and visual
memory, working memory, and problem solving. There is a loss of, on average, one stan-
dard deviation of preillness IQ, with the average IQ of between 80 and 84.
antipsychotics without any primary or secondary dopamine- to impaired self-care. Sleep and appetite are often disturbed.
modulating properties have been ineffective for the treatment People with schizophrenia often have difculty living independ-
of positive symptoms of schizophrenia. ently in the community and have difculty forming close rela-
tionships with others. Additionally, they have problems with ini-
tiating or maintaining employment. Rates of illness denial are
CLINICAL PRESENTATION AND DIAGNOSIS high, as is non-compliance with medications, particularly early
in the course of illness, increasing the risk for relapse and hospi-
People with schizophrenia may appear uncooperative, suspi- talization. Comorbid medical disorders, such as type 2 diabetes
cious, hostile, anxious, or aggressive due to their misinterpreta- and chronic obstructive pulmonary disease, are prevalent in
tion of reality. They may have poor hygiene and appear schizophrenia due to sedentary lifestyles, poor dietary habits
unkempt, as psychosis, as well as depressive symptoms, may lead leading to obesity, and heavy cigarette smoking. Approximately
85% of people with schizophrenia smoke, and approximately COURSE AND PROGNOSIS
50% use drugs and alcohol, rates that are much higher than in
the general population.6 The onset of psychosis, whether insidious or acute, is marked by
There is no objective diagnostic or laboratory measure or difculties for patients, families, and clinicians. The severity of
brain imaging technique to diagnose schizophrenia. Biological symptoms may be denied, and the nature of behavioral distur-
markers are being investigated, but currently, the diagnosis is made bances may be misunderstood. Patients may try to keep symptoms
by ruling out other causes of psychosis and meeting specied diag- hidden from family and friends; they may remove themselves
nostic criteria that are based on symptoms and functioning. Family emotionally and geographically from social support networks.
history of psychiatric disorders is helpful in supporting the diagno- The onset of psychosis may be confounded by substance abuse.
sis. The commonly accepted diagnostic criteria for schizophrenia are The gradual development of psychosis, combined with the fre-
from the Diagnostic and Statistical Manual of Mental Disorders, quent misunderstanding of symptoms, generally leads to a sub-
Fourth Edition, Text Revision (DSM-IV-TR)7 (Table 341). stantial time period between symptom onset and diagnosis and
treatment. While not unequivocal, recent data suggest that peo-
ple with fewer episodes of acute psychosis and those treated
early on in their illness may have a better prognosis. Therefore,
TABLE 341. Diagnostic Criteria for Schizophrenia the rst challenge of optimal therapy is to move treatment ini-
A. Characteristic symptoms: Two (or more) of the following, each
tiation closer to the onset of psychosis.
present for a signicant portion of time during a 1-month Although the course of schizophrenia is variable, the long-
period (or less if successfully treated):a term prognosis for independent function is often poor. The
Delusions course of illness is marked by intermittent acute psychotic
Hallucinations episodes with a downward decline in psychosocial functioning.
Disorganized speech (e.g., frequent derailment/incoherence)
Grossly disorganized/catatonic behavior
Over time, a patient may become more withdrawn, bizarre, and
Negative symptoms (e.g., at affect, alogia, avolition) non-functional. Complete return to full premorbid functioning
B. Social/occupational dysfunction: For a signicant portion of the is uncommon. Many of the more dramatic and acute symptoms
time since the onset of the disturbance, one or more major fade with time, but severe residual symptoms may persist.
areas of functioning such as work, interpersonal relations, or Family and friends often nd this illness difcult to interpret
self-care are markedly below the level achieved prior to onset and understand. Involvement with the law is fairly common for
(or when onset is in childhood or adolescence, failure to
misdemeanors such as vagrancy, loitering, and disturbing the
achieve the expected level of interpersonal, academic, or occu-
pational achievement). peace. The overall life expectancy is shortened primarily due to
C. Duration: Continuous signs of disturbance persist for at least 6
suicide, accidents, and the inability of self-care. The lifetime risk
months. This 6-month period must include at least 1 month of of suicide for people with schizophrenia is about 10%.8
symptoms (or less if successfully treated) that meet criterion A Persistent compliance with a tolerable drug regimen improves
(i.e., active-phase symptoms), and may include periods of pro- prognosis, though relapse without medication exceeds 50%
dromal or residual symptoms. During these prodromal or resid- annually.
ual periods, the signs of disturbance may be manifested by
only negative symptoms, or by two or more symptoms listed in
category A present in an attenuated form (e.g., odd beliefs,
unusual perceptual experiences).
D. Ruling out other disorders: TREATMENT
Schizoaffective and mood disorder exclusion: Schizoaffective
disorder and mood disorder with psychotic features have been Desired Outcomes
ruled out because either (1) no major depressive, manic, or
mixed episodes have occurred concurrently with the active- The goal is for people with schizophrenia to receive, as early
phase symptoms; or (2) if mood episodes have occurred in their course as possible, comprehensive treatment designed to
during active-phase symptoms, their total duration has been achieve functional outcomes. While in the past, the primary treat-
brief relative to the duration of the active and residual periods. ment goal was to decrease positive symptoms and the associated
Substance/general medical condition exclusion: The disturbance
is not due to the direct physiologic effects of a substance (e.g., hostile and aggressive behaviors, newer approaches to treatment
drug of abuse or medication) or a general medical condition. have a wider focus, treating not only positive symptoms, but also
Pervasive developmental disorder: If there is a history of negative, depressive, and anxious symptoms. The aim is to not only
autistic disorder or another pervasive developmental disorder, reduce symptomatology and psychotic relapses, but also to improve
the additional diagnosis of schizophrenia is made only if functional and social outcomes.9 It is important to keep in mind
prominent delusions or hallucinations are also present for at
least a month (or less if successfully treated). that some symptoms respond earlier than others. Combativeness,
hostility, sleep disturbances, appetite, and hallucinations may be
a
Only one symptom from category A is required if delusions are bizarre some of the rst symptoms to improve. Improvements in nega-
or hallucinations consist of a voice maintaining a running commentary
on the persons behavior or thoughts, or two or more voices conversing. tive symptoms, cognitive functioning, social skills, and judgment
Adapted from reference 7 with permission. generally require a longer period to improve.
Past Psychiatric History

Though AG describes himself as being depressed all my life and remembers that he felt
able to read peoples minds in high school, he denied prior psychiatric treatment until his
rst hospitalization 2 years ago at the height of his paranoia. At that time, he believed there
was a conspiracy against him. He lived in constant fear that his phone was tapped and his
home was bugged. He felt he was being watched in public places, and therefore he began
avoiding going out. He experienced voices commenting on his behavior and believed the
television was talking to him and that shows were about him. At times he felt his brain was
being squeezed for information, so that his mind was being read. He believed his girlfriend
was having affairs, and he could not be reassured. He reported decreased appetite, difculty
sleeping, and suicidal ideation. His toxicology screen and blood alcohol test in the
emergency department were negative. In the hospital he was given a diagnosis of major
depressive disorder with psychotic features. He was started on olanzapine 10 mg/day for
psychosis and uoxetine 20 mg/day for depression, with some improvement.
Past Medical History
He has no history of medical illness, head trauma, or seizure disorder.
Social History
He grew up in an upper middle class family, completed high school, and entered the Navy
where he was discharged dishonorably due to not following rules. He began using alcohol
in high school and continued to use other substances intermittently since then. He has
held several jobs, the longest for 6 months. He thinks he might apply for disability.
Family Psychiatric History
His father had an alcohol problem.
Mental Status Exam
Appearance: Nicely dressed and groomed. No abnormal movements. Poor eye contact.
Speech: Quiet and somewhat monotonous.
Mood: Nervous.
Affect: Guarded and mildly anxious with restricted range.
Thought content: Adequate historian but with a tendency to leave out detail.
Experiences hearing others call his name, and interpreting the car lights coming down
his street as meaning people are out to get him. He denies suicidal or homicidal
thoughts.
Thought processes: Logical but vague.
Cognition: Grossly intact.
Insight and judgment: Mixed, as he can at times question his thinking, but at other times
has full conviction of his beliefs. He is currently taking his medication and cooperating
with the evaluation appointments.
Given this additional information, how was your differential changed?

What would the goals of outpatient treatment be?
What pitfalls are likely to occur during outpatient treatment?
Over the past few years, partial recovery and remission services to people with schizophrenia. Also, newer trends
have become an increasingly prominent paradigm for concep- such as evidence-based practice, whereby new information
tualizing the treatment of schizophrenia. In working toward from the published literature gets incorporated into clini-
these goals, a range of interventions must be incorporated cians prescribing behavior, have led to the use of interven-
into long-term treatment strategies, including not only phar- tions that promote a remission or recovery attitude.10
macologic interventions, but psychosocial therapies as well. Moreover, recent attempts have been made to address and
Current treatment planning is increasingly focused on func- measure patient satisfaction with treatments and instill hope
tional outcomes by providing treatment and recovery-oriented and optimism in order to attempt to empower patients.
Unfortunately, this new paradigm is in the earliest stages of minimal response. Patients who do respond often continue to
implementation, and despite these advances and recent treat- have residual symptoms such as amotivation, isolation, and
ment improvements, long-term outcomes currently remain impaired social functioning, thus limiting their participation in
poor, and many patients fail to receive comprehensive care. social, vocational, and educational endeavors. Psychosocial
interventions are based on the premise that increased psychoso-
General Approach to Treatment cial functioning will lead to improvements in subjective feelings
of self-esteem and life satisfaction. However, generalizability
A person presenting with the initial episode of psychosis
from studies in this area are confounded by differences in treat-
requires a comprehensive assessment and careful diagnosis, as
ment settings, severity of illness, insurance status of patients,
psychosis is not pathognomonic for schizophrenia. The differ-
and the presence of comorbid conditions. A few of the best-
ential diagnosis includes a wide array of neurologic, psychiatric,
supported and most promising approaches to psychosocial reha-
and general medical conditions (Table 342). Often, people
bilitation are social skills training (SST), cognitive-behavioral
present with a short history of psychopathology and cannot
therapy (CBT), and cognitive remediation (CR). These treat-
recall historical information accurately. This lack of informa-
ments are used most appropriately as targeted treatments for
tion, along with frequent comorbid substance abuse, medical ill-
social and cognitive impairments and not as sole treatments for
nesses, and psychosocial stressors often confound the case.
psychotic symptoms.13 Most psychosocial studies have been car-
Patients presenting with psychotic symptoms, particularly those
ried out in the United Kingdom, and ndings are not yet widely
in their initial episode, should have a thorough medical and lab-
utilized in the United States. Nonetheless, there are substantial
oratory (electrolytes, blood urea nitrogen, serum creatinine, uri-
data to support that family education and vocational support
nalysis, liver and thyroid function prole, syphilis serology,
help to improve long-term functional outcomes.
serum pregnancy test, and urine toxicology) evaluation, includ-
ing a careful review of systems and a physical exam that includes
a neurologic evaluation. At the minimum, in accordance with
the American Psychiatric Association Practice Guidelines11 and There are more choices of antipsychotic medications than ever
the Expert Consensus Guideline Series for Schizophrenia,12 psy- before. Generally, all people with schizophrenia should be
chotic patients should have a medical workup at the time of treated with antipsychotics, and adjunctive medications should
admission to rule out other diagnoses or contributing factors. be used when necessary to treat specic symptoms or comorbid
diagnoses. Medications specically targeting negative symptoms
Since early detection and intervention in schizophrenia is
and cognitive decits are actively being investigated. Because each
important for maximizing outcomes, treatment with antipsychotic
schizophrenic patient presents differently, each treatment regi-
medications should begin as soon as psychotic symptoms are recog-
men should be individually tailored. After a period of nearly
nized. Antipsychotic medications are the cornerstone of therapy for
20 years during which only rst-generation antipsychotics
people with schizophrenia, and most patients are on lifelong ther-
(FGAs; typical antipsychotics) were available, six new antipsy-
apy since non-adherence and discontinuation of antipsychotics are
chotics have been marketed in the United States since 1990.
associated with high relapse rates. If other symptoms are present
These agents, known as second-generation antipsychotics (SGAs;
such as depression and anxiety, these symptoms should also be
atypical antipsychotics), include risperidone (Risperdal), olan-
aggressively treated. Additionally, psychosocial treatments
zapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon),
should be used concomitantly to improve patient outcomes.
aripiprazole (Abilify), and clozapine (Clozaril). Clozapine, the
prototype of this class of medications, is reserved as second-line
therapy due to its unusual side-effect prole (see below). As a
Psychosocial support is needed to help improve functional class the SGAs offer greater tolerability, with less risk of extrapyra-
outcomes. Only 30% of patients respond robustly to antipsy- midal side effects (EPSs) and tardive dyskinesia (TD; see below),
chotics, another 30% respond partially, and another 30% have a and possibly better treatment for mood symptoms, negative symp-
toms, and cognitive decits. There are some data to show that they
are associated with lower rates of relapse. Unfortunately, these med-
TABLE 342. Disorders That May Present with Psychotic ications are more expensive than older medications and have sim-
Symptoms ilar efcacy for psychotic symptoms, thus pharmacoeconomic
cost:benet proles provide information essential for designing
Addisons disease Huntingtons disease appropriate therapeutic regimens. The FGAs are currently used in
Aspergers disorder Major depression less than 10% of the schizophrenic population, primarily in
Autism Posttraumatic stress disorder
Bipolar disorder Sarcoidosis patients who cannot afford newer medications and those who
Cancer Seizure disorder have responded well and tolerated these medications in the past.
Cushings disease Substance abuse
Delirium Syphilis Second-Generation (Atypical) Antipsychotics
Dementia Thyrotoxicosis While FGAs exert most of their effect through dopamine
Head trauma Viral encephalitis
receptor blockade at the dopamine (D2) receptor, the SGAs
FIGURE 341. Proles for receptor binding of second-generation antipsychotics and haloperidol.
a
Partial agonist activity at D2 receptors, whereas all others are D2 antagonists. D, dopamine receptor; H1, histamine
receptor; 5-HT, serotonin receptor; Musc, muscarinic receptor; 1 and 2, 1 and 2 receptors. (Adapted and reprinted
from The Journal of Clinical Psychiatry and Physicians Post Graduate Press. Collaborative Working Group on Clinical
Trial Evaluations. J Clin Psychiatry 1998; 59[Suppl 12]:7, and Pharmacologic Treatment of Schizophrenia. Caddo, OK.
Professional Communications, Inc, 2003: 52, with permission.)
may work through a more complicated mechanism, as SGAs proles of the SGAs and haloperidol. Clozapine is discussed in
have greater afnity for serotonin receptors than for the section on treatment-resistant patients.
dopamine receptors (Fig. 341). Despite being very heteroge-
neous with regard to receptor binding, the overall efcacy Risperidone
among the SGAs is similar.14 Recently new comparative data Risperidone, a benzisoxazole derivative, was the rst SGA to be
among SGAs and FGAs (lower doses) have reported that over- marketed following the release of clozapine. It has high binding
all efcacy is similar between groups, which suggests a reeval- afnity to both serotonin (5-HT2A) and D2 receptors and binds
uation of the place of FGAs in therapy is needed.14 Only cloza- to 1 and 2 receptors, with very little blockade of cholinergic
pine, however, has demonstrated superior efcacy for some receptors.16 Multicenter registry trials found risperidone efcacy
patients (see section below on treatment-resistant patients). to be at least equal to that of haloperidol while producing sig-
An important distinction of the SGAs as a class is their lower nicantly fewer extrapyramidal symptoms.17 Risperidone is the
propensity to cause EPS and TD. The annual risk of TD is only SGA approved for relapse prevention and is associated with
considered to be less than 1.5% per year in adults (less than signicantly lower relapse rates than long-term haloperidol
54 years old) taking SGAs as compared to approximately a treatment.18 At clinically effective doses (less than or equal to
5%-per-year risk in those taking FGAs.15 Pharmacologic pro- 6 mg/day), EPSs are low, although higher doses are clearly asso-
les and side-effect proles, however, are very different among ciated with a greater incidence of EPS. Risperidone is associated
the agents. Table 343 lists the SGA agents, recommended with serum prolactin elevations that are similar to or greater
dosing, and dosage forms available. Table 344 lists the side-effect than those seen with the FGAs. Elevated prolactin levels can, but
TABLE 343. Second-Generation (Atypical) Antipsychotics
Second-Generation Usual Target Maximal Dose Likely to

Antipsychotic Dose (mg/day) Be Benecial (mg/day) Available Dosage Forms
Aripiprazole (Abilify) 1530 30 2-, 5-, 10-, 15-, 20-, and 30-mg tablets
1 mg/mL oral solution
10- and 15-mg discmelt orally disintegrating tablets
IM 9.75 mg/1.3 mL
Clozapine (Clozaril) 400 500800 25- and 100-mg tablets
FazaClo (orally disintegrating tablets) 25 and 100 mg
Olanzapine (Zyprexa) 1520 30-40a 2.5-, 5-, 7.5-, 10-, 15-, and 20-mg tablets
Zyprexa Zydis (orally disintegrating tablets) 5,10,15, and 20 mg
IM 10mg vial (after reconsitution, approx. 5 mg/mL)
Quetiapine (Seroquel) 400600 8001200a 25-, 100-, 200-, and 300-mg tablets
Risperidone (Risperdal) 24 6 0.25-, 0.5-, 1-, 2-, 3-, and 4-mg tablets
1 mg/mL (30 mL) solution
Risperidal M-tab (orally disintegrating tablets) 0.5, 1, and 2 mg
Risperdal Consta long-acting injectable 25-, 37.5-, and 50-mg vial/kit
Ziprasidone (Geodon) 100120 160240a 20-, 40-, 60-, and 80-mg capsules
IM 20 mg/mL
a
Outside product labeling guidelines.
TABLE 344. Comparative Side Effects among the Second-Generation Antipsychotics and Haloperidol
Side Effect Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Haloperidol

Anti-cholinergic side effects +++ ++ (higher +
(dry mouth, constipation, doses)
blurred vision, urinary hesitancy)
EPS at clinical doses + ++
Dose-dependent EPS 0 ++ + 0 + +++
Orthostatic hypotension +++ ++ + ++ + + +
Prolactin elevation 0 +++ + + 0 ++
QTc prolongation + +
Sedation +++ + + ++ + + +
Seizures ++
Weight gain +++ ++ +++ ++ + +
Glucose dysregulation ++ + ++ +
Lipid abnormalities +++ + +++ ++
0, absent; , minimal; +, mild or low risk; ++, moderate; +++, severe; EPS, extrapyramidal side effects.
do not always, lead to clinical symptoms such as hormonal afnity for D2 and D1 receptors. This drug has some afnity
problems (e.g., amenorrhea, galactorrhea, and gynecomastia) or for 1, 2, and H1 receptors, and very little for muscarinic
sexual dysfunction. Risperidone is associated with mild to mod- receptors. The efcacy of quetiapine for psychosis was estab-
erate weight gain and mild elevations in lipid and glucose may lished in two controlled trials, which found that maximum
occur. However, patients chronically treated with other antipsy- benets occurred at 300 mg per day or greater.22,23 The most
chotics such as olanzapine may have declines in cholesterol and effective doses of quetiapine may be higher than 500 mg/day.
triglyceride levels when changed to risperidone monotherapy.14 Quetiapine has not been shown to be superior to haloperidol
in any symptom dimension; however, it has benecial effects
Olanzapine for anxious and depressive symptoms. Because of its low D2
Olanzapine has greater afnity for 5-HT2A than for D2 receptors. occupancy, motor side effects and prolactin elevations are
In addition, the compound has afnity at the binding sites of D4, usually not seen with quetiapine. Sedation may occur but is
D3, 5-HT3, 5-HT6, 1-adrenergic, muscarinic (M15), and hista- generally transient. Mild weight gain and minor elevations in
mine (H1) receptors.19 Multicenter clinical trials have reported triglycerides can occur.
that the effectiveness of olanzapine is at least equal to that of
haloperidol for the treatment of positive symptoms20,21 and Ziprasidone
equal or superior to haloperidol for the treatment of negative Ziprasidone was developed specically to be a compound that
symptoms. The premarketing clinical trials reported no signi- blocks D2 receptors, but also binds with even greater affin-
cant differences in efcacy among dosage groups. However, the ity to central 5-HT2A receptors. As a result, ziprasidone has
higher dose range appeared to offer the greatest benets for both a binding affinity ratio of 11:1 for 5-HT2A:D2 receptors.
positive and negative symptoms when compared to haloperidol Ziprasidone also has a relatively high affinity for 5-HT2C,
(20 mg). Among the rst-line antipsychotic agents, olanzapine is 5-HT1D, 1-adrenergic, and D1 receptors.24 Several short-
associated with the longest time to treatment discontinuation, a term, placebo-controlled, premarketing clinical trials led to
nding that suggests that olanzapine may somewhat differ from the recommended dose range of 40 to 160 mg daily with
the other SGAs in effectiveness.14 Olanzapine has a low rate of food.25,26 Current dosing suggests that efcacy may be greater
EPS and causes slight, transient prolactin elevations. However, at doses over 200 mg/day. Liability for EPS, weight gain, and
clinically signicant weight gain occurs with olanzapine across lipid elevations were very low in the clinical trials. Ziprasidone
the dosage range. The degree of weight gain is similar to that is associated with some prolongation of the QTc interval in
seen with clozapine and greater than that observed with the adults. However, drug overdose data and studies of pharma-
other SGAs. Olanzapine is also associated with hypertriglyc- cokinetic interactions have thus far shown little evidence that
eridemia, increased fasting glucose, and new-onset type 2 dia- signicant QTc prolongation may occur.
betes (i.e., metabolic syndrome), and among the rst-line SGAs,
it is associated with the greatest elevations in these metabolic Aripiprazole
parameters.14 Aripiprazole was formulated in the early 1980s to function as a
potential dopamine modulator, with both antagonist and agonist
Quetiapine activity at the D2 receptor. It is the rst D2 partial agonist available
Structurally quetiapine is related to clozapine and olanzapine. for the treatment of schizophrenia and is sometimes referred to
Quetiapine has high afnity for 5-HT2A receptors and lower as a third-generation antipsychotic. This novel mechanism is
required, as the starting dose is an effective dose. The recom-

Patient Encounter, Part 3 mended dosing range is 10 to 30 mg/day; doses greater than
30 mg have not been systematically evaluated. Doses less than
10 mg/day have not been consistently found to be effective. Side
effects are low with sedation and nausea and vomiting occurring
Soon after his discharge from the hospital, AG stopped taking
his olanzapine. He had gained a lot of weight, and he didnt
the most frequently. Elevations in weight, lipids, and glucose are
believe the medication was helping. He continued to have generally negligible to minor.
difculties maintaining employment and being involved
socially. With encouragement from his girlfriend, AG sought
treatment again and was started on risperidone 2.5 mg a day. First-Generation (Typical) Antipsychotics
He continued to experience paranoia, still feeling unable to First-generation antipsychotics (FGAs), also referred to as con-
function up to his potential at work, and still tending to be ventional, traditional, or typical antipsychotic agents, are high-
reclusive. A new therapist supported his involvement in afnity D2 receptor antagonists. During chronic treatment,
Alcoholics Anonymous, and with AG began to question the these agents block 65% to 80% of D2 receptors in the striatum
depression diagnosis. She referred him to a center specializing and block dopamine receptors in the other dopamine tracts in
in schizophrenia where the diagnosis was claried as schizo- the brain as well.28 Clinical response is generally associated
phrenia, paranoid type, continuous with depressive episode, with 60% D2-receptor blockade, while 70% and 80% are asso-
single episode, alcohol dependence, early full remission; and
ciated with hyperprolactinemia and EPS, respectively. This
polysubstance abuse, early full remission.
group of antipsychotics was widely used from the 1950s to the
List a reason why risperidone was selected as the next 1990s, until the SGAs began to replace these agents as rst-line
antipsychotic choice for AG. therapy.
Describe nonpharmacologic treatment strategies that may Dosages for these agents are frequently given as chlorpro-
be appropriate for AG. mazine equivalent dosages, which are dened as the dosage of
Discuss a risperidone dosing plan and list side effects AG any of the FGAs equipotent with 100 mg of chlorpromazine. The
may experience on this medication. target dose recommendation is 400 to 600 chlorpromazine equiv-
alents, unless the patients history indicates that this dose may
result in intolerable side effects. Generally maintenance therapy
termed a dopamine system stabilizer, functioning as an antag- should provide a dose of 300 to 600 chlorpromazine equiva-
onist in a hyperdopaminergic state and as an agonist when in a lents for maximum efcacy. Information on dosing and
hypodopaminergic state. Aripiprazole is also a partial agonist at available dosage forms is provided in Table 345. All FGAs are
5-HT1A receptors, an antagonist at 5-HT2A receptors, and also equally efcacious in groups of patients when used in equipo-
has afnity for D3 receptors. Additionally, it has a moderate tent doses. However, individual variation does occur, such that
afnity for 1 and H1 receptors with no appreciable afnity a patient may not respond equally to each antipsychotic.
for the M1 receptor.27 The recommended starting dose is 10 to Selection of a particular antipsychotic should be based on
15 mg daily given without regard to meals. No titration is patient variables, such as the need to avoid certain side effects
TABLE 345. First-Generation (Typical) Antipsychotics
Chlorpromazine
Class Agent (Brand Name) Dosage Range (mg/day) Equivalents (mg) Available Formulations
Butryphenone Haloperidol (Haldol) 530 2 T, LC, I
Dibenzoxazepine Loxapine (Loxitane) 25100 10 C
Diphenylbutylpiperidone Pimozide (Orap) 110 12 T
Indole Molindone (Moban) 25100 10 T
Phenothiazines Chlorpromazine (Thorazine) 300800 100 T, LC, I, R
Fluphenazine (Prolixin) 240 2 T, L, I
Mesoridazine (Serentil) 150500 50 T, LC
Perphenazine (Trilafon) 864 10 T, LC
Thioridazine (Mellaril) 300800 100 T, LC
Triuoperazine (Stelazine) 1530 5 T
Thioxanthenes Thiothixine (Navane) 540 4 C
Low-potency antipsychotics include thioridazine, mesoridazine, and chlorpromazine.

High-potency antipsychotics include haloperidol, uphenazine, thiothixine, and pimozide.
T, tablet; C, capsule; C-SR, controlled- or sustained-release; I, injection; L, liquid solution, elixir, or suspension; LC, liquid concentrate, R, rectal
suppository.
or interactions with concomitant medications. Previous antipsychotics should be discontinued and supportive and
patient or family history of response is also helpful in the symptomatic treatment begun (e.g., antipyretics, cooling
selection of a particular agent. blanket, intravenous uids, oxygen, monitoring of liver
enzymes, and complete blood cell count). Dopamine agonists
Decanoates (i.e., bromocriptine) should be considered in moderate to
Long-acting, depot preparations are available for two FGAs severe cases. Additionally, dermatologic side effects, photosen-
(uphenazine decanoate and haloperidol decanoate) in the sitivity, and cataracts may occur with the phenothiazine
United States. These compounds are esteried antipsychotics agents. Sedation is caused from H1-receptor antagonism, anti-
formulated in sesame seed oil for deep intramuscular injection. cholinergic side effects (constipation, blurred vision, dry
Because these are long-acting preparations, patients should be mouth, and urinary retention) are caused from M1-receptor
exposed to the oral form of the drug rst to ensure tolerability. antagonism, and 1-receptor blockade is associated with
With initial dosing of haloperidol decanoate, oral supplementa- orthostatic hypotension and tachycardia (Table 347.) QTc
tion may temporarily be necessary, as the drug accumulates over prolongation may occur with lower-potency FGAs such that
many weeks, not reaching steady state until 4 to 5 dosing inter- thioridazine has a black box warning for QTc prolongation.
vals have elapsed. The pharmacokinetic proles of the depot The other group of major adverse effects associated with
agents are useful parameters for strategic dosing. Patients may FGAs are EPS and include akathisia (restlessness), dystonia
be dosed with uphenazine decanoate on a 1- to 3-week inter- (muscle spasm), and pseudoparkinsonism (akinesia, tremor,
val, while haloperidol decanoate is usually dosed once a month. and rigidity). These fairly common motor side effects are caused
Conversion from oral to depot and maintenance dosing recom- by dopamine antagonism in the nigrostriatal pathways. Akathisia
mendations are shown in Table 346. Based on these recom- is the most frequently occurring motor side effect, with approx-
mendations, a reasonable estimate is that 12.5 mg (0.5 mL) of imately 20% to 40% of people treated with FGA drugs experi-
uphenazine decanoate given every 2 weeks is approximately encing an objective or subjective feeling of restlessness. The
equivalent to 10 mg/day of uphenazine orally. A maintenance onset of akathisia is usually 5 to 10 days after the rst dose or
haloperidol decanoate dose of 150 mg every 4 weeks is approxi- increase in dosage, but it can occur later. Younger people and
mately equivalent to 10 mg/day of oral haloperidol. Initial those taking high doses of high-potency antipsychotics are at
decanoate injections should be preceded by a small test dose. greater risk for the development of akathisia. Acute dystonic
reactions are abrupt in onset and are usually seen within 24 to
Side Effects of First-Generation Antipsychotics 96 hours after a rst dose or increase in dosage. Characteristic
FGAs cause a wide range of adverse events, affecting many signs and symptoms include abnormal positioning or spasm of
organ systems. In general, the low-potency agents are less the muscles of the head, neck, limbs, or trunk. Dystonia may
likely to cause EPS than the high-potency agents. Neuroleptic occur in 10% to 20% of patients. Younger patients are at high-
malignant syndrome (NMS), a life-threatening emergency est risk. Pseudoparkinsonism resembles idiopathic Parkinsons
characterized by severe muscular rigidity, autonomic instabil- disease, and features may be present in up to 30% to 60% of
ity, and altered consciousness, can occur uncommonly with all people treated with FGAs. The onset of symptoms is usually
the FGAs. Rapid dose escalation, the use of high-potency FGAs seen within 1 to 2 weeks following initiation of dosing or a dose
at higher doses, and younger patients are associated with a increase. Risk factors include older age, female gender, high
higher risk of NMS. When NMS is diagnosed or suspected, doses, and possibly those with depressive symptoms.29 Using
TABLE 346. First-Generation (Typical) Antipsychotic Dosing of Decanoate Preparations
Drug Starting Dose Maintenance Dose Comments

Haloperidol 20 oral haloperidol daily dose; 1015 oral haloperidol dose, With initial dosing, oral supplementation
decanoate in the elderly use 1015 oral generally 50300 mg/month may temporarily be necessary; deep IM
haloperidol daily dose injection generally with 21-gauge
Generally 100450 mg/month needle; maximum volume per injection
Initial dose should not exceed 100 mg site should not exceed 3 mL
regardless of previous dose Available in 5 mg/mL and 100 mg/mL
requirements (if greater than (5-mL vials and 1-mL ampules)
100 mg give 37 days apart)
Fluphenazine 1.2 oral uphenazine daily dose, Based on starting dose and Can be administered IM or SC;
decanoate generally 12.575 mg/23 weeks clinical response 21-gauge needed, must be dry
Generally 12.525 mg dosed Should not exceed 100 mg; when dosing
every 36 weeks above 50 mg, should increase in
increments of 12.5 mg
Available in 25 mg/mL (5-mL vials)
IM, intramuscular, SC, subcutaneous.

TABLE 347. Side Effects of First-Generation (Typical) Antipsychotics
Anticholinergic Cardiovascular Seizure Effects/

EPS Sedation Side Effects Side Effects QTc Prolongation
Chlorpromazine XX XXXX XXX XXXX XX
Thioridazine XX XXXX XXXX XXXX XXX
Mesoridazine XX XXX XXX XXX XX
Loxapine XXX XXX XX XXX X
Triuoperazine XXX XX XX XX X
Molindone XX X XX XX X
Perphenazine XXX XX XX XX X
Thiothixene XXX XX XX XX X
Fluphenazine XXXX XX XX XX X
Haloperidol XXXX X X X X
EPS, extrapyramidal side effects; X, very low; XX, low; XXX, moderate; XXXX, high.
decanoate formulations to minimize peak levels may minimize and the Schizophrenia Patient Outcomes Research Team
the incidence of EPS. (PORT) Treatment Recommendations.32
TD is a movement disorder characterized by abnormal
choreiform (rapid, objectively purposeless, irregular, and Treatment Adherence
spontaneous movement) and athetoid (slow and irregular) Medication non-adherence in schizophrenia is common and
movements occurring late in onset in relation to initiation of often associated with symptom relapse.33 Estimates of non-
antipsychotic therapy. This adverse effect usually develops adherence on FGAs range from approximately 24% to 88% with
over several months or after at least 3 months of cumulative a mean of approximately 50%.34 Subjects who are non-compliant
exposure to neuroleptic medications. The estimated average have approximately a four-fold greater risk of a relapse than
prevalence is 20% with a range of 13% to 36%. The incidence those who are compliant. Adherence to antipsychotic regimens
of new cases per treatment year with FGAs is approximately is problematic for many reasons. Neurocognitive decits and
5%.30 TD is reversible in one-third to one-half of cases with paranoid symptoms may hamper compliance, and identica-
the cessation of the antipsychotic. When the antipsychotic is tion of non-compliance by caretakers and providers can be
tapered or discontinued, there is initially usual worsening of challenging. Frequently, there is no obvious connection
abnormal movements. Risk factors for TD include older age, between non-compliance and symptom exacerbation, as there
longer duration of antipsychotic treatment, and higher rates may be no immediate consequences of missing a dose, and
of EPS, substance abuse, and mood disorders. patients may relapse suddenly after only several weeks or
months of non-adherence. Side effects from antipsychotics are
Treatment Guidelines and Algorithms also a major contributing factor to treatment non-adherence,
Due to the plethora of choices and the rising costs of SGAs, with 25% to 66% of subjects citing adverse effects as the pri-
algorithms and treatment/consensus guidelines have been mary reason for non-adherence.33 EPS, most notably akathisia,
developed for the treatment of schizophrenia. The most widely sexual dysfunction, and weight gain are adverse effects that
accepted algorithm in the United States was developed as part commonly lead to non-adherence.35 Several factors are associ-
of the Texas Implementation of Medication Algorithms ated with non-compliance, including younger age, grandiosity,
(TIMA). A national panel of experts developed this algorithm, substance abuse, and decit symptoms. SGAs may be associ-
most recently updated in 2003.31 Algorithms go beyond ated with somewhat better rates of adherence, most likely
guidelines, providing a framework for clinical decision mak- attributable to a lower incidence of dysphoria and EPS; how-
ing at critical decision points. According to the TIMA schizo- ever, rates of medication discontinuation remain high.14,36
phrenia algorithm, SGAs (except clozapine) should be utilized For patients who have relapsed several times due to non-
as rst-line treatment. The choice of SGA is guided by consid- adherence, have a history of dangerous behavior, or risk a sig-
eration of the side-effect proles and the clinical characteris- nicant loss of social/vocational gains when relapsed, treat-
tics of the patient. Treatment should be continued for 4 to 6 ment with long-acting formulations should be strongly
weeks in order to assess response. If only partial response or encouraged. Risperidone is currently the only SGA with a
non-response is noted, a trial of a second SGA should be ini- long-acting formulation available. It uses a microsphere tech-
tiated (Fig. 342). Other similar guidelines include the nology that maintains stable blood levels for about 2 weeks.
American Psychiatric Association Practice Guidelines for Dosing is generally 25 to 75 mg every 2 weeks with oral sup-
schizophrenia,11 The Expert Consensus Guideline Series,12 plementation in the rst 3 weeks.
FIGURE 342. TIMA

algorithm for antipsy-
chotic treatment in
schizophrenia. Choice
of antipsychotic should
be guided by consider-
ing the clinical charac-
teristics of the patient
and the efcacy and
side-effect proles of
the medication. Any
stage may be skipped
depending on the clini-
cal picture or history of
antipsychotic failures.
ECT, electroconvulsive
therapy; FGA, rst-
generation antipsy-
chotic; SGA, second-
generation antipsy-
chotic. (Adapted from
www.dshs.state.tx.us/
mhprograms/
tmasczman.pdf.)
Patient-Specic Antipsychotic Selection Special Populations

Patient-specic characteristics may help guide the selection of
antipsychotic treatment. Based on expert consensus guide- Adolescents
lines, Table 348 provides evidence-based suggestions for SGA Epidemiologic data show that 10% to 30% of patients with
selection to aid the clinician in individualizing treatment. schizophrenia develop their rst psychotic symptoms prior to
FGAs continue to have a place in therapy for patients who their eighteenth birthday. Onset between puberty and age of
cannot afford the SGAs or for those who have responded 18 is sometimes classied as early-onset schizophrenia (EOS)
favorably to these agents in the past. Currently, however, SGAs or intermediate onset schizophrenia, and those presenting with
are recommended as rst-line therapy. symptoms before puberty are classied as very early-onset
TABLE 348. Suggestions for First-Line Antipsychotic Therapy in Specic Patients
Clinical Condition First-Line Treatment Other Options

Diabetes or family history of diabetes Aripiprazole, quetiapine, ziprasidone Risperidone
Hyperlipidemia or signicant family history Aripiprazole, ziprasidone Risperidone, quetiapine
of hyperlipidemia
Hypertriglyceridemia or signicant family history of Aripiprazole, ziprasidone Risperidone, quetiapine
elevated triglycerides
Overweight or obese, or concerns about weight Aripiprazole, ziprasidone Risperidone, quetiapine
Current sexual dysfunction or concerns about Aripiprazole, quetiapine, clozapine Olanzapine, ziprasidone
sexual dysfunction
Amenorrhea or problems with menstrual period Aripiprazole, quetiapine, clozapine Olanzapine, ziprasidone
Cardiac arrhythmias or current anti-arrhythmic NOT ziprasidone or clozapine
treatment
Suicidal or history of frequent suicide attempts Clozapine
Current or past anti-cholinergic side effects Risperidone, quetiapine, aripiprazole Olanzapine (low dose)
ziprasidone
EPS or severe EPS in the past Quetiapine, aripiprazole, clozapine Ziprasidone
Current tardive dyskinesia Clozapine, quetiapine Risperidone, olanzapine, ziprasidone
History of non-adherence Long-acting risperidone
Difculty swallowing tablets/capsules Risperidone or aripiprazole liquid, orally- Long-acting risperidone
disintegrating tablets (risperidone,
olanzapine, clozapine)
EPS, extrapyramidal symptoms.

Data from references 11, 12, and 32 and 51.
schizophrenia (VEOS) or as having childhood-onset schizo- tend to gain more weight on these agents. Young patients should
phrenia. The diagnosis of schizophrenia in children and adoles- be started on lower doses than adults and should be titrated at a
cents is often difcult to make, and the differential diagnosis slower rate. Side effects should be monitored closely during ini-
includes pervasive developmental disorders, attention-decit/ tiation and throughout maintenance therapy. Informed consent,
hyperactivity disorder, and language or communication disor- addressing the rationale for treatment and potential risks and
ders. The existence of prominent hallucinations or delusions, benets of therapy, should be obtained from the parents or
however, help make the diagnosis, as they are not a prominent guardians prior to treatment with any antipsychotic medication,
part of the other disorders. Auditory hallucinations are com- and assent should be obtained from the child as well.
mon and occur in approximately 80% of children and adoles- Standardized clinician ratings such as the Positive and Negative
cents with schizophrenia. Command hallucinations are the Syndrome Scales derived from the Childrens Psychiatric Rating
most frequently occurring type of hallucination. The content Scale can be helpful in assessing the effects of antipsychotic ther-
and context of delusions in children and adolescents vary by apy. Dosing in children and adolescents is initiated lower and
age. Younger children tend to have delusions that are less com- titration is slower than in adults.
plex and xed. Fifty-four to ninety percent of patients develop-
ing schizophrenia before age 18 have premorbid abnormalities Elderly
such as withdrawal, odd traits, and isolation.37 Psychotic symptoms in late life (greater than 65 years of age) are
Treatment for psychotic children and adolescents ideally generally a result of an ongoing chronic illness carried over from
involves an intensive and comprehensive program with a highly younger life; however, a small percentage of patients develop
structured environment that includes special education and psychotic symptoms de novo, dened as late-life schizophrenia.
psychoeducation. Day treatment, hospitalization, or long-term The 6-month prevalence rate of schizophrenia in the elderly is
residential treatment may be necessary. Pharmacologic treat- around 1%. However, other illnesses presenting with psychotic
ment is indicated if psychotic symptoms cause signicant symptoms are common in this population, as approximately
impairments or interfere with other interventions. Children and one-third of patients with Alzheimers disease, Parkinsons
adolescents are more vulnerable to EPS, particularly dystonias, disease, and vascular dementia experience psychotic symptoms.
than are adults. Due to concerns about EPS and TD, pharma- The majority of data for antipsychotic use in the elderly comes
cotherapy in children and adolescents should be initiated with from experience treating these other disease states.
SGAs. Agents with signicant sedation and anti-cholinergic side Antipsychotics can be safe and effective for the treatment of
effects are not preferred, as they can cause attention difculties psychosis in the elderly, if used at lower doses than those com-
and cognitive dulling that may interfere with optimal school monly used in younger adults. Older adults are particularly vul-
performance. Compared to adults, children and adolescents nerable to the side effects of FGAs. Parkinsonian symptoms
reportedly occur in over 50% of all elderly patients receiving Treatment-Resistant Patients
these agents, and the cumulative annual incidence of TD in mid- For approximately 20% to 30% of people with schizophrenia,
dle-aged and elderly patients is over 25%. With the SGAs, the drug treatment is ineffective. A standard denition of treat-
risk appears to be approximately 4%.38 The likelihood of revers- ment resistance includes patients who have persistent positive
ing this potentially debilitating condition diminishes with age. symptoms despite treatment with at least two different
Other adverse effects of these agents that are often intolerable in antipsychotics given at adequate doses (at least 600 chlorpro-
the older population include orthostatic hypotension and anti- mazine equivalents) for an adequate duration (4 to 6 weeks).
cholinergic effects. For example, orthostasis, estimated to occur In addition, patients must have a moderately severe illness as
in 5% to 30% of geriatric patients, is a major contributing factor dened by rating instruments, and have a persistence of illness
to the occurrence of falls that often leads to fractures, injuries, for at least 5 years.40 These patients are often highly sympto-
and loss of independence. Low-potency antipsychotics and matic and require extensive periods of hospital care.
clozapine are more likely to cause signicant drops in orthosta-
tic blood pressure. Antipsychotics may cause or worsen anti- Clozapine
cholinergic effects including constipation, dry mouth, urinary
To date, clozapine remains the only drug with proven and
retention, and cognitive impairment. Cognitive impairment
superior efcacy in treatment-resistant patients, and it is cur-
may lead to decreased independence, and a more rapid decline
rently the only drug approved for the treatment-resistant
in cognitive functioning may occur in the elderly treated with
schizophrenic. Studies have shown a response of approxi-
antipsychotics than the younger adult population. Using lower
mately 30% to 50% in these well-dened treatment-resistant
doses and remaining vigilant to side effects is essential in this
patients. Clinical trials have consistently found clozapine to
population. Recently published data reported a statistically sig-
be superior to traditional antipsychotics for treatment-
nicant increase in mortality rate due to stroke in elderly
refractory patients, and it is efcacious even after non-
dementia patients who are treated with SGAs. All SGAs now
response to other SGAs and in partially responsive patients. It
carry this warning, and patients and families should be informed
is often rapidly effective even in those who have had a poor
of this risk prior to treatment with these agents. Dosing in the
response to other medication for years. Recent studies have
elderly is initiated lower and titration is slower than in adults.
demonstrated that it has a benecial effect for aggression and
Maximum doses are often one-half of adult doses.
suicidality, which led to the Food and Drug Administration
Dually Diagnosed
(FDA) approval for the treatment of suicidal behavior in
The prevalence of substance dependence and abuse among per- people with psychosis.41
sons with schizophrenia is signicantly higher than in the gen- A great deal of interest has been generated in understanding
eral population. Conservative estimates of the proportion of what pharmacologic properties of clozapine contribute to its
schizophrenic patients abusing alcohol and/or illicit drugs superior efcacy, but to date this has not been clearly elucidated.
range from one-third to as many as one-half.39 The most com- Clozapine has a low afnity for D2 receptors, works also on D1
mon drugs of abuse are alcohol, cannabis, and cocaine. receptors, and is a 5-HT2A antagonist. Its unsurpassed efcacy
Although, the reasons for this high comorbidity are unclear, a suggests that there is a neuropharmacologic effect associated
number of theories have been postulated, including the possi- with clozapine that is to date unique to this agent.
bility of a deciency in the dopamine-mediated brain reward Clozapines use is limited by its association with the rare but
circuit. According to this theory, patients use substances as a life-threatening risk of agranulocytosis and seizures, as well as
way to replete dopamine in the reward centers of the brain. This common unpleasant side effects including sedation, enuresis,
pleasure-seeking behavior serves in part as the basis for what is anti-cholinergic effects, weight gain, and hypersalivation. The
termed the self-medication hypothesis, in which patients are long-term hematologic monitoring (see monitoring section)
described as self-medicating with substances sometimes as a required for prevention of agranulocytosis can represent a bar-
way to counter depression, reduce anxiety, or induce sleep. rier to both patients and care providers. The optimal plasma level
Unfortunately, substance use often worsens the course and of clozapine is a minimum trough level of 300 to 350 ng/mL (300
complicates the treatment of schizophrenia. Dually-diagnosed to 350 g/L or 9181071 nmol/L), usually corresponding to a
patients are more likely to be non-compliant with treatment. daily dose of 200 to 400 mg, although dosage must be individu-
Characteristically, they have a poorer response rate to tradi- alized. According to published guidelines and recommendations,
tional antipsychotics, have more severe psychosis, and have clozapine should be considered after two failed antipsychotic
higher rates of relapse and rehospitalization compared to trials.31 Fewer than 8% of new antipsychotic prescriptions are
patients who are not abusing substances. Some studies have written for this medication annually in the United States.
found that EPS may occur more frequently in substance-
Other Strategies
abusing patients, and alcohol use is a risk factor for developing
TD. There is a growing body of literature indicating that SGAs Approximately 30% of patients treated with clozapine will not
are effective in this population, and some studies have shown a respond, and another 30% will have only a partial response to
reduction in the use of drugs and alcohol with SGAs. the drug. Treatment options with other medications are limited
after clozapine non-response. For these patients, the best evi- Generally, monotherapy at the lowest effective dose for the
dence points to augmentation using an FGA, SGA, or electro- shortest period necessary is the best strategy. High-potency
convulsive therapy (ECT). The only available data support the FGAs are associated with a low risk for congenital abnormalities;
combination of clozapine with risperidone; however, controlled however, limb defects and dyskinesias have been reported.43
trial results are mixed. Other potential strategies include com- Low-potency phenothiazine antipsychotics may increase the
bining antipsychotics with mood stabilizers (e.g., lithium, risk of congenital abnormalities when used in the rst trimester.
lamotrigine, valproate, and topiramate).31 According to the relevant literature published to date, there
appears to be little risk associated with the rst-line SGAs.44
Acutely Psychotic Patients However, on the basis of available data, generalization is impos-
Psychiatric emergencies occur in a variety of settings, including sible, and each case and specic antipsychotic should be weighed
emergency departments, psychiatric units, medical facilities, and on an individual basis. While SGAs are excreted in breast milk,
outpatient settings. Most psychiatric emergencies require both most case reports have reported a low frequency of deleterious
pharmacologic and psychological interventions. Often, the psy- effects on the infant. Women taking SGAs may have enhanced
chiatrist must make decisions based on limited information and fertility compared to women taking FGAs, as SGAs (except
history. Intramuscular (IM) formulations are available for a risperidone) are less likely to cause prolactin elevations leading
number of FGAs and two SGAs (ziprasidone and olanzapine). to anovulation. Therefore, careful discussion with patients,
These formulations are safe and effective in treating acute psy- including education about birth control, must occur.
chosis. These SGAs are now recommended as rst-line therapy
in agitated schizophrenia patients; however, IM lorazepam with
or without concomitant oral (tablets, liquid, or disintegrating Pharmacokinetics
tablets) SGAs are also used. High dosing of FGAs, termed rapid Pharmacokinetic and pharmacodynamic issues are not generally
neuroleptization, is no longer recommended. a major concern with antipsychotic treatment; however, additive
side effects may occur with combined treatment, and a few clin-
Pregnancy and Lactation ically signicant drug interactions are notable (Table 349). All of
When to use antipsychotics in pregnancy and during lactation the antipsychotics are highly protein-bound; however, protein-
remains a complicated decision based on a careful analysis of binding interactions are generally not clinically signicant.
risks and benets. Women with schizophrenia have a signi- Absorption of most antipsychotics is not affected by food, with
cantly greater risk for stillbirth, infant death, preterm delivery, the exception of ziprasidone, whose absorption is increased
low infant birth weight, and infants that are small for gesta- by 60% to 70% when given with meals. The absorption of
tional age, even in unmedicated patients. Furthermore, women quetiapine may be slightly increased when given with food.
who experience a relapse in psychotic symptoms during preg- All antipsychotics are metabolized by hepatic microsomal
nancy are at the greatest risk for birth complications.42 Because enzymes to water-soluble compounds that are excreted by the
risks related to psychotic relapse may be more detrimental kidneys. The most important of the microsomal enzymes are
than antipsychotic treatment to both mother and baby, the cytochrome P-450 (CYP450) enzymes, a group of
antipsychotics are often continued during this period. enzymes that play a major role in oxidative drug metabolism.
Essentially all antipsychotic medications pass through the Although over 30 isoenzymes of the CYP450 system have been
placenta. The use of these drugs requires critical attention to identied in humans, three play a signicant role in the
the timing of the exposure, the dose and duration of use, and metabolism of antipsychotic medications: CYP4502D6,
fetal susceptibility. When possible, discontinuing antipsy- CYP4501A2, and CYP4503A3/4. Substances that inhibit or
chotics for the rst trimester is the safest option, as weeks 6 to induce the function of these enzymes can change antipsy-
10 are the most vulnerable period for organ formation. chotic blood concentrations. For example cigarette smoking
TABLE 349. Metabolism and Drug Interactions with Antipsychotics
Major CYP450 Other CYP450 Increase Antipsychotic Decrease Antipsychotic

Antipsychotic Metabolic Enzyme Metabolic Pathways Concentrations Concentrations
Clozapine 1A2 3A3/4, 2D6, 2C19 Fluvoxamine, ciprooxacin, paroxetine Cigarette smoking
Risperidone 2D6 3A3/4
Olanzapine 1A2 2D6 Fluvoxamine, ciprooxacin, paroxetine Cigarette smoking
Quetiapine 3A3/4 2D6 Fluvoxamine, ketoconazole Carbamazepine
Ziprasidone 3A3/4 Fluvoxamine, ketoconazole Carbamazepine
Aripiprazole 3A3/4 2D6 Fluvoxamine, ketoconazole Carbamazepine
Haloperidol 2D6, 3A3/4 Fluvoxamine, uoxetine, ketoconazole Carbamazepine
Thioridazine 2D6 1A2 Fluvoxamine Cigarette smoking
Perphenazine 2D6 Fluvoxamine, uoxetine, paroxetine
CYP, cytochrome P-450 isoenzyme.
induces CYP4501A2, and therefore can decrease clozapine and Antidepressants may be useful for patients with depressive
olanzapine plasma concentrations. Table 349 lists the primary symptoms that are not due to negative symptomatology or emo-
metabolic enzymes and some potential drug interactions for the tional blunting secondary to parkinsonian-type side effects.
antipsychotic medications. Clinicians should assess the clinical Sometimes it is necessary for the clinician to treat with an anti-
impact of the addition or discontinuation of these drugs in indi- depressant to rule out depression, as it is not always possible to
vidual patients and should make appropriate adjustments when differentiate these conditions. Since suicide and depression are
necessary. Unlike the other antipsychotics, ziprasidone is mostly interconnected, aggressive treatment is necessary when depres-
metabolized by aldehyde oxidase, a metabolic system independ- sion is present. Selective serotonin reuptake inhibitors (SSRIs)
ent of the CYP450 system. Another recent discovery in drug are the preferred agents, but may inhibit the CYP450 enzymes,
metabolism of antipsychotics and their distribution involves thus raising plasma concentrations of clozapine, olanzapine, and
the transmembrane energy-dependent efux transporter, haloperidol. Mood stabilizers, such as lithium and the anticon-
P-glycoprotein, which may limit a number of drugs from pen- vulsants, have long been used adjunctively with antipsychotics to
etrating into the extracellular space.45 Antipsychotics currently treat the affective component of schizoaffective disorder.
known to use this pathway include perphenazine, haloperidol, Valproate is currently the most commonly used mood stabilizer
uphenazine, quetiapine, risperidone, and olanzapine.46 in schizophrenic patients, and its use in conjunction with cloza-
Due to its propensity to cause prolongation of the QTc inter- pine may protect against a pre-epileptic condition known as
val, the use of ziprasidone with other agents that prolong the myoclonic jerking. And nally, much research is currently
QTc interval should be avoided. These other agents include, but underway to develop better treatments for primary negative
are not limited to, anti-arrhythmic medications such as quini- symptoms and cognitive impairment; however, no approved
dine and sotalol, certain FGAs (chlorpromazine, droperidol, treatments are yet available.
mesoridazine, pimozide, and thioridazine), and certain antibi-
otics (gatioxacin, halofantrine, meoquine, moxioxacin, and
pentamidine). Ziprasidone has not been shown to have clinically OUTCOME EVALUATION
signicant drug interactions with the CYP4503A3/4 inhibitors
regarding increasing the QTc; however, higher doses, especially Patient Education
given with inhibitors of CYP4503A3/4 (e.g., ketoconazole and
Frequently, patients receive little education about schizophrenia
erythromycin), should be used cautiously. Other risk factors for
and may not have a good understanding of their diagnosis.
prolongation of the QTc interval include comorbid diabetes,
Meetings for purposes of medication management offer an
electrolyte disturbances (e.g., low sodium and potassium serum
opportunity to provide some education on the general illness.
concentrations), heavy alcohol consumption, female gender, and
Discuss the nature and course of schizophrenia and be prepared
congenital QTc disorder. Clinicians should also be vigilant to
to accept that the patient might have a different understanding
avoid pharmacodynamic interactions with any of the antipsy-
of the nature of his or her illness. Key points to cover include:
chotics involving additive side effects from combination thera-
pies. Side effects that may be worsened with combination thera-
Involve families in the education and treatment plans, since
pies include sedation, hypotension, anti-cholinergic symptoms,
family psychoeducation may decrease relapse, improve
and weight gain or metabolic abnormalities.
symptomatology, and enhance psychosocial and family
outcomes.47
Adjunct Pharmacologic Treatments Be clear that there is no cure for schizophrenia and that med-
The judicious use of pharmacologic therapies other than ications only help to decrease the symptoms.
antipsychotics may be necessary in the treatment of schizo- Explain common side effects of medications.
phrenia. Concomitant medications may be indicated for the Discuss rare but dangerous side effects which may also occur.
treatment of motor side effects, anxiety, depression, mood ele- Stress the importance of medication and treatment adher-
vation, and possibly refractory psychotic symptoms. Anti- ence for improving long-term outcomes in schizophrenia.
cholinergic medications (e.g., benztropine, 1 to 2 mg two times
daily; trihexyphenidyl, 1 to 3 mg three times daily; and diphen-
Symptom Monitoring
hydramine, 25 to 50 mg two times daily) are used to effectively
treat EPS, thereby improving the tolerability of these medica- Develop a good working alliance with the patient. When a
tions. They are usually prescribed prophylactically with high-D2- solid therapeutic foundation is not formed, patients are fre-
binding agents or in patients at risk for EPS. -Blockers (e.g., quently reluctant to share their psychotic experiences.
propranolol in doses of 30 to 120 mg/day) are sometimes effec- Frequently, patients fear that others will interpret their
tive for patients who develop akathisia. In some situations, such descriptions as crazy. Alternatively, some care providers have
as on an inpatient unit, the concomitant use of benzodiazepines told patients to keep their beliefs to themselves, as a way to
(e.g., lorazepam in doses of 1 to 3 mg/day) with the SGAs may cope with their illness in the community. In these instances, it
be necessary for agitation and insomnia. may take time to gain the patients trust and to learn enough
about the details of their life experience to explore their more

personal experiences. Once a solid working relationship and Patient Encounter, Part 4
some knowledge of the patients psychotic experiences exist,
perform a more structured interview. Many assessments are
available to more objectively rate positive and negative symp-
With his care providers, AG discussed several possible med-
toms, level of function, and life satisfaction. The most com-
ication choices. Because there had been improvement of
monly used scales include: auditory hallucinations on risperidone, the initial choice was
made to increase the dose to target the ongoing paranoid
The Positive and Negative Symptom Scale (PANSS) thinking. AG was seen weekly to monitor for emergence of
The Brief Psychiatric Rating Scale (BPRS) EPS or akathisia. He was able to tolerate an increase to 4 mg
The Clinical Global Impression (CGI) scale of risperidone daily with improvement in his paranoid
thinking. He went on several interviews for jobs and accepted
Using these scales on a regular basis, particularly when switch- part-time employment at a coffee shop. When he complained
ing medications or changing doses, is a more reliable means of of emergence of sexual dysfunction, his prolactin level was
monitoring for improvement. Certainly symptom assess- determined to be 42 ng/mL (42 g/L). He discussed risks and
benets of therapy with his clinicians and decided to continue
ments cannot capture the full range of possible improvements
risperidone for now, as he had improved in his ability to work
a patient may experience, but they can be useful in deciding
and get out more in the community. He remains interested
whether a medication is having substantial benet. in having an aripiprazole trial in the future, as he hopes he
might more easily lose the weight he gained while taking
Side Effect Monitoring olanzapine and resume normal sexual functioning. He is no
longer taking an antidepressant, and though he has some low
Regularly monitor patients for side effects and overall health
days, he does not meet the criteria for diagnosis of depressive
status while taking antipsychotic medications.48,49 Perform orthosta-
episode. He continues to be free of substance abuse, and his
tic blood pressure measurements at the initiation of antipsychotics girlfriend continues to support his treatment. He still hopes to
and throughout treatment. Ask about impaired menstruation, return to work in his eld of expertise someday.
libido, and sexual performance regularly. Encourage patients to have
annual eye exams, as several of the antipsychotic medications have Based on the information above, create a care plan for
been associated with the premature development of cataracts. Check this patients treatment. Your plan should include: (1) a
body weight, fasting glucose, glycosylated hemoglobin, and lipid statement of the drug-related concerns and/or problems,
prole at baseline, at 4 months after initiation of medication, and (2) the goals of therapy, and (3) a plan for monitoring and
then yearly.50 For patients who are at higher risk of developing follow-up to determine whether the goals have been
diabetes and those who gain weight, check body weight more achieved and adverse effects minimized.
often (Table 3410). Encourage patients to act proactively against
weight gain through healthier eating and exercise. Perform a base-
line electrocardiogram (ECG) for patients with preexisting cardio- Symptom Rating Scale (ESRS). Akathisia is commonly moni-
vascular disease and risk for arrhythmia. With clozapine therapy tored by the Barnes Akathisia Scale (BAS). The emergence of
there is a risk for the development of agranulocytosis, which is dyskinesias (writhing or involuntary movements) could
greatest in the rst 6 months of treatment. Current guidelines represent the emergence of TD. Monitor for TD at least
require the monitoring of white blood cell counts (WBC) prior to annually, and if FGAs are used patients should be evaluated
drug dispensing (Table 3411). at each visit. The most commonly used instrument to meas-
Commonly used rating scales to monitor for EPS include ure these symptoms is the Abnormal Involuntary Movement
the Simpson Angus Scale (SAS) and the Extrapyramidal Scale (AIMS).
TABLE 3410. Monitoring Protocol for Patients on Second-Generation (Atypical) Antipsychotics
Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 Years

Personal/family historya X X
Weight X X X X X
Waist circumference X X
Blood pressure X X X
Fasting plasma glucose X X X
Fasting plasma lipids X X X
a
Of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease.
From American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American
Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:
TABLE 3411. Monitoring of White Blood Cell Count and Absolute Neutrophil Count during Clozapine Treatment
Hematologic Values Frequency of WBC and ANC Monitoring

Prior to clozapine initiation Recommended levels: WBC greater than
or equal to 3,500/mm3 and ANC greater
than or equal to 2,000/mm3
No history of a myeloproliferative disorder
or clozapine-induced agranulocytosis
Initiation to 6 months WBC greater than or equal to 3,500/mm3 and Weekly for 6 months
ANC greater than or equal to 2,000/mm3
6 to 12 months WBC greater than or equal to 3,500/mm3 and Every 2 weeks for 6 months
After 12 months of therapy WBC greater than or equal to 3,500/mm3 and Every 4 weeks
Clozapine discontinuation Weekly for at least 4 weeks from day of
discontinuation
Mild leukopenia or granulocytopenia 3,500/mm3 greater than WBC greater than Twice weekly until returned to
or equal to 3,000/mm3 and/or 2,000/mm3 recommended levels
greater than ANC greater than or equal
to 1,500/mm3
Moderate leukopenia or granulocytopenia 3,000/mm3 greater than WBC greater than Interrupt therapy; monitor daily until
or equal to 2,000/mm3 and/or 1,500/mm3 WBC greater than 3,000/mm3 and
greater than ANC greater than or equal ANC greater than 1,500/mm3, then
to 1,000/mm3 twice weekly until back to
recommended levels
Severe leukopenia or granulocytopenia WBC less than 2,000/mm3 and/or Discontinue treatment and do not
or agranulocytosis ANC less than 1,000/mm3 ANC rechallenge; monitor daily until WBC
less than or equal to 500/mm3 greater than 3,000/mm3 and ANC
greater than 1,500/mm3, then twice
weekly until back to recommended
levels
ANC, absolute neutrophil count; WBC, white blood cell.

ANC = Absolute Neutrophil Count, 3500/mm3 = 3.5 103/L or 3.5 109L; 3000/mm3 = 3 103/L or 3 109L; 2000/mm3 = 2 103/L or 2 109L;
1500/mm3 = 1.5 103/L or 1.5 109L; 1000/mm3 = 1 103/L or 1 109L; 500/mm3 = 0.5 103/L or 0.5 109L.
1. Assess the patients symptoms, review patient and family history, and obtain initial medical evaluation to rule out other
causes of psychosis.
2. Periodically review patient data for consistency with diagnostic criteria, and regularly monitor changes in symptomatology.
3. Obtain a thorough history of prescription medication use, and determine what treatments have been helpful in the past,
which treatments the patient is currently receiving, and previous side effects experienced.
4. Determine whether the patient is taking an appropriate antipsychotic drug and dose and whether the patient has other
symptoms that may need to be treated.
5. Educate the patient, and the family if possible, about the disease state, medication treatments, possible side effects, and goals
of treatment.
6. Develop a plan to assess the effectiveness of the current treatment regimen. Also, consider alternative treatments if current
treatment is ineffective.
7. Encourage a healthy lifestyle, including eliminating or decreasing substance abuse and cigarette use, as well as appropriate
nutritional counseling and exercise suggestions.
8. Determine the role of psychosocial treatments.
9. Evaluate the patient for the presence of adverse drug reactions, drug interactions, and allergies.
10. Monitor the appropriate laboratory measures to prevent or minimize metabolic abnormalities and other side effects.
11. Stress the importance of adherence with the treatment regimen, and maintain treatment even if the patient is feeling well.
5-HT: serotonin American Diabetes Association, American Psychiatric Association,

AIMS: Abnormal Involuntary Movement Scale American Association of Clinical Endocrinologists, North
ANC: absolute neutrophil count American Association for the Study of Obesity. Consensus
BAS: Barnes Akathisia Scale development conference on antipsychotic drugs and obesity
BPRS: Brief Psychiatric Rating Scale and diabetes. Diabetes Care 2004;27:596601.
CBT: cognitive-behavioral therapy American Psychiatric Association. Practice guidelines for the treat-
CGI: Clinical Global Impression scale ment of patients with schizophrenia. Am J Psychiatry 2004;
COMT: catechol-O-methyltransferase 161(Feb. Suppl):156.
CR: cognitive remediation Conley RR, Kelly DL. Management of treatment resistance in schizo-
CT: computed tomography phrenia. Biol Psychiatry 2001;50:898911.
CYP450: cytochrome P-450 isoenzyme Kelly DL, Carpenter WT, Conley RR. First episode schizophrenia: A
D: dopamine focus on pharmacologic treatment and safety considerations.
DSM-IV-TR: Diagnostic and Statistical Manual of Mental Drugs 2005;65:11131138.
Disorders, Fourth Edition, Text Revision Lehman AF, Kreyenbuhl J, Buchanan RW, et al. The schizophrenia
ECG: electrocardiogram patient outcomes research team (PORT): updated treatment
ECT: electroconvulsive therapy recommendations 2003. Schizophr Bull 2004;30:193217.
EOS: early-onset schizophrenia Lieberman JA, Stroup TS, McEvoy JP, et al. Clinical antipsychotic trials
EPS: extrapyramidal side effects of intervention effectiveness (CATIE) investigators. Effectiveness
ESRS: Extrapyramidal Symptom Rating Scale of antipsychotic drugs in people with chronic schizophrenia. N
FDA: Food and Drug Administration Engl J Med 2005;353:12091223.
FGA: rst-generation antipsychotic Maguire GA. Comprehensive understanding of schizophrenia and its
H: histamine treatment. Am J Health Syst Pharm 2002; 59(17 Suppl 5):S4S11.
IM: intramuscular Marder SR, Essock SM, Miller AL, et al. Physical health monitoring of
M: muscarinic patients with schizophrenia. Am J Psychiatry 2004;161:13341349.
MRI: magnetic resonance imaging Perkins DO. Predictors of noncompliance in patients with schizo-
NMS: neuroleptic malignant syndrome phrenia. J Clin Psychiatry 2002;63:11211128.
PANSS: Positive and Negative Symptom Scale Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic
PET: positron emission tomography drug-drug interactions. Psychosomatics 2005;46:464494.
PORT: Schizophrenia Patient Research Outcomes Team
SAS: Simpson Angus Scale
SGA: second-generation antipsychotic
SSRI: selective serotonin reuptake inhibitor
SST: social skills training
TD: tardive dyskinesia
TIMA: Texas Implementation of Medication Algorithms
VEOS: very early-onset schizophrenia
WBC: white blood cell


this chapter.
35 MAJOR DEPRESSIVE DISORDER
Marshall Cates, Angela Ann Boggs, and Jacqueline Feldman
LEARNING OBJECTIVES
1. Explain the etiology and pathophysiology of major depressive disorder.

2. Identify symptoms and clinical features of major depressive disorder.
3. Differentiate antidepressants according to pharmacologic properties, adverse-effect proles,
pharmacokinetic proles, drug interaction proles, and dosing features.
4. Predict adverse-effect proles of antidepressants based on pharmacology.
5. State the goals of pharmacotherapy in major depressive disorder.
6. Educate patients and caregivers on the proper use of antidepressants.
KEY CONCEPTS Pediatric patients should be observed closely for suicidality,

worsened depression, agitation, irritability, and unusual changes
Classic views as to the cause of major depressive disorder focus in behavior, especially during the initial few months of therapy or
on the monoamine neurotransmitters norepinephrine (NE), at times of dosage changes. Furthermore, families and caregivers
serotonin (5-HT), and to a lesser extent, dopamine (DA) in should be advised to monitor patients for such symptoms.
terms of both synaptic concentrations and receptor functioning. Lack of patient understanding concerning optimal antide-
It is not uncommon for a patient to experience only a single pressant drug therapy frequently leads to partial compliance
major depressive episode, but most patients with major or non-compliance with therapy; thus, the primary purpose
depressive disorder will experience multiple episodes. of antidepressant counseling is to enhance compliance and
One extremely important outcome in the treatment of major improve outcomes.
depressive disorder is the prevention of suicidal attempts.
Sexual dysfunction is common and challenging to manage and My spirit is broken,
often leads to non-compliance with serotonergic medications. my days are cut short,
Each antidepressant has a response rate of approximately 60% the grave awaits me.
to 80%, and no antidepressant medication or class has been Job 17:1
reliably shown to be more efcacious than another.
It is widely accepted that it takes approximately 2 to 4 weeks of Contrary to popular belief, major depression is not a eeting
treatment before improvement is seen in emotional symptoms bad day, is not the result of personal weaknesses or charac-
of depression, such as sadness and anhedonia. Furthermore, it ter aws, and does not respond to volitional efforts simply to
may take as long as 6 to 8 weeks of treatment to see the full feel better. Rather, major depressive disorder (MDD) is a seri-
effects of antidepressant therapy. ous medical condition with a biologic foundation, and it
Since the typical major depressive episode lasts 6 months or responds to biologic and psychological treatments. Individuals
longer, if antidepressant therapy is interrupted for any reason who suffer from MDD experience signicant and pervasive
following the acute phase, the patient may relapse into the symptoms that can affect such things as mood, thinking,
depressive episode. When treating the rst depressive episode, physical health, work, and relationships. Unfortunately, sui-
antidepressants must be given for an additional 4 to 9 months in cide is often the result of MDD that has not been diagnosed
the continuation phase for the purpose of preventing relapse. and treated adequately.
569
ETIOLOGY/PATHOPHYSIOLOGY
The exact cause of MDD remains unknown, but it is probably
multifactorial. Biologic, psychological, and social theories
ML, a 28-year-old white woman, comes into your clinic for the
abound, and many practitioners suggest that the development
rst time complaining of decreased sleep, pain, and lack of of depression often is predicated on the complex synthesis of
energy. On interviewing her, you learn that she is also having genetic predisposition, psychological stressors, and biologic
frequent crying spells and no longer participates in the bowl- pathophysiology. Although knowledge certainly continues to
ing league, which she used to enjoy every weekend. She fears accumulate in this area, there are currently no accepted unify-
that she is about to be red from her job because of numerous ing theories that explain these various factors adequately.
sick days and the inability to concentrate on tasks when she is
at work, and she claims that she is already under a great deal
of nancial stress owing to the fact that her husband lost his Genetics
job several months ago. She states that she has been suffering
The occurrence of MDD shows a familial pattern because
from these problems for the past two months and is feeling
frustrated and hopeless. She admits to drinking about three to
rst-degree relatives of MDD patients are about three times
four beers per night in order to relax and fall asleep. more likely to develop MDD compared with rst-degree rela-
tives of normal control individuals. Adoption studies and twin
What information is suggestive of MDD? studies reveal that the familial aggregation of MDD is due to
What medical or psychiatric issues could be contributing genetic inuences.5
to her symptoms?
Does she have risk factors for depression?
What additional information do you need to know before Life Stress
creating a treatment plan for this patient? Depression can occur despite the absence of major life stressors,
and conversely, major life stressors do not invariably cause
depression. Nevertheless, there is an undeniable association
Owing to increased awareness of the illness and the advent of between life stressors and depression, and there appears to be a
newer and safer antidepressant medications, the past two signicant interaction between life stressors and genetic liabil-
decades have seen improvements in the screening, diagnosis, ity in causing depression.6 Although acute stressors may pre-
and treatment of MDD. The willingness of generalist practition- cipitate depression, chronic stressors have a longer risk period,
ers to involve themselves in the identication and treatment of cause longer episodes, and are more likely to lead to relapse and
MDD is noteworthy. To that end, antidepressants have become recurrence.6
some of the most commonly prescribed drugs, and they account
for 10 of the top 100 prescription drugs dispensed in the United
States.1 Despite recent increases in the treatment of MDD, inad- Monoamine Neurotransmitter and
equate treatment remains a serious concern.2 Receptor Hypotheses
Classic views as to the cause of MDD focus on the
EPIDEMIOLOGY monoamine neurotransmitters norepinephrine (NE), sero-
tonin (5-HT), and to a lesser extent, dopamine (DA) in terms
MDD is quite common; lifetime and 12-month prevalence of both synaptic concentrations and receptor functioning. The
estimates are 16.2% and 6.6%, respectively. Thus, approxi- monoamine hypothesis asserts that depression is due to a
mately 35 million United States adults will experience MDD deciency of monoamine neurotransmitters. The major sup-
in their lifetime.2 Females are approximately twice as likely as porting evidence for this hypothesis is that existing antide-
males to experience MDD.2 Although MDD may begin at any pressants increase synaptic monoamine concentrations
age, the average age at onset is the mid-20s.3 Interestingly, through various mechanisms (see Pharmacology section).
MDD appears to occur earlier in life in people born in more One argument against the monoamine hypothesis is that
recent decades.2 Most patients with MDD also suffer from depressed patients do not consistently exhibit decreased
comorbid psychiatric disorders, especially anxiety disorders monoamine concentrations. Another problem is that
and substance-use disorders.2 whereas monoamine levels are altered within hours of the
MDD causes serious impairment. According to the World introduction of antidepressant therapy, there is a latency
Health Organization (WHO), depression is the leading cause of period of weeks before the actual antidepressant effect typi-
disability (based on years lived with disability) and the fourth cally is evident.79
leading contributor to the global burden of disease (based on The neurotransmitter receptor hypothesis suggests that
disability adjusted life years).4 Those with 12-month MDD depression is related to abnormal functioning of neurotransmit-
reported a mean of about 35 days in the past year in which they ter receptors. In this model, antidepressants presumably exert
were unable to work or carry out usual activities.2 therapeutic effects by altering receptor sensitivity. In fact,
CHAPTER 35 / MAJOR DEPRESSIVE DISORDER 571
chronic administration of antidepressants has been shown to

cause desensitization, or down-regulation, of -adrenergic Clinical Presentation
receptors and various 5-HT receptors. Importantly, the time
required for changes in receptor sensitivity corresponds to the
onset of action of antidepressant therapy.79
Patients typically present with a combination of emotional,
While such models of depression are quite useful in concep-
physical, and cognitive symptoms:
tualizing the mechanisms behind antidepressant activity, they Emotional
are assuredly an oversimplication of the actual pathophysio- Sadness
logic process of the disorder. Depression probably involves a Anhedonia
complex dysregulation of monoamine systems, and these sys- Pessimism
tems, in turn, modulate and are modulated by other neurobio- Feeling of emptiness
logic systems. Thus, the underlying cause of depression may well Irritability
extend beyond dysfunction of the monoamine system.10 Anxiety
Worthlessness
Thoughts of death/suicidal ideation (SI)
Other Neurobiologic Hypotheses Physical
Disturbed sleep
Various other hypotheses have been proposed to help explain
Change in appetite/weight
the cause of depression. These hypotheses are related to such Psychomotor changes
things as the role of non-monoamine neurotransmitters [e.g., Decreased energy
glutamate and gamma-aminobutyric acid (GABA)], neuroen- Fatigue
docrine systems (e.g., the hypothalamic-pituitary-adrenal Bodily aches and pain
axis), neurosteroids (e.g., allopregnanolone), and neuronal Cognitive
plasticity [e.g., brain-derived neurotrophic factor (BDNF)].11 Impaired concentration
Researchers are even starting to gain insight on the intracellu- Indecisiveness
lar level with ndings related to messenger cascades and gene Poor memory
expression.12
Occasionally, severely depressed patients also will present
with psychotic symptoms:
CLINICAL PRESENTATION AND DIAGNOSIS Hallucinations
Delusions
The diagnosis of a major depressive episode requires the pres-
ence of a certain number of depressive symptoms (ve) for a Some patients present with atypical features of depression:
minimum specied duration (2 weeks) that cause clinically
signicant effects (Table 351).3 Reactive mood (i.e., mood improves in response to posi-
tive events)
Signicant increase in appetite/weight gain
Hypersomnia
TABLE 351. Diagnostic Criteria for Major Depressive Episode3 Heavy feelings in arms or legs
Sensitivity to interpersonal rejection
At least ve of the following symptoms have been present during
the same 2-week period and represent a change from previous
functioning:
Depressed mooda HIINT: In order to remember the nine diagnostic symptoms
Markedly diminished interest or pleasure in usual activitiesa for a major depressive episode, learn the following mnemonic:
Increase or decrease in appetite or weight Depression = SIG E CAPS (depression, sleep, interest, guilt,
Increase or decrease in amount of sleep
Increase or decrease in psychomotor activity energy, concentration, appetite, psychomotor, suicide).
Fatigue or loss of energy In turn, the diagnosis of MDD is based on the presence
Feelings of worthlessness or guilt of one or more major depressive episodes during a persons
Diminished ability to think, concentrate, or make decisions lifetime.3
Recurrent thoughts of death, suicidal ideation, or suicide
attempt
Differential Diagnosis
The symptoms cause clinically signicant distress or impairment in
functioning. Major depressive episodes also occur in the context of bipolar
The symptoms are not due to the direct physiologic effects of a disorder. The key difference is that persons with bipolar disorder
substance or medical condition. also experience manic, hypomanic, and/or mixed episodes (see
a
One of these two symptoms must be present. Chap. 36) during the course of their illness, whereas persons
With permission. with MDD experience only major depressive episodes.3
The presence of a signicant medical disorder can produce

depressive symptoms via either psychological or physiologic Patient Encounter, Part 2: The Medical
mechanisms. Examples include hypothyroidism, anemia, infec- History, Physical Exam and Diagnostic
tions, electrolyte disturbances, cardiovascular diseases, neuro- Tests
logic disorders, and many others.9 Various psychiatric condi-
The work-up on ML reveals
tions, such as substance-use disorders and anxiety disorders,
have been associated with depression as well.9 The use of central PMH
Chronic back pain since motor vehicle accident 3 years
nervous system (CNS) depressants, such as benzodiazepines and
ago.
narcotics, is associated with increased propensity for depres-
sion.13 Medical drugs that reportedly cause depressive symp- PPH
Non-contributory
toms or depressive-like side effects include corticosteroids, con-
traceptives, gonadotropin-releasing hormone agonists, inter- FH
feron-, interleukin-2, meoquine, propranolol, and sotalol.14 Mother with diabetes mellitus and MDD.
Father is alive and well with no medical problems.
Brother is a recovered alcoholic.
COURSE/PROGNOSIS SH
Works as a secretary for a construction company. For the past
several months has been drinking three to four beers per night.
Symptoms of a major depressive episode usually develop
She denies smoking cigarettes or using illicit substances.
over days to weeks, but mild depressive and anxiety symp-
Current Meds
toms may last for weeks to months prior to the onset of the
Lo/Ovral 1 tablet every day
full syndrome. Left untreated, major depressive episodes
Oxycontin 10-mg tablet twice daily
typically last 6 months or more, but a minority of patients
ROS
experience chronic episodes that can last for at least 2 years.
Decreased energy
Approximately two-thirds of patients will recover fully from
Decreased sleep
major depressive episodes and return to usual mood and full All others non-contributory
functioning, whereas the other third will have partial remis-
PE
sion and may continue to experience detrimental effects.3
Height: 5 ft, 2 in (157 cm); weight: 116 lbs (52.7 kg);
The course of MDD varies markedly from patient to weight loss of 10 lbs (4.5 kg) over past 2 months
patient. It is not uncommon for a patient to experience only
MSE
a single major depressive episode, but most patients with MDD
Depressed mood
will experience multiple episodes. Some patients experience Decreased concentration
isolated episodes separated by many years, others have clusters Thoughts of dying, but no suicidal ideation
of episodes, and still others will suffer more frequent episodes
Labs
as they age. The number of prior episodes predicts the likeli- Within normal limits. Pregnancy test negative.
hood of developing subsequent episodes such that by the time
a patient experiences a third major depressive episode, there is Given this additional information, what is your assess-
about a 90% chance that he or she will have a fourth one. ment of the patients condition?
MDD is associated with a high mortality rate because about Identify your treatment goals for the patient.
15% of patients ultimately will commit suicide.3 What non-phamacologic and pharmacologic alternatives
are available for this patient?
TREATMENT
Nonpharmacologic/Alternative Therapies
Desired Outcomes Interpersonal therapy and cognitive behavioral therapy are types
The obvious goal of therapy for the depressed patient is the of psychotherapy that have well-documented efcacy for the
resolution of depressive symptoms and a return to euthymia. treatment of MDD. Psychotherapy alone is an initial treatment
Once symptoms have resolved, then the purpose of ongoing option for mild to moderate cases of depression, and it may be
therapy is to prevent relapse and recurrence of depressive useful when combined with pharmacotherapy in the treatment
symptoms. One extremely important outcome in the treat- of more severe cases of depression. In fact, the combination of
ment of MDD is the prevention of suicidal attempts. Other psychotherapy and pharmacotherapy can be more effective than
essential outcomes include improvement of the patients qual- either treatment modality alone in cases of severe or recurrent
ity of life, normalization of functioning in areas such as work MDD. Psychotherapy can be especially helpful for patients with
and relationships, avoidance or minimization of adverse signicant psychosocial stressors, interpersonal difculties, or
effects, and reduction of health care costs.15 comorbid personality disorders.16
Electroconvulsive therapy (ECT) is a highly efcacious may reduce depressive symptoms, but well-controlled studies
treatment for MDD. The response rate is about 80% to 90% are needed to clarify its role in the treatment of depression.18
and even exceeds 50% for patients who have failed pharma-
cotherapy.16,17 ECT may be particularly benecial for MDD
that is complicated by psychotic features, severe suicidality,
refusal to eat, pregnancy, or contraindication/non-response to Clinical Distinctions
pharmacotherapy.16,17 ECT is typically a very safe treatment Given that there are now about 25 antidepressant medica-
alternative, but various cautions do exist, and the chief side tions, one apparent clinical perplexity is for the clinician to
effects are confusion and memory impairment.16 distinguish the various agents. But each antidepressant has its
St. Johns wort (Hypericum perforatum) is an herbal med- unique blend of characteristics, and in fact, even individual
ication that has shown some efcacy in mild to moderate drugs within the same class have important differences.22
depression but minimal efcacy for moderate to severe
depression.18 Many patients may believe that herbal medica- General Pharmacology
tions, being natural products, are devoid of adverse effects Table 352 demonstrates the differing pharmacologic proper-
and drug interactions; however, St. Johns wort can cause gas- ties of the antidepressant medications,79 whereas Table 353
trointestinal irritation, headache, fatigue, and nervousness,17 delineates the results of those pharmacologic actions.7,8
and it triggers drug interactions through induction of Monoamine oxidase inhibitors (MAOIs) inhibit the enzyme
CYP3A4, as well as other potential mechanisms.19 The safety responsible for the intraneuronal breakdown of 5-HT, NE,
and efcacy of St. Johns wort combined with standard anti- and DA. Tricyclic antidepressants (TCAs) possess both 5-HT
depressant medications remain unknown.16 reuptake inhibition (SRI) and NE reuptake inhibition (NRI)
Light therapy is an alternative treatment for depression properties but unfortunately also block the so-called dirty
associated with seasonal (e.g., winter) exacerbations. Possible receptors, including 1-adrenergic, histamine-1, and mus-
side effects include eye strain, headache, insomnia, and hypo- carinic cholinergic receptors, which do not contribute to ef-
mania.16,17 Also, potentially vulnerable patients, such as those cacy but do cause problematic adverse effects. The selective
with photosensitivity or a history of skin cancer, should be eval- serotonin reuptake inhibitors (SSRIs) are classied as such
uated carefully prior to therapy.16 because SRI is the predominant effect. Bupropion is an NE
Vagus nerve stimulation (VNS) may be used for adult and DA reuptake inhibitor (NDRI). Venlafaxine and duloxe-
patients with treatment-resistant depression. A pulse gener- tine are 5-HT and NE reuptake inhibitors (SNRIs) but are also
ator is surgically implanted under the skin of the left chest, weak inhibitors of DA reuptake. Compared with venlafaxine,
and an electrical lead connects the generator to the left vagus which has primarily SRI activity, duloxetine has more bal-
nerve. Stimulation of this nerve sends signals to the brain. anced SRI and NRI activities and has a higher afnity for the reup-
This therapy is intended to be used along with traditional take sites. Nefazodone and trazodone are 5-HT antagonists/
therapies, such as pharmacotherapy and ECT.20 reuptake inhibitors (SARIs). Their SRI activity is not as
Transcranial magnetic stimulation is a non-invasive and pronounced as that of SSRIs, but they potently block 5-HT2A
well-tolerated procedure that has shown promise as a novel anti- receptors, which allows more 5-HT to interact at postsynaptic
depressant treatment.21 Some data show that physical exercise 5-HT1A sites. In addition, trazodone blocks histaminergic and
TABLE 352. Primary Pharmacologic Actions of Antidepressantsa79
Action MAOIs TCAs SSRIs Bupropion Venlafaxine Duloxetine Trazodone Nefazodone Mirtazapine
Monoamine oxidase inhibition X
Serotonin reuptake inhibition X X X X X X
Norepinephrine reuptake inhibition X X X X
Dopamine reuptake inhibition X
2-Adrenergic receptor blockade X
Serotonin-2A receptor blockade X X X
Serotonin-2C receptor blockade X
Serotonin-3 receptor blockade X
1-Adrenergic receptor blockade X X X
Histamine-1 receptor blockade X X X
Muscarinic cholinergic X
receptor blockade
a
Please see text for discussion of more secondary pharmacologic actions.
MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
TABLE 353. Efcacy/Adverse-Effect Proles Based on extreme form can lead to paralytic ileus. It is very important
Pharmacology7,8 to note that TCAs have a quinidine-like effect on the heart,
which makes them quite toxic in overdose situations. The
Pharmacologic Action Result
average lethal dose in a young adult is only 30 mg/kg, which is
Serotonin reuptake Antidepressant and antianxiety efcacy typically less than a 1-months supply of medicine.7,9,22,23
inhibition (SRI) (via interaction of serotonin
The adverse-effect prole of the SSRIs reveals the strong sero-
at 5HT-1A receptors)
Anxiety, insomnia, sexual dysfunction tonergic inuence of these drugs. Sexual dysfunction (e.g., delayed
(via interaction of serotonin at or absent orgasms), CNS stimulation (e.g., nervousness and
5HT-2A receptors) insomnia), and gastrointestinal disturbances (e.g., nausea
Anxiety, anorexia (via interaction of and diarrhea) are frequent serotonergic adverse effects.7,9,22,23
serotonin at 5HT-2C receptors)
Nausea, GI problems (via interaction
Sexual dysfunction is common and challenging to manage and
of serotonin at 5HT-3 receptors) often leads to non-compliance with serotonergic medications.24
Norepinephrine reuptake Antidepressant efcacy Various strategies have been used by clinicians to deal with anti-
inhibition (NRI) Tremor, tachycardia, sweating, depressant-induced sexual dysfunction, including waiting for
jitteriness, increased blood pressure symptoms to subside, reducing the dosage, permitting periodic
Dopamine reuptake Antidepressant efcacy
drug holidays, prescribing adjunctive therapy, and switching
inhibition (DRI) Euphoria, psychomotor activation,
aggravation of psychosis antidepressants.25 However, waiting for symptoms to subside
2-Adrenergic receptor Increase in serotonergic and usually does not work because sexual dysfunction may very
blockade noradrenergic activitysee actions well persist throughout the duration of therapy, and both
of SRI and NRI above reducing the dose and using drug holidays have the potential
Serotonin-2A receptor Antianxiety efcacy
for weakening the therapeutic effects of the medications.
blockade Increased REM sleep, decreased
sexual dysfunction Thus, clinicians often prescribe adjunctive therapy, such as
Serotonin-2C receptor Antianxiety efcacy dopaminergic drugs (e.g., bupropion or amantadine), 5-HT2
blockade Increased appetite/weight gain antagonists (e.g., cyproheptadine and nefazodone), and phos-
Serotonin-3 receptor Antinauseant, decreased GI problems phodiesterase inhibitors (e.g., sildenal), or simply switch to
blockade
antidepressants with far less chance of causing these effects,
1-Adrenergic receptor Orthostatic hypotension, dizziness,
blockade reex tachycardia such as bupropion, mirtazapine, and nefazodone.24,25
Histamine-1 receptor Sedation, weight gain Bupropion causes insomnia, nightmares, decreased appetite,
blockade anxiety, and tremors, but the most concerning adverse effect is
Muscarinic cholinergic Dry mouth, blurred vision, seizures. Because of the risk for seizures, patients who should not
receptor blockade constipation, urinary hesitancy,
receive the drug include those with a CNS lesion or those with a
sinus tachycardia, memory
problems history of seizures, head trauma, or bulimia. The daily dose of
bupropion should not exceed 450 mg/day, and any single dose of
the immediate-release formulation should not exceed 150 mg/day
Occurrences of insomnia and/or nightmares often respond to
moving the last daily dose from bedtime to late afternoon.7,9,22,23
-adrenergic receptors, whereas nefazodone possesses weak The adverse effects of SNRIs look fairly similar to those of
NRI and -adrenergic blocking properties. Finally, mirtaza- SSRIs. Nausea can be particularly troublesome with venlafaxine,
pine is a noradrenergic and specic serotonergic antidepressant which sometimes necessitates using lower starting dosages than
(NaSSA). It blocks presynaptic 2 receptors, both autorecep- usual and giving the medication with food. A dose-related ele-
tors on noradrenergic neurons and heteroreceptors on sero- vation in blood pressure can occur at higher doses, probably
tonergic neurons, with resulting increases in NE and 5-HT owing to the NRI effects. Blood pressure monitoring should be
synaptic concentrations, respectively. Mirtazapine also blocks conducted for patients receiving venlafaxine therapy. As a rule,
various postsynaptic serotonergic receptors and histamine-1 duloxetine should not be prescribed to patients with extensive
receptors.79 alcohol use or evidence of chronic liver disease owing to the
potential for hepatic injury.9,22,26,27
Adverse Effects Trazodone routinely causes sedation, which is why it is used
The important adverse effects of the various antidepressants are far more often as an adjunct with other antidepressants for
often a function of their underlying pharmacologic proles7,8 sleep than as a primary agent for the treatment of depression.
(Table 353). TCAs cause problematic sedative, anticholinergic, Priapism is a rare but serious adverse effect in males who take
and cardiovascular adverse effects owing to their interaction trazodone. In addition, orthostatic hypotension and dizziness
with dirty receptors. While these adverse effects generally are are more common with trazodone than with nefazodone
considered to be common and bothersome, they can be quite because the latter agent has a weaker effect at -adrenergic
serious in certain cases. For example, constipation in its receptors and also has a balancing of adrenergic effects owing
TABLE 354. Relative Incidence of Adverse Effects of Various Newer Antidepressants9,13,28
Sexual
Drug Sedation Activation Weight Gain Weight Loss GI Upset Dysfunction
Bupropion Min High Min Low Mod Min
Citalopram Min Min Min Min High High
Fluoxetine Min High Min Min High High
Mirtazapine Mod Min Low Min Min Min
Nefazodone Low Min Min Min Low Min
Paroxetine Low Low Min Min High High
Sertraline Min Mod Min Min High High
Venlafaxine Low Mod Min Min High High
Min, minimal; mod, moderate.

High greater than Mod greater than Low greater than Min.
to weak NRI activity. Unfortunately, nefazodone has been venlafaxine are relatively short compared with the other agents.
associated with development of hepatotoxicity, which has led Conversely, uoxetine has a very long half-life (i.e., many days)
to a black-box warning and a great reduction in its use.7,9,22,23 with chronic dosing, and its active metabolite (noruoxetine)
Mirtazapine can cause sedation and weight gain by virtue has an even longer half-life. Owing to the extremely long half-
of blocking histamine-1 receptors. Despite being partially a life of uoxetine and its active metabolite, the clinician must be
serotonergic drug, it rarely causes serotonergic-related adverse aware that about 5 weeks are required to either reach steady-
effects because it blocks the various postsynaptic 5-HT recep- state levels or to wash out after discontinuation of therapy.
tors. Although it carries a black-box warning for neutropenia Sertraline and citalopram are the other SSRIs with active
owing to a handful of cases reported during clinical trials, it is metabolites, but these metabolites (desmethylsertraline and
questionable whether neutropenia is any more problematic desmethylcitalopram, respectively) are only about one-eighth
with this agent versus other antidepressants.9,22,23 as potent as the parent compounds in terms of SRI activity.
The relative incidence of adverse effects among some of the
newer antidepressant agents are shown in Table 354.9,13,28 Drug Interactions
The major drug interactions of antidepressants are shown in
Pharmacokinetic Parameters Table 356.9,19,30 Antidepressants cause both pharmacody-
Pharmacokinetic parameters of the newer antidepressants namic (e.g., additive pharmacologic effects) and pharmacoki-
are shown in Table 355.9,29 Several antidepressants are not netic (e.g., changes in drug levels) interactions with other
very highly protein bound, and the most notable of these is medications.
venlafaxine. The elimination half-lives of nefazodone and The usual pharmacodynamic interactions involve the
dirty receptors blocked by some antidepressants. Hence
TABLE 355. Pharmacokinetic Parameters of Newer especially TCAs can cause signicant additive effects with
Antidepressants drugs that cause sedation, hypotension, or anticholinergic
effects. Similarly, nefazodone and mirtazapine can interact
Protein Half-Life Active with other drugs that cause hypotensive and sedative effects,
Drug Binding (%) (hours) Metabolite(s)
respectively. By far the most concerning pharmacodynamic
Bupropion 84 1021 Yes interactions are hypertensive crisis and serotonin syndrome,
Citalopram 80 33 Yes which are both potentially life-threatening when they occur.
Duloxetine 90 919 No
Escitalopram 56 2732 No
Hypertensive crisis is characterized by sharply elevated
Fluoxetine 94 46 days with Yes blood pressure, occipital headache, stiff or sore neck, nausea,
chronic dosing; vomiting, and sweating. It may result during MAOI therapy
416 days if the patient takes a sympathomimetic drug, such as
(active ephedrine, pseudoephedrine, phenylephrine, or phenyl-
metabolite)
Fluvoxamine 77 1526 No
propanolamine, or if the patient consumes foods rich in tyra-
Mirtazapine 85 2040 No mine, such as tap beers, aged cheeses, fava beans, yeast extracts,
Nefazodone 99 24 Yes liver, dry sausage, sauerkraut, or tofu.23 There are extensive lists
Paroxetine 95 21 No of foods and drinks that are permitted and not permitted dur-
Sertraline 98 27 Yes ing therapy with MAOIs, and these always should be provided
Venlafaxine 27 5 Yes
to patients for their safety. Furthermore, since many over-the-
Data from references 9 (with permission) and 29. counter products contain sympathomimetics, patients always
TABLE 356. Drug Interactions of Antidepressantsa9,19,30
Antidepressants Type of Interaction Examples of Interacting Drugs

TCAs Pharmacodynamicadditive sedation Benzodiazepines
Trazodone Alcohol
Mirtazapine Antihistamines
TCAs Pharmacodynamicadditive Prazosin
Trazodone hypotensive effects Antipsychotics
TCAs Pharmacodynamicadditive Phenothiazines
anticholinergic effects Benztropine
TCAs Pharmacodynamicadditive Thioridazine
cardiac toxicity Quinidine
TCAs Pharmacodynamicdecreased Guanethidine
antihypertensive effect Clonidine
Methyldopa
Bupropion Pharmacodynamicincreased TCAs
seizure risk Phenothiazines
MAOIs Pharmacodynamichypertensive crisis Tyramine-rich foods
Sympathomimetics
MAOIs Pharmacodynamicserotonin syndrome Serotonergic antidepressants
TCAs Meperidine
SSRIs Dextromethorphan
SNRIs Tramadol
SARIs
Fluvoxamine PharmacokineticCYP1A2 inhibition TCAs
Clozapine
Theophylline
Fluoxetine PharmacokineticCYP2C inhibition TCAs
Fluvoxamine Phenytoin
Sertraline Warfarin
Tolbutamide
Fluoxetine PharmacokineticCYP2D6 inhibition TCAs
Paroxetine Haloperidol
Duloxetine Risperidone
Sertraline Codeine
Propranolol
Propafenone
Nefazodone PharmacokineticCYP3A4 inhibition TCAs
Fluoxetine Alprazolam
Fluvoxamine Verapamil
Carbamazepine
Lovastatin
a
Not an all-inclusive list.
MAOI, monoamine oxidase inhibitor; SARI, serotonin antagonist and reuptake inhibitor; SNRI, serotonin and
norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
should be told to consult with their clinician and/or pharma- Several antidepressants, including most of the SSRIs, nefa-
cist prior to using these drugs. Serotonin syndrome is charac- zodone, and duloxetine, are known to inhibit various cytochrome
terized by confusion, restlessness, fever, abnormal muscle P-450 isoenzymes, thereby elevating plasma levels of substrates
movements, hyperreexia, sweating, diarrhea, and shivering.31 for those isoenzymes and thus potentially leading to increased
It may result when a serotonergic agent is added to any sero- adverse effects or toxicity of those drugs. The propensity to cause
tonergic antidepressant, but the MAOIs are strongly associated these drug interactions will vary with the particular antidepres-
with severe cases of serotonin syndrome.31 Serotonin syn- sant and the precise isoenzyme9,19,30 (Table 356).
drome is complicated by the general unawareness of clinicians
of its diagnosis,31 as well as the fact that many drugs are not Dosing
obviously serotonergic in nature, such as dextromethorphan, As can be seen in Table 357, antidepressants are available in
meperidine, and tramadol. several different dosage forms.13,1618,29,32 The extended-release
TABLE 357. Dosing of Antidepressants in Adult Patients13,1618,29,32
Initial Dose Usual Dosage Usual Dosing

Generic Name Brand Name Generic Dosage Forms (mg/day) Range (mg/day) Schedule
MAOIs
Phenelzine Nardil No Tablet 1530 1590 Twice daily
Tranylcypromine Parnate No Tablet 1020 3060 Twice daily
TCAs and Tetracyclics
Amitriptyline Elavila Yes Tablet 2550 100300 Once daily
Amoxapine Asendina Yes Tablet 2550 100400 Once to twice daily
Clomipramine Anafranil Yes Capsule 25 100250 Once daily
Desipramine Norpramin Yes Tablet 2550 100300 Once daily
Doxepin Sinequan Yes Capsule, solution 2550 100300 Once daily
Imipramine Tofranil Yes Tablet, capsule (PM) 2550 100300 Once daily
Maprotiline Ludiomila Yes Tablet 5075 100225 Once to twice daily
Nortriptyline Pamelor Yes Capsule, solution 25 50150 Once daily
Protriptyline Vivactil No Tablet 510 1560 Once daily
Trimipramine Surmontil No Capsule 2550 100300 Once daily
SSRIs
Citalopram Celexa Yes Tablet, solution 20 2060 Once daily
Escitalopram Lexapro No Tablet, solution 10 1020 Once daily
Fluoxetine Prozac Yes Tablet, capsule; 1020 2080 Once daily
solution
Prozac No Delayed-release capsule 90 Once weekly
Weekly
Fluvoxamine Luvoxa Yes Tablet 50 50300 Twice daily
Paroxetine Paxil Yes Tablet, suspension 1020 2050 Once daily
Paxil CR No Controlled-release tablet 12.525 2562.5 Once daily
Sertraline Zoloft No Tablet, concentrate 2550 50200 Once daily
NDRI
Bupropion Wellbutrin Yes Tablet 150200 300450 Twice to thrice daily
Wellbutrin SR Yes Sustained-release tablet 150 300400 Twice daily
Wellbutrin XL No Extended-release tablet 150 300450 Once daily
SNRIs
Duloxetine Cymbalta No Capsule 4060 4060 Once to twice daily
Venlafaxine Effexor No Tablet 37.575 75375 Twice daily
Effexor XR No Extended-release capsule 37.575 75225 Once daily
SARIs
Nefazodone Serzonea Yes Tablet 100200 300600 Twice daily
Trazodone Desyrel Yes Tablet 50150 200600 Twice daily
NaSSA
Mirtazapine Remeron Yes Tablet, disintegrating tablet (SolTab) 15 1545 Once daily
a
Brand name no longer available in the United States.
MAOI, monoamine oxidase inhibitor; NaSSA, noradrenergic and specic serotonergic antidepressant; NDRI, norepinephrine and dopamine reuptake
inhibitor; SARI, serotonin antagonist and reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake
inhibitor; TCA, tricyclic antidepressant.
formulations of venlafaxine and bupropion allow for once- and nefazodone. A particular disadvantage of TCAs is that the
daily dosing. The delayed-release capsule of uoxetine can be customary way of dosing them involves meticulous upward titra-
given once weekly, which can be started 7 days after the last tion from a small starting dose to a wide usual therapeutic dosage
regular-release capsule or tablet. Liquid dosage forms and dis- range. On the other hand, one advantage is that plasma levels
integrating tablets of various antidepressants are ideal for may be used to help guide dosing, especially for those that
patients who have difculty swallowing tablets or capsules or have well-dened therapeutic plasma level ranges, including
those who otherwise may attempt to cheek their medication. nortriptyline (50150 ng/mL or mcg/L, or 190570 nmol/L),
The starting dose is the usual therapeutic dose for most of desipramine (100160 ng/mL or mcg/L, or 375600 nmol/L),
the SSRIs, duloxetine, and mirtazapine, whereas there is usually amitriptyline (75175 ng/mL or mcg/L, 255595 nmol/L), and
need for at least some upward titration of venlafaxine, bupropion, imipramine (greater than 200 ng/mL or mcg/L, or 714 nmol/L).28
Efcacy of Pharmacotherapy Time Course of Response

Each antidepressant has a response rate of approximately Unfortunately, antidepressants do not produce a clinical
60% to 80%, and no antidepressant medication or class has been response immediately. Improvement in physical symptoms,
reliably shown to be more efcacious than another.7,22 MAOIs may such as sleep, appetite, and energy, can occur within the rst
be the most effective therapy for atypical depression, but MAOI week or so of treatment. Although a recent meta-analysis sug-
use continues to wane because of problematic adverse effects, gests earlier effects of antidepressant treatment,36 it is
dietary restrictions, and possibility of fatal drug interactions.22,28 widely accepted that it takes approximately 2 to 4 weeks of treat-
There is some evidence that dual-action antidepressants, such as ment before improvement is seen in emotional symptoms of
TCAs and SNRIs, may be more effective for inpatients with depression, such as sadness and anhedonia. Furthermore, it may
severe depression than are the single-action drugs such as take as long as 6 to 8 weeks of treatment to see the full effects of
SSRIs,22,28 but the more general assertion that multiple mecha- antidepressant therapy.7,22,23
nisms of action confer efcacy advantages is quite controversial.33
Managing Partial Response or Non-response
Selection of Medication Approximately one-third of patients with MDD do not respond
Figure 351 depicts a well-known algorithm for the pharmaco- satisfactorily to their rst antidepressant medication.37 In such
logic treatment of non-psychotic MDDthe Texas Medication cases, the clinician must evaluate the adequacy of antidepressant
Algorithm Project.34 Notable aspects of this algorithm include therapy, including dosage, duration, and patient compliance.17
the preferential use of newer antidepressants in the earlier stages Treatment reappraisal also should include verication of the
of treatment and sequential trials of antidepressant mono- patients diagnosis and reconsideration of clinical factors that
therapy prior to the use of combination therapy (see Managing could be impeding successful therapy, such as concurrent med-
Partial Response or Non-response). It has been shown that ical conditions (e.g., thyroid disorder), comorbid psychiatric
patients undergoing treatment guided by this algorithm conditions (e.g., alcohol abuse), and psychosocial issues (e.g.,
fared better than those who received treatment as usual during marital stress).16
a 1-year period, as measured by clinician-rated symptoms, self- For patients who have experienced a partial response,
reported symptoms, and overall mental functioning.35 Anti- extending the medication trial and/or using higher doses
psychotic medication should be combined with antidepressant within the recommended dosage range of the antidepressant
medication in cases of depression with psychotic features.16 may be helpful.16 Another option is to employ augmentation
Various factors must be taken into account when selecting therapy, i.e., adding another medication that generally is not
antidepressant therapy for a particular patient. The most reli- used as an antidepressant.37 Augmenting agents with clear
able predictor of response is the patients past history of efcacy include lithium and thyroid hormone (e.g., liothyro-
response (e.g., efcacy, side effects, and overall satisfaction) to nine), whereas initial enthusiasm has lessened to some extent
antidepressants. To a lesser extent, the past history of a rst- for the serotonergic drugs buspirone and pindolol owing to
degree relatives response to antidepressants may be used to negative ndings in controlled trials.38 Efcacy has been sug-
predict a patients response. Adverse-effect proles should be gested for dopaminergic drugs (e.g., pramipexole), psycho-
considered because compliance is inuenced greatly by toler- stimulants (e.g., methylphenidate), and atypical antipsychotics
ability. In this regard, a frank discussion should occur with the (e.g., olanzapine), whereas various other medications, such as
patient in order to determine which adverse effects are accept- anticonvulsants (e.g., valproic acid), modafanil, and estrogen,
able and which are not. The clinician must be careful to con- have anecdotal evidence to support their use.38 A third option
template potential drug-drug interactions and disease-state is to make use of combination therapy, whereby another anti-
interactions. For instance, a patient with seizure disorder depressant, typically from a different pharmacologic class, is
would be an inappropriate candidate for bupropion therapy. added to the rst antidepressant medication. Examples
The presence of comorbid psychiatric conditions can help the include combining bupropion and SSRIs and combining
clinician to determine the best antidepressant to choose for a TCAs and SSRIs.38,39
patient. For example, an SSRI can treat both MDD and panic Switching to a different antidepressant is a common strat-
disorder, obviating the need for separate medication therapy. egy for patients who have had no response to initial antide-
The patient must be willing and able to comply with dosing pressant therapy but also is acceptable in cases of partial
schedules (e.g., upward titration of TCAs or twice-daily dos- response.16 Relative to augmentation/combination, advan-
ing of nefazodone) and special instructions (e.g., diet with tages of switching include improved compliance, decreased
MAOI therapy) associated with certain antidepressants. costs, and less concern over drug interactions, whereas disad-
Another patient-specic factor is the potential for accidental vantages include loss of time (reset the clock) and loss of
or intentional overdosing because certain antidepressants any improvement seen with the initial drug.39 When switching
(e.g., TCAs) are quite toxic in those situations. Finally, the from one antidepressant to another, clinicians may choose to
patient should be able to comfortably afford the chosen med- stay within the same class (e.g., sertraline to uoxetine) or go
ication or else compliance is at risk.22 outside of the class (e.g., paroxetine to venlafaxine).37,39
FIGURE 351. Strategies for the treatment of non-psychotic major depression.34 (Used, with permission)
Euthymia Remission
Partial
remission
Response
Acute Relapse Untreated Recurrence

episode episode
Major
depressive
episode
Acute Continuation Maintenance
phase phase phase
FIGURE 352. The course of depression and phases of treatment.7,8
Nonpharmacologic interventions in cases of treatment (i.e., 90%) chance of experiencing additional episodes. Other
non-response include adding or changing to psychotherapy factors to consider are the severity of previous episodes, espe-
or initiating ECT.16 cially if suicidal attempts were made or psychotic features
were present, and patient preference.16 In general, the dose of
the antidepressant required in the acute phase of treatment
Duration of Therapy
should be sustained during the continuation and mainte-
Treatment of MDD can be conceptualized as a series of three
nance phases.16
phases: acute, continuation, and maintenance7,8,16 (Fig. 352).
During a major depressive episode, a clinician will initiate
antidepressant therapy for the purpose of attaining remission Discontinuation of Therapy
of symptoms. This acute phase of treatment typically lasts 6 to When the clinician and patient are ready to attempt discon-
12 weeks. Since the typical major depressive episode lasts 6 tinuation of therapy, whether at the end of the continuation
months or longer, if antidepressant therapy is interrupted for any phase or during the maintenance phase, it is best to do so via
reason following the acute phase, the patient may relapse into gradual taper of the antidepressant. This is done for two rea-
the depressive episode. When treating the rst depressive episode, sons. First, almost all antidepressants can produce withdrawal
antidepressants must be given for an additional 4 to 9 months in syndromes if discontinued abruptly or tapered too rapidly,
the continuation phase for the purpose of preventing relapse. especially antidepressants with shorter half-lives (e.g., ven-
Maintenance treatment takes place after the normal course of lafaxine, paroxetine, and uvoxamine).17 These withdrawal
a major depressive episode in order to prevent recurrence, syndromes can cause sleep disturbances, anxiety, fatigue,
which is the development of future episodes. This phase can mood changes, malaise, gastrointestinal disturbances, and a
last for years, if not for a lifetime. Whereas all patients who host of other symptoms17 and often are confused with depres-
suffer a major depressive episode should receive both acute sive relapse or recurrence.16 In general, a tapering schedule
and continuation treatment, not all of them will require involving a small dosage decrement (e.g., paroxetine 5 mg)
maintenance treatment. The reason for this is because not all every 3 to 5 days should prevent signicant withdrawal
patients experience multiple major depressive episodes, and symptoms.17 Second, depressive symptoms may return on
even in many cases in which they do, many years may separate taper or discontinuation of the antidepressant. If antidepres-
the episodes. Therefore, the clinician must consider various sant therapy is discontinued abruptly and depressive symp-
factors in determining whether an individual patient requires toms return weeks later, then the lag time to onset of action
maintenance treatment. A major factor is the number of prior must be observed once the antidepressant is restarted (reset
episodes experienced by the patient. As discussed earlier, the the clock); however, if gradual tapering is carried out, then early
more episodes experienced, the more likely future episodes signs of depression can be countered with a return to the ori-
will occur. This has led many clinicians to adopt the three ginal dosage and a potentially quicker response.16 Depending on
strikes and youre on approach, whereby a patient with a the patients illness and the clinical circumstances, tapering of
history of three or more major depressive episodes is given the antidepressant can be extended for weeks or even months
lifelong maintenance treatment because of the very high because of the concern over relapse or recurrence.
Special Considerations (e.g., pain and gastrointestinal problems) instead of mood

symptoms, the frequent presence of medical illnesses, and the
Pregnant/Breast-Feeding Patients overlap of mood and cognitive symptoms with those of
It is a common misconception that pregnancy protects against dementia.15,43 Age-related pharmacokinetic and pharmacody-
depression (i.e., the glow of pregnancy). Depression actually namic changes cause geriatric patients to be more sensitive to
is quite common in pregnancy, especially for women with a the effects of antidepressant medications.15 Thus, lower start-
history of recurrent depression. Both maternal and fetal well- ing doses of antidepressants with slow upward titrations as
being must be taken into account when weighing the benets tolerated are recommended for geriatric patients.13,16,43 SSRIs
and risks of using antidepressant therapy during pregnancy.40 are chosen frequently to treat geriatric depression because of
In general, studies have not demonstrated an increased risk of their overall favorable adverse-effect proles and low toxic-
miscarriage or congenital malformations with antidepressant ity, whereas most TCAs are avoided owing to problematic
use,40 but the prescribing information for paroxetine was anticholinergic, cardiovascular, and sedative properties.43
changed recently to reect the ndings of epidemiologic stud- Desipramine and nortriptyline are two TCAs that are more
ies in which an increased risk of congenital malformations, in tolerable in terms of these adverse effects and thus may be
particular atrial or ventricular septal defects, was seen in used in geriatric depression.43 Other newer antidepressants,
infants born to women taking the drug during the rst such as bupropion, venlafaxine, nefazodone, and mirtazapine,
trimester of pregnancy.41 Antidepressants have been reported are alternatives for the treatment of geriatric patients as well.43
occasionally to cause perinatal sequelae, such as poor neo-
natal adaptation, respiratory distress, feeding problems, and Pediatric Patients
jitteriness.40 Data concerning the long-term neurobehavioral Antidepressant medications appear to be useful for certain
effects of in utero antidepressant exposure remain quite limited.40 children and adolescents, particularly those who have severe
Fluoxetine, citalopram, and TCAs have the greatest reproduc- or psychotic depression, fail psychotherapeutic measures, or
tive safety data and should be considered rst-line treatments experience chronic or recurrent depression. SSRIs generally
when pharmacotherapy is indicated.40 are considered the initial antidepressants of choice, although
There will be at least some drug exposure to the infant comorbid conditions may favor alternative agents. Clinicians
from nursing mothers taking antidepressant medications. should be aware of the possibility of behavioral activation
Although there have been rare anecdotal reports of adverse with the SSRIs, including such symptoms as impulsivity, silli-
effects (i.e., respiratory depression and seizure-like episodes) ness, daring conduct, and agitation.44 Desipramine should be
in infants exposed to antidepressants through breast milk, no used with caution in this population because of several
rigorous study has conrmed adverse effects of these drugs, reports of sudden death, and a baseline and follow-up elec-
and it is generally accepted that the benets of breast-feeding trocardiogram (ECG) may be warranted when this medica-
outweigh the risks to the infant of antidepressant exposure. tion is used to treat pediatric patients.9
However, the decision needs to be made on an individual The Food and Drug Administration (FDA) has warned
basis.42 that antidepressants increase the risk of suicidality (i.e.,
suicidal thinking and behavior) in children and adolescents.
Geriatric Patients A large analysis of clinical trials revealed that the risk of
It is generally agreed that depression in older adults is under- such events was 4% for antidepressant medications versus
recognized and undertreated.43 Although not uncommon in 2% for placebo, although no completed suicides occurred in
community samples, MDD is particularly prevalent among the trials. Because of this increased risk, antidepressants
those living in long-term care facilities.15,43 Barriers to recog- have black-box warnings concerning the matter, and patient
nition of geriatric depression include the tendency toward medication guides are required to be distributed with each
masked presentations, i.e., complaints of physical symptoms prescription or refill of antidepressant medications.
Pediatric patients should be observed closely for suicidality,
worsened depression, agitation, irritability, and unusual
Patient Encounter, Part 3: Creating a changes in behavior, especially during the initial few months
Care Plan of therapy or at times of dosage changes. Furthermore, families
and caregivers should be advised to monitor patients for such
symptoms.45
Based on the information presented, create a care plan for
ML. Your plan should include: (1) a statement of the drug-
related needs and/or problems, (2) the goals of therapy, Suicidal Patients
(3) a patient-specic detailed therapeutic plan, and (4) a The FDA is in the process of analyzing data to determine
plan for follow-up to determine whether the goals have whether there is an increased risk of suicidality in adult patients
been achieved. similar to that seen in pediatric patients (see above). Even though
the suicidality risk for adults taking antidepressant medications
TABLE 358. Patient Counseling28,47
Counseling Point Clinical Rationale

Mechanism of actionThe medication works Patient may feel that depression is a character
by affecting certain chemicals in the brain. weakness or personality aw instead of a
biologic disorder.
Lack of addiction potentialAlthough the Patient may worry that since the
medication affects certain chemicals in the antidepressant is psychoactive, it must be
brain, it is not addicting. addicting.
Need for routine useThe medication will Patient may try taking the medication on an
only work if it is taken as prescribed as-needed basis.
every day.
Delayed onset of actionIt may take several Patient may prematurely discontinue therapy
weeks to see signicant improvement prior to onset of benecial effects.
in symptoms.
Prolonged duration of therapyThe medication Patient may prematurely discontinue therapy
should be taken for at least 6 to 12 months; after symptoms have remitted, which
do not discontinue it without consulting could lead to relapse or recurrence.
with the prescriber.
Adverse effectsMention common and Patient may be more likely to discontinue
expected adverse effects as well as what to therapy and distrust the prescriber if
do should they occur. adverse effects occur without forewarning.
Avoidance of alcohol/CNS depressants Patient may be unaware of the possible
Use of alcohol or other CNS depressants consequences of drinking alcohol or
could cause worsened depression and taking other drugs with antidepressants.
additive adverse effects with the medicine.
Risk of suicidalityBe alert to symptoms of Patient may become suicidal while taking the
worsening depression and suicidality. antidepressant.
Data from references 28 and 47.
is currently unknown, similar monitoring for suicidality and clinicians about the possibility of increased absorption of
clinical worsening that is mandated for pediatric patients should medication if the patch is exposed to direct heat.48 A mild skin
be followed for adult patients.46 reaction at the site of patch placement is a common side
The clinician should bear in mind the toxic potential for effect. As with oral MAOIs, decreased blood pressure and
the various antidepressant medications when patients already light-headedness are possible.48
have or develop suicidality. The TCAs and MAOIs have nar-
row therapeutic indices, whereas the SSRIs, SNRIs, nefa-
zodone, and mirtazapine have wide therapeutic indices.22 OUTCOME EVALUATION
Patient Counseling Review the patients medication prole to ensure that there are
Major counseling points and the clinical rationale behind no potential/actual pharmacotherapy problems related to dos-
them are outlined in Table 358.28,47 Lack of patient under- ing, disease-state precautions or contraindications, drug-drug
standing concerning optimal antidepressant drug therapy fre- interactions, unnecessary therapeutic duplication, etc.
quently leads to partial compliance or non-compliance with Verify the extent of compliance with pharmacotherapy.
therapy; thus, the primary purpose of antidepressant counseling Assess the response to pharmacotherapy, especially with
is to enhance compliance and improve outcomes.47 regard to suicidality and those symptoms that cause signi-
cant subjective distress and/or functional impairment.
Recent Developments Determine whether the patient is experiencing adverse
The FDA recently approved selegiline (Emsam) as the rst effects of pharmacotherapy. Although general questioning
transdermal patch for use in treating MDD.48 Despite belong- (e.g., Are you having any side effects?) may reveal some
ing to the MAOI class of antidepressants, the lowest dose of problems with therapy, it is better to use direct questioning
the patch, 6 mg/24 hours, can be used without the usual concerning adverse effects that are most common and/or
dietary restrictions associated with MAOI use.48 Patients most problematic (e.g., Have you noticed any change in
receiving the higher doses, 9 and 12 mg/24 hours, should fol- your sexual functioning?).
low the usual dietary restrictions.48 Patients are advised to Provide counseling to enhance patient understanding of
change the patch daily. Also, drug labeling advises patients and MDD and its pharmacotherapy.
Patient Care and Monitoring What lifestyle modications could be made to improve
condition (e.g. exercise)?
How should the medication be taken?
What potential adverse effects may occur?
1. Assess the patients severity of symptoms to determine if Which drugs may interact with their therapy?
patient-directed therapy is appropriate or whether a Educate on warning signs and prevention of suicidal
psychiatrist should evaluate the patient. and/or homicidal ideation.
2. Obtain a thorough history of prescription, nonprescription, 6. Develop a plan to assess effectiveness of pharmacologic
natural, and illicit drug product use. Rule out medications therapy after 4 weeks of being on a clinically effective
or medical disorders that may cause or mimic depressive dose.
symptoms. 7. Evaluate the patient for the presence of adverse drug
3. Review Diagnostic and Statistical Manual of Mental reactions, drug allergies, and drug interactions.
Disorders, 4th edition, Text Revision (DSM-IV-TR) criteria 8. Assess improvement in quality-of-life measures such
to determine an appropriate diagnosis. as physical, psychological, and social functioning and
4. Determine appropriate pharmacologic and psychological well-being.
treatments (e.g., cognitive-behavioral therapy), including 9. If the patient does not respond, determine if the patient is
what has been helpful to the patient in the past. taking the appropriate medication and dose.
5. Educate patient and/or caretaker about the disease state, 10. Recommend changes in therapy if the patient does not
lifestyle modications, and medication therapy. respond.
What risk factors are present that could contribute to 11. Determine long-term maintenance therapy.
depression?
BDNF: brain-derived neurotrophic factor ASHP therapeutic position statement on the recognition and treat-
DA: dopamine ment of depression in older adults. Am J Health Syst Pharm
DRI: dopamine reuptake inhibitor 1998; 55:25142518.
DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;
4th ed., text revision 352:11121120.
ECT: electroconvulsive therapy Cassano P, Fava M. Tolerability issues during long-term treatment
5-HT: serotonin with antidepressants. Ann Clin Psychiatry 2004;16:1525.
GABA: gamma-aminobutyric acid Cohen LS, Nonacs R, Viguera AC, Reminick A. Diagnosis and treat-
MAOI: monoamine oxidase inhibitor ment of depression during pregnancy. CNS Spectr 2004;
MDD: major depressive disorder 9:209216.
NaSSA: noradrenergic and specic serotonergic Fava M. Augmentation and combination strategies in treatment-
antidepressant resistant depression. J Clin Psychiatry 2001;62(suppl 18):411.
NDRI: norepinephrine and dopamine reuptake inhibitor Practice guideline for the treatment of patients with major depressive
NE: norepinephrine disorder (revision). Am J Psychiatry 2000;157(4 suppl):145.
NRI: norepinephrine reuptake inhibitor Stahl SM. Essential Psychopharmacology: Neuroscientic Basis and
SARI: serotonin antagonist and reuptake inhibitor Practical Applications. 2nd ed. New York: Cambridge University
SI: suicidal ideation Press, 2000:135295.
SNRI: serotonin and norepinephrine reuptake inhibitor Stimmel GL. How to counsel patients about depression and its treat-
SRI: serotonin reuptake inhibition ment. Pharmacotherapy 1995; 15(6 pt 2):100S104S.
SSRI: selective serotonin reuptake inhibitor
TCA: tricyclic antidepressant
VNS: vagus nerve stimulation


this chapter.
36 BIPOLAR DISORDER
Brian L. Crabtree and Martha J. Faulkner
LEARNING OBJECTIVES
1. Explain the pathophysiologic mechanisms underlying bipolar disorder.

2. Recognize the symptoms of a manic episode and depressive episode in patients with
bipolar disorder.
3. Identify common comorbidities of bipolar disorder.
4. Recognize the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision criteria for bipolar disorder as well as the subtypes of bipolar I disorder, bipolar II
disorder, and cyclothymic disorder.
5. List the desired therapeutic outcomes for patients with bipolar disorder.
6. Explain the use of drugs as rst-line therapy in bipolar disorder, including appropriate
dosing, expected therapeutic effects, potential adverse effects, and important drug-drug
interactions.
7. Recommend individualized drug therapy for acute treatment and relapse prevention based
on patient-specic data.
8. Recommend monitoring methods for assessment of therapeutic and adverse effects of
drugs used in the treatment of bipolar disorder.
9. Recommend treatment approaches for special populations of patients with bipolar
disorder, including pediatric patients, geriatric patients, and pregnant patients.
10. Educate patients with bipolar disorder about their illness, drug therapy required for
effective treatment, and the importance of adherence.
KEY CONCEPTS The primary treatment for depressive episodes in bipolar dis-
order is mood-stabilizing agents, often combined with antide-
Patients presenting with depressive or elevated mood features pressant drugs.
and a history of abnormal or unusual mood swings should be The primary treatment for relapse prevention is mood-
assessed for bipolar disorder. stabilizing agents.
The diagnosis of bipolar disorder is made based on clinical Education of the patient regarding benets and risks of drug
presentation, a careful diagnostic interview, and review of the therapy and the importance of adherence to treatment must
history. There are no laboratory examinations, brain imaging be integrated into pharmacologic management.
studies, or other procedures that conrm the diagnosis.
Goals of treatment are to reduce symptoms, induce remission, Bipolar disorder is a mood disorder characterized by one or
prevent relapse, improve patient functioning, and minimize more episodes of mania or hypomania, often with a history of
adverse effects of drug therapy. one or more major depressive episodes.1 It is a chronic illness
Psychotherapy is needed to improve functional outcomes. with a course characterized by relapses and improvements or
The primary treatment modality for manic episodes is mood- remissions. Mood episodes can be manic, depressed, or mixed.
stabilizing agents, often combined with antipsychotic drugs. They can be separated by long periods of stability or can cycle
585
The mean age of onset of bipolar disorder is 20, although

Patient Encounter, Part 1 onset may occur in early childhood to the mid-40s.1 If the
onset of symptoms occurs after 60 years of age, the condition
is probably secondary to medical causes. Early onset of bipo-
lar disorder is associated with greater comorbidities, more
MW, a 43-year-old Caucasian female, is a married mother
mood episodes, a greater proportion of days depressed, and
of two boys and is moderately obese. She is wearing a short
skirt, low-cut blouse, and heavy makeup, and is somewhat greater lifetime risk of suicide attempts, compared to bipolar
disheveled. She is mildly agitated, speaking rapidly, has fair disorder with a later onset. Substance abuse and anxiety dis-
eye contact, and appears tired and anxious. Her chief com- orders are more common in patients with an early onset.
plaint: I am about to get red from my job, and I cant Patients with bipolar disorder also have higher rates of suici-
seem to get any sleep. dal thinking, suicidal attempts, and completed suicides.
What diagnoses are suggested by this patients presentation?

What additional information is needed to clarify the Etiology
diagnoses?
The precise etiology of bipolar disorder is unknown. Thought to
be genetically based, bipolar disorder is inuenced by a variety
of factors that may enhance gene expression. These include
rapidly. They occur with or without psychosis. Disability and
trauma, environmental factors, anatomic abnormalities, expo-
other consequences of bipolar disorder can be devastating to
sure to chemicals or drugs, and others.35 Neurochemical abnor-
patients, including an increased risk of suicide. Correct diagnosis
malities in bipolar disorder may be caused by these factors, as
and treatment are essential as early as possible in the course of
discussed further in the pathophysiology section.
the illness to prevent complications and maximize response to
treatment. Both pharmacologic and nonpharmacologic treat-
ments are required for maximum benet.
PATHOPHYSIOLOGY
EPIDEMIOLOGY AND ETIOLOGY Neurochemical
Epidemiology The pathophysiology of bipolar disorder has been poorly

understood, but imaging techniques such as positron emission
Bipolar disorders have been categorized into bipolar I disor- tomography (PET) scans and functional magnetic resonance
der, bipolar II disorder, and bipolar disorder, not otherwise imaging (fMRI) are now being used to elucidate the cause.
specied (NOS). Bipolar I disorder is characterized by one or Research in the 1970s focused on neurotransmitters such as
more manic or mixed mood episodes. Bipolar II disorder is norepinephrine, dopamine, and serotonin. One hypothesis was
characterized by one or more major depressive episodes and that bipolar disorder is caused by an imbalance of cholin-
at least one hypomanic episode. Hypomania is an abnormally ergic and catecholaminergic neuronal activity. Serotonin
and persistently elevated, expansive, or irritable mood, but not (5-HT) has been suggested to modulate catecholamine
of sufcient severity to cause signicant impairment in social activity. Dysregulation of this relationship could cause a mood
or occupational function and does not require hospitaliza- disturbance.6 An early theory was that elevation of nor-
tion. Most epidemiologic studies have looked at bipolar dis- epinephrine (NE) and dopamine (DA) caused mania, and a
order of all types (bipolar I and bipolar II), or the bipolar reduction caused depression, but this theory is now considered
spectrum, which includes all clinical conditions thought to be overly simplistic.7 Other neurotransmitters are involved and
closely related to bipolar disorder. The lifetime prevalence of interact with multiple neurochemical and neuroanatomic
bipolar I disorder is estimated to be between 0.3% and 2.4%. mechanisms and pathways. The pathophysiology of bipolar
The lifetime prevalence of bipolar II disorder ranges from disorder has also been hypothesized from the mechanisms of
0.2% to 5%. When including the bipolar spectrum, the life- action of lithium and other mood stabilizers. Lithium, val-
time prevalence is between 3% and 6.5%.1 proate, and carbamazepine all have similar effects on neuronal
Bipolar I disorder affects men and women equally; bipolar II growth that are reversible by inositol, supporting the hypothe-
seems to be more common in women. Rapid cycling and mixed sis that bipolar disorder is related to inositol depletion.8
mania occur more often in women. Individuals with bipolar
disorder commonly have another psychiatric disease with
Genetic
78% to 85% reporting another Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition, Text Revision Results of family and twin studies suggest a genetic basis for
(DSM-IV-TR) diagnosis during their lifetime. The most com- bipolar disorder.4 The lifetime risk of bipolar disorder in rela-
mon comorbid conditions include anxiety, substance abuse, tives of a bipolar patient is 40% to 70% for a monozygotic
and eating disorders.2 twin and 5% to 10% for another rst-degree relative.
CHAPTER 36 / BIPOLAR DISORDER 587
Patient Encounter, Part 2: The Medical Clinical Presentation and Diagnosis1,3,7

History, Physical Exam, and Laboratory
Exam
The interview reveals the following additional information General
about MW: The patient may present in a hypomanic, manic, depressed,
PMH or mixed state, and may or may not be in acute distress.
Para 2, gravida 2
Symptoms
Hx Mood and affect:
Sexually transmitted disease (unspecied) as a teen and in her Mood elevation
twenties, but has been monogamous since her last marriage in Expansive mood
her mid-thirties; she states, It has not always been easy to stay Irritable mood
with my husband; she feels sexually attracted to many men. Depression
Past Psychiatric Hx Hopelessness
Hospitalized at age 15 for physical aggression towards Suicidality
parents, suicidality, and running away; does not remem- Physical/behavioral:
ber if she was placed on medication or if she was given a Agitation
diagnosis; admits history of sleep disturbance that alter- Impulsivity
nates between hyposomnia and hypersomnia and moodi- Aggression
ness, when she shifts from feeling on top of the world
Rapid, pressured speech
to very depressed, like Im a nobody.
Decreased need for sleep
FH Insomnia (sometimes for days or weeks)
Father was an alcoholic and died in his 50s of cirrhosis; mother Hypersexuality
is alive and has an anxiety disorder and emphysema; brother Increased physical energy
was incarcerated for attempted murder and drug trafcking; Inated self-esteem, boasting, grandiosity
sister has an anxiety disorder and self-medicates with marijuana
Heightened interest in pleasurable activities with high risk of
SH negative consequences (e.g., spending sprees and promiscuity)
Obtained GED; smokes 2 packs of cigarettes per day; has had Fatigue
multiple jobs and two previous marriages; currently works as Hypersomnia
a salesperson in an auto parts store; lives with her husband Thought Processes, Content, and Perceptions:
who is a mechanic, and two elementary schoolaged sons Racing thoughts, ight of ideas (FOI), distractibility
Substance Abuse Hx Delusions of grandeur; ideas of reference (IOR): persecu-
In late teens into mid-twenties, heavy abuse of stimulants, tion, wealth, religion
barbiturates, and alcohol; currently smokes marijuana three Psychosocial:
times per week and states it calms me down and helps me Substance use
sleep; occasionally drinks on weekends Disrupted relationships
Meds Job loss
Antacids as needed for heartburn, ibuprofen as needed for
headache Laboratory and Other Diagnostic Assessments
ROS
There are no objective laboratory tests or procedures to
(+) Increased energy, irritability, and anger outbursts, racing diagnose bipolar disorder, but such testing can be done to rule
thoughts, decreased need for sleep; () heart palpitations, out other medical diagnoses.
weight loss, nausea, vomiting, diarrhea
PE Perform urinalysis, urine toxicology, thyroid function, and
VS: Blood pressure 130/88 mm Hg, pulse 88 beats per minute, white blood cell count in the elderly to rule out urinary
respiratory rate 20/minute, temperature 37.0C (98.6F) tract infection
HEENT: Neck supple; thyroid smooth, symmetrical, non- A mood disorder questionnaire is completed by the patient
tender, moveable that asks about common symptoms of bipolar disorder,
CV: RRR, normal S1, S2; no murmurs, rubs, gallops, or heaves problems caused by the symptoms, and family history in a
Abd: Soft, non-tender, non-distended; (+) bowel sounds, no yes-or-no answer format. It is then scored by the clinician.
hepatosplenomegaly
Suicidality risk is increased in the presence of:
Labs
WNL except + tetrahydrocannabinol (THC).
Substance abuse
Prior suicide attempts and lethality of attempts
Considering this additional information, what is the most
Access to a means of suicide
likely diagnosis?
What are the key pieces of information leading you to Command hallucinations/psychosis
this conclusion? Severe anxiety
Family history of attempted or completed suicide
CLINICAL PRESENTATION AND DIAGNOSIS and depressive symptoms. Hypomanic symptoms include
inated self-esteem or grandiosity (non-delusional),
Diagnosis of Bipolar Disorder decreased need for sleep, pressure of speech, ight of ideas,
distractibility, and increased involvement in goal-directed
Bipolar disorder can be conceptualized as a continuum or activities, not causing severe impairment in social or occupa-
spectrum of mood disorders and is not comprised solely of tional functioning or requiring hospitalization. Psychotic fea-
bipolar I disorder.9 They include four subtypes: bipolar I tures are not found in cyclothymic disorder.1
(periods of major depressive, manic, and/or mixed episodes);
bipolar II (periods of major depression and hypomania);
cyclothymic disorder (periods of hypomanic episodes and
depressive episodes that do not meet all criteria for diagnosis
Suicide
of a major depressive episode); and bipolar disorder, NOS. Patients with bipolar disorder have a high risk of suicide.
The dening feature of bipolar disorders is one or more manic Factors that increase that risk are early age at disease onset,
or hypomanic episodes in addition to depressive episodes that high number of depressive episodes, comorbid alcohol abuse,
are not caused by any medical condition, substance abuse, or personal history of antidepressant-induced mania, and family
other psychiatric disorder.1 history of suicidal behavior.15 In those with bipolar disorder, 1
Initial and subsequent episodes of bipolar disorder are mostly of 5 suicide attempts are lethal, in contrast to 1 of 10 to 1 of
depressive,10 although this varies depending on type of bipolar 20 in the general population.
disorder. In males, the initial episode in bipolar I disorder is more
likely to be mania, and the number of manic episodes is equal to
or greater than depressive episodes.1 Often misdiagnosed and Differential Diagnosis
underdiagnosed, bipolar I and II disorders were correctly diag-
nosed only 20% of the time, whereas 31% received the misdiag- Schizophrenia and bipolar disorder often share certain symp-
nosis of unipolar depression.11 It is helpful to utilize a screening toms, including psychosis in some patients. The prominence
tool such as the mood disorder questionnaire.12 of mood symptoms and the history of mood episodes distin-
DSM-IV-TR criteria for the diagnosis of bipolar disorder guish bipolar disorder and schizophrenia. In addition, the
are summarized in Table 361. psychosis of schizophrenia occurs in the absence of promi-
nent mood symptoms.
Bipolar I Disorder Personality disorders are inexible and maladaptive patterns
of behavior that deviate markedly from expectations of society.
Bipolar I disorder diagnosis necessitates at least one episode of These patterns are stable over time, pervasive and rigid, and
mania, for at least 1 week or longer, with a persistently elevated, lead to distress or impairment in the individuals life. Onset is
expansive, or irritable mood with related symptoms of decreased in adolescence or early adulthood.1 Personality disorders and
need for sleep, excessive energy, racing thoughts, a propensity to bipolar disorder may be comorbid, and patients with personal-
be involved in high-risk activities, and excessive talkativeness.1 ity disorders may have mood symptoms. The two diagnoses are
Bipolar I depression can be misdiagnosed as major depressive distinguished, however, by the predominance of mood symp-
disorder; therefore, it is essential to rule out past episodes of toms and the episodic course of bipolar disorder, in contrast to
hypomania or mania. If bipolar depression is mistaken for major the stability and persistence of the behavioral patterns of per-
depressive disorder and the patient is treated with antidepres- sonality disorders.
sants, this can precipitate a manic episode or induce rapid cycling Delirium is characterized by a disturbance of consciousness
of depression and mania. and a change in cognition that develops over a short period of
time, usually hours or days. The course can uctuate over the
Bipolar II Disorder course of the day, usually worsening in the evening. Underlying
The distinguishing feature of bipolar II disorder is depression medical problems such as urinary tract infections in the elderly,
with past hypomanic episodes that often are not recalled by substance abuse, or withdrawal symptoms in adults may pre-
the individual as being unusual. Irritability and anger episodes cipitate delirium.1
are also common. Collateral information is essential to obtain Dementia is the loss of function in multiple cognitive
the entire history (i.e., there cannot have been a prior full domains that occurs over a longer period of time, usually
manic episode).1,14 months to years. Diagnostic features include memory impair-
ment and at least one of the following: aphasia (deterioration
of speech), apraxia (impaired ability to execute motor activities
Cyclothymic Disorder despite intact motor abilities, sensory function, and compre-
Cyclothymic disorder is a chronic mood disturbance generally hension of the required task), agnosia (failure to recognize or
lasting at least 2 years (1 year in children and adolescents) and identify objects despite intact sensory function), or distur-
characterized by mood swings including periods of hypomania bances in executive functioning.1
TABLE 361. Evaluation and Diagnostic Criteria of Mood Episodes
Diagnostic work-up depends on clinical Mental status examination

presentation and ndings Psychiatric, medical, and medication history
Physical and neurologic examination
Basic laboratory tests: complete blood count, blood chemistry
screen, thyroid function, urinalysis, urine drug screen
Psychological testing
Brain imaging: magnetic resonance imaging and functional scan;
alternative: computed tomography scan, positron emission
tomography scan
Lumbar puncture
Diagnosis
Impairment of Functioning or
Episode Need for Hospitalizationa DSM-IV-TR Criteriab
Major depressive Yes Greater than 2-week period of either depressed mood or loss of interest or
pleasure in normal activities, associated with at least ve of the following
symptoms:
Depressed, sad mood (adults); may be irritable mood in children
Decreased interest and pleasure in normal activities
Decreased appetite, weight loss
Insomnia or hypersomnia
Psychomotor retardation or agitation
Decreased energy or fatigue
Feeling of guilt or worthlessness
Impaired concentration and decision making
Suicidal thoughts or attempts
Manic Yes Greater than 1-week period of abnormal and persistent elevated mood
(expansive or irritable), associated with at least three of the following
symptoms (four if the mood is only irritable):
Inated self-esteem (grandiosity)
Increased talking (pressure of speech)
Racing thoughts (ight of ideas)
Distractible (poor attention)
Increased activity (either socially, at work, or sexually) or increased motor
activity or agitation
Excessive involvement in activities that are pleasurable but have a high
risk for serious consequences (buying sprees, sexual indiscretions, poor
judgment in business ventures)
Hypomanic No At least 4 days of abnormal and persistent elevated mood (expansive or
irritable); associated with at least three of the following symptoms (four
if the mood is only irritable):
Inated self-esteem (grandiosity)
Increased talking (pressure of speech)
Racing thoughts (ight of ideas)
Increased activity (either socially, at work, or sexually) or increased motor
activity or agitation
Excessive involvement in activities that are pleasurable but have a high
risk for serious consequences (buying sprees, sexual indiscretions, poor
judgment in business ventures)
Mixed Yes Criteria for both a major depressive episode and manic episode (except for
duration) occur nearly every day for at least a 1-week period
Rapid cycling Yes Greater than 3 major depressive or manic episodes (manic, mixed, or
hypomanic) in 12 months
a
Impairment in social or occupational functioning; need for hospitalization due to potential self-harm, harm to others, or psychotic symptoms.
b
The disorder is not due to a medical condition (e.g., hypothyroidism) or substance-induced disorder (e.g., antidepressant treatment, medications, elec-
troconvulsive therapy).
From Fankhauser MP, Freeman MP. Bipolar disorder. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach.
6th ed. New York: McGraw-Hill; 2005: 1261, with permission.
Comorbid Psychiatric and Medical Conditions Although not all patients achieve asymptomatic remis-
sion, this is a goal of treatment. The mainstay of drug ther-
Psychiatric apy is mood-stabilizing drugs, summarized below. A person
Lifetime prevalence rates of psychiatric comorbidity co-existing entering treatment for a rst mood episode in bipolar dis-
with bipolar disorder are 42% to 50%.16 Comorbidities, espe- order must have a complete assessment and careful diagnosis
cially substance abuse, make it difcult to establish a denitive to rule out non-psychiatric causes. A variety of conditions
diagnosis and complicate treatment. Comorbidities also place can cause similar symptoms (Table 363). Since early and
the patient at risk for a poorer outcome, high rates of suicidal- accurate diagnosis is essential to maximizing response to
ity, and onset of depression.2 Psychiatric comorbidities include: treatment, pharmacologic and nonpharmacologic therapy
should begin as soon as possible. Treatment is often life-
Personality disorders long. Comorbid conditions should likewise be addressed
Alcohol and substance abuse or dependence aggressively.
Anxiety disorders, including panic disorder, obsessive-
compulsive disorder, and social phobia Suicidality Risk
Eating disorders Assess for the safety of others and potential for violence. If
Attention-decit/hyperactivity disorder accompanied by friends or family with whom the patient is
living, ask them to remove from the home all guns, caustic
Medical comorbidities include: chemicals, medications, and objects the person might use
to harm self or others. Risk factors for suicide include
Migraine severity of depression, feelings of hopelessness, comorbid
Multiple sclerosis personality disorder, and a history of a previous suicide
Cushings syndrome attempt.19
Brain tumor
Head trauma
Interpersonal, family, or group therapy with a licensed psy-
TREATMENT chiatric nurse practitioner/clinical nurse specialist, psychologist,
social worker, or counselor assists individuals with bipolar disor-
Desired Outcomes der to establish and maintain a daily routine and sleep schedule
Desired outcomes for the treatment of bipolar disorder are to: and to improve interpersonal relationships.3,20 These therapies
may help treat and protect against manic episodes.
Reduce the symptoms of mania Cognitive-behavioral therapy (CBT) is a type of psychother-
Reduce the symptoms of bipolar depression apy that combines cognitive and behavioral theories. It
Prevent the recurrence of a manic or depressive episode stresses the importance of recognizing patterns of cognition
Avoid or minimize adverse treatment effects (thought) and how thoughts inuence subsequent feelings
Promote treatment adherence and behaviors. Other people, situations, and events external to
Maintain or improve quality of life and improving function the individual are not seen as the sources of thoughts and
behaviors. An advantage of CBT is that patients are taught
self-management skills to change their negative thoughts in
order to feel and function better, even if external circum-
Treatment algorithms for manic and depressive episodes of stances do not change.
bipolar disorder are included in Table 362. Electroconvulsive therapy (ECT) is the application of pre-
scribed electrical impulses to the brain for the treatment of
severe depression, mixed states, psychotic depression, and
Patient Encounter, Part 3: Creating a treatment-refractory mania in patients who are at high risk of
Care Plan suicide. It also may be used in pregnant women who cannot
take carbamazepine, lithium, or divalproex.
Based on all information presented, create a care plan for Psychoeducation for patients, their families, and groups
this patients bipolar disorder. Your plan should include: (1) a regarding chronicity of bipolar disorders; self-management
statement of the drug-related needs and/or problems, (2) the through sleep hygiene, nutrition, exercise, and stress reduc-
goals of therapy, (3) a patient-specic therapeutic plan, and tion; and abstinence from alcohol or drugs is critical to the
(4) a plan for follow-up to assess therapeutic response and success of supporting the individual in managing bipolar
adverse effects. disorder. The development of a crisis intervention plan is
essential.
TABLE 362. Algorithm and Guidelines for the Acute Treatment of Mood Episodes in Patients with Bipolar I Disorder
Acute Manic or Mixed Episode Acute Depressive Episode

General guidelines General guidelines
Assess for secondary causes of mania or mixed states Assess for secondary causes of depression (e.g., alcohol
(e.g., alcohol or drug use) or drug use)
Taper off antidepressants, stimulants, and caffeine if possible Taper off antipsychotics, benzodiazepines or sedative-hypnotic
Treat substance abuse agents if possible
Encourage good nutrition (with regular protein and essential fatty Treat substance abuse
acid intake), exercise, adequate sleep, stress reduction, and Encourage good nutrition (with regular protein and essential fatty
psychosocial therapy acid intake), exercise, adequate sleep, stress reduction, and psy-
Optimize the dose of mood-stabilizing medication(s) before chosocial therapy
adding on benzodiazepines; if psychotic features are present, add Optimize the dose of mood stabilizing medication(s) before
on antipsychotic; ECT used for severe or treatment-resistant adding on lithium, lamotrigine, or antidepressant (e.g., bupropion or
manic/mixed episodes or psychotic features an SSRI); if psychotic features are present, add on an antipsy-
chotic; ECT used for severe or treatment-resistant depressive
episodes or for psychosis or catatonia
Mild to moderate symptoms of Moderate to severe symptoms of Mild to moderate symptoms Moderate to severe symptoms
mania or mixed episode mania or mixed episode of depressive episode of depressive episode
First, initiate and/or optimize First, two-drug combinations: lithiuma First, initiate and/or opti- First, two-drug combinations:
mood-stabilizing medica- or valproatea plus an atypical mize mood-stabilizing lithiuma or lamotrigineb plus
tion: lithiuma or valproatea antipsychotic (e.g., olanzapine, medication: lithiuma an antidepressantc; lithium
or atypical antipsychotic quetiapine, risperidone) for short- or lamotrigineb plus lamotrigine
(e.g., olanzapine, quetiapine, term adjunctive treatment of psy- Alternative anticonvul- Alternative anticonvulsants: car-
risperidone) chotic features (e.g., delusions or sants: carba- bamazepine, oxcarbazepine,
Alternative anticonvulsants: hallucinations) mazepine, oxcar- or valproate
carbamazepine, lamotrigine,b Alternative anticonvulsants: carba- bazepine, or val-
or oxcarbazepine mazepine, lamotrigine,b or oxcar- proate
bazepine
Second, if response is inade- Second, if response is inadequate, con- Second, if response is inadequate,
quate, consider adding a ben- sider adding a benzodiazepine consider adding an atypical
zodiazepine (lorazepam or (lorazepam or clonazepam) for short- antipsychotic for short-term
clonazepam) for short-term term adjunctive treatment of agitation adjunctive treatment of psy-
adjunctive treatment of agita- or insomnia if needed; lorazepam is chotic features (e.g., delusions
tion or insomnia if needed recommended for catatonia or hallucinations) if needed
Third, if response is inadequate, Third, if response is inadequate, con- Third, if response is inadequate, con-
consider a two-drug combi- sider a three-drug combination: sider a three-drug combination:
nation: Lithium plus an anticonvulsant Lithium plus an anticonvul-
Lithium plus an anticon- plus an atypical antipsychotic sant plus an antidepressant
vulsant or an atypical Anticonvulsant plus an anticonvul- Lamotrigineb plus an anticon-
antipsychotic sant plus an atypical antipsychotic vulsant plus an antidepressant
Anticonvulsant plus an Fourth, if response is inadequate, Fourth, if response is inadequate,
anticonvulsant or atypical consider ECT for mania with psy- consider ECT for treatment-
antipsychotic chosis or catatonia;d or add clozapine refractory illness and depression
for treatment-refractory illness with psychosis or catatoniad
Fifth, if response is inadequate, consider Fifth, if response is inadequate,
adding adjunctive therapiese consider adding adjunctive
therapiese
a
Utilize standard therapeutic serum concentration ranges; if partial response or breakthrough episode, adjust dose to achieve higher serum concentra-
tions without causing intolerable adverse effects; valproate is preferred over lithium for mixed episodes and rapid cycling; lithium and/or lamotrigine
is preferred over valproate for bipolar depression.
b
Lamotrigine is not approved for the acute treatment of depression, and the dose must be started low and slowly titrated up to decrease adverse effects
if used for maintenance therapy of bipolar I disorder. A drug interaction and a severe dermatologic rash may occur when lamotrigine is combined with
valproate (i.e., lamotrigine doses must be halved from standard dosing titration).
c
Antidepressant monotherapy is not recommended for bipolar depression. Bupropion, selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram,
escitalopram, or sertraline), and serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine) have shown good efcacy and fewer adverse
effects in the treatment of unipolar depression; monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) have more adverse effects
(e.g., weight gain) and may have a higher risk of causing antidepressant-induced mania; uoxetine, uvoxamine, nefazodone, and paroxetine inhibit
liver metabolism and should be used with caution in patients on concomitant medications that require cytochrome P450 clearance; paroxetine and
venlafaxine have a higher risk for causing a discontinuation syndrome.
d
Electroconvulsive therapy (ECT) is used for severe mania or depression during pregnancy and for mixed episodes; prior to treatment, anticonvulsants,
lithium, and benzodiazepines should be tapered off to maximize therapy and minimize adverse effects.
e
There are minimal or no efcacy data for some adjunctive (add-on) therapies: a2-adrenergic agonists, calcium channel blockers, gabapentin, tiagabine,
topiramate, and zonisamide; topiramate may have efcacy as an adjunctive agent with standard agents for maintenance therapy, based on initial trials.
From Fankhauser MP, Freeman MP. Bipolar disorder. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed.
New York: McGraw-Hill; 2005: 1266, with permission.
TABLE 363. Secondary Causes of Mania18 Mood-stabilizing drugs are considered the primary phar-
macotherapy for relapse prevention. Olanzapine and aripipra-
General Medical Conditions zole are also approved for maintenance therapy.
Alzheimers disease
Cerebral infarction Table 364 includes a summary of current drug therapy for
Cerebral tumors bipolar disorder. An algorithm for treatment of bipolar mania
Closed head injury is shown in Table 362.
Cushings syndrome
Hemodialysis Mood-Stabilizing Drugs
Hepatic encephalopathy The ideal mood-stabilizing drug has four desired effects: treat-
Huntingtons disease
Hyperthyroidism
ment of acute mania, treatment of acute bipolar depression,
Ictal or post-ictal mania prevention of manic relapse, and prevention of bipolar depres-
Multiple sclerosis sion relapse. All currently approved mood-stabilizing drugs
Neurosyphilis have demonstrated efcacy over placebo for one or more of
Systemic lupus erythematosus these effects, but there are differences among them with regard
Vitamin B deciency
to specic patient populations. Choice of treatment is dictated
Medications by individual patient characteristics and history. Few studies
Corticosteroids
Diltiazem have compared mood-stabilizing drugs to each other in sys-
Levodopa tematic clinical trials. Effect sizes across placebo-controlled trials
Oral contraceptives of individual agents are generally similar. Lithium is often con-
Zidovudine sidered the rst-choice drug for the classic presentation of
Illicit Substances bipolar disorder. Treatment of childhood bipolar disorder is
Anabolic steroids less well researched. Only lithium is FDA-approved in children
Hallucinogens
Stimulants (cocaine, amphetamines)
and adolescents as young as age 12. Treatment of bipolar dis-
order during pregnancy is a particular challenge because of the
risks of drug exposure in utero.
Lithium
The following Web sites provide additional information: Lithium was the rst approved mood-stabilizing drug. It
remains a rst-line agent and sets the standard for efcacy
National Association of Cognitive Behavioral Therapists against which other drugs are usually measured. It has anti-
http://www.nacbt.org manic efcacy, prevents bipolar disorder relapse, and has more
National Association for the Mentally Illhttp://www. modest efcacy for bipolar depression.22 It remains the only
nami.org/ Hometemplate.cfm drug supported by multiple controlled trials in mania, depres-
National Institutes for Mental Health, Bipolar Disorder sion, and relapse prevention. In most studies, lithiums efcacy
http://www.nimh.nih.gov/healthinformation/bipolarmenu.cfm is equivalent to that of the anticonvulsant mood-stabilizers and
the atypical antipsychotic drugs.17 It is most effective for
patients with few previous episodes, symptom-free interepisode
Pharmacologic Therapy remission, and a family history of bipolar disorder with good
response to lithium. Patients with rapid cycling bipolar disorder
Pharmacotherapy is the cornerstone of acute and mainte-
are less responsive to lithium, however, than to other mood-
nance treatment of bipolar disorder. Mood-stabilizing drugs are
stabilizing drugs such as divalproex.26 Additionally, its effect on
the usual rst-choice treatments and include lithium, divalproex,
bipolar depression is less robust than for mania.27 It may also be
carbamazepine, and lamotrigine. Atypical antipsychotics other
less effective in patients with mixed mood episodes (symptoms
than clozapine are also approved for treatment of acute mania.
of mania and depression occurring simultaneously) and in
Lithium, lamotrigine, olanzapine, and aripiprazole are
mania secondary to non-psychiatric illness.
approved for maintenance therapy. Drugs used with less
Increasing evidence shows an effect of lithium on suicidal
research support and without Food and Drug Administration
behavior that is superior to other mood-stabilizing drugs.28
(FDA) approval include topiramate and oxcarbazepine.
Lithium reduces the risk of deliberate self-harm or suicide by
Benzodiazepines are used adjunctively for mania.
about 70%.
Antidepressants may be used for bipolar depression, but
usually along with a mood-stabilizing agent to prevent a mood Mechanism of Action Lithiums pharmacologic mechanism of
switch to mania, and only after the patient has failed to respond action is not well understood and probably involves multiple
adequately to optimal mood-stabilizing therapy.21 Combinations effects. Possibilities include altered ion transport, increased
of two mood-stabilizing drugs or a mood-stabilizing drug and intraneuronal catecholamine metabolism, neuroprotection or
either an antipsychotic or antidepressant drug are common, increased brain-derived neurotrophic factor, inhibition of second
especially in acute mood episodes. messenger systems, and reprogramming of gene expression.29
TABLE 364. Product Formulation, Dosage, and Information, and Clinical Use of Agents Used in the Treatment of Bipolar Disorder3,2225
Generic Name Brand Names Formulations Dosages Clinical Use

Lithium Salts
FDA-approved for use in bipolar disorder
Lithium carbonate Eskalith Capsule: 300 mg 9002400 mg/day in 24 divided Monotherapy or in combina-
Eskalith CR ER tablet: 450 mg doses, preferably with meals; tion with other drugs for
Lithobid ER tablet: 300 mg there is wide variation in the the acute treatment of
Generic Tablet: 300 mg dosage needed to achieve mania and for
Capsule: 150, 300, therapeutic response and 12-hour maintenance treatment
600mg serum lithium concentration
(i.e., 0.61.2 mEq/L or mmol/L for
maintenance therapy and
1.01.5 mEq/L or mmol/L for
acute mood episodes taken
12 hours after the last dose); single
daily dosing is effective and causes
fewer adverse renal effects
Lithium citrate Generic 300 mg (8 mEq)/5 mL
Anticonvulsants
FDA-approved for use in bipolar disorder
Carbamazepine Equetro Capsule: 100, 200, 300 mg Start at 100200 mg bid; increase Monotherapy or in
SR; may open capsule by 200 mg every 34 days combination with other
but do not crush or chew 2001800 mg/day in 24 drugs for the acute
beads; take with food divided doses treatment of mania
Tablet: 200 mg or mixed episodes
Tegretol Chewable tablet: 100 mg Target serum concentration for bipolar I disorder.
Suspension: 100 mg/5 mL is 412 mcg/mL
Tegretol XR ER tablet: 100, 200, 400 mg (1751 mol/L)
Carbatrol ER capsule: 200, 300 mg
Divalproex sodium Depakote Enteric-coated, 7503000 mg/day (2060 mg/kg Monotherapy or in
delayed-release tablet: per day) in 23 divided doses combination with other
125, 250, 500 mg for delayed-release divalproex drugs for the acute
Sprinkles: 125 mg or valproic acid treatment of mania
Depakote ER Extended-release tablet: Extended release divalproex may and for maintenance
250, 500 mg be given once daily at bedtime treatment.
Valproic acid Depakene, Capsules: 250 mg A loading dose of divalproex
generic (2030 mg/kg per day) can be
given, then 20 mg/kg per day
and titrated to a serum
Valproic acid syrup Depakene, 250 mg/5 mL concentration of 50125 mcg/mL
generic (346866 mol/L)
Lamotrigine Lamictal Tablet: 25, 100, 150, 50400 mg/day in divided doses. Monotherapy or in
200 mg Dosage should be slowly combination with other
increased by following prescribing drugs for the long-term
information; if valproate is added maintenance treatment of
to Lamictal, the Lamictal dosage bipolar depression; may
should be reduced by half have efcacy for prevention
of bipolar depression
Anticonvulsants and Other Drugs
Not FDA-Approved for Use in Bipolar Disorder
Clonazepam Klonopin Tablet: 0.5, 1, 2 mg 0.520 mg/day in divided doses or Use in combination with
one dose at bedtime other drugs for the acute
Dosage should be slowly treatment of mania or
adjusted up and down mixed episodes. Use as a
according to response and short-term adjunctive
adverse effects sedative-hypnotic agent
Lorazepam Ativan Tablet: 0.5, 1, 2 mg 24 mg/day in divided doses or
Oral solution: 2 mg/mL just one dose at bedtime
Injection: 2, 4 mg/mL Dosage should be slowly adjusted
up and down according to
response and adverse effects
(Continued)
TABLE 364. Product Formulation, Dosage, and Information, and Clinical Use of Agents Used in the Treatment of Bipolar
Disorder3,2225 (Continued)
Generic Name Brand Names Formulations Dosages Clinical Use
Oxcarbazepine Trileptal Tablets: 150, 300, 600 mg 3001200 mg/day in two divided doses May cause fewer adverse
Suspension: 300 mg/5 mL Doses should be slowly drug-drug interactions than
adjusted up and down according carbamazepine, but causes
to response and adverse effects more gastrointestinal side
(e.g., 150300 mg twice daily and effects and hyponatremia
increase by 300600 mg/day at Evidence is limited
weekly intervals) regarding efcacy
Topiramate Topamax Tablet: 25, 100, 200 mg 50200 mg/day in divided doses Not recommended for the
Sprinkle capsule: 15, 25 mg Dosage should be slowly increased acute treatment of mania
to minimize adverse effects (e.g., or mixed episodes due
25 mg at bedtime for 1 week, then to lack of efcacy; used
2550 mg/day increments at as an adjunctive agent
weekly intervals) with established mood
stabilizers
Atypical Antipsychotics
FDA approved for use in bipolar disorder
Aripiprazole Abilify Tablets: 5, 10, 15, 1030 mg/day once daily Use as monotherapy or in
20, 30 mg combination with lithium
or valproate for the acute
treatment of mania or
mixed states for bipolar I
disorder. Olanzapine
and aripiprazole are
approved for relapse
prevention as well as for
acute therapy
Olanzapine Zyprexa Tablets: 2.5, 5, 7.5, 10, 520 mg/day in 1 or 2 doses
15, 20 mg
Zyprexa, Zydis Tablet, orally disintegrating:
5, 10, 15, 20 mg
Quetiapine Seroquel Tablet 25, 100, 200, 300 mg 50800 mg/day in divided doses or
once daily when stabilized
Risperidone Risperdal Tablet: 0.25, 0.5, 0.56 mg/day in 1 or 2 doses Risperidone microspheres
1, 2, 3, 4 mg is not approved at present
Oral solution: 1 mg/mL for bipolar disorder
Risperdal Long-acting injectable:
Consta 25, 37.5, 50 mg
Ziprasidone Geodon Capsule: 20, 40, 60 80 mg 40160 mg/day in divided doses
Dosing and Monitoring Lithium is usually initiated at a dosage lithium concentration of 0.6 to 1.4 mEq/L (0.61.4 mmol/L).
of 600 to 900 mg per day. Although it is most commonly given Higher serum concentrations are usually required to treat an
in a divided dosage, once-daily dosing is acceptable, especially acute episode than to prevent relapse. However, serum
with sustained-release formulations, and can improve patient lithium maintained above 0.8 mEq/L (0.8 mmol/L) may be
adherence and reduce some side effects. It has a narrow thera- more effective in preventing relapse than lower serum con-
peutic index, meaning the toxic dosage is not much greater than centrations. The suggested therapeutic serum concentration
the therapeutic dosage, and requires regular serum concentra- range is based on a 12-hour post-dose sample collection, usu-
tion monitoring as a guide to dosage titration and to minimize ally a morning trough in patients taking more than one dose
risk of adverse effects. At least weekly monitoring is recom- per day. At least 2 weeks at a suggested therapeutic serum
mended until the patient is stabilized, then in decreasing fre- concentration is required for an adequate trial of lithium.
quency. Well-maintained patients who tolerate lithium without Table 365 shows pharmacokinetic parameters and desired
difculty can be monitored by serum concentration as infre- serum concentrations of mood-stabilizing drugs used for
quently as twice yearly. Dosage is titrated to achieve a serum bipolar disorder.
TABLE 365. Pharmacokinetics and Therapeutic Serum Concentrations of Lithium and Anticonvulsants Used in the Treatment of Bipolar Disorder
Divalproex (DVPX)
Sodium/Valproic
Lithium Carbamazepine Oxcarbazepine Acid (VPA) Lamotrigine
Gastrointestinal absorption
Regular release Rapid: 95100% Slow and erratic: Slow and complete: Rapid and complete (VPA) Rapid: 98%
within 16 hours 8590% 100%
Syrup/suspension/ Faster rate of Faster rate of absorption Unknown Faster rate of absorption than tablets NA
solution absorption: 100% Extended-release: 90% of intravenous NA
Extended-release/ Delayed absorption: Delayed absorption: 89% NA dose. Delayed-release: 8190%
enteric-coated 6090% of the suspension; and of intravenous dose
tablets less than regular-release Delayed absorption with delayed-
tablets release tablets; valproate is
rapidlyconverted to VPA in
the stomach, then is rapidly and
almost completely absorbed
from the GI tract
Delay in absorption Yes No; reports of increased Unknown Yes; food slows the rate of Bioavailability not
by food rate of absorption with absorption but not the affected by food
fatty meals (extended- extent for DVPX
release capsule)
Time to reach 0.53 hours (regular- 4.5 hours (regular- 4.5 hours (range of 14 hours (VPA) 14 hours
peak serum release) release); 1.5 hours 313 hours) 35 hours (DVPX single dose)
concentrations 412 hours (suspension); 312 714 hours (DVPX
(extended-release) hours (extended-release extended-release
0.251 hours (oral tablets); 4.17.7 hours multiple dosing)
solution) (extended-release capsules);
higher peak concentrations
with chewable tablets
Distribution
Volume of distribution Initial: 0.30.4 L/kg 0.62 L/kg (adults) 10-monohydroxy 11 L/1.73 m2 (total 0.91.3 L/kg
Steady-state: 0.71 carbazepine valproate); 92 L/1.73
L/kg (metabolite): m2 (free valproate)
49 L/kg
Crosses the placenta Yes; pregnancy risk Yes; pregnancy risk Yes; pregnancy risk Yes: pregnancy risk Yes; pregnancy risk
category: D category: D category: C category: D category: C
Risk of cardiac Risk of neural tube defects:
defects: 0.10.5% 15%
Crosses into breast Yes: 3550% of Yes: ratio of concentration Yes: both drug and Yes: considered compatible Yes: breast-feeding not
milk mothers serum in breast milk to plasma active metabolite; with breast-feeding recommended
concentration; is 0.4 for drug and 0.5 for breast-feeding
breast-feeding not epoxide metabolite; not recommended
recommended considered compatible
with breast-feeding
Protein binding No 7590% 40% of active 8090% (dose dependent) 55%
metabolite
(Continued)
595
596
TABLE 365. Pharmacokinetics and Therapeutic Serum Concentrations of Lithium and Anticonvulsants Used in the Treatment of Bipolar Disorder (Continued)
Divalproex (DVPX)
Sodium/Valproic
Lithium Carbamazepine Oxcarbazepine Acid (VPA) Lamotrigine
Renal clearance Yes: 1040 mL/minute Yes: 13% excreted Yes: 95% excreted in Yes: 3050% excreted Yes: 94% excreted as
with 9098% of unchanged in urine the urine less than 1% as glucuronide glucuronide
dose excreted in excreted unchanged conjugate; less conjugate
urine; 80% of than 3% excreted
lithium that is unchanged
ltered by the renal
glomeruli is
reabsorbed
Metabolism
Hepatic metabolism No Yes: oxidation and Yes: oxidation and Yes: oxidation and Yes: glucuronic acid
hydroxylation induces conjugation glucuronide conjugation Induces
liver enzymes to conjugation its own metabolism
increase its metabolism in normal volunteers
and other drugs
Metabolites No Yes: 10, 11-epoxide (active) Yes: 10-monohydroxy Yes (not active) No
carbazepine (active)
Kinetics First-order First-order after initial First-order First-order First-order
enzyme induction phase
Half-life (t1/2) 1827 hours (adult); t1/2 decreases over time 2 hours (parent) 520 hours (adult) 25 hours; increases to
greater than 36 hours due to autoinduction: 9 hours (metabolite) 59 hours with
(elderly or patients 2565 hours (initial) concomitant
with renal impairment) 1217 hours (adult valproic acid therapy
multiple dosing)
814 hours (children
multiple dosing)
Cytochrome P-450 (CYP450) isoenzyme
CYP450 substrate No 2C8 and 3A3/4 Unknown 2C19 Unknown
CYP450 inhibitor No No 2C19 2C9, 2D6, and 3A3/4 Unknown
CYP450 inducer No 1A2, 2C9/10, and 3A3/4 3A3/4 No Unknown
Therapeutic serum/plasma concentrations
Obtain blood level 11.5 mEq/L: 412 mcg/mL:
1012 hours for adult, for adult,
postdose acute mania acute mania
0.40.6 mEq/L: for and maintenance No established 50125 mcg/mL: adult, No established
elderly or 48 mcg/mL: for therapeutic range; acute mania and therapeutic range:
medically ill elderly or 1230 mcg/mL maintenance 4-20 mcg/mL
0.61.2 mEq/L: for medically ill for 10-hydroxy 4075 mcg/mL: based on
adult, maintenance carbazepine based elderly or epilepsy trials
on epilepsy trials medically ill
NA, not applicable.

From Fankhauser MP, Freeman MP. Bipolar disorder. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:
It is common for lithium to be combined with other mood- kidney damage have been reported. Treatment includes discon-
stabilizing drugs or antipsychotic drugs, if necessary, in order to tinuation of lithium, intravenous uids to correct uid and elec-
achieve more complete remission of symptoms. Studies indi- trolyte imbalance, and osmotic diuresis or hemodialysis. In case
cate that monotherapy is often insufcient to reach this goal.17 of overdose, gastric lavage is indicated. Clinical symptoms can
continue well after the serum concentration is lowered, as clear-
Adverse Effects The most common adverse effects are gas- ance from the central nervous system is slower than from the
trointestinal upset, tremor, and polyuria,30 which are dose- serum. Factors predisposing to lithium toxicity include uid and
related. Nausea, dyspepsia, and diarrhea can be minimized by sodium loss due to hot weather or exercise or drug interactions
coadministration with food, use of sustained-release formula- that increase serum lithium.30
tions, and giving smaller doses more frequently to reduce the
amount of drug in the gastrointestinal tract at a given time. Drug Interactions Drug interactions involving lithium are
Tremor is present in up to 50% of patients. In addition to the common. Since lithium is not metabolized or protein bound,
approaches above, low-dose -blocker therapy such as propra- however, it is not associated with metabolic drug interactions
nolol 20 to 60 mg/day often reduces the tremor. that occur with other mood-stabilizing drugs. Common and
Lithium impairs the kidneys ability to concentrate urine due signicant drug interactions involve thiazide diuretics, non-
to its inhibitory effect on vasopressin. This causes an increase in steroidal anti-inammatory drugs (NSAIDs), and angiotensin-
urine volume and frequency and a consequent increase in thirst. converting enzyme inhibitors (ACEIs). If a diuretic must be
Polyuria and polydipsia occur in up to 70% of patients. A severe used with lithium and a thiazide is not required, loop diuretics
form of polyuria when urine volume exceeds 3 L/day is known such as furosemide are less likely to increase lithium retention.
as nephrogenic lithium-induced diabetes insipidus. It can be The ACEIs can abruptly increase serum lithium with the
treated with amiloride or hydrochlorothiazide. If the latter is potential for acute and fatal toxicity, even after months of no
used, the lithium dosage should be reduced by 33% to 50% to effect. This combination is strongly discouraged.35
account for the drug-drug interaction that could increase serum
lithium and cause toxicity. Long-term lithium therapy can cause Divalproex Sodium and Valproic Acid
structural kidney changes such as glomerular sclerosis or tubu- Divalproex sodium is comprised of sodium valproate and val-
lar atrophy. Once-daily dosing of lithium is less likely to cause proic acid. The delayed-release and extended-release formula-
renal adverse effects than divided-daily dosing. tions are converted in the small intestine into valproic acid,
Lithium is concentrated in the thyroid gland and can impair which is the systemically absorbed form. It was developed as an
thyroid hormone synthesis. Although goiter is uncommon, as antiepileptic drug, but also has efcacy for mood stabilization
many as 30% of patients develop at least transiently elevated and migraine headaches. It is FDA-approved for the treatment
thyroid-stimulating hormone values. Lithium-induced hypothy- of the manic phase of bipolar disorder. It is generally equal in
roidism is not usually an indication to discontinue the drug. efcacy to lithium and some other drugs for bipolar mania. It
Patients can be supplemented with levothyroxine if continua- has particular utility in bipolar disorder patients with rapid
tion of lithium is desired.30 cycling, mixed mood features, and substance abuse comorbidity.
Other common adverse effects include poor concentration, Although not FDA-approved for relapse prevention, studies
acneiform rash, alopecia, worsening of psoriasis, weight gain, support this use, and it is widely prescribed for maintenance
metallic taste, and glucose dysfunction. Lithium causes a benign therapy. Divalproex can be used as monotherapy or in combi-
attening or inversion of the T wave on the electrocardiogram nation with lithium or an antipsychotic drug.31
(ECG). Less commonly, it can cause or worsen arrhythmias.
Cardiologic evaluation is recommended for patients with pre- Mechanism of Action The mechanism of action of divalproex
existing cardiac disease who are candidates for lithium therapy. is not well understood. It is known to affect ion transport and
A benign leukocytosis is also common.30 enhances the activity of -aminobutyric acid. Like lithium, it
Lithium and other mood-stabilizing drugs require baseline also has possible neuroprotective effects through enhance-
and routine laboratory monitoring to help determine medical ment of brain-derived neurotrophic factor.31
appropriateness for initiation of therapy and monitoring of
potential adverse effects. Guidelines for such monitoring are out- Dosing and Monitoring Divalproex is often initiated at 500 to
lined in Table 366. 1000 mg per day, but studies indicate a therapeutic serum val-
Acute lithium toxicity, which can occur at serum concentra- proic acid concentration can be reached more quickly through
tions over 2 mEq/L, can be severe and life-threatening, necessi- a loading dose approach of 20 to 30 mg/kg per day. Using this
tating emergency medical treatment. Symptoms include wors- approach, patients may respond with a signicant reduction in
ening of gastrointestinal distress to include severe vomiting and symptoms within the rst few days of treatment. The dosage is
diarrhea; deterioration in motor coordination including a then titrated according to response, tolerability, and serum
coarse tremor, ataxia, and dysarthria; and impaired cognition. In concentration. The most often referenced desired serum valproic
its most severe form, seizures, cardiac arrhythmias, coma, and acid concentration is 50 to 100 mcg/mL (346693 mol/L), but
598
TABLE 366. Guidelines for Baseline and Routine Laboratory Tests and Monitoring for Agents Used in the Treatment of Bipolar Disorder
Baseline:
Physical
Exam & Liver Renal Thyroid
General Hematologic Metabolic Function Function Function Serum
Chemistrya Testsc Testsb Testsd Testse Testsf Electrolytesg Dermatologich
Baseline Baseline 612 Baseline 612 Baseline 612 Baseline 612 Baseline 612 Baseline 612 Baseline 36
months months months months months months months
Atypical X X X
antipsychoticsi
Carbamazepinej X X X X X X X X X X
Lamotriginek X X X
Lithiuml X X X X X X X X X X X X X
Oxcarbazepinem X X X
Valproaten X X X X X X X X X
a
Screen for drug abuse and serum pregnancy.
b
Complete blood cell count (CBC) with differential and platelets.
c
Fasting glucose, serum lipids, weight.
d
Lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase.
e
Serum creatinine, blood urea nitrogen, urinalysis, urine osmolality, specic gravity.
f
Triiodothyronine, total thyroxine, thyroxine uptake, and thyroid-stimulating hormone.
g
Serum sodium.
h
Rashes, hair thinning, alopecia.
i
Atypical antipsychotics: Monitor for increased appetite with weight gain (primarily in patients with initial low or normal body mass index); monitor closely if rapid or signicant weight gain
occurs during early therapy; cases of hyperlipidemia and diabetes reported.
j
Carbamazepine: Manufacturer recommends CBC and platelets (and possibly reticulocyte counts and serum iron) at baseline, and that subsequent monitoring be individualized by the cli-
nician (e.g., CBC, platelet counts, and liver function tests every 2 weeks during the rst 2 months of treatment, then every 3 months if normal). Monitor more closely if patient exhibits hema-
tologic or hepatic abnormalities or if the patient is receiving a myelotoxic drug; discontinue if platelets are less than 100,000/mm3, if white blood cell (WBC) count is less than 3,000/mm3
or if there is evidence of bone marrow suppression or liver dysfunction. Serum electrolyte levels should be monitored in the elderly or those at risk for hyponatremia. Carbamazepine inter-
feres with some pregnancy tests.
k
Lamotrigine: If renal or hepatic impairment, monitor closely and adjust dosage according to manufacturers guidelines. Serious dermatologic reactions have occurred within 28 weeks of
initiating treatment and are more likely to occur in patients receiving concomitant valproate, with rapid dosage escalation, or using doses exceeding the recommended titration schedule.
l
Lithium: Obtain baseline electrocardiogram for patients over age 40 or if preexisting cardiac disease (benign, reversible T-wave depression may occur). Renal function tests should be obtained
every 23 months during the rst 6 months, then every 612 months; if impaired renal function, monitor 24-hour urine volume and creatinine every 3 months; if urine volume greater than
3 L/day, monitor urinalysis, osmolality, and specic gravity every 3 months. Thyroid function tests should be obtained once or twice during the rst 6 months, then every 612 months; mon-
itor for signs and symptoms of hypothyroidism; if supplemental thyroid therapy is required, monitor thyroid function tests and adjust thyroid dose every 12 months until thyroid function
indices are within normal range, then monitor every 36 months.
m
Oxcarbazepine: Hyponatremia (serum sodium concentrations less than 125 mEq/L) has been reported and occurs more frequently during the rst 3 months of therapy; serum sodium con-
centrations should be monitored in patients receiving drugs that lower serum sodium concentrations (e.g., diuretics or drugs that cause inappropriate antidiuretic hormone secretion) or in
patients with symptoms of hyponatremia (e.g., confusion, headache, lethargy, and malaise). Hypersensitivity reactions have occurred in approximately 2530% of patients with a history of
carbamazepine hypersensitivity and requires immediate discontinuation.
n
Valproate: Weight gain reported in patients with low or normal body mass index. Monitor platelets and liver function during rst 36 months if evidence of increased bruising or bleeding.
Monitor closely if patients exhibit hematologic or hepatic abnormalities or in patients receiving drugs that affect coagulation, such as aspirin or warfarin; discontinue if platelets are Less than
100,000/mm3/L or if prolonged bleeding time. Pancreatitis, hyperammonemic encephalopathy, polycystic ovary syndrome, increased testosterone, and menstrual irregularities have been
reported; not recommended during rst trimester of pregnancy due to risk of neural tube defects.
From Fankhauser MP, Freeman MP. Bipolar disorder. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:
it is not unusual for patients to require over 100 mcg/mL 50%. Conversely, the metabolism of divalproex can be
(693 mol/L) for optimal efcacy. Some patients require high- increased by enzyme-inducing drugs such as carbamazepine
milligram dosages in order to reach a desired serum concentra- and phenytoin, while divalproex may simultaneously slow
tion. The suggested serum concentration range is based on metabolism of the other agents.35
morning sampling, which is a trough value for patients taking
divided-daily dosing. Serum concentration monitoring is Carbamazepine
recommended at least every 2 weeks until stabilized, then less Although long utilized as a mood-stabilizing drug, an
frequently, sometimes as infrequently as twice yearly. The extended-release formulation of carbamazepine has only
extended-release formulation can be taken once daily, usually at recently received FDA approval for treatment of bipolar dis-
night. In this instance also, a morning blood sampling is recom- order. Like divalproex, it also has efcacy for mood stabiliza-
mended. The systemic bioavailability of extended-release dival- tion, but is considered possibly less desirable as a rst-line
proex is about 15% less than that of the delayed-release formula- agent because of safety and drug interactions. It is sometimes
tion. Patients who have difculty swallowing large tablets can use reserved for patients who fail to respond to lithium or for
the sprinkle formulation. Valproic acid is available in a syrup for- patients with rapid cycling or mixed bipolar disorder.
mulation, which is generally given three or four times per day.31 Carbamazepine can be used as monotherapy or in combina-
tion with lithium or an antipsychotic drug.24,32
Adverse Effects The most common adverse effects of dival-
proex are gastrointestinal (loss of appetite, nausea, dyspepsia, Mechanism of Action The mechanism of action of carba-
and diarrhea), tremor, and drowsiness. Gastrointestinal dis- mazepine is not well understood. It blocks ion channels and
tress can be reduced by coadministration with food. The inhibits sustained repetitive neuronal excitation, but whether
delayed-release and extended-release formulations are less this explains its effect as a mood-stabilizing drug is not known.32
likely to cause gastric distress than the immediate-release val-
proic acid. This is an advantage for divalproex, along with Dosing and Monitoring Carbamazepine is usually initiated at
fewer daily doses, which can improve patient adherence to 400 to 600 mg/day. The sustained-release formulation can be
treatment. Dosage reduction can reduce all of the common given in two divided doses. In addition to a formulation that is
divalproex side effects. As with lithium, a low-dose -blocker completely sustained-release, an additional extended-release
may alleviate the tremor. Weight gain is also common, occur- formulation contains a matrix of 25% immediate-release, 40%
ring in up to 50% of patients on maintenance therapy.31 extended-release, and 35% enteric-release beads.24 The sug-
Other adverse effects that are less common include alopecia or gested therapeutic serum concentration is 4 to 12 mcg/mL
a change in hair color or texture. Hair loss can be minimized by (1751 mol/L). As with divalproex, some patients require high-
supplementation with a vitamin containing selenium and zinc. milligram dosages to achieve a desired serum concentration and
Polycystic ovarian syndrome associated with increased androgen therapeutic effect. The dosage can be increased by 200 to 400 mg
production has been reported. Thrombocytopenia is not uncom- per day as often as every 2 to 4 days to achieve the desired
mon, and the platelet count should be monitored periodically. It effect. Serum concentration monitoring is suggested at least
is a dose-related adverse effect and usually asymptomatic, but the every 2 weeks until stabilized, then less frequently.32
drug is usually stopped if the platelet count decreases to less than
100,000/mm3 (100 103/L or 100 109/L). More rare are Adverse Effects The most common adverse effects are drowsi-
hepatic toxicity and pancreatitis, which are not always dose- ness, dizziness, ataxia, lethargy, and confusion. At mildly toxic
related. Severe gastrointestinal symptoms of hepatic or pancre- serum concentrations, it also causes diplopia and dysarthria.
atic toxicity include vomiting, pain, and loss of appetite. When These effects can be minimized through dosage adjustments,
these occur, the patient should be evaluated for possible hepatitis use of sustained-release formulations, and giving more of the
or pancreatitis. Divalproex has a wide therapeutic index. Acute drug late in the day. Gastrointestinal upset is also common.
toxicity for high dosages or overdosage is not life-threatening.31 Carbamazepine has an antidiuretic effect similar to the syn-
drome of inappropriate antidiuretic hormone secretion and
Drug Interactions Drug interactions involving divalproex can cause hyponatremia. Mild elevations in liver enzymes can
are common. It is a weak inhibitor of some of the drug- occur, but hepatitis is less common. Mild, dose-related leukope-
metabolizing liver enzymes and can affect the metabolism of nia is not unusual and not usually an indication for stopping
other drugs. These include other antiepileptic drugs and tri- the drug. More serious blood count abnormalities such as aplas-
cyclic antidepressants. The interaction between divalproex tic anemia and agranulocytosis are rare, but life-threatening.32
and lamotrigine is particularly important. The risk of a dan- Suggested baseline and routine laboratory monitoring is
gerous rash due to lamotrigine is increased when given con- reviewed in Table 366.
currently with divalproex. When lamotrigine is added to dival-
proex, the initial lamotrigine dosage should be reduced, and Drug Interactions Carbamazepine induces the hepatic metab-
titrated more slowly than usual. When divalproex is added to olism of many drugs, including other antiepileptic drugs,
lamotrigine, the lamotrigine dosage should be reduced by antipsychotics, some antidepressants, oral contraceptives, and
antiretroviral agents. Carbamazepine is also an autoinducer these pathways can have a signicant effect on lamotrigines
(i.e., it induces its own metabolism). The dosage may require clearance. In particular, divalproex slows the rate of elimina-
an increase after 1 month or so of therapy because of this tion of lamotrigine by about half, necessitating dosage reduc-
effect. Conversely, the metabolism of carbamazepine can be tion. Conversely, carbamazepine increases the rate of lamot-
slowed by enzyme-inhibiting drugs such as some antidepres- rigine metabolism. Upward adjustment in the lamotrigine
sants, macrolide antibiotics including erythromycin and clar- dosage may be needed as a result.35
ithromycin, azole antifungal drugs including ketoconazole
and itraconazole, and grapefruit juice. Carbamazepine should Oxcarbazepine
not be given concurrently with clozapine because of the added Oxcarbazepine is an analogue of carbamazepine, developed as
risk of agranulocytosis.35 an antiepileptic drug. An advantage over carbamazepine is that
routine monitoring of hematology proles and serum concen-
Lamotrigine trations are not indicated, as the drug is less likely to cause
Lamotrigine is effective for the maintenance treatment of hematologic abnormalities. Additionally, drug interactions are
bipolar disorder. It is more effective for depression relapse less signicant, although it is at least a mild inducer of certain
prevention than for mania relapse. Its primary limitation as metabolic pathways, and vigilance for drug interactions is
an acute treatment is the time required for titration to an needed, especially with oral contraceptives. Oxcarbazepine
effective dosage. In addition to maintenance monotherapy, it appears in the most recent treatment algorithms for bipolar
is sometimes used in combination with lithium or divalproex, disorder,17 but clinical trial data are limited and do not include
although combination with divalproex increases the risk of randomized, prospective, controlled trials at the time of this
rash, and lamotrigine dosage adjustment is required.37 writing. Data are limited to open-label and retrospective stud-
ies or add-on therapy with other mood-stabilizing agents.38
Mechanism of Action The mechanism of action of lamotrig-
ine appears to involve blockage of ion channels and effects on Adverse Effects Adverse effects due to oxcarbazepine include
glutamate transmission, although the precise mechanism in drowsiness, dizziness, gastrointestinal upset, and hypona-
bipolar disorder is not clear.33 tremia, the latter two of which may be more likely than with
carbamazepine. It is less likely than carbamazepine to cause
Dosing and Monitoring Lamotrigine is usually initiated at hematologic abnormalities.34
25 mg daily for the rst 1 to 2 weeks, then increasing in a dose-
doubling fashion every 1 to 2 weeks to a target dosage of 200 Others
to 400 mg per day. If lamotrigine is added to divalproex, the High-potency benzodiazepine agents such as clonazepam have
starting dosage is 25 mg every other day with a slower titration been used as adjunctive therapy, especially during acute mania
to reduce the risk of rash. If divalproex is added to lamotrig- episodes, to reduce anxiety and improve sleep.39 Topiramate is
ine, the lamotrigine dosage should be reduced by 50% for the commonly used for its putative mood-stabilizing effects, but
same reason. If lamotrigine therapy is interrupted for more unpublished, well-designed, randomized, controlled trials
than a few days, it should be restarted at the initial dosage. sponsored by the manufacturer showed no difference between
Serum concentration monitoring is not routinely recom- topiramate and placebo for treatment of bipolar disorder.
mended for patients with bipolar disorder.33 Uncontrolled, open-label data suggest possible use as an
adjunctive agent.38 Gabapentin has shown no efcacy over
Adverse Effects The lamotrigine adverse effect of greatest sig- placebo and is not recommended for patients with bipolar
nicance is a maculopapular rash, occurring in up to 10% of disorder. Case reports or case series involving zonisamide,
patients.33 Although usually benign and temporary, some tiagabine, pregabalin, and levetiracetam have been published,
rashes can progress to life-threatening Stevens-Johnson syn- but no controlled trials have been conducted to date.38
drome. The risk of rash is greater with a rapid dosage titration
and when given concurrently with divalproex. The risk is min- Antipsychotic Drugs
imal when the dosage titration schedule is slow. Other side Conventional antipsychotic drugs such as chlorpromazine
effects include dizziness, drowsiness, headache, blurred vision, and haloperidol have long been used in the treatment of acute
and nausea. In contrast to other mood-stabilizing drugs such mania. More recently, atypical antipsychotic drugs including
as lithium and divalproex, lamotrigine does not signicantly aripiprazole, olanzapine, quetiapine, risperidone, and ziprasi-
inuence body weight. done have been approved for the treatment of bipolar mania
or mixed mood episodes as monotherapy or in combination
Drug Interactions Drug interactions involving lamotrigine with mood-stabilizing drugs.25 Aripiprazole and olanzapine
are usually due to induction or inhibition of its metabolism are also approved for maintenance therapy. The combination
by other drugs. It does not affect drug-metabolizing of olanzapine and uoxetine is approved for treatment of
hepatic enzymes on its own, but other drugs that affect bipolar depression. Quetiapine is approved for treatment of
bipolar depression. Approval of antipsychotic drugs in bipolar Special Populations

disorder patients applies without regard to the presence of psy-
Assessment and management by appropriate psychiatric spe-
chotic symptoms. In comparative studies, atypical antipsy-
cialists is important for special populations such as pediatrics,
chotic drugs are equivalent in efcacy to lithium and dival-
geriatrics, pregnancy, and others.
proex for treatment of acute mania. Treatment guidelines
include antipsychotic drugs as rst-line therapy.17 More limited
Pediatrics
studies in maintenance therapy indicate equivalent or possibly
Evidence regarding treatment of bipolar disorder in children
superior efcacy of atypical antipsychotic drugs compared to
and adolescents is more limited than in adults, reecting the
lithium, but these studies are sponsored and developed by
difculty of conducting research in this population. Psychiatric
manufacturers and have not been replicated widely.
comorbidity is common, which makes treatment and research
The mechanisms of action, usual dosages, pharmacokinetics,
more challenging. With these caveats, an increasing body of
adverse effects, and drug interactions involving antipsychotic
evidence supports the use of mood-stabilizing drugs and
drugs are discussed in detail in the chapter on schizophrenia.
atypical antipsychotic drugs in children and adolescents with
Dosages in bipolar disorder are similar to those used in schizo-
bipolar disorder.44 The approach is similar to that used in
phrenia. Higher dosages are often required to treat an acute
adults, with monotherapy as rst-line therapy, but only
episode than to prevent relapse. The recommended dosage of
lithium is FDA-approved for children and adolescents as young
aripiprazole for bipolar disorder is 20 to 30 mg per day, some-
as age 12. The guidelines additionally support divalproex, car-
what higher than the average dosage used in schizophrenia.40
bamazepine, olanzapine, quetiapine, and risperidone.44
Atypical antipsychotic drugs are less likely than conven-
Aripiprazole and ziprasidone are not recommended at present
tional agents to cause neurologic side effects, especially move-
because of a lack of published research, but evidence to sup-
ment abnormalities. As a group, however, they are more
port the other agents is mostly open-label trials or studies with
likely to cause metabolic side effects such as weight gain, glu-
small sample sizes. For patients with psychotic features, rst-
cose dysregulation, and dyslipidemia.36 Among the atypical
line therapy should include combined mood stabilizer and
antipsychotic drugs approved for treatment of bipolar disor-
antipsychotic drugs. Patients who fail the initial choice of treat-
der, olanzapine is more likely to cause metabolic side effects.
ment can be switched to a different agent or augmented with
Quetiapine and risperidone cause fewer metabolic effects than
the addition of a second agent.
olanzapine. Aripiprazole and ziprasidone are neutral in effects
Initial dosages of drug therapy in the pediatric population
on weight, glucose, and lipids. Adverse effects are discussed in
are lower than in adults. Metabolic elimination rates of many
detail in the chapter on schizophrenia.
drugs are increased in children, however, so they may actually
require higher dosages on a weight-adjusted basis. Dosages are
Antidepressants titrated carefully according to response and tolerability. For
Treatment of depressive episodes in bipolar disorder patients lithium, divalproex, and carbamazepine, serum concentration
presents a particular challenge because of the risk of a phar- monitoring is recommended as a guide to dosage adjustment
macologic mood switch to mania, although there is not com- and to minimize adverse effects.
plete agreement about such risk. Treatment guidelines suggest Children and adolescent patients are often more sensitive
lithium or lamotrigine as rst-line therapy.17,41 Olanzapine to drug side effects than adults. In particular, they are more
has also demonstrated efcacy in treatment of bipolar depres- likely than adults to experience signicant weight gain due to
sion, and quetiapine is under review for approval of treatment atypical antipsychotic drugs.45 Cognitive toxicity, manifested
of bipolar depression.42 When these fail, efcacy data support as confusion, memory or concentration impairment, or
use of antidepressants. impaired learning, is often difcult to detect and is a special
Guidelines agree that when antidepressants must be used, consideration in the pediatric population so intellectual and
they should be combined with a mood-stabilizing drug to educational development is not hindered by drug therapy.
reduce the risk of mood switch to hypomania or mania.17,41 The Comorbid conditions must be addressed in order to maxi-
question of which antidepressant drugs are less likely to cause a mize desired outcomes. For comorbid bipolar disorder and
mood switch is not resolved. Anecdotal reports suggested attention-decit/hyperactivity disorder when stimulant ther-
bupropion may be less likely to cause this effect, but systematic apy is indicated, treatment of mania is recommended before
reviews have not supported this conclusion. Prevailing evidence starting the stimulant in order to avoid exacerbation of mood
recommends that tricyclic antidepressants be avoided.41,43 symptoms by the stimulant.
Duration of antidepressant therapy is also an unsettled
question. It may be possible in some patients to prevent Geriatrics
depressive relapse with a mood-stabilizing drug without Treatment of elderly patients with bipolar disorder requires
maintenance antidepressant therapy following acute treat- special care because of increased risks associated with concur-
ment with an antidepressant. If so, the risk of a mood switch rent non-psychiatric medical conditions and drug-drug inter-
with continued antidepressant therapy would be reduced. actions. General medical conditions including endocrine,
metabolic, or infectious diseases can mimic mood disorders. toxicity postpartum when there is a large reduction in uid
Patients should be evaluated for such medical illnesses that volume.46
may cause or worsen mood symptoms. As physiologic systems Lithium can cause hypotonicity and cyanosis in the
change with aging, elimination of drugs is often slowed. neonate, usually termed the oppy baby syndrome. Most
Examples are slowed renal elimination of lithium and slowed data indicate normal neurobehavioral development once these
hepatic metabolism of carbamazepine and valproic acid. As a symptoms resolve. Lithium is readily transferred via breast
result, dosages of drugs required for therapeutic effect are milk. Breast-feeding is not advised for patients who are taking
generally lower in geriatric patients. Also, changes in mem- lithium.30
brane permeability with aging increase risk of central nerv- Valproic acid and carbamazepine are human teratogens.
ous system side effects. Increased frequency of patient moni- Neural tube defects such as spina bida occur in up to 9% of
toring is often required, including serum drug concentration infants exposed during the rst trimester. The risk is related to
monitoring. exposure during the third and fourth weeks following concep-
Vigilance for drug-drug interactions is required because of the tion. As such, women with unplanned pregnancies may not
greater number of medications prescribed to elderly patients know they are pregnant until after the risk of exposure has
and enhanced sensitivity to adverse effects. Pharmacokinetic occurred. Carbamazepine can cause fetal vitamin K deciency.
interactions include metabolic enzyme induction or inhibition Vitamin K is important for facial growth and for clotting
and protein binding displacement interactions (e.g., divalproex factors. Risk of facial abnormalities and neonatal bleeding is
and warfarin). Pharmacodynamic interactions include additive increased in infants of mothers who are treated with carba-
sedation and cognitive toxicity, which increases risk of falls and mazepine during pregnancy.46
other impairments. Less data are available on other antiepileptic mood-
stabilizing drugs. Birth defects in children of women who
Pregnancy are prescribed lamotrigine during pregnancy appear to be
Treatment of bipolar disorder during pregnancy is fraught with no greater than in the general population, but based on an
controversy and conicting recommendations. The key issue is analysis of only several hundred cases.47 The FDA has noted
the relative risk of teratogenicity with drug use during preg- a possible, but inconclusive association between lamotrigine
nancy versus risk of bipolar relapse without treatment with exposure during the rst trimester and cleft lip and/or cleft
consequent potential harm to both the pregnant patient and palate.
the fetus. Judgment on an issue of such gravity depends on the
history of the patient and whether the pregnancy is planned or
unplanned. Treatment is best managed when the pregnancy is Patient Encounter, Part 4: Outcome
planned. Clinicians should discuss the issue with every patient Evaluation
with bipolar disorder who is of childbearing potential. A preg-
nancy test should be obtained prior to initiating drug therapy.
For a patient with severe bipolar disorder, a history of multiple Following initial assessment, including evaluation of poten-
mood episodes, rapid cycling, or suicide attempt, discontinuing tial suicidality, support systems, and need for inpatient versus
outpatient treatment, MW was hospitalized briey, then
treatment, even for a planned pregnancy, is unwise. For a
followed in the community on medication along with psy-
patient with a remote history of a single mood episode with chotherapy. She has abstained from illicit substances and
subsequent long-term stability and who is contemplating preg- has returned to her job. She has responded well to treat-
nancy, the answer is less clear. Patients should be provided clear ment with sustained-release lithium carbonate 900 mg
and reliable information about risks versus benets of stopping once daily at bedtime with a snack. Steady-state 12-hour
or continuing therapy in order to make an informed decision. serum lithium concentrations have stabilized at 0.9 mEq/L
Patients who decide to discontinue drug therapy prior to preg- (0.9 mmol/L). She now returns to clinic for routine follow-
nancy should taper medications slowly in order to reduce risk up. She has tolerated the lithium except for a mild tremor
of relapse.46 and a gain of 7 pounds (3.2 kg). She is willing to accept
Lithium is associated with Ebsteins anomaly, a downward these side effects for now, but asks about how long she
displacement of the tricuspid valve into the right ventricle. must take medication since she is now feeling well.
Although more likely to occur in children of patients who
Assess therapeutic and adverse effects of treatment for
took lithium during pregnancy, the absolute risk is considered this patient.
small, around 0.1%. Pharmacokinetic handling of lithium Recommend strategies to maintain therapeutic efcacy
changes as pregnancy progresses. Renal lithium clearance while reducing or eliminating adverse effects.
increases, which requires a dosage increase to maintain a ther- Educate the patient regarding need for continued mainte-
apeutic serum concentration. It may be advisable to decrease nance treatment.
or discontinue lithium at term or the onset of labor to avoid
First-generation antipsychotic drugs have been available

for many years, and more data are available on their use in Patient Care and Monitoring
pregnancy than for atypical antipsychotic drugs. Since experi-
ence with atypical antipsychotic drugs during pregnancy is
limited, rst-generation agents are often recommended for
1. Assess the patients symptoms and review the past his-
the treatment of acute mania during pregnancy.
tory. Review the family history, including the history of
Use of antidepressant drugs during pregnancy is discussed response to treatment by family members.
in the chapter on depression.
2. Obtain an initial medical evaluation to rule out other
causes of mood episodes.
3. Obtain a thorough medication use history, including pres-
OUTCOME EVALUATION ent and past drugs; prescription and nonprescription drugs;
the patients self-assessment of response and side-effect
Assessment of Therapeutic Effects problems; use of alcohol, tobacco, caffeine, and illicit sub-
stances; and use of herbal products and dietary supple-
Effective interviewing skills and a therapeutic relationship with
ments, as well as any allergies and adherence difculties.
the patient are essential to assessing response to treatment.
4. Assess potential drug-disease, drug-drug, and drug-food
Understand the particular symptom prole and needs of indi-
interactions.
vidual patients. These become the primary therapeutic moni-
toring parameters. In addition to the clinical interview, some 5. Evaluate physiologic parameters that may inuence
pharmacokinetics.
clinicians utilize symptom rating scales such as the Young
Mania Rating Scale for mania and the Hamilton Depression 6. Develop a plan for monitoring therapeutic outcomes,
Rating Scale (discussed in the chapter on depression). Check focusing on the individual symptom prole and level of
function of each patient. Include a plan for dosage
serum concentrations of mood-stabilizing drugs as a guide
adjustments or alternate therapy if the patient fails to
to dosage adjustment for optimal efcacy. The frequency of
respond adequately. Include serum drug concentration
follow-up visits depends on response, tolerability, adherence, monitoring as appropriate.
and other factors.
7. Develop a monitoring plan for drug side effects. Include
Adverse effects cause more non-adherence to prescribed ther-
measures to prevent side effects as well as management
apy than any other factor. Monitor patients regularly for adverse if they occur. Include appropriate laboratory measures.
effects and health status, especially since mood-stabilizing drugs
8. Determine the role of nonpharmacologic therapy and
and antipsychotic drugs commonly cause metabolic side
how it is to be integrated with drug therapy.
effects such as weight gain. Repeat laboratory tests for renal
9. Educate the patient on the nature of bipolar disorder
and thyroid function for patients taking lithium, and hematol-
and its treatment, what to expect with regard to
ogy and liver function for patients taking carbamazepine or
response and side effects, and stress the need for adher-
divalproex. Annual measurement of serum lipase may be ence to treatment, even when feeling well.
advisable for patients taking divalproex. More specic discus-
10. Encourage a healthy lifestyle, including eliminating or
sion of metabolic side-effect monitoring of patients taking
stopping substance abuse and smoking, and encourag-
atypical antipsychotic drugs is discussed in the chapter on ing proper nutrition and exercise.
schizophrenia.
Patient education improves adherence to treatment, which
reduces risk of relapse. This is especially important since respon-
siveness to treatment declines as the number of mood episodes ABBREVIATIONS
increases. Discuss the nature and chronic course of bipolar dis-
order and the risks of repeated relapses. Help patients under- ACE-I: angiotensin-converting enzyme inhibitor
stand that treatment of bipolar disorder is not a cure, but many CBT: cognitive-behavioral therapy
patients can enjoy symptom-free or nearly symptom-free func- DA dopamine
tion. Make clear that long-term recovery is dependent on adher- DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision
ence to both pharmacologic and nonpharmacologic treatment.
ECG: electrocardiogram
Explain the purpose of medication, common side effects to ECT: electroconvulsive therapy
expect, and how to respond to them. Provide the patient and FDA: Food and Drug Administration
family with written information about medication indications, fMRI: functional magnetic resonance imaging
benets, risks, and side effects. Discuss less frequent, but more FOI: ight of ideas
dangerous side effects of drugs, and give written instructions on GED: general education diploma
seeking medical attention immediately should they occur. 5-HT: serotonin
IOR: ideas of reference Gijsman HJ, Geddes JR, Rendell JM, et al. Antidepressants for bipolar
NE: norepinephrine depression: a systematic review of randomized, controlled trials.
NOS: not otherwise specied Am J Psychiatry 2004;161:15371547.
NSAID: non-steroidal anti-inammatory drug Kowatch RA, Fristad M, Birmaher B, et al. Treatment guidelines for
PET: positron emission tomography children and adolescents with bipolar disorder. J Am Acad Child
THC: tetrahydrocannabinol Adolesc Psychiatry 2005;44:213235.
Otto MW, Reilly-Harrington N, Sachs GS. Psychoeducational and
Reference lists and self-assessment questions and answers are cognitive-behavioral strategies in the management of bipolar
available at www.ChisholmPharmacotherapy.com. disorder. J Affect Disord 2003;73:171181.
Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the
Log into the website: www.pharmacotherapyprinciples.com treatment of mania: a meta-analysis of randomized, placebo-
for information on obtaining continuing education credit for controlled trials. J Clin Psychiatry 2006;67:509516.
this chapter. Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic
drug-drug interactions. Psychosomatics 2005;46:464494.
Suppes T, Dennehy EB, Hirschfeld RM, et al. The Texas implementa-
KEY REFERENCES AND READINGS tion of medication algorithms: update to the algorithms for treat-
ment of bipolar I disorder. J Clin Psychiatry 2005;66:870886.
Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar dis-
bipolar disorder: systematic review and meta-analysis of ran- order during pregnancy and the postpartum period. Am J
domized controlled trials. Am J Psychiatry 2004;161:217222. Psychiatry 2004;161:608620.
37 GENERALIZED ANXIETY DISORDER, PANIC
DISORDER, AND SOCIAL ANXIETY DISORDER
Sheila Botts, Tawny Bettinger, and Brian Greenlee
LEARNING OBJECTIVES
1. Describe pathophysiologic ndings in generalized anxiety, panic, and social anxiety

disorder patients.
2. List common presenting symptoms of generalized anxiety, panic, and social anxiety
disorders.
3. Identify the desired therapeutic outcomes for patients with generalized anxiety, panic, and
social anxiety disorders.
4. Discuss appropriate lifestyle modications and over-the-counter medication use.
5. Recommend psychotherapy and pharmacotherapy interventions for patients with
generalized anxiety, panic, and social anxiety disorders.
6. Develop a monitoring plan for anxiety patients placed on specic medications.
7. Educate patients about their disease state and appropriate lifestyle modications, as well as
psychotherapy and pharmacotherapy for effective treatment.
KEY CONCEPTS Antidepressants should be tapered when treatment is discon-

tinued to avoid withdrawal symptoms, which include dys-
The goals of therapy for generalized anxiety disorder are to phoric mood, irritability, and agitation.
acutely reduce the severity and duration of anxiety symptoms and The dose of benzodiazepine required for improvement in
restore overall functioning. The long-term goal in generalized panic disorder generally is higher than that used in other anx-
anxiety disorder is to achieve and maintain remission. iety disorders.
Antidepressants are considered rst-line agents in the man- Selective serotonin reuptake inhibitors (SSRIs) are considered
agement of chronic generalized anxiety disorder. the drugs of choice based on their tolerability and efcacy for
Benzodiazepines are recommended for acute treatment of social anxiety disorder as well as comorbid disorders.
generalized anxiety disorder when short-term relief is needed, The onset of response to antidepressants in social anxiety dis-
as an adjunct during initiation of antidepressant therapy, or order is delayed and may be as long as 8 to 12 weeks. Patients
to improve sleep. responding to medication should be continued on treatment
The acute phase of panic disorder treatment lasts about for at least 1 year.
12 weeks and should result in marked reduction in panic Pharmacotherapy of social anxiety disorder should lead to
attacks, ideally total elimination, and minimal anticipatory improvement in physiologic symptoms of anxiety and fear,
anxiety and social anxiety avoidance. Treatment should be con- functionality, and overall well-being.
tinued to prevent relapse for an additional 12 to 18 months
before attempting discontinuation. Anxiety is a normal response to stressful or fearful circum-
Panic disorder patients are more likely to experience stimulant- stances. Most people experience some degree of anxiety in
like side effects than patients with major depression and reaction to stressful situations, such as nal exams or giving a
should be initiated on lower doses of antidepressant than speech. This allows an individual to adapt to or manage the
those that are used for depression or other anxiety disorders. stressful/threatening situation. Anxiety symptoms generally
605
NCS-R show that while, in general, prevalence rates across the

Patient Encounter 1, Part 1 anxiety spectrum increase from the younger age group (1829)
to older age groups (3044 and 4559), rates are substantially
lower for those older than age 59.3
AX, a 27-year-old African-American woman, presents to
your clinic with gastrointestinal complaints (e.g., constipa- Course of Illness
tion, bloating, and cramping) and fatigue. She is a single Anxiety disorders represent a diverse class of illnesses, with var-
mother of three (ages 2, 3, and 6 years) and is a full-time ied ages of onset. For example, according to the NCS-R epidemi-
college student. She states that she worries about everything: ologic study,3 PD and GAD had a median age of onset of 24 and
her grades, nances, the 6-year-old riding the school bus, 31 years, respectively, whereas specic phobia and social anxiety
etc. She states that even if its not important, I still worry. disorder (SAD) tend to develop much earlier (median age of
She has difculty sleeping and says that she often feels like onset 7 and 13 years, respectively). Although GAD and PD may
she might jump out of her skin. On one occasion she felt not manifest fully until adulthood, as many as half of adult anx-
like she might be having a heart attack or something.
iety patients report subthreshold symptoms during childhood.6
Anxiety disorders are characterized as chronic in nature
What manifestations described above are suggestive of an
anxiety disorder? with low rates of spontaneous symptom remission and high
What additional information do you need to establish a rates of relapse. Research illustrates that symptoms of anxi-
diagnosis and develop a treatment plan? ety disorders tend to wax and wane, with less than a third of
patients remitting spontaneously.7 In a 12-year follow-up
study of anxiety disorder patients, recurrence rates were simi-
lar between PD with and without agoraphobia (56% and 58%,
are short-lived and do not necessarily impair function. Anxiety respectively) despite great differences seen in reported rates of
that becomes excessive, causes irrational thinking or behavior, remission (48% and 82% with treatment, respectively).8 Fifty-
and impairs a persons functioning is considered an anxiety eight percent of treated GAD patients experienced symptom
disorder. remission, with 55% experiencing recurrence during the
Anxiety disorders are among the most frequent mental dis- follow-up period. While individuals with SAD had the lowest
orders encountered by clinicians. Anxiety disorders often are remission rate with treatment (37%), those who did respond
missed or attributed incorrectly to other medical illnesses, with had the lowest rate of recurrence (39%) compared with patients
most patients being treated inadequately. The burden of detec- with other anxiety disorders.
tion and diagnosis most often falls to primary-care clinicians, Remission, if achieved with treatment, is most likely to occur
to whom most patients present in the context of other com- within the rst 2 years of an index episode.9 Similarly, the high-
plaints. Untreated anxiety disorders may result in increased est rates of relapse are seen within the rst 2 years of the index
healthcare utilization, morbidity and mortality, and poorer episode. This suggests that many patients need ongoing mainte-
quality of life. nance treatment. Rates of remission do not appear to vary by
sex.9 Likewise, relapse rates do not appear to differ by sex for
those who suffer from PD, GAD, or SAD. However, one study
EPIDEMIOLOGY AND ETIOLOGY reported that women with PD without agoraphobia were three
times more likely than men to experience a relapse of symptoms.
Epidemiology Patients tend to spend a signicant portion of time being ill
during a particular episode. For example, in the 12-month
Prevalence follow-up study,8 the average time spent being ill during an
With a lifetime prevalence of 28.8%, anxiety disorders collec- episode was 80% for SAD, 78% for PD, 74% for GAD, and 41%
tively represent the most prevalent Diagnostic and Statistical for PD without agoraphobia. With such a chronic course of ill-
Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV- ness and signicant portion of time spent being ill during a
TR)2 class of disorders, with specic phobia (12.5%) and social particular episode, it is not surprising that patients aficted with
anxiety disorder (12.1%) being the most common.3 Recent an anxiety disorder have been shown to display impaired psy-
reports from the National Comorbidity Survey Revised (NCS-R) chosocial functioning and a compromised quality of life.10,11
estimate the lifetime and 1-year prevalence of generalized anx- Appropriate treatment of an anxiety disorder has been shown to
iety disorder (GAD) for those 18 years of age and older to be improve the patients overall quality of life and psychosocial
5.7% and 3.1%, respectively.3,4 Rates for panic disorder (PD) are functioning.11
slightly lower, with an estimated 12-month prevalence of 2.7%
and lifetime prevalence of 4.7%. Comorbidity
Most studies report higher rates of anxiety disorders among Anxiety disorders rarely exist alone. More than 90% of indi-
women (2:1 female:male) and older adults.5 Data from the viduals with an anxiety disorder have a lifetime history of one
CHAPTER 37 / GENERALIZED ANXIETY DISORDER, PANIC DISORDER, AND SOCIAL ANXIETY DISORDER 607
or more other psychiatric disorders.12 Depression is the most PATHOPHYSIOLOGY

common lifetime comorbid illness, followed by alcohol- or
substance-use disorders, as well as other co-occurring anxiety The thalamus and amygdala are important in the generation of a
disorders, especially GAD and PD.12 Generally speaking, the normal fear response and play a central role in most anxiety
onset of SAD and GAD symptoms precedes major depressive disorders. They support the fundamental requirements of the
disorder (MDD), whereas there is an equal chance of PD onset nervous systems rapid detection and response system. Any such
before, during, or after MDD. Regardless of when the comor- system requires a mechanism to detect a potential threat, evaluate
bid psychiatric illness occurs, it can further complicate the the actual threat, and respond in a defensive or evasive manner.
anxiety picture and often is associated with even lower rates of The thalamus plays a vital role in nearly every sensory modality,
remission and higher rates of relapse. It is essential that both excluding olfaction and visceral sensation.15 It provides the rst
disorders are addressed and treated appropriately. real processing region to organize sensory data obtained from the
environment. The thalamus passes information to higher cortical
centers for ner processing and to the amygdala for rapid assess-
Etiology
ment of highly charged emotional information. The amygdala
Both genetic and psychosocial factors appear to play a role in the serves to provide emotional valence or the emotional importance
initiation and expression of anxiety disorders.13 Documentation of the information.16 This helps the organism to act quickly on
of moderate genetic risk has been identied for all anxiety dis- ambiguous but vital events. The cortex then performs a more
orders, although some conicting data do exist. Currently, no detailed analysis, sending updates to the amygdala for compari-
denitive gene or set of genes has been identied as being the son and any needed course corrections.17 This ner evaluative
causative factor for a specic anxiety disorder. Additionally, it is process enables a decision on a course of action.
unclear if anxiety disorders share common genetic risk factors. Anxiety becomes an anxiety disorder when activity of the fear-
Recent research suggests that genetic overlap may exist between response network leads to maladaptive behavior or distress.
GAD and PD and, to a lesser extent, SAD.13 Anxiety can become independent of stimuli as in PD, can be asso-
It is possible that while genetics may create a vulnerable phe- ciated with benign stimuli as in phobias, or can continue beyond
notype for an anxiety disorder, an individuals life stressors and the necessary duration as in GAD. The precise mechanism by
means of coping with the stress also can play a signicant role in which these changes occur is unknown, but much has been dis-
precipitation and continued expression of the anxiety disorder.14 covered regarding how the amygdala effects changes throughout
In fact, some researchers believe that stressful life events may play the brain and how this may be regulated by treatment15 (Fig. 371).
a strong role in the onset of anxiety disorders, especially in GAD Direct and indirect connections to the reticular activating
and PD.13 It has been reported that those experiencing one or system (RAS), a region spanning the medulla, pons, and mid-
more negative life events have a three-fold increased chance of brain, help to regulate arousal, vigilance, and fear. Modulation
developing GAD.5 Similar ndings have been reported with PD.14 of these connections relies on the neurotransmitters serotonin
FIGURE 371. Neurocircuitry and key neuro-

transmitters involved in mediating anxiety
disorders.
Stimulus Thalamus
Cortex
Amygdala
Autonomic Hypothalamus R
nervous CRF A 5HT, NE, DA
system S
Pituitary
ACTH
Adrenals
Heart rate
Blood pressure
Cortisol
and norepinephrine, which have their primary origins in the systems. Several important hormones, including corticotropin-
RAS.18 The amygdala sends projections to the hypothalamus releasing hormone and cortisol, are involved in this pathway.
inuencing the autonomic nervous system to affect heart rate, These hormones regulate the effects of anxiety on the body and
blood pressure, and stress-associated changes. The amydala provide positive feedback to the brain.19 A cycle of anxiety and
also inuences the hypothalamic-pituitary-adrenal axis sensitization by such feedback could, if unchecked, result in
(HPA axis), leading to a cascade of stress hormones.19 One escalation of symptoms. Neuropeptides provide one mecha-
such hormone is cortisol, which, if elevated for prolonged nism to balance positive and negative feedback, helping to min-
periods, can have damaging effects on the brain and other imize such escalation.
organs. These are important targets in our understanding of
how the amygdala regulates the fear response because they
provide useful targets for current drug treatment and inform Neuropeptides
further research on anxiety disorders.
Several neuropeptides are under current investigation for their
role in anxiety disorders. Important neuropeptides include neu-
Noradrenergic System ropeptide Y (NPY), substance P, and cholecystokinin. NPY
appears to have a role in reducing the effect of stress hormones
Norepinephrine (NE)producing cells reside primarily in
and inhibiting activity of the LC. Both mechanisms may con-
a region of the brain called the locus ceruleus (LC). An
tribute to the anxiolytic properties seen experimentally.
increase in activity of cells in this region is associated with
Substance P may have anxiolytic and antidepressant properties.
an increase in arousal, anxiety, and panic. Drugs such as
This may be due in part to its effects on corticotropin-releasing
yohimbine that increase activity of the LC can be anxio-
hormone.21
genic, whereas drugs that decrease activity of the LC
appear to improve anxiety symptoms. Furthermore, dys-
regulation of this region is implicated by elevated levels of
NE or its metabolites in subjects with GAD, PD, and spe- CLINICAL PRESENTATION AND DIAGNOSIS
cific phobias.19
Serotonergic System Clinical Presentation and Diagnosis

The raphe nuclei and the resident cell bodies of serotonin of GAD
(5-HT)producing neurons have an interesting yet compli-
cated role in producing anxiety symptoms. One important
General
role may be their ability to directly regulate the activity of cells
Onset is typically in early adulthood. Anxiety emerges and
in the LC. Activity of 5-HT cells in the raphe nuclei over time
dissipates more gradually than in PD. Laboratory evaluation
inhibits ring of noradrenergic cells in the LC. Other inu- usually is reserved for later onset, atypical presentation, or
ences may be their ability to regulate cells in the prefrontal poor response to treatment.
cortex and amygdala. Perhaps the strongest evidence for the
Symptoms2
involvement of the serotonergic system is the success of sero-
Excessive anxiety or worry involving multiple events or
tonin reuptake inhibitors in clinical treatment.19
activities occurring more days than not for at least 6 months
and associated with at least three of the following:
GABA Restlessness
Gamma-aminobutyric acid (GABA) plays an important role Easily fatigued
as an inhibitory neurotransmitter. The effects of GABA are Poor concentration
Irritability
nonspecic, and its role is complex. GABAergic drugs are used
Muscle tension
for acute anxiety reduction, but the lack of a specic target for Insomnia or unsatisfying sleep
their effect leads to multiple undesirable effects. Current
research is focused on dening receptor subtypes that may Differential Diagnosis
allow for greater specicity in targeting anxiety symptoms.20 Rule out underlying medical or psychiatric disorders and
medications that may cause anxiety (Tables 371 and 372)
Laboratory Evaluation
HPA Axis Basic metabolic panel
Thyroid-stimulating hormone
The HPA axis provides a critical mechanism for regulation of Polysomnogram
the stress response and its effects on the brain and other organ
Clinical Presentation and Diagnosis Clinical Presentation and Diagnosis

of PD of SAD
General General
Typically presents in late adolescence or early adulthood. Often occurs in context of other anxiety disorders. The feared
Onset in older adults increases suspicion of relationship social or performance situation can be limited to a specic
to medical disorders or substance use. Laboratory evalua- social interaction (e.g., public speaking) or generalized to
tion must be driven by history and physical examination. most any social interaction. Differs from specic phobia, in
which the fear and anxiety are limited to a particular object
Symptoms2
or situation (e.g., insects, heights, public transportation).
Recurrent, discrete episodes that typically develop rapidly
and peak within 10 minutes involving at least four of the Symptoms2
following symptoms: Persistent fear of social interactions, during which time
the individual is concerned about being embarrassed or
Palpitations or rapid heart rate being under scrutiny.
Sweating Engaging in the feared activities can lead to extreme anxi-
Trembling or shaking ety and panic.
Sensation of shortness of breath or smothering The fear leads to distress or avoidance of the situation
Feeling of choking sufcient enough to cause trouble in the patients life.
Chest pain or discomfort
Feeling dizzy or lightheaded
Rule out underlying medical or psychiatric disorders and
Feeling of unreality or being detached from oneself
medications that may cause anxiety (Tables 371 and 372).
Fear of dying
Numbness or tingling sensation Laboratory Evaluation
Chills or hot ushes Limited value. Laboratory investigation is of limited value
and should be pursued only in context of other history or
physical examination ndings.
Rule out underlying medical or psychiatric disorders and
medications that may cause anxiety (Tables 371 and 372).
Laboratory Evaluation
Urine drug screen
Basic metabolic panel
Thyroid-stimulating hormone
Electrocardiogram
Holter monitor
AX returns to your clinic 4 months later stating that despite
meeting with the school psychologist a few times, she con-
Urine vanillylmandelic acid (VMA)
tinues to have problems. In addition to worrying and feeling
nervous, she feels down a lot. I dont have the energy to
TREATMENT: GENERALIZED ANXIETY DISORDER play with my children. I obsess over everything. My grades
have really gone down hill. I cry a lot and feel hopeless.
Desired Outcomes PMH
Irritable bowel syndrome, GAD
The goals of therapy for GAD are to acutely reduce the FH
severity and duration of anxiety symptoms and restore overall Mother treated for depression; father, ETOH dependence
functioning. The long-term goal in GAD is to achieve and main-
tain remission. With a positive response to treatment, patients SH
Drinks ETOH occasionally; cigarettes, 1 pack per day; lives
with GAD and comorbid depression should have minimal
independently with 3 children
depressive symptoms.
Meds
General Approach to Treatment Centrum multivitamin
Patients with GAD may be managed with psychotherapy, phar- Given this information, what is your assessment of this
macotherapy, or both. The treatment plan should be individu- patient?
alized based on the patients symptom severity, comordid ill- Develop a treatment plan, including nonpharmacologic
nesses, medical status, age, and preference. Patients with severe and pharmacologic recommendations, duration of therapy,
symptoms resulting in functional impairment should receive and monitoring plan.
antianxiety medication.
TABLE 371. Medical Conditions That Can Cause Anxiety2,22,23 suggest that treatment gains with CBT may be maintained for
up to 1 year.25 It is unclear if the combination of CBT and med-
Psychiatric Disorders ication is more effective than either treatment alone.
Mood disorders, hypochondriasis, personality disorders, alcohol/
substance abuse, alcohol/substance withdrawal, other anxiety
disorders Pharmacologic Therapy
Neurologic Disorders Antidepressants, benzodiazepines, buspirone, hydroxyzine, and
CVA, seizure disorders, dementia, stroke, migraine, encephalitis,
pregabalin all have controlled clinical trial data supporting their
vestibular dysfunction
use in GAD. Antidepressants have replaced benzodiazepines as
Cardiovascular Disorders
Angina, arrhythmias, congestive heart failure, mitral valve
the drugs of choice for chronic GAD owing to a tolerable side-
prolapse, myocardial infarction effect prole, no risk for dependency, and efcacy in common
Endocrine and Metabolic Disorders comorbid conditions including depression, panic, obsessive-
Hypo/hyperthyroidism, hypoglycemia, Cushings disease, compulsive disorder (OCD), and SAD. Benzodiazepines remain
Addisons disease, pheochromocytoma, hyperadrenocorticism, the most effective and commonly used treatment for short-term
hyponatremia, hyperkalemia, vitamin B12 deciency management of anxiety where immediate relief of symptoms is
Respiratory Disorders desired. They are also recommended for intermittent or adjunc-
Asthma, COPD, pulmonary embolism, pneumonia, hyperventilation tive use during GAD exacerbation or for sleep disturbance dur-
Other ing the initiation of antidepressant treatment.26 Buspirone and
Carcinoid syndrome, anemias, systemic lupus erythematosus
pregabalin are alternative agents for patients with GAD without
COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular depression. Hydroxyzine use is less desirable for long-term treat-
accident.
ment owing to side effects.
Patients with GAD should be treated to remission of
Nonpharmacologic Therapy symptoms. While data are lacking on the optimal duration of
Nonpharmacologic therapy includes psychoeducation, exercise, pharmacotherapy, most guidelines recommend continuing treat-
stress management, and psychotherapy. Psychoeducation ment for an additional 3 to 10 months.2528 An algorithm for
should address pertinent information on GAD and its manage- the pharmacologic management of GAD is shown in Fig. 372.
ment. Patients should be instructed to avoid stimulating agents
such as caffeine, decongestants, diet pills, and excessive alcohol
use. Regular exercise is also recommended. Cognitive-behavioral GAD
therapy (CBT) is the most effective psychological therapy for
GAD patients. CBT helps patients to recognize and alter patterns BZ for Acute relief
26 weeks Yes needed
of distorted thinking and dysfunctional behavior. Some trials
No
Adequate
response?
TABLE 372. Medications Associated with Anxiety Symptoms2,2224 Venlafaxine or SSRI
Yes Adequate response?
Category Examples
No
Anticonvulsants Carbamazepine, ethosuximide
Antidepressants Bupropion, SSRIs, TCAs Switch to
venlafaxine or SSRI
Antihypertensives Felodipine
Antimicrobials Cephalosporins, ooxacin, isoniazid Continue
therapy
Antiparkinson drugs Levodopa 310 months No
Bronchodilators Albuterol, isoproterenol, theophylline
Corticosteroids Prednisone, methylprednisolone Switch to another
Decongestants Pseudoephedrine, phenylephrine anxiolytic
1. SSRI
Herbals Ma huang, St. Johns wort, ginseng, 2. imipramine
guarana, belladonna 3. buspirone
NSAIDs Ibuprofen, indomethacin 4. hydroxyzine
Stimulants Amphetamines, caffeine, cocaine,
methylphenidate Yes Adequate response?
Thyroid hormones Levothyroxine No
Toxicity Anticholinergics, antihistamines,
digoxin Add BZ for somatic symptoms
for 24 weeks
Withdrawal of CNS Alcohol, barbiturates, benzodiazepines
depressants
(abrupt) FIGURE 372. Treatment alogorithm for GAD. SSRI = selective
serotonin reuptake inhibitor; BZ = benzodiazepine. (Reprinted,
SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepres- with permission, from reference 24.)
sants; NSAIDs, non-steroidal anti-inammatory drugs.
TABLE 373. Antidepressants Used in the Treatment of depression. Venlafaxine was shown to reduce anxiety effectively
Generalized Anxiety Disorder24,29,30 at doses 75 to 225 mg/day in 8-week trials, and response was
maintained over an additional 6 months of treatment.32,33
Usual Therapeutic
Medication Recommended Dosage
Venlafaxine has more favorable safety and side-effect proles
Class Starting Dose (mg/day) Range (mg/day) than TCAs. The most common side effects reported with ven-
lafaxine by GAD patients are nausea, somnolence, dry mouth,
SSRIs
Citalopram 20 2050 dizziness, sweating, constipation, and anorexia.34
(Celexa)
Escitaloprama 10 1020 SSRIs
(Lexapro) The SSRIs paroxetine, escitalopram, and sertraline have been
Fluoxetine 20 2080
shown to be signicantly more effective than placebo in reduc-
(Prozac)
Fluvoxamine 50 100300 ing anxiety symptoms. Paroxetine at doses of 20 and 40 mg/day
(Luvox) achieved response in 62% and 68% of patients, respectively, over
Paroxetine 20 2050 8 weeks of treatment.35 Remission occurred in 30% and 36%,
Paroxetine CR 25 2562.5 respectively. In a 24-week relapse-prevention study, paroxetine
(Paxil, Paxil CR)
was more effective than placebo at maintaining response, and
Sertraline 50100 50200
(Zoloft) patients were more likely to achieve remission with continued
SNRI
treatment (42.5% at 8 weeks versus 73% at 24 weeks).36 In GAD
Venlafaxine XRa 75 75300 trials, paroxetine was associated with a high rate of somnolence,
(Effexor XR) nausea, abnormal ejaculation, dry mouth, decreased libido, and
TCAs asthenia compared with placebo.35 Escitalopram, in a dose range
Imipramine 5075 75200 of 10 to 20 mg/day, was more effective than placebo in patients
(Tofranil) with GAD without depression. Fifty-eight percent of patients on
a
FDA approved for use in generalized anxiety disorder. escitalopram achieved response versus 38% on placebo over the
SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin and 8 weeks of treatment.37 Escitalopram was associated with
norepinephrine reuptake inhibitors; TCAs, tricyclic antidepressant headache, nausea, somnolence, upper respiratory tract infection,
decreased libido, ejaculation disorder, and anorgasmia.37
Antidepressants
Sertraline was more efcacious than placebo in patients with
Antidepressants (Table 373) are considered rst-line GAD being treated for 12 weeks. Sertraline treatment resulted in
agents in the management of chronic GAD. These agents reduce 56% of patients achieving response, whereas 31% achieved
the psychic symptoms (e.g., worry and apprehension) of anxiety remission.38 Sertraline was associated with increased rates of
with a modest effect on autonomic or somatic symptoms (e.g., nausea, insomnia, sweating, decreased libido, diarrhea, fatigue,
tremor, rapid heart rate, and/or sweating). All antidepressants and ejaculation disorder.38 Limited comparative trial data sug-
evaluated have resulted in a similar degree of anxiety reduc- gest comparable outcomes between these SSRIs.39,40 SSRI ther-
tion. The onset of antianxiety effect is delayed 2 to 4 weeks. apy is better tolerated than TCAs, and tolerability is similar to
Venlafaxine and SSRIs usually are preferred over tricyclic anti- that with venlafaxine.
depressants (TCAs) such as imipramine owing to improved
TCAs
safety and tolerability. Selection of a particular antidepressant
agent generally is based on history of prior response, side- Imipramine treatment resulted in a higher rate of remission
effect prole, drug-interaction prole (discussed Chap. 35), of anxiety symptoms than trazodone, diazepam, or placebo
cost, or formulary availability. (e.g., 73% versus 69% versus 66% versus 47%) in an 8-week
Antidepressants modulate synaptic 5-HT, NE, and/or controlled trial of DSM-IIIdiagnosed GAD patients. Anti-
dopamine (DA) reuptake and receptor-activated neuronal signal depressants were more effective than diazepam or placebo in
transduction. These intracellular changes ultimately modify the reducing psychic symptoms of anxiety. The use of TCAs
expression of genes and proteins important in stress response generally is limited by bothersome adverse effects (e.g.,
(e.g., increase messenger RNA for glucocorticoid receptors and sedation, orthostatic hypotension, anticholinergic effects,
brain-derived neurotrophic factor and decrease mRNA expres- and weight gain).
sion for corticotropin-releasing factor).31 Activation of these
stress adapting pathways is thought to improve both somatic Benzodiazepines
symptoms and psychic distress experienced in anxiety.31 Benzodiazepines are recommended for acute treatment of
GAD when short-term relief is needed, as an adjunct during ini-
SNRI (Venlafaxine) tiation of antidepressant therapy, or to improve sleep.25,26
Venlafaxine, a serotonin-norepinephrine reuptake inhibitor Benzodiazepine treatment results in a signicant improve-
(SNRI), alleviates anxiety in GAD patients with and without ment in 65% to 75% of GAD patients, with most of the
improvement occurring in the initial 2 weeks of therapy.41 impairment, and ataxia) and cognitive effects (e.g., poor recall
They are more effective in reducing somatic symptoms of memory and anterograde amnesia). Anterograde amnesia is
anxiety than psychic symptoms. The major disadvantages of more likely to occur with high-potency benzodiazepines such
benzodiazepines are their lack of effectiveness in treating as lorazepam or alprazolam.42 Some patients also may be dis-
depression and the risk for dependency and abuse. inhibited with benzodiazepine treatment and experience con-
Benzodiazepines should be avoided in patients with chemical fusion, irritability, aggression, and excitement.42
dependency. Discontinuation of benzodiazepines may be associated
Benzodiazepines exert their effects by enhancing transmis- with withdrawal, rebound anxiety, and a high rate of relapse.
sion of the inhibitory neurotransmitter GABA through Higher doses of benzodiazepines and longer duration of ther-
interaction with the GABAA-receptor complex.25 Although all apy increase the severity of withdrawal and risk of seizures
benzodiazepines possess anxiolytic properties, only 7 of the after abrupt or rapid discontinuation. Patients should be
13 currently marketed agents are approved by the Food and tapered rather than discontinued abruptly from benzodi-
Drug Administration (FDA) for the treatment of anxiety dis- azepine therapy to avoid withdrawal symptoms. The dura-
orders (Table 374). All benzodiazepines are expected to pro- tion of the taper should increase with extended duration of
vide equivalent benet when given in comparable doses. benzodiazepine therapy.27 For example, patients on benzodi-
Benzodiazpines differ substantially in their pharmacokinetic azepine therapy over 2 to 6 months should be tapered over 2
properties and potency for the GABAA-receptor site. to 8 weeks, whereas patients receiving 12 months of treat-
Benzodiazepines are metabolized by hepatic oxidation ment should be tapered over 2 to 4 months. A general
(cytochrome P-450 3A4) and glucuronide conjugation. approach to the taper is to reduce the dose by 25% every 5 to
Lorazepam and oxazepam bypass hepatic oxidation and are 7 days until reaching half the original dose and then decreas-
conjugated only. They are preferred agents for patients with ing by 10% to 12% per week until discontinued. Patients
reduced hepatic function secondary to aging or disease. should expect minor withdrawal symptoms and discomfort
Many benzodiazepines are metabolized to long-acting even when tapering. Rebound symptoms (e.g., return of orig-
metabolites (Table 374) that provide long-lasting anxiety inal symptoms at increased intensity) are transient. The
relief. Drugs that either inhibit or induce CYP450 isozymes patient should be counseled so that rebound anxiety is not
or glucuronidation are the major source of drug interactions interpreted as a relapse. Relapse or recurrence of anxiety may
(Table 375). occur in as many as 50% of patients discontinuing benzodi-
The most common side effects associated with benzodiazepine treatment.41,43 It is unclear if this relapse rate repre-
azepine therapy include central nervous system (CNS) sents an inferiority of benzodiazepines or supports the
depressive effects (e.g., drowsiness, sedation, psychomotor chronic nature of GAD.
TABLE 374. Benzodiazepine Comparison Chart24,30
Drug Name Time to Peak Half-Life Approved Dose

(Brand Name) Active Metabolites Concentration (hour) Range (hour) Dosage Range (mg/day) Equivalent (mg)
Alprazolama,b (Xanax) 12 1215 14 (GAD) 0.5
110 (PD)
Chlordiazepoxidea (Librium) 14 530 25100 10
Desmethylchlordiazepoxide 18
Demoxepam 1495
Desmethyldiazepam 40120
Oxazepam 515
Clonazepamb (Klonopin) 14 1850 14 0.25
Clorazepatea (Tranzene) 12 7.560 7.5
Oxazepam 515
Diazepama (Valium) 0.52 2080 240 5
Temazepam 815
Oxazepam 515
Lorazepama (Ativan) 24 1020 0.510 0.751
Oxazepama (Serax) 24 515 30120 15
a
FDA approved for use in generalized anxiety disorder.
b
FDA approved for use in panic disorder.
GAD, generalized anxiety disorder; PD, panic disorder.
TABLE 375. Pharmacokinetic Drug Interactions with Buspirone should be initiated at a dose of 7.5 mg twice
Benzodiazepines44 daily and titrated in 5 mg/day increments (every 23 days) to
a usual target dose of 20 to 30 mg/day.41 The maximum daily
Drug Effect
dose is considered to be 60 mg/day.
Alcohol (chronic) Increased CI of BZs Buspirone generally is well tolerated and does not cause
Carbamazepine Increased CI of alprazolam
sedation. Most common side effects include dizziness,
Cimetidine Decreased CI of alprazolam, diazepam,
chlordiazepoxide, and clorazepate nausea, and headaches. Drugs that inhibit CYP3A4 (e.g.,
and increased t1/2 verapamil, diltiazem, itraconazole, fluvoxamine, nefa-
Disulram Decreased CI of alprazolam and zodone, and erythromycin) can increase buspirone levels.
diazepam Likewise, enzyme inducers such as rifampin can reduce
Erythromycin Decreased CI of alprazolam
buspirone levels signicantly. Bupirone may increase blood
Fluoxetine Decreased CI of alprazolam and
diazepam pressure when coadministered with an monoamine oxidase
Fluvoxamine Decreased CI of alprazolam and inhibitor (MAOI).
prolonged t1/2
Itraconazole Potentially decreased CI of alprazolam
and diazepam Alternative Agents
Ketaconazole Potentially decreased CI of alprazolam
Hydroxyzine, kava kava, and pregabalin are alternative agents.
Nefazodone Decreased CI of alprazolam, AUC
doubled, and t1/2 prolonged Hydroxyzine may be effective for acute reduction of somatic
Omeprazole Decreased CI of diazepam symptoms of anxiety.26 It does not improve psychic features of
Oral contraceptives Increased free concentration of anxiety and does not treat depression or other common
chlordiazepoxide and slightly comorbid anxiety disorders. Kava kava, while potentially
decreased CI; decreased CI and
effective, is no longer recommended owing to reports of hepa-
increased t1/2 of diazepam and
alprazolam totoxicity.46 Pregabalin is mechanistically unique for an anxi-
Paroxetine Decreased CI of alprazolam olytic. It is a presynaptic modulator of excessive excitatory
Phenobarbital Increased CI of clonazepam and reduced t1/2 neurotransmitter release. It accomplishes this by selectively
Phenytoin Increased CI of clonazepam and reduced t1/2 binding to the 2- subunit of voltage-gated calcium channels.
Probenecid Decreased CI of lorazepam and
In a 4-week controlled trial versus alprazolam and placebo,
prolonged t1/2
Propranolol Decreased CI of diazepam and pregabalin was effective for both somatic and psychic symp-
prolonged t1/2 toms of anxiety with an onset of effect similar to alprazolam.47
Ranitidine Decreased absorption of diazepam Pregabalin has an elimination half-life of approximately
Rifampin Increased metabolism of diazepam 6 hours and must be dosed two to three times daily. It is
Theophylline Decreased alprazolam concentrations
excreted renally and has a low risk of drug-drug interactions.
Valproate Decreased CI of lorazepam
Pregabalin is a schedule V controlled substance owing to a
AUC, area under the plasma concentration curve; BZ, benzodi- propensity to cause euphoria and risk of withdrawal symp-
azepine; CI, clearance; t1/2, elimination half-life.
Compiled from reference 49.
toms when discontinued abruptly. Pregabalin should be used
Reprinted, with permission, from Kirkwood CK, Melton ST. Anxiety with caution in patients with a current or past history of sub-
disorders: I. Generalized anxiety, panic, and social anxiety disor- stance abuse. Pregabalin is not benecial for depression or
ders. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy:
A Pathophysiologic Approach. 6th ed. New York: McGraw Hill;
other anxiety disorders, and long-term effectiveness in GAD is
2005: 1294. not yet established.
Outcome Evaluation
Buspirone
Buspirone, a 5-HT1A partial agonist, is thought to exert its anx- Assess patients for improvement of anxiety symptoms and
iolytic effects by reducing presynaptic 5-HT ring.44 Unlike for return to baseline occupational, social, and interper-
benzodiazepines, it does not have abuse potential, cause with- sonal functioning. With effective treatment, the patient
drawal reactions, or potentiate alcohol and sedative-hypnotic should have no or minimal symptoms of anxiety or
effects. However, it has a gradual onset of action (i.e., 2 weeks) depression. While drug therapy is being initiated, evaluate
and does not provide immediate anxiety relief. Buspirone is patients more frequently to ensure tolerability and
considered a second-line agent for GAD owing to inconsistent response. Increase the dose in patients exhibiting a partial
data regarding its efcacy in chronic GAD or GAD with comor- response after 2 to 4 weeks on an antidepressant or 2 weeks
bid depression.25,26 Some research suggests that buspirone is less on a benzodiazepine. Individualize the duration of treat-
effective in patients who have been treated previously (4 weeks ment because some patients require up to one year of
to 5 years) with benzodiazepines.45 treatment.27
TREATMENT: PANIC DISORDER Nonpharmacologic Therapy

Patients with PD should be counseled to avoid stimulant agents
Desired Outcomes
(e.g., decongestants, diet pills, and caffeine) that may precipitate
The main objectives of treatment are to reduce the severity a panic attack. CBT consists of psychoeducation, continuous
and frequency of panic attacks, reduce anticipatory anxiety panic monitoring, breathing retraining, cognitive restructur-
and agoraphobic behavior, and minimize symptoms of ing, and exposure to fear cues.48 CBT is not a standardized
depression or other comorbid disorders.48 The long-term goal treatment and may involve these features to varying degree. It
is to achieve and sustain remission. is unclear if the individual components have differential ben-
ets. Exposure therapy is useful for patients with phobic
General Approach to Treatment avoidance. CBT is considered a rst-line treatment of PD,
with efcacy similar to that of pharmacotherapy. In a large
Treatment options include medication, psychotherapy (e.g.,
placebo-controlled trial comparing CBT with imipramine or
CBT preferred), or a combination of both. In some cases,
combination (CBT + imipramine), CBT was as effective as
pharmacotherapy will follow psychotherapy treatments when
the antidepressant after 12 weeks. Patients receiving CBT
full response is not realized. Patients with panic symptoms
were less likely to relapse during the 6 months after treatment
without agoraphobia may respond to pharmacotherapy
discontinuation.50,51
alone. Agoraphobic symptoms generally take longer to
respond than panic symptoms. The acute phase of PD
treatment lasts about 12 weeks and should result in marked Pharmacologic Therapy
reduction in panic attacks, ideally total elimination, and mini-
mal anticipatory anxiety and phobic avoidance. Treatment PD may be treated successfully with TCAs, SSRIs, SNRIs, or
should be continued to prevent relapse for an additional 12 to MAOIs, as well as benzodiazepines51,52 (Table 376). While all
18 months before attempting discontinuation.48,49 Patients who these agents are similarly effective, SSRIs have become the
relapse following discontinuation of medication should have treatment of choice in PD. Benzodiazepines often are used con-
therapy resumed.49 comitantly with antidepressants, especially early in treatment,
TABLE 376. Antidepressants Used in the Treatment of Panic Disorder24,30,51
Usual Therapeutic
Recommended Starting Dosage
Medication Class Dose (mg/day) Range (mg/day) Advantages Disadvantages
SSRIs/SNRI SSRIs (in general) SSRIs (in general)
Citalopram 10 2060 Antidepressant Activation;
Escitalopram 510 1020 activity; antianxiety delayed onset of
Fluoxetinea 510 2060 activity; single action; may
Fluvoxamine 25 100300 daily dosing (all but precipitate mania;
Paroxetinea 10 2060 uvoxamine); low sexual side effects;
Sertralinea 25 50200 toxicity; some GI side effects
Venlafaxine XRa 37.5 75225 available in generic
TCAs TCAs (in general) TCAs (in general)
Clomipramine 25 mg (twice 75250 Established efcacy; available Activation; sedation;
a day) in generic anticholinergic effects;
Imipraminea 1025 75250 cardiovascular effects;
delayed onset of action;
may precipitate mania;
sexual side effects;
toxic in overdose;
weight gain
MAOI
Phenelzine 15 4590 Antidepressant effects; Dietary restrictions; drug
available in generic interactions; weight
gain; orthostasis; may
precipitate mania
a
FDA approved for use in panic disorder.
SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; MAOI, monoamine oxidase inhibitor.
anxiety disorders. Target doses are similar to those used in

Panic disorder depression. Antidepressants should be tapered when treatment
is discontinued to avoid withdrawal symptoms.
Severe
BZ Yes
urgency? TCAs
Treatment with imipramine, the most studied TCA, leaves
Adequate
45% to 70% of patients panic free. Both desipramine and
No
response? clomipramine have demonstrated effectiveness in PD as well.
Despite their efcacy, TCAs are considered second- or third-
SSRI
line pharmacotherapy due to poorer tolerability and toxicity
Yes Adequate response? on overdose.48,49 TCAs are associated with a greater rate of dis-
No continuation from treatment than SSRIs.53 PD patients taking
TCAs may experience anticholinergic effects, orthostatic
Switch to
another SSRI
hypotension, sweating, sleep disturbances, dizziness, fatigue,
Continue sexual dysfunction, and weight gain. Stimulant-like side
therapy effects occur in up to 40% of patients.49
No
Switch to another
antidepressant SSRIs
1. another SSRI or
venlafaxine
SSRIs are the drugs of choice for PD. All SSRIs have demon-
2. imipramine strated effectiveness in controlled trials, with 60% to 80% of
Yes Adequate response? patients achieving a panic-free state.28,48,49 With similar ef-
No
cacy reported and no trials comparing SSRIs with other
SSRIs, selection generally is based on pharmacokinetics,
Add BZ or pindolol to drug interactions, side effects, and cost differences (see
antidepressant
Chap. 35 for more discussion). The most common side
Yes Adequate response? effects of SSRIs include headaches, irritability, nausea and
No other gastrointestinal complaints, insomnia, sexual dysfunc-
tion, increased anxiety, drowsiness, and tremor.49 SSRIs
Switch to phenelzine should not be discontinued abruptly to avoid a withdrawal
or divalproex if
mood swings
syndrome characterized by dysphoric mood, irritability, and
agitation.
SNRIs
FIGURE 373. Algorithm for the pharmacotherapy of panic
disorder. (Reprinted, with permission, from reference 24.) Venlafaxine was approved by the FDA recently for the treat-
ment of PD. Venlafaxine in doses of 75 to 225 mg/day reduced
panic and anticipatory anxiety in short-term controlled trials.
The most common side effects include anorexia, dry mouth,
constipation, somnolence, tremor, abnormal ejaculation, and
or as monotherapy to acutely reduce panic symptoms. They
sweating.52
are not preferred for long-term treatment but may be used
when patients fail several antidepressant trials.49 PD patients
with comorbid depression should be treated with an antide- MAOIs
pressant. An algorithm for pharmacologic management of PD MAOIs have not been evaluated systematically for treatment
appears in Fig. 373. of PD under the current diagnostic classication and gener-
ally are reserved for patients who are refractory to other
Antidepressants treatments.48,49 MAOIs have signicant side effects that limit
Antidepressants have a delayed onset of antipanic effect, typi- adherence. Additionally, patients must adhere to dietary
cally 4 weeks, with optimal response at 6 to 12 weeks. Reduction restriction of tyramine and avoid sympathomimetic drugs to
of anticipatory anxiety and phobic avoidance generally follows avoid hypertensive crisis.
improvement in panic symptoms. PD patients are more likely The reversible inhibitors of monoamine oxidase (RIMAs)
to experience stimulant-like side effects than patients with depres- brofaramine and meclobemide have been studied with mixed
sion, and they should be initiated on lower doses (Table 376) results.48 Neither is approved for use in the United States, but
of antidepressant than those that are used for depression or other they are available in Canada.
Others as well as adverse effects that may emerge with continued

Bupropion, trazodone, and nefazodone are not recommended treatment (e.g., weight gain and sexual dysfunction). During
for treatment of PD. drug discontinuation, monitor frequently for withdrawal,
rebound anxiety, and relapse.
Benzodiazepines
Benzodiazpines are effective antipanic agents with signicant
effects on anticipatory anxiety and phobic behaviors. TREATMENT: SOCIAL ANXIETY DISORDER
Alprazolam, the one studied most extensively, is associated
with signicant panic reduction after 1 week of therapy Desired Outcomes
(e.g., 55%75% panic free).49 Benzodiazepines achieve similar SAD is a chronic disorder that begins in adolescence and
outcomes to antidepressants over extended treatment, but occurs with signicant functional impairment and high rates
benzodiazepine-treated patients are more likely to relapse of comorbidity. The goal of acute treatment is to reduce
when the drug is discontinued.49 The risk for dependence and physiologic symptoms of anxiety, fear of social situations,
withdrawal and lack of efcacy for depression are signicant and phobic behaviors. Patients with comordid depression
concerns for long-term treatment of PD.49 There is no evi- should have a signicant reduction in depressive symptoms.
dence, however, that patients require dose escalation during The long-term goal is to restore social functioning and
extended treatment. This suggests that tolerance to therapeu- improve the patients quality of life.
tic effect does not occur. Patients with PD do experience
greater rebound anxiety and relapse when discontinuing ben- General Approach to Treatment
zodiazepines than do GAD patients. Tapering should be done
at a slower rate and over a more extended period of time than Patients with SAD may be managed with pharmacotherapy or
with other anxiety disorders.28,49 psychotherapy. There is insufcient evidence to recommend
one treatment over the other, and data are lacking on the ben-
The dose of benzodiazepine required for improvement gen- ets of combining treatment modalities. Pharmacotherapy
erally is higher than that used in other anxiety disorders, and this often is the rst choice of treatment owing to relative greater
may explain why high-potency agents such as alprazolam and access and reduced cost compared with psychotherapy.56
clonazepam generally are preferred. Lorazepam and diazepam, Patients with SAD generally respond slowly to treatment, and
when given in equivalent doses, produce similar treatment many will not achieve a full response. Relapse is common when
benets.48,49 Doses should be titrated to response (Table 374). patients are discontinued after effective short-term treatment.
The use of extended-release alprazolam or clonazepam will Patients generally are continued on treatment for at least 1 year
minimize breakthrough panic symptoms that are sometimes before attempting discontinuation.
observed with immediate-release alprazolam.55
Side effects associated with benzodiazepines in PD patients
are similar to those observed in other disorders. Sedation,
fatigue, and cognitive impairment are the most commonly Patient Encounter 2
reported side effects.49 Benzodiazepines should be avoided in
patients with current substance abuse, a history of such,
dependence, or sleep apnea. Additionally, caution should be BB, a 34-year-old white woman with generalized social
used in older adults because they have more pronounced psy- anxiety disorder, is transferring her care to your clinic. She
chomotor and cognitive effects. has been maintained on diazepam 10 mg twice daily for
the past 4 years for her SAD. She states that her current
therapy has her anxiety under control, and she is perform-
Outcome Evaluation
ing her duties as an ofce manager without problems. She
Evaluate patients for symptom improvement frequently (e.g., has joined a gym recently and is attending a church social
weekly) during the rst 4 weeks of therapy. The goal is to alle- for single women once monthly. She has noticed she has
viate panic attacks and reduce anticipatory anxiety and pho- difculty thinking sharply and is more forgetful. She
bic avoidance with resumption of normal activities. Alter the occasionally feels sad and becomes tearful but is usually
able to pick herself up. She is moderately overweight
therapy of patients who do not achieve a signicant reduction
(BMI 29) with no other current medical problems. Denies
in panic symptoms after 6 to 8 weeks of an adequate dose of ETOH or other substance use.
antidepressant or 3 weeks of a benzodiazepine. Regularly eval-
uate patients for adverse effects, and educate them about Develop a treatment plan for this patient. Include (1) goals
appropriate expectations of drug therapy. of therapy, (2) a detailed therapeutic plan, and (3) a moni-
Once the patient has achieved a signicant response, con- toring plan for recommended therapy.
tinue therapy for at least 1 year. Evaluate for symptom relapse
Nonpharmacologic Therapy Approximately 50% of patients achieve response during acute

treatment. Limited data suggest that both uvoxamine and
Patient education on disease course, treatment options, and
citalopram are effective in SAD. Fluoxetine is not effective.57,58
expectations is essential given the chronic nature and func-
The initial dose of SSRI is similar to that used in depres-
tional impairment of SAD. Support groups may be bene-
sion. Patients should be titrated as tolerated to response.
cial for some patients. CBT targets avoidance-learning and
Many patients will require maximum recommended daily
negative-thinking patterns associated with social anxiety by
doses. Patients with comorbid panic disorder should be
exposing the patient to a feared situation. CBT is effective for
started on lower doses (Table 374). When discontinuing
reducing anxiety and phobic behaviors and leads to a greater
SSRIs, the dose should be tapered slowly to avoid withdrawal
likelihood of maintaining response after treatment discontin-
symptoms, with the possible exception of uoxetine. Relapse
uation than does pharmacotherapy.56
rates may be as high as 50%, and patients should be moni-
tored closely for several weeks.58 Side effects of SSRIs in SAD
Pharmacologic Therapy patients are similar to those seen in depression and most
Several pharmacologic agents have demonstrated effective- commonly include nausea, sexual dysfunction, somnolence,
ness in SAD, including SSRIs, venlafaxine, phenelzine, RIMAs, and sweating.
benzodiazepines, gabapentin, and pregabalin. SSRIs are Venlafaxine extended release, in doses of 75 to 225 mg/day,
considered the drugs of choice based on their tolerability and ef- improves social anxiety, performance, and avoidance behavior
cacy for SAD as well as comorbid disorders. The onset of with a reduction in disability.61 Treatment with venlafaxine
response for antidepressants is delayed and may be as long as results in response rates similar to those seen with paroxetine.60
8 to 12 weeks.28,57 Patients responding to medication should be Venlafaxine may be effective in SSRI non-responders.62 As with
continued on treatment for at least 1 year. Many will relapse on SSRIs, doses should be tapered slowly when discontinuing
discontinuation, and there are no clear predictive factors of therapy. Tolerability is similar to that observed in depres-
who will maintain response.58 Some patients may elect more sion trials with venlafaxine extended release. Common side
long-term treatment owing to fear of relapse. The clinician effects are anorexia, dry mouth, nausea, insomnia, and sexual
may use the suggested treatment algorithm (Fig. 374) to dysfunction.
develop a treatment plan.
MAOIs/RIMAs
SSRIs and Venlafaxine The MAOI phenelzine and the RIMAs brofaramine and
The efcacy of paroxetine, sertraline, and escitalopram was meclobemide are effective in SAD. Phenelzine is effective in
established in large controlled trials.5860 SSRIs improve social 64% to 69% of SAD patients.58 It is generally reserved for
anxiety and phobic avoidance and reduce overall disability. treatment-refractory patients owing to dietary restrictions,
FIGURE 374. Algorithm for the phar-

Generalized social macotherapy of SAD. (Reprinted, with
anxiety disorder permission, from reference 24.)
Comorbid depression, second anxiety Urgency to treat, no history of

disorder, or substance abuse substance abuse
Paroxetine, sertraline, BZ
or venlafaxine XR
No response: Partial response:

Response:
switch to another SSRI or Consider augmentation
continue for 12 months
venlafaxine XR with buspirone
Inadequate response: Inadequate response: Response:

switch to phenelzine SSRI BZ continue for 12 months
Nonresponse: Response:
Consider gabapentin Continue for 12 months
drug interactions, and side effects. Neither brofaramine nor

meclobemide is currently available in the United States, but Patient Care and Monitoring
they are available in Canada.
Alternative Agents
1. Review medical and laboratory data to rule out con-
tributing causes of anxiety.
Benzodiazepines
2. Assess the patients symptoms and level of functional
Benzodiazepines are used commonly in SAD; however,
impairment to determine if pharmacotherapy is appro-
there are limited data supporting their use. Clonazepam has
priate for the anxiety disorder.
been effective for social anxiety, fear, and phobic avoidance,
3. Obtain a thorough history of prescription, non-prescription,
and it reduced social and work disability during acute
and natural product use.
treatment.58 Long-term treatment is not desirable for many
SAD patients owing to the risk of withdrawal and difculty 4. Determine what treatments have been tried or were
useful in the past. Is the patient taking medication that
with discontinuation, cognitive side effects, and lack of effect
may cause anxiety?
on depressive symptoms. Benzodiazepines may be useful for
acute relief of physiologic symptoms of anxiety when used 5. Educate the patient about lifestyle changes that will
improve symptoms of anxiety. These include adequate
concomitantly with antidepressants or psychotherapy.
sleep and exercise, stress management, meditation, and
Benzodiazepines are contraindicated in SAD patients with
coping skills.
alcohol or substance abuse or history of such.
6. Inform patients of treatment options for anxiety disor-
ders and the expected benets of each (e.g., pharma-
Anticonvulsants (Gabapentin, Pregabalin)
cotherapy, psychotherapy, and combination treatment).
Gabapentin, a non-benzodiazapine GABA analog, was mod-
7. Develop a plan to assess the effectiveness of drug ther-
estly effective in a 14-week controlled trial in SAD. Most
apy during the rst 12 weeks.
patients were titrated to a maximal dose of 3600 mg/day.58
Pregabalin 600 mg/day was effective for social anxiety, fear, and 8. Determine an appropriate duration of treatment. Is
long-term maintenance treatment needed?
avoidance behavior in a 10-week controlled trial.63 Pregabalin
was well tolerated, and the most common side effects were 9. Assess improvement in academic, social, interpersonal,
somnolence and dizziness. and occupational functioning; quality of life; and well-
being.
b-Blockers 10. Evaluate the patient for the presence of adverse drug
-Blockers decrease physiologic symptoms of anxiety and are effects, drug-drug interactions, and drug allergies.
useful for reducing performance anxiety. Propranolol or 11. Stress the importance of adherence to medications to
atenolol should be administered 1 hour before a performance achieve and maintain response.
situation. -Blockers are not useful in generalized SAD.58 12. Provide patient education regarding disease state,
lifestyle modications, and pharmacotherapy.
Outcome Evaluation What differentiates anxiety from an anxiety disorder?

How should it be treated?
Pharmacotherapy of SAD should lead to improvement Potential complications of an untreated anxiety disorder.
in physiologic symptoms of anxiety and fear, functionality, What potential adverse effects may occur? Is there a
and overall well-being.26 Many patients may not achieve full risk of dependence?
remission of symptoms but should have significant Which drugs may interact with therapy?
improvement. Monitor patients weekly during acute treat- How to record symptoms (e.g., fears, panic attacks,
ment (e.g., initiation and titration of pharmacotherapy). avoidance behaviors) and report back to their clinician.
Once patients are stabilized, monitor monthly. Inquire about
adverse effects and SAD symptoms at each visit. To aid in
assessing improvement, ask patients to keep a diary to record
fears, anxiety levels, and behaviors in social situations.26 You
ABBREVIATIONS
may administer the Leibowitz Social Anxiety Scale (LSAS)
CBT: cognitive behavioral therapy
to rate SAD severity and change, and the Social Phobia DA: dopamine
Inventory can be used as a self-assessment tool for SAD DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders,
patients. 4th edition, Text Revision
Counsel patients on appropriate expectations of pharma- FDA: Food and Drug Administration
cotherapy in SAD, including the gradual onset of effect and GABA: gamma-aminobutyric acid
the need for extended treatment of at least 1 year. GAD: generalized anxiety disorder
5-HT: serotonin Ballanger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on
LC: locus ceruleus generalized anxiety disorder from the international consensus
LSAS: Liebowitz Social Anxiety Scale group on depression and anxiety. J Clin Psychiatry 2001;
NCS-R: National Comorbidity Survey, Revised 62(suppl 11):5358.
NE: norepinephrine Bandelow B, Zohar J, Hollander E, et al. Guidelines for the pharma-
NPY: neuropeptide Y cological treatment of anxiety, obsessive-compulsive and post-
PD: panic disorder traumatic stress disorders. World J Biol Psychiatry 2002;3:
PDA: panic disorder with agoraphobia 171199.
RAS: reticular activating system Blanco C, Smita XA, Liebowitz MR. Pharmacotherapy of social anx-
RIMA: reversible inhibitors of monoamine oxidase A iety disorder. Biol Psychiatry 2002;51:109120.
SAD: social anxiety disorder Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-
SNRI: serotonin-norepinephrine reuptake inhibitor of-onset distributions of the DSM-IV disorders in the National
SSRI: selective serotonin reuptake inhibitor Comorbidity Survey Replication. Arch Gen Psychiatry 2005;
TCA: tricyclic antidepressant 62:593602.
Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and
Reference lists and self-assessment questions and answers are comorbidity of 12-month DSM-IV disorders in the National
available at www.ChisholmPharmacotherapy.com. Comorbidity Survey Replication. Arch Gen Psychiatry 2005;
62:61727.
Log into the website: www.pharmacotherapyprinciples.com Mendolwicz MV, Stein MB. Quality of life in individuals with anxi-
ety disorders. Am J Psychiatry 2000;157:722728.
Rickels R, Ryan M. Pharmacotherapy of generalized anxiety disorder.
this chapter. J Clin Psychiatry 2002;63(suppl 14):916.
Sramek JJ, Zarotsky V, Cutler NR. Generalised anxiety disorder.
KEY REFERENCES AND READINGS Drugs 2002;62:16351648.
Work Group on Panic Disorder. Practice guideline for the treatment
Allgulander C, Bandelow B, Hollander E, et al. WCA recommenda- of patients with panic disorder. Am J Psychiatry 1998;
tions for the long-term treatment of generalized anxiety disor- 155(suppl 5):134.
der. CNS Spectrum 2003;8(8 Suppl 1):5361.
38 SLEEP DISORDERS
John M. Dopp and Bradley G. Phillips
LEARNING OBJECTIVES
1. Articulate the incidence and prevalence of sleep disorders, list the sequelae of undiagnosed
or untreated sleep disorders, and appreciate the importance of successful treatment of sleep
disorders.
2. Describe the mechanisms of the sleep disorders covered in this chapter, including insomnia,
narcolepsy, restless-legs syndrome, obstructive sleep apnea, and parasomnias.
3. Assess patient sleep complaints, conduct sleep histories, and evaluate sleep studies to
recognize day- and nighttime symptoms and characteristics of common sleep disorders.
4. Recommend and optimize appropriate sleep hygiene and nonpharmacologic therapies for
the management and prevention of sleep disorders.
5. Recommend and optimize appropriate pharmacotherapy for sleep disorders.
6. Describe the components of a monitoring plan to assess safety and efcacy of
pharmacotherapy for common sleep disorders.
7. Educate patients about preventive behavior, appropriate lifestyle modications, and drug
therapy required for effective treatment and control of sleep disorders.
KEY CONCEPTS by the Food and Drug Administration (FDA) for the treat-
ment of insomnia and are rst-line therapies.
Insomnia is most frequently a symptom or manifestation of Treatment of excessive daytime sleepiness in narcolepsy and
an underlying disorder (secondary insomnia) but may occur other sleep disorders may require the use of sustained- and
in the absence of contributing factors (primary insomnia). immediate-release stimulants to effectively promote wakeful-
Early treatment of insomnia may prevent the development of ness throughout the day and at key times that require alertness.
psychopathologic complications. Restless-legs syndrome treatment involves suppression of
Patients with sleep complaints should have a careful sleep his- abnormal sensations and leg movements and consolidation of
tory performed to assess for possible sleep disorders and to sleep. Dopaminergic and sedative-hypnotic medications are
guide diagnostic and therapeutic decisions. prescribed commonly.
Although clinical history guides diagnosis and therapy, only The main therapy for obstructive sleep apnea is nasal contin-
overnight polysomnography and multiple sleep latency tests uous positive airway pressure (CPAP) therapy because of its
(MSLTs) can denitively diagnose and/or guide therapy for effectiveness.
obstructive sleep apnea, narcolepsy, and periodic limb move- It is important to review patient medication proles for drugs
ments of sleep. that may aggravate sleep disorders. Patients should be moni-
Treatment goals vary between different sleep disorders but tored for adverse drug reactions, potential drug-drug interac-
generally include restoration of normal sleep patterns, elimi- tions, and adherence to their therapeutic regimens.
nation of daytime sequelae, improvement in quality of life, and
prevention of complications and adverse effects from therapy. Normal humans sleep up to one-third of their lives and spend
Benzodiazepine receptor agonists, including traditional benzo- more time sleeping compared with any other single activity.
diazepines, zolpidem, zaleplon, and eszopiclone, are approved Despite this, our understanding of the full purpose of sleep
621
and the mechanisms regulating sleep homeostasis remains and unresponsiveness to the environment.3 As a result, indivi-
incomplete. Sleep is necessary to maintain wakefulness, health, duals with sleep disorders will exhibit or complain about conse-
and welfare. Unfortunately, disruption of normal sleep is preva- quent symptoms (e.g., daytime sleepiness), or a bed partner will
lent and represents a major cause of societal morbidity, lost observe hallmark characteristics of the sleep disorder. Insomnia,
productivity, and reduced quality of life.1 The link between ade- restless-legs syndrome (RLS), and sleep-related breathing dis-
quate sleep and optimal health is becoming increasingly appar- orders are the most common sleep disorders.
ent, and sleep disturbances may contribute to the development
and progression of comorbid medical conditions. Insomnia
Sleep is governed and paced by the suprachiasmic nucleus in
the brain that regulates circadian rhythm. Environmental cues The prevalence of insomnia increases with age and is nearly
and amount of previous sleep also inuence sleep on a daily basis. 1.5 times greater in females than in males. Approximately one-
There are two main types of sleep: rapid-eye-movement (REM) third of patients older than age 65 have persistent insomnia.4,5 In
sleep, where eye movements and dreaming occur but the body is the adult population, about 10% will experience chronic insom-
mostly paralyzed, and non-REM sleep, which consists of four nia and slightly more will experience short-term insomnia.
substages (stages 1 to 4). Stage 1 serves as a transition between Insomnia is most frequently a symptom or manifestation of an
wake and sleep. Most of the time asleep is spent in stage 2 non- underlying disorder (secondary insomnia) but may occur in the
REM sleep. Stage 3 and stage 4 sleep often are grouped together absence of contributing factors (primary insomnia). Early treat-
and referred to as deep sleep, or delta sleep, because prominent ment of insomnia may prevent the development of psychopatho-
delta waves are seen on the electroencephalogram (EEG) during logic complications. Forty percent of patients with psychiatric
these sleep stages. conditions will have accompanying insomnia.6 Secondary
insomnia is triggered by acute stress and disappears when the
stress resolves. Numerous co-existing medical conditions, such
EPIDEMIOLOGY AND ETIOLOGY as pain, thyroid abnormalities, asthma, reux, and medications,
including selective serotonin reuptake inhibitors (SSRIs),
Sleep disorders are common. Approximately 50% of adults will steroids, stimulants, and -agonists, can interfere with sleep and
report a sleep complaint over the course of their lives.2 In general, cause secondary insomnia. In cases of secondary insomnia, the
sleep disturbances increase with age, and each disorder may have clinician should treat the underlying primary cause along with
gender differences. The full extent and impact of disordered sleep insomnia symptoms.
on our society are not known because many patients sleep dis-
orders remain undiagnosed. Normal sleep, by denition, is Narcolepsy
a reversible behavioral state of perceptual disengagement from
Although difcult to estimate, the prevalence of narcolepsy is
between 0.03% and 0.06%.7 Signicant differences have been
reported for various ethnic groups. Narcolepsy has a higher
Patient Encounter, Part 1 prevalence in the Japanese and a lower prevalence in the
Israeli populations.8,9 Cataplexy is not required for diagnosis;
however, between 50% and 80% of patients with narcolepsy
have accompanying cataplexy.10
CH, a 53-year-old man with a history of hypertension, comes
to your clinic complaining of sleepiness in the daytime,
crawly legs at bedtime, and frequent awakenings at night. Restless-Legs Syndrome
After further questioning, he explains that for the last hour or Restless-legs syndrome occurs in 5% to 15% of the popula-
so before bedtime he cannot keep his legs still. He reports tion, making it a common sleep disorder.11,12 The prevalence
that he falls asleep relatively easily during the day. The symp-
of RLS increases with age and in various medical conditions
toms have been worsening gradually over the past year and
occur nightly. His wife reports that he kicks his legs the rst
such as end-stage renal disease (ESRD), pregnancy, and iron
part of the night, snores, and occasionally gasps for air after a deciency.13 RLS appears to be more common in women than
breathing pause. His body mass index (BMI) is 30 kg/m2, and in men and has a genetic link. The majority of RLS patients
he has experienced recent weight gain and complains about (63% to 92%) report a positive family history.14
morning headaches.
Obstructive Sleep Apnea
What sleep disorders do his symptoms suggest?
What sleep disorders could you diagnose subjectively? Obstructive sleep apnea (OSA) is a common disorder that is
What is your initial recommendation? often unrecognized, affecting 4% of middle-aged white men and
What additional information do you need to know before 2% of middle-aged white women.15 In women, the frequency of
creating a treatment plan for this patient? OSA increases after menopause. OSA is as common or more
common in African Americans and less common in Asian
CHAPTER 38 / SLEEP DISORDERS 623
populations. The risk of OSA increases with age and obesity. environmental inuence to develop. Currently, it is believed
Individuals with OSA experience repetitive upper airway col- that narcolepsy results from autoimmune insult to the CNS
lapse during sleep, which decreases or stops airow, with subse- because it is associated with HLA (major histocompatibility
quent arousal from sleep to resume breathing. The severity is complex) DQB10602 and DQ1A10102.17,18 Concentrations
determined by overnight nocturnal polysomnography and is of hypocretin (a wake-promoting neuropeptide) in the cere-
graded by the number of episodes of apnea (total cessation of brospinal uid (CSF) of narcolepsy patients are reduced sig-
airow) and hypopnea (partial airway closure with blood oxy- nicantly, suggesting that the autoimmune attack is against
gen desaturation) experienced during sleep. The severity is hypocretin-producing cells in the hypothalamus.19 Intact
expressed as the respiratory disturbance index (RDI), quanti- hypocretin neurons normally stimulate arousal and wake-
ed in events per hour. Mild sleep apneics have an RDI of promoting neurons to stimulate cortical activation and
between 5 and 15 episodes per hour; moderate, 15 to 30; and behavioral arousal.
individuals with severe OSA can exhibit more than 30 episodes
per hour.
Restless-Legs Syndrome and Periodic Limb
Movements of Sleep (PLMS)
Parasomnias
RLS is a neurologic medical condition characterized by an
Non-REM parasomnias have variable prevalence rates depend- irresistible desire to move the limbs. It is thought that these
ing on patient age and different diagnoses. Sleep talking, brux- abnormal sensations are a result of iron deciency in the
ism, sleepwalking, sleep terrors, and enuresis occur more fre- brain and iron-handling abnormalities in the CNS. Iron and
quently in childhood than in adulthood. Nightmares appear to H-ferritin concentrations, along with transferrin receptor and
occur with similar frequency in adults and children. REM iron transporter numbers, are reduced in the substantia nigra
behavior disorder (RBD), an REM-sleep parasomnia, has a of patients with RLS.20 These iron abnormalities lead to dys-
reported prevalence of 0.5% and frequently is associated with function of dopaminergic transmission in the substantia
concomitant neurologic conditions.16 Chronic RBD is more nigra.
common in elderly men and may have a familial disposition.

PATHOPHYSIOLOGY At least 20 muscles and soft-tissue structures control patency
of the upper airway. Patients with OSA may have differences
Complicated processes govern wakefulness, sleep, and the in upper airway muscle activity during sleep and may have
transitions leading to sleep initiation and maintenance. smaller airways, predisposing them to upper airway collapse
Although the neurophysiology of sleep is complex, certain and consequent apneic episodes during sleep. The inability of
neurotransmitters promote sleep and wakefulness in different the upper airway to contend with factors that promote col-
areas of the central nervous system (CNS). Serotonin is lapse, including fat deposition in the neck, negative pressure
thought to control non-REM sleep, whereas cholinergic and in the airway during inspiration, and a smaller lower jawbone,
adrenergic transmitters mediate REM sleep. Dopamine, nor- also may play a role in the pathogenesis of OSA. Hallmarks of
epinephrine, hypocretin, substance P, and histamine all play a OSA include witnessed apneas, gasping, or both.
role in wakefulness. Perturbations of various neurotransmit- Poor sleep architecture and fragmented sleep secondary to
ters are responsible for some sleep disorders and explain why OSA can cause excessive daytime sleepiness (EDS) and neu-
various treatment modalities are benecial. rocognitive decits. These sequelae can affect quality of life and
work performance and may be linked to occupational and
Insomnia motor vehicle accidents. OSA is also associated with systemic
disease such as hypertension, heart failure, and stroke.2123 OSA
Since insomnia is a complex and multifaceted disorder, there is is likely an independent risk factor for the development of
no single pathophysiologic explanation for its various manifes- hypertension.24 Further, when hypertension is present, it is often
tations. Current hypotheses focus on a combination of possible resistant to antihypertensive therapy. Fatal and non-fatal cardio-
models that incorporate physiologic, cognitive, and cortical vascular events are two- to threefold higher in male patients with
arousal. Most insomnia models focus on hyperarousal and its severe OSA.25 OSA is associated with or aggravates biomarkers
interference with the initiation or maintenance of sleep. for cardiovascular disease, including C-reactive protein and
leptin.26,27 Patients with sleep apnea often are obese and may be
predisposed to weight gain. Hence, obesity may further con-
Narcolepsy
tribute to cardiovascular disease in this patient population.
The onset of narcolepsy-cataplexy is typically in adolescence Several factors suggest an association between OSA and sys-
and not at birth, suggesting that the disease may require temic disease. Breathing against a closed upper airway during
sleep causes intermittent and repetitive episodes of hypoxemia state dissociation, whereby two states of being overlap simul-
and hypercapnia, dramatic changes in intrathoracic pressure, taneously. For example, abnormal activation of the central
and activation of the sympathetic nervous system. These pattern generator of the spinal cord that produces motor
responses can produce acute hemodynamic and humoral movements is hypothesized to underlie sleepwalking behavior.
responses. Blood pressure can increase to 220/120 mm Hg with In RBD, active inhibition of motor activity in the perilocus
each apneic episode.28 Concentrations of circulating vasocon- coeruleus region is lost, resulting in loss of paralysis and
strictors, such as endothelin-1 and norepinephrine, are dream enactment.
increased during OSA.29 These acute responses to OSA may
predispose to and enhance the progression of vascular disease
in the longer term. This is supported by studies showing CLINICAL PRESENTATION AND DIAGNOSIS
impaired endothelium-dependent vasodilation, an early
marker for vascular disease, in patients with untreated moder- Although clinical history guides diagnosis and therapy,
ate to severe OSA.30 only overnight polysomnography and/or multiple sleep latency
tests (MSLTs) can denitively diagnose and guide therapy for
Parasomnias OSA, narcolepsy, and periodic limb movements of sleep.
The pathogenesis of parasomnias (e.g., sleepwalking, enuresis,
sleep talking) is variable and not well described and involves Insomnia (Difculty Initiating or Maintaining Sleep)
Insomnia is often characterized by difculty falling asleep, fre-
quent nocturnal awakenings, and early-morning awakenings.
Clinical Presentation Difculty initiating or maintaining sleep may result in day-
time impairments in concentration and school or work per-
formance. In secondary insomnia, social factors (e.g., family
Patients with sleep disorders may complain about daytime difculties, bereavement), medications, and co-existing med-
symptoms. A bed partner may witness hallmark characteris- ical conditions (e.g., depression, bipolar disorder) may help to
tics of the sleep disorder. Patients with sleep complaints explain difculties in initiating and maintaining sleep.
should have a careful sleep history performed to assess their Insomnia may be described as transient (a few days), short
possible sleep disorder in order to guide diagnostic and term (less than 3 weeks), or chronic (greater than 1 month) in
therapeutic decisions. duration.
Daytime Symptoms and Associated Characteristics
EDS is the primary symptom described by patients with
sleep disorders. It is usually described as not waking up Narcolepsy
refreshed in the morning or falling asleep or ghting the The hallmark of narcolepsy is EDS and the need for unwanted
urge to sleep during the day despite a night of sleep. Other episodes of sleep during the day during favorable and unfa-
daytime characteristics of sleep disorders include:
vorable conditions. Patients with narcolepsy may experience
Irritability, fatigue, or depression
repeated nighttime awakenings and terrifying dreams, along
Confusion or impaired performance at work or school with difculty falling asleep. Narcoleptics frequently experi-
Cataplexy ence abnormal manifestations of REM sleep, including hallu-
Hypertension cinations and sleep paralysis that occur on falling asleep
and/or awakening. Cataplexy is a weakness or loss of skeletal
Nighttime Sleep Complaints
Depending on the sleep disorder, patients may exhibit or
muscle tone in the jaw, legs, or arms that is elicited by emotion
experience various nocturnal complaints during sleep (e.g., anger, surprise, laughter, or sadness).
hours. Some of these complaints can be uncovered by clini-
cal history alone (e.g., hallucinations, RLS, and snoring),
whereas others can be diagnosed only during sleep studies
(e.g., OSA, nighttime awakenings, somnambulism, PLMS, Common characteristics of OSA include snoring, choking,
etc.). Frequent complaints include: gasping for air, nocturnal reux symptoms, and morning
headaches. A bed partner or roommate may observe these
Inability to fall asleep, nighttime awakenings characteristics and witness episodes where the patient stops
Sleepwalking (somnambulism), sleep talking (somniloquy)
breathing during sleep. Obesity predisposes to and can worsen
Cessation of breathing (apnea), snoring
Sleep paralysis and/or hallucinations when waking or
OSA. Patients with large neck sizes (greater than 45 cm or
falling asleep 17.7'' neck circumference) and a BMI of 30 kg/m2 or greater
Restlessness (PLMS or RLS) are at higher risk for OSA. Hypertension, depression, and
hypothyroidism are found frequently in patients with OSA.
Periodic Limb Movements of Sleep or Restless-Legs sleepy. The occurrence of an REM onset period during two naps
Syndrome is indicative of a diagnosis of narcolepsy. The MWT is per-
formed to assess a patients ability to avoid succumbing to sleepi-
Although RLS symptoms can vary, patients commonly report
ness (manifest sleepiness). Similar nap opportunities are set up
creepy-crawly, burning, tingling, or achy feelings in the legs or
for the MWT, with the exception that the patient is instructed to
arms. These sensations create a desire to move the limbs and may
lie down in bed and attempt to stay awake. A subjective assess-
produce motor restlessness. Symptoms are worse in the evening
ment of sleepiness can be completed using the Epworth
and are worse or exclusively present at rest, with temporary relief
Sleepiness Scale (ESS). The ESS is a validated questionnaire that
with movement. Symptoms also can occur during sleep and
is easy to use and reliably predicts subjective sleepiness. The
often lead to semirhythmic (periodic) limb movements during
maximum score is 24, and any patient with a score greater than
sleep (PLMS). PLMS are objective ndings during overnight
10 is considered sleepy.
polysomnography recorded by leg electrodes. PLMS are present
in most patients with RLS but can occur independently. PLMS
frequently are described by a bed partner as restlessness or
repeated kicking of legs or thrashing of arms during sleep.
Patient Encounter, Part 2: The Medical
Parasomnias History, Physical Examination, and
Diagnostic Test
Parasomnias are characterized by undesirable physical or
behavioral phenomena that occur during sleep [e.g., sleep- CH undergoes nocturnal polysomnography and returns to
walking, sleep talking, bruxism (grinding of teeth), enuresis, your clinic for follow-up.
night terrors, and RBD]. RBD patients act out their dreams
PMH
during sleep, often in a violent manner.
Hypertension poorly controlled since 1999.
Circadian Rhythm Disorders (CRDs) FH
Father died at age 70 from stroke. Mother is still alive with
The most common CRDs include jet lag, shift-work sleep dis- history of restless legs and hypothyroidism.
ruption, delayed sleep-phase disorder, and advanced sleep-
SH
phase disorder. Jet lag occurs when a person travels across Married, works as an accountant, never has smoked, 2 drinks
time zones, and the external environmental time is mis- per night on the weekends.
matched with the internal circadian clock. Delayed and
Meds
advanced sleep-phase disorders occur when bed and wake Hydrochlorothiazide 25 mg PO once daily
times are delayed or advanced (by 3 or more hours) compared Amlodipine 10 mg PO once daily
with socially prescribed bed and wake times.
ROS
Sleep Diagnostics (+) daytime sleepiness (ESS: 18/24).
PE
Complete overnight polysomnography is the gold standard for VS: BP 154/84, P 78, RR 16, T 37.0C (98.6F).
diagnosing and identifying sleep-disordered breathing, PLMS, Mouth: Airway crowded, large tonsils and uvula.
parasomnias, and nocturnal sleep irregularities related to nar- Labs
colepsy. Sleep is observed and monitored in a controlled setting Within normal limits.
using an EEG, electro-oculogram, electromyogram, electrocar-
Overnight polysomnogram: Frequent obstructive apneas,
diogram, air thermistors, abdominal and thoracic strain belts, hypopneas, and leg movements.
and an oxygen saturation monitor. This setup assesses and
records sleep onset, arousals, sleep stages, eye movements, leg RDI: 12 events/hour
and jaw movements, heart rhythm, arrhythmias, airow during 310 leg movements, mostly occurring in rst half of the
sleep, respiratory effort, and oxygen desaturations. night
Successful alleviation of apneas and hypopneas with nasal
Evaluations of Daytime Sleepiness continuous positive airway pressure
The two most commonly performed objective evaluations to
Given this additional information, summarize the patients
assess daytime sleepiness are the multiple sleep latency test diagnosis.
(MSLT) and the maintenance of wakefulness test (MWT). The Identify your treatment goals and recommendations for the
MSLT is a series of four to six 20-minute naps every 2 hours dur- patient.
ing the day beginning 2 hours after morning awakening (follow- What nonpharmacologic and pharmacologic alternatives
ing a normal nights sleep) to evaluate physiologic sleepiness. are available for this patient if prescribed therapy is not
The patient is instructed not to resist the urge to fall asleep. Sleep successful or not tolerated?
latency of less than 5 or 6 minutes is considered pathologically
TREATMENT FDA for chronic use up to 6 months.33 Although not rst line-
agents for insomnia, sedating antihistamines are prescribed
Treatment goals vary between different sleep disorders but commonly, and the number of prescriptions has increased
generally include restoration of normal sleep patterns, elimination dramatically over the last 20 years.34 These and other thera-
of daytime sequelae, improved quality of life, and prevention of pies, detailed below, are used to treat insomnia.
complications and adverse effects from therapy. All patients pre-
senting with sleep complaints should have a thorough inventory Benzodiazepine Receptor Agonists (BZDRAs)
of their sleep habits and sleep hygiene investigated during the There are currently eight BZDRAs approved for insomnia, and
interview and history taking. Nonpharmacologic interventions the pharmacokinetic differences between these agents help to
for insomnia are outlined in Table 381. Sleep hygiene should be guide selection depending on patient considerations and specic
reinforced in all patients, and behavioral, cognitive, and stimulus- sleep complaints (Table 382). These agents occupy the benzo-
control interventions are used mainly for patients with insomnia- diazepine receptors on the gamma-aminobutyric acid (GABA)
type complaints. Both pharmacologic and nonpharmacologic type A receptor complex, resulting in opening of chloride chan-
therapies are effective at improving sleep and reducing insomnia nels that facilitate GABA inhibition and promote sleepiness.35
complaints. An algorithm for the initial assessment and rst BZDRAs have become the rst-line agents for treating insomnia
treatment step is provided in Fig. 381. and sleep-maintenance problems because they are all efca-
cious, have wide therapeutic indices, and in clinical use have a
low incidence of abuse.31,35
Insomnia
Patients should be instructed to take BZDRAs at bedtime and
The ideal hypnotic drug would be effective at reducing sleep to avoid engaging in activities requiring alertness after ingestion.
latency and increasing total sleep time and be free of The BZDRAs come closer to the ideal hypnotic compared with
unwanted side effects. Benzodiazepine receptor agonists, other agents because they reduce sleep latency and increase
including traditional benzodiazepines, zolpidem, zaleplon, and total sleep time (except for zaleplon) with fewer adverse effects.
eszopiclone, are approved by the Food and Drug Administra- Although BZDRAs generally are well tolerated and have good
tion (FDA) for the treatment of insomnia and are rst-line safety proles, mild to moderate side effects can occur, and pre-
therapies.31,32 Not all products are available in all countries. cautions are warranted, especially in high-risk populations.
Pharmacologic treatment of insomnia is recommended for
transient and short-term insomnia. Long-term use of hyp- Precautions and Safety
notics is not contraindicated unless the patient has another The most common side effects associated with BZDRAs
contraindication to their use. Eszopiclone is approved by the include residual sedation (a prolongation of the sedative
effects into the waking hours after sleep), grogginess, and psy-
chomotor impairment.36 Careful selection of a hypnotic agent
TABLE 381. Nonpharmacologic Therapies for Sleep with a duration of action matching the patients budgeted
Sleep Hygiene sleep time can help minimize the risk of residual sedation.
Keep a regular sleep schedule. BZDRAs should be initiated at low doses, and agents with
Exercise frequently but not immediately before bedtime. active metabolites (Table 382) should be avoided in elderly
Avoid alcohol and stimulants (caffeine, nicotine) in the late patients. BZDRAs may cause anterograde amnesia, dened as
afternoon and evening. memory loss of activities and interactions after ingestion of
Maintain a comfortable sleeping environment that is dark, quiet,
and free of intrusions. the drug. All hypnotics can cause anterograde amnesia, and
Avoid consuming large quantities of food or liquids immediately higher doses increase the extent of amnesia.37,38
before bedtime. On discontinuation of hypnotic BZDRAs, patients can expe-
Stimulus Control rience rebound effects, specically rebound insomnia that may
Go to bed only when sleepy. last for one to two nights. Rebound insomnia occurs more fre-
Avoid daytime naps. quently after discontinuation of shorter-duration BZDRAs
If you cannot sleep, get out of bed and go to another room
only return to your bed when you feel the need to sleep.
compared with long-duration BZDRAs. Intermittent hypnotic
Bed is for sleep and intimacy only (no eating or watching TV in therapy with the lowest dose possible reduces the likelihood of
bed). tolerance, dependence, and withdrawal when therapy is
Always wake up at the same time each day. stopped. Patients should be counseled that rebound insomnia is
Relaxation Training not necessarily a return of their original symptoms, and it may
Reduce somatic arousal (muscle relaxation). take a few nights for rebound symptoms to subside.
Reduce mental arousal (attention focusing procedures, imagery
training, meditation, etc.). Sedating Antidepressants
Biofeedback (use of visual or auditory feedback to reduce tension).
The increasing popularity of sedating antidepressants for the
Cognitive Therapy
Alter beliefs, attitudes, and expectations about sleep.
treatment of insomnia resulted in trazodone being the most
prescribed drug in 2002.39 Other common antidepressants also
FIGURE 381. Primary assessment

and initial treatment for complaint
of excessive daytime sleepiness.
RLS, restless-legs syndrome; NPSG,
nocturnal polysomnography; OSA,
obstructive sleep apnea; DA,
dopamine agonist; MSLT, multiple
sleep latency test; BZDRA, benzo-
diazepine receptor agonist; SNRI,
serotonin and norepinephrine
reuptake inhibitor; TCA, tricyclic
antidepressant; CPAP, continuous
positive airway pressure.
TABLE 382. Pharmacokinetics of Prescription Medications Used to Treat Insomnia
Clinically
Parent Duration of Daily Dose Metabolic Signicant Advantages and/
Generic Name t1/2 (hour) Action (hour) Range (mg) Pathway Metabolites or Disadvantages
Estazolam 2 1215 12 Oxidation Moderate duration
(Prosom)
Eszopiclone 6 8 23 Oxidation Can be used up to 6 months
(Lunesta) Demethylation for chronic insomnia
Flurazepam 8 1030 1530 Oxidation Hydroxyethylurazepam High risk of hangover and
(Dalmane) N-dealkylation Flurazepam aldehyde residual effects
N-DAFb
Quazepam 2 2541 7.515 Oxidation 2-Oxo-quazepam High risk of hangover and
(Doral) N-dealkylation N-DAFa residual effects
Ramelteon 12.6 Unpublishedb 8 Oxidation M-IIc Non-controlled substance,
(Rozerem) Glucuronidation may be useful in patients
with history of substance
abuse
Temazepam 1015 7 7.530 Conjugation Moderate duration, well-
(Restoril) tolerated, inexpensive
Triazolam 2 67 0.1250.25 Oxidation Short-acting, little residual
(Halcion) hangover
Zaleplon 1 6 510 Oxidation Short-acting, only for
(Sonata) difculty falling asleep
Zolpidem 22.6 68 510 Oxidation Shortmoderate duration,
(Ambien) no effects on sleep
architecture
Zolpidem CR Perhaps 6.2512.5
(AmbienCR) longer
a
N-desalkyl urazepam.
b
Data not available.
c
M-II is the major active metabolite of ramelteon.
Adapted, with permission, from Pharmacotherapy: A Pathophysiologic Approach. 6th ed. Table 714, p. 1325.
prescribed for insomnia include amitriptyline, mirtazapine, regimen includes a sustained-release preparation rst thing in
nefazadone, and doxepin. Antidepressants may be an appealing the morning and again at noon, followed by an immediate-
option for insomnia in patients with concomitant depression. release preparation as needed in the late afternoon or prior to
However, at the doses frequently used for sleep, none of the driving to maintain wakefulness. One advantage of traditional
agents exhibit signicant antidepressant activity. Further, quality CNS stimulants over modanil is their ability to suppress REM
clinical studies demonstrating efcacy for treating insomnia are sleep, which also may help to control cataplexy and REM-sleep
lacking. Side effects from antidepressants can be frequent and abnormalities.
often are unpleasant, including carryover sedation, grogginess, Traditional CNS stimulants have the potential to increase
anticholinergic effects, and weight gain. Tricyclic antidepressants blood pressure and heart rate when used long term. In addi-
(TCAs) should be used with caution in the elderly and patients tion, excessive CNS stimulation can cause tremors and tics
with cardiovascular and hepatic impairment. Mirtazapine can and can carry over into evening hours, where initiation of
cause daytime sedation, dizziness, and weight gain, a side effect normal nighttime sleep can be disrupted. Caution should be
that may worsen concomitant OSA.40 Trazodone can cause used in patients with underlying cardiovascular or cere-
hypotension and dizziness and should be used with caution in brovascular disease and in patients with a history of seizures
patients with heart disease or hypertension and those taking car- because stimulants may lower the seizure threshold.
diovascular agents.41,42
Cataplexy
Over-the-Counter and Miscellaneous Agents Traditionally, aminergic signaling antidepressants have been
Antihistamines such as diphenhydramine are known for their used effectively to control symptoms of cataplexy, sleep paraly-
sedating properties and are frequently used over-the-counter sis, and other REM-sleep manifestations of narcolepsy. These
medications (usual doses 2550 mg) for difculty sleeping. include TCAs and certain selective serotonin and serotonin/
Diphenhydramine is approved by the FDA for the treatment of norepinephrine reuptake inhibitors (SSRIs and SNRIs).
insomnia and can be effective at reducing sleep latency and Clomipramine, protriptyline, imipramine, venlafaxine, and u-
increasing sleep time.43 However, diphenhydramine produces oxetine are the agents that have been used most frequently. In
undesirable anticholinergic effects and carryover sedation that addition, low-dose selegiline also has been effective at reducing
limit its use. As with TCAs and BZDRAs, diphenhydramine cataplexy. Although these drugs are not approved by the FDA for
should be used with caution in the elderly. Valerian root is an treatment of cataplexy, they effectively suppress REM sleep and
herbal sleep remedy that has inconsistent effects on sleep but have been the mainstay of anticataplectic therapy for years.
may reduce sleep latency and efciency at commonly used doses Recently, sodium oxybate, a potent sedative with a very short
of 400 to 900 mg valerian extract. Ramelteon, a new melatonin duration of action, gained FDA approval for the treatment of
receptor agonist, is indicated for insomnia characterized by dif- narcolepsy with cataplexy. The mechanism whereby it reduces
culty with sleep onset. The recommended dose is 8 mg at bed- cataplexy is unknown. Two doses per night are taken, one at bed-
time. Ramelteon is not a controlled substance and thus may be time and one follow-up dose taken 21/2 to 4 hours later. Patients
a viable option for patients with a history of substance abuse. frequently need to set an alarm to wake up to take their second
dose. Sodium oxybate is tightly regulated and is only available
Narcolepsy from one central pharmacy owing to the high abuse potential of
Therapy for narcolepsy involves two key principles: (1) treat- its active ingredient (gamma-hydroxybutyrate).
ment of EDS with scheduled naps and CNS stimulants and
(2) suppression of cataplexy and REM-sleep abnormalities with
Restless-Legs Syndrome
aminergic signaling drugs. Modanil, methylphenidate, and
amphetamines are effective FDA-approved drugs for the treat- RLS treatment involves suppression of abnormal sensations
ment of EDS with narcolepsy.44 Modanil is potentially advan- and leg movements and consolidation of sleep. Dopaminergic and
tageous in part because it is a schedule IV medication in contrast sedative hypnotic medications are prescribed commonly. In the last
to CNS stimulants, which are schedule II. Modanil is renewable few years, dopamine agonists (DAs) have become the therapy of
for 6 months at a time and may have fewer peripheral and car- choice for the treatment of RLS, replacing levodopa/carbidopa
diovascular effects than traditional stimulants. Selegiline, a selec- as rst-line agents. The DAs offer many advantages over levodopa/
tive monoamine oxidase B enzyme inhibitor, is metabolized to carbidopa, including longer half-lives to cover overnight symp-
amphetamines and can be successful at reducing daytime sleepi- toms, exible dosing, and a reduced incidence of symptom aug-
ness. In an individual patient, one wake-promoting agent may mentation. Up to 80% of patients who take levodopa/carbidopa
work better than another, and if the rst drug selected is not suc- eventually will experience symptom augmentation: RLS symp-
cessful at adequate doses, a trial with another agent should be toms appear earlier in the day, previously unaffected body parts
attempted. Treatment of EDS in narcolepsy and other sleep become involved, and higher doses of medication are required
disorders may require the use of sustained- and immediate-release to control symptoms.45 Ropinirole (Requip) recently gained
stimulants to effectively promote wakefulness throughout the day FDA approval for the treatment of RLS. Pramipexole and per-
and at key times that require alertness. One potential treatment golide are also prescribed and have demonstrated efcacy in
clinical trials.46,47 Gabapentin is an effective treatment for RLS, breathing is eliminated. CPAP therapy has been shown to have
particularly in patients with painful symptoms.48 BZDRAs such a favorable impact on blood pressure and to attenuate some of
as temazepam, clonazepam, zolpidem, and zaleplon effectively the potential hemodynamic and neurohumoral responses that
reduce arousals associated with PLMS in patients with RLS.49 may link OSA to systemic disease.
Their main benet is derived from improving sleep continuity Not all individuals tolerate CPAP therapy in part because it
in patients with RLS, particularly as adjunct treatment with requires wearing a mask during sleep, and therapy can dry and
other pharmacologic therapies. Opioids are effective for some irritate the upper airway. In some individuals, these barriers for
patients RLS symptoms, with oxycodone, propoxyphene, adherence may be lessened or eliminated by properly tting the
hydrocodone, and codeine being used most frequently. For both mask, adding humidity or heat to therapy, or using bi-level
BZDRAs and opioids, caution should be used in the elderly, in positive airway pressure (BiPAP) therapy. BiPAP therapy
patients who snore and are at risk for sleep apnea, and in applies a variable pressure into the airway during the inspira-
patients with a history of substance abuse. Low iron levels fre- tory phase of respiration but, unlike CPAP, reduces the applied
quently exacerbate RLS symptoms. Iron supplementation pressure during the expiratory phase of respiration.
should be prescribed in patients who are iron-decient. Iron There are other non-invasive therapies for OSA. Obesity can
supplementation in patients with serum ferritin concentrations worsen sleep apnea, and weight management should be imple-
of less than 50 mcg/L improves RLS symptoms. Medications fre- mented for all overweight patients with OSA. In obese patients
quently used for RLS are shown in Table 383. with mild OSA, weight loss alone can be effective, and studies
have reported improvement in severity of OSA with gastric sta-
pling. Oral appliances can be used to advance the lower jawbone
Obstructive Sleep Apnea and to keep the tongue forward to enlarge the upper airway. For
The main therapy for OSA is nasal continuous positive individuals who suffer OSA only during certain positions (e.g.,
airway pressure (CPAP) therapy because of its effectiveness. when on their back) during sleep, positional therapies may be
CPAP alleviates sleep-disordered breathing by producing a effective. Surgical therapy (uvulopalatopharyngoplasty)
positive pressure column in the upper airway using room air. opens the upper airway by removing the tonsils, trimming
The CPAP machine is small enough to be transportable and and reorienting the posterior and anterior tonsillar pillars,
sits at the bedside. A exible tube connects the CPAP machine and removing the uvula and posterior portion of the palate.
to a mask that covers the nose. During overnight polysomno- This is not a rst-line option because it is invasive. In very
graphy, the pressure setting is increased until sleep-disordered severe cases, tracheostomy may be necessary. This procedure
TABLE 383. Frequently Used Medications for Restless-Legs Syndrome49
Dose Range Potential Side

Medication Half-Life (hour) (mg/day)d Effect or Disadvantage
Dopaminergic Agentsa
Levodopa/carbidopa 1.52 100200 Nausea/vomiting, high incidence
(Sinemet) of levodopa of symptom augmentation
Pramipexole (Mirapex) 812b 0.1251.5 Nausea/vomiting
Ropinirole (Requip 6c 0.253 Nausea/vomiting
Pergolide (Permax) 27 0.0250.5 Nausea/vomiting, rare but serious
heart valvulopathy and pleural
brosis
Anticonvulsants
Gabapentin (Neurontin) 57b 3003600 Dizziness, ataxia
Hypnotic Agents
Clonazepam (Klonopin) 3040 0.52 Tolerance, carryover sedation
Temazepam (Restoril) 1015 7.530 Tolerance, sedation
Zolpidem (Ambien) 22.6c 510 Tolerance, sedation
Zaleplon (Sonata) 1c 510 Tolerance, sedation
Opioids
Hydrocodone 3.84.5c 510 Constipation, nausea, sedation
Codeine 2.53.5c 3060 Constipation, nausea, sedation
Propoxyphene 612c 100600 Constipation, nausea, sedation
Oxycodone 3.212b 530 Constipation, nausea, sedation
a
Dopaminergic agents are frequently given at bedtime or 2 hours prior to bedtime or the anticipated onset of RLS
symptoms.
b
May be longer in patients with renal dysfunction.
c
May be longer in patients with hepatic dysfunction.
d
Usual range, dosed at bedtime.
may be indicated in selected individuals who are morbidly

obese, have severe facial skeletal deformity, experience severe Patient Encounter, Part 3: Modifying
drops in oxygen saturation (e.g., Sao2 less than 70%), or have Treatment Plan
signicant cardiac arrhythmias associated with their OSA.
There is no drug therapy for OSA. Drug therapy for symp-
CH returns to the clinic 3 months later. The physician previ-
toms of OSA may be considered in selected patients. For exam-
ously diagnosed him with obstructive sleep apnea and RLS.
ple, modanil (Provigil) is a wake-promoting medication that He received a prescription for CPAP, for OSA and ropinirole
is approved by the FDA to improve wakefulness in patients who 0.5 mg at bedtime for RLS at his last visit. Via phone calls,
have residual daytime sleepiness while treated with CPAP. his ropinirole dose has been increased to 3 mg at bedtime.
Initiation of wake-promoting medications should be attempted He has received moderate relief of his RLS symptoms, but
only after patients are using optimal CPAP therapy to alleviate on occasion, he still awakens and cannot fall back asleep.
sleep-disordered breathing. Other therapies (e.g., medroxypro- His sleepiness and RLS symptoms are improved: ESS: 13/24.
gesterone) are not effective and may worsen OSA. Untreated or
inadequately treated sleep apnea may hinder achieving blood Based on the information presented, recommend addi-
pressure control in hypertensive patients. OSA should be con- tional therapy for the patient.
What medications would you consider adding to reduce
sidered and evaluated in hypertensive patients who are resistant
RLS symptoms and reduce awakenings?
to therapy or have signs and symptoms of OSA.
How would you assess the patients CPAP therapy and
adherence?
Parasomnias What precautions would you want to counsel the patient
on about his therapy?
Non-REM parasomnias usually do not require treatment. If
needed, low-dose benzodiazepines such as clonazepam can be
prescribed for bothersome episodes. Clonazepam reduces the analgesics, sedatives, and muscle relaxants, can worsen OSA,
amount of sleep time spent in stages 3 and 4 of non-REM even in small doses, by reducing respiratory drive and relaxing
sleep, where most non-REM parasomnias occur. For treating the upper airway muscles responsible for maintaining
RBD, clonazepam 0.5 to 2 mg at bedtime is the drug of choice, patency. CNS depressants should be avoided, and if they are
although melatonin 3 to 12 mg at bedtime also may be effec- necessary, they should not be administered before sleep. Drug
tive. Patients with RBD also should have dangerous objects therapy for sleep disorders should be patient-specic, and
removed from the bedroom and cushions placed on the oor careful consideration should be given to co-existing diseases,
to reduce the chance of injury from breakthrough episodes. concomitant medications, and potential drug-drug and drug-
disease interactions to optimize patient care and treatment.
Circadian Rhythm Disorders
Melatonin at doses of 0.5 to 5 mg taken at appropriate target OUTCOME EVALUATION
bedtimes for east or west travel is becoming the drug of choice
for jet lag. Melatonin signicantly reduces jet lag and shortens To determine the success of treatment, evaluate whether the
sleep latency in travelers.50 Hypnotic agents with relatively short treatment plan restored normal sleep patterns, reduced day-
durations of action (3 to 5 hours) also may be used to sustain time sequelae, and improved quality of life without causing
sleep during the initial adaptation to the new time zone. adverse effects. Schedule patients for follow-up within 3 weeks
for insomnia and within 3 months for other sleep disorders.
Perform a detailed clinical history to determine the patients
Drug-Disease and Drug-Drug Interactions
perception of treatment progress and symptoms along with
It is important to review patient medication proles for medication effectiveness and side effects.
drugs that may aggravate sleep disorders. Patients should be Instruct patients to keep sleep diaries of nightly sleep (number
monitored for adverse drug reactions and potential drug-drug of hours, number of awakenings, and worsening or improved
interactions. They should be assessed for adherence to their ther- sleep) and daytime symptoms, along with documentation of
apeutic regimens. Pharmacotherapy for sleep disorders should episodes such as cataplexy or RBD. Increase medication to
be individualized. Medications can be used commonly to treat effective doses, and if necessary, start additional therapy to
several concomitant sleep disorders. Conversely, drug therapy control symptoms. Patients with sleep disorders should expe-
may be effective for one sleep disorder and exacerbate rience relief of symptoms the rst night of drug therapy but
another. For example, antidepressants may alleviate depressive may not receive maximal benet (effect on daytime symptoms)
symptoms but exacerbate symptoms of RLS. Medications that for a few weeks. Perform a detailed history of prescription,
block dopaminergic transmission may worsen RLS symptoms. non-prescription, and non-traditional medications, and
Smoking can worsen OSA, presumably by increasing upper review the patients sleep diary, daytime symptoms, and non-
airway edema. Alcohol and CNS depressants, including opiate pharmacologic therapies on a regular basis.
Patient Care and Monitoring 2. Measurement of sleepiness (via ESS) and RLS symptoms
should be completed at each visit to track progress with
therapy.
3. Evaluate potential side effects of therapy, including nausea,
Insomnia drowsiness, sleep attacks, and headaches for the DA
1. Ideally limit hypnotic therapy to short-term use, and agents.
reevaluate after 2 to 3 weeks of therapy. 4. Review the sleep diaries and timing of RLS symptoms to
2. Evaluate improvement in the specic sleep complaint watch for possible symptom augmentation.
(e.g., how has therapy affected sleep latency?). 5. If symptoms are not resolved, increase the dose of DA
3. Inquire about carryover sedation and other side effects agent or add another agent such as gabapentin or a hyp-
associated with the selected agent. Use a lower dose or notic benzodiazepine.
select a drug with a shorter duration of action if the patient
experiences carryover sedation. OSA
4. Address other medical conditions that frequently coexist 1. Evaluate CPAP therapy annually or at any time individuals
with insomnia and can worsen a patients symptoms (e.g., experience symptoms (e.g., daytime sleepiness) despite
psychiatric disorders, benign prostatic hypertrophy). CPAP therapy. For example, change in pressure settings to
alleviate OSA may be needed if weight gain occurs.
Narcolepsy
1. Administer the ESS at each visit to monitor progress with 2. Monitor compliance with CPAP therapy. CPAP machines
modanil or stimulant therapy. Unfortunately, EDS in nar- have a built-in compliance meter to measure the hours
colepsy patients rarely is fully reversed. used at effective pressure. Patients should use CPAP ther-
apy for at least 5 hours each night. In addition to alleviat-
2. Evaluate how sleepiness changes throughout the day to best ing sleep-disordered breathing, CPAP therapy may
determine how to use sustained- and immediate-release improve cardiovascular outcomes.
stimulants to maintain wakefulness. If the patient complains
of sleep disruption from stimulant therapy, move the dosing Parasomnias
time a few hours earlier until sleep disruption is avoided. 1. Ask patients and family members about any bothersome or
3. Review patients sleep diaries to track the number of cata- dangerous sleepwalking episodes since the last visit and if
plexy, sleep paralysis, and hallucinatory events and when therapy has reduced the frequency of these events.
they occur. 2. For RBD, review the sleep diaries and interview bed part-
RLS ners to determine the number and nature of episodes.
1. Carefully assess both the patients and bed partners 3. Inquire about carryover sedation and anterograde amnesia
reports of the patients nighttime limb movements. from therapy.
ABBREVIATIONS RLS: restless-legs syndrome

SNRI: serotonin norepinephrine reuptake inhibitor
BiPAP: bi-level positive airway pressure SSRI: selective serotonin reuptake inhibitor
BMI: body mass index TCA: tricyclic antidepressant
BZDRA: benzodiazepine receptor agonist
CPAP: continuous positive airway pressure Reference lists and self-assessment questions and answers are
CRD: circadian rhythm disorder available at www.ChisholmPharmacotherapy.com.
DA: dopamine agonist
EDS: excessive daytime sleepiness Log into the website: www.pharmacotherapyprinciples.com
ESRD: end-stage renal disease for information on obtaining continuing education credit for
ESS: Epworth Sleepiness Scale this chapter.
GABA: gamma-aminobutyric acid
HLA: histocompatibility leukocyte antigen
MSLT: multiple sleep latency test KEY REFERENCES AND READINGS
MWT: maintenance of wakefulness test
NPSG: nocturnal polysomnography Dement WC. The proper use of sleeping pills in the primary care set-
NREM: nonrapid eye movement ting. J Clin Psychiatry 1992;53(suppl12):5056.
OSA: obstructive sleep apnea Hening WA, Allen RP, Earley CJ, et al. Restless Legs Syndrome Task
PLMS: periodic limb movements of sleep Force of the Standards of Practice Committee of the American
RBD: REM-sleep behavior disorder Academy of Sleep Medicine. An update on the dopaminergic
RDI: respiratory disturbance index treatment of restless legs syndrome and periodic limb move-
REM: rapid eye movement ment disorder. Sleep 2004;27:560583.
Krystal AD, Walsh JK, Laska E, et al. Sustained efcacy of eszopiclone Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deciency
over 6 months of nightly treatment: Results of a randomized, in human narcolepsy. Lancet 2000;355:3940.
double-blind, placebo-controlled study in adults with chronic Peppard P, Young T, Palta M, et al. Prospective study of the associa-
insomnia. Sleep 2003;26:793799. tion between sleep-disordered breathing and hypertension.
Kudo Y, Kurihara M. Clinical evaluation of diphenhydramine N Engl J Med 2000;342:13781384.
hydrochloride for the treatment of insomnia in psychiatric Scammell TE. The neurobiology, diagnosis, and treatment of
patients. J Clin Pharmacol 1990;30:10411048. narcolepsy. Ann Neurol 2003;53:154166.
Littner M, Johnson SF, McCall WV, et al. Practice parameters for the treat- Walsh JK, Schweitzer PK. Ten-year trends in the pharmacological
ment of narcolepsy: An update for 2000. Sleep 2001; 24:451455. treatment of insomnia. Sleep 1999;22:371375.
Morgenthaler TI, Kapen S, Lee-Chiong T, et al. Practice parameters
for the medical therapy of obstructive sleep apnea. Sleep 2006;
29:10311035.
39 ATTENTION-DEFICIT HYPERACTIVITY DISORDER
Kevin W. Cleveland and John Erramouspe
LEARNING OBJECTIVES
1. Explain the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision
criteria necessary for the diagnosis of attention-decit hyperactivity disorder.
2. Recommend a therapeutic plan, including initial doses, dosage forms, and monitoring
parameters, for a patient with attention-decit hyperactivity disorder.
3. Differentiate between the available pharmacotherapy used for attention-decit hyperactivity
disorder with respect to pharmacology and pharmaceutical formulation.
4. Recommend second-line and/or adjunctive agents that can be effective alternatives in the
treatment of attention-decit hyperactivity disorder when stimulant therapy is less than
adequate.
5. Address potential cost-benet issues associated with pharmacotherapy of attention-decit
hyperactivity disorder.
6. Recommend strategies for minimizing adverse effects of attention-decit hyperactivity
disorder medications.
KEY CONCEPTS therapy fails, then a second trial of an alternative stimulant

should be tried. On failure of a second trial of stimulant phar-
To meet present attention-decit hyperactivity disorder diag- macotherapy, it is rational to attempt a third trial with
nostic criteria, patients need to display either hyperactivity, another stimulant formulation or select a non-stimulant agent
impulsivity, and/or inattentiveness before 7 years of age. such as bupropion, imipramine, or atomoxetine.
The exact cause of attention-decit hyperactivity disorder is
unknown, but dysfunction in neurotransmitters norepineph- Attention-deficit hyperactivity disorder (ADHD) is the
rine and dopamine has been implicated as a key component. most common mental disorder that occurs in the pediatric
Attention-decit hyperactivity disorder is rarely encountered population.13 This disorder must begin in childhood before
without comorbid conditions. 7 years of age and can continue into adulthood. ADHD is
Treatment goals for attention-decit hyperactivity disorder characterized by a core group of symptoms: hyperactivity,
are to improve behavior, increase attention/response inhibi- impulsivity, and inattention. Further, ADHD can be classied
tion (ability to stay on task), and minimize side effects associ- into three basic forms: inattentive, hyperactive/impulsive,
ated with pharmacotherapy. and combined. It can have a severe impact on a patients
Pharmacotherapy is superior to behavioral therapy in the ability to function in both academic and social environ-
treatment of attention-decit hyperactivity disorder. Behavior ments, leading to a signicant burden on family and school
modication provided by parents and teachers in conjunction personnel. The exact cause of ADHD is unknown, but twin
with pharmacotherapy improves treatment outcomes more studies strongly suggest a genetic etiology.35 Early diagnosis
than behavior therapy alone. and appropriate treatment are essential to compensate for
Stimulants are rst-line agents for the treatment of attention- areas of decit and to allow the patient to cope in both family
decit hyperactivity disorder. If the initial trial of a stimulant and social environments.
633
and concentrating on ideas.4,6 Further, children with ADHD

Patient Encounter, Part 1 often alternate between inattentiveness to monotonous tasks
and overexcitement. Multiple brain studies have failed to eluci-
date any pathophysiologic basis for ADHD, although they have
associated ADHD with atypical brain development in early
A single mother and her rambunctious 6-year-old boy, AD,
come to your clinic. The mother is concerned because her childhood. Cerebral volume, the prefrontal cortex, the basal gan-
neighbor, who watches AD after school for no charge, has glia, and the caudate tend to be signicantly smaller in children
complained about the problems he is causing among her own with ADHD than in children without the disorder.4
children (41/2- and 6-year-old boys). AD refuses to wait for his Dysfunction in the roles of the neurotransmitters dopamine
own turn in games and frequently hits the younger boy. The and norepinephrine is thought to be key in the pathology of
neighbor has said that unless AD becomes more manageable, ADHD. Norepinephrine is responsible for maintaining alert-
she will not watch him after school. This is very distressing to ness and attention, whereas dopamine is responsible for regu-
ADs mother, who barely provides for her son and herself by lating learning, motivation, goal setting, and memory. Both
working at the local convenience store for minimum wage. these neurotransmitters predominate in the frontal subcortical
She cannot afford a professional babysitter for AD. She does
system, an area of the brain responsible for maintaining atten-
not qualify for medical assistance. Further, she explains that
tion and memory. Also, the propensity for a genetic link with
his performance at school is getting worse, and he is becom-
ing unmanageable in the classroom. this disorder is high. There is a 50% chance that a child who
has a parent with ADHD will develop ADHD. Further, studies
Which of the patients symptoms are suggestive of ADHD? of twins have demonstrated a concordance rate of 92% for
What other information do you need to assess for ADHD? ADHD. An association has been made between the develop-
What help/suggestions could you offer to ADs mother? ment of ADHD and predisposing factors such as fetal alcohol
syndrome, lead poisoning, maternal smoking, and hypoxia.4

Clinical Presentation
This disorder usually begins by 3 years of age but must
occur prior to 7 years of age to meet diagnostic criteria. In the
United States, ADHD is the most common neurobehavioral
disorder that affects children.13,6 ADHD has been estimated General
to occur between 4.3% and 12% of school-aged children.6,7 Patients with ADHD can present with inattention and/or
hyperactivity-impulsivity. ADHD is rarely encountered
ADHD tends to occur at a greater incidence in males than in
without comorbid conditions.
females by approximately 3:1 in school-aged children.7
However, during adolescence, the incidence of ADHD is equal Symptoms
between males and females. As adults, females have a greater Inattentionhas difculty paying attention to details in
incidence of ADHD symptoms than males. school, work, and social activities, difculty completing
tasks that require a lot of mental effort; is easily dis-
Although ADHD generally is considered a childhood dis-
tracted, forgetful.
order, symptoms can persist into adolescence and adulthood. Hyperactivity/impulsivityhas difculty sitting still, dg-
The prevalence of adulthood ADHD is estimated to be 4%, ets, has trouble playing quietly and waiting turns, fre-
with 60% of adults having manifested symptoms of ADHD quently interrupts.
from childhood.8,9 Further, problems associated with ADHD Combinedexhibit both inattention and hyperactivity/
(e.g., social, marital, academic, career, anxiety, depression, impulsivity.
smoking, and substance-abuse problems) increase with the Diagnostic Criteria
transition of patients into adulthood. Must exhibit symptoms before 7 years of age that persist
for greater than 6 months.
Symptoms must be present in two or more settings and
PATHOPHYSIOLOGY adversely affect functioning in social situations, school, or
work.
Must meet the diagnostic criteria in DSM-IV-TR
The exact pathologic cause of ADHD has not been identied. (Table 391).
ADHD is generally thought of as a disorder of self-regulation or Symptoms cannot be better explained by another mental
response inhibition. Patients who meet the criteria for ADHD disorder (e.g., autism).
have difculty maintaining self-control, resisting distractions,
CHAPTER 39 / ATTENTION-DEFICIT HYPERACTIVITY DISORDER 635
TABLE 391. DSM-IV Diagnostic Criteria for ADHD obtained from various settings, including the family and
school. Information is gathered from parent interviews,
I. Either A or B:
school reports, and an interview with and observation of the
A. Inattention. Must have at least six or more of the following
symptoms of inattention for at least 6 months: patient. This information should include the age of onset, fre-
1. Does not pay close attention to details in schoolwork, quency, severity, and duration of symptoms.10
work, or other activities. The most useful diagnostic criteria for ADHD is the
2. Has trouble maintaining attention to tasks or activities. Diagnostic and Statistical Manual of Mental Health Disorders,
3. Has trouble actively listening when directly spoken to.
4th edition, Text Revision (DSM-IV-TR) (Table 391). The
4. Has difculty following instructions and fails to nish impor-
tant daily tasks (i.e., homework, chores, responsibilities at DSM-IV-TR denes three subtypes of ADHD: (1) predomi-
work). nately inattentive, (2) predominantly hyperactive/impulsive,
5. Demonstrates difculty in organizing tasks/activities. and (3) combined, in which both inattentive and hyperactive
6. Tends to avoid or put off activities that require concentration. symptoms are evident.11
7. Tends to misplace items needed to complete tasks or
Other diagnostic tests, such as brain imaging, elec-
activities.
8. Is easily distracted from current tasks or activities. troencephalograms, and continuous performance exami-
9. Forgetful. nations, should be regarded as investigational and not
B. Hyperactivity/impulsivity. Must have at least six or more of used clinically for diagnosis. While some brain studies have
the following symptoms of hyperactivity/impulsivity for at demonstrated differences in brain morphology between
least 6 months:
ADHD patients and control individuals, these differences
Hyperactivity
1. Fidgets and is restless in a sitting position. are not diagnostic.4
2. Cannot sit still for extended periods. Although ADHD is considered a childhood disorder, signs
3. Runs around when it is not appropriate. and symptoms persist into adolescence and adulthood in
4. Cannot play quietly. approximately 40% to 80% and 60% of cases, repectively.1,9
5. Often on the move.
Adult ADHD is difcult to assess, and diagnosis is always
6 Talks excessively.
Impulsivity suspect in patients failing to display clear symptoms prior to
7. Answers questions prematurely. 7 years of age.4 Adults with ADHD have higher rates of
8. Difculty waiting ones turn. psychopathology, substance abuse, social dysfunction, and
9. Interruptive or intrudes on others. occupational underachievement.
II. Above symptoms were present before 7 years of age.
III. Above symptoms are present in two or more settings.
IV. Impairment is clearly evident in social, school, or work
functioning.
V. Symptoms cannot be attributed to another mental disorder
Patient Encounter, Part 2: Medical
(e.g., anxiety, depression, autism, or a personality disorder). History, Physical Examination, and
ADHD Evaluation
Based on the above criteria, ADHD can be divided into three
types:
1. ADHD combined type: Both 1A and 1B. ADs baseline physical examination was unremarkable.
2. ADHD inattentive type: 1A criteria are met. Family history is positive for cardiovascular disease, and
3. ADHD hyperactive-impulsive type: 1B criteria are met. there is no documented history of ADHD in the family.
Patient weight: 20 kg (44 lbs)
Reprinted, with permission, from the Diagnostic and Statistical Manual
of Mental Disorders, 4th edition, Text Revision, (Copyright 2000). Allergies
American Psychiatric Association.11 None known
Patient height: 45 in (144 cm)
BP: 96/55 mm Hg
Pulse: 80 beats/minute
ADHD is rarely encountered without comorbid conditions ADs mother does not qualify for medical assistance, and
and often is underdiagnosed. Between 40% and 75% of she can hardly afford the monthly expenses.
patients with ADHD will have one or more comorbidities
(e.g., learning disabilities, oppositional deant conduct, anx- What stimulant and/or non-stimulant regimen(s) is(are)
available that might control ADs symptoms?
iety, or depressive disorders).10 It is important to identify
Which medications will facilitate adherence, minimize
other coexisting conditions in patients with ADHD to assist potential side effects, and offer an acceptable cost for
in initial and ongoing selection of treatment. ADs mother?
When a patient presents with inattention, hyperactivity, What other information do you need before starting
academic underachievement, and/or behavior problems, he or certain pharmacotherapy options?
she should be evaluated for ADHD. Initial evaluation of the What are important counseling points to discuss with
patient primarily should be for the purpose of information ADs mother?
gathering. Evidence of the patients behavior should be
TREATMENT of a reward/consequence system.13 Success of behavioral mod-

ications depends on the cooperation and involvement of the
Desired Outcomes patients parents and teachers.
The primary therapeutic objectives in ADHD are to
improve behavior and increase attention; secondary goals of Pharmacologic Therapy
treatment are to
The proposed mechanism of ADHD pharmacotherapy is to
modulate neurotransmitters in order to improve academic and
Improve relationships with family, teachers, and peers
social functioning. Pharmacologic therapy can be divided into
Decrease disruptive behavior in academic and social settings
two categories: stimulants and non-stimulants. Stimulant med-
Improve academic performance
ications include methylphenidate, dexmethylphenidate, amphet-
Increase independence in activities
amine salts, and dextroamphetamine, whereas non-stimulant
Minimize undesirable adverse effects of therapy
medications include atomoxetine, tricyclic antidepressants (e.g.,
imipramine), clonidine, guanfacine, and bupropion.
Nonpharmacologic (Behavioral) Therapy
Behavioral therapy can be used to treat patients with ADHD; Stimulants
however, it is generally not recommended as rst-line Psychostimulants (e.g., methylphenidate and dextroam-
monotherapy.8 Several studies have demonstrated that treat- phetamine with or without amphetamine) are the most effective
ment with medication alone is superior to behavioral interven- agents in treating ADHD. Once the diagnosis of ADHD has been
tion alone in improving attention.12 However, behavioral therapy made, a stimulant medication should be used rst line in treat-
in combination with stimulant therapy was better at improving ing ADHD (Fig. 391). Stimulants are safe and effective, with
oppositional and aggressive behaviors.12 Behavioral modica- a response rate of 70% to 90% in patients with ADHD.3,13,14
tion involves training parents, teachers, and caregivers to Generally, a trial of at least 3 months on a stimulant is
change the physical and social environment and establishment appropriate, and this includes dose titration to response
FIGURE 391. ADHD diagnosis and treatment algorithm.8,13,16

while balancing side effects.8,13 If treatment with the rst managed by changing dosing routine (i.e., giving with food,
stimulant formulation fails, it is recommended to switch to a dif- dividing daily dose, or giving the dose earlier in the day).
ferent stimulant formulation.13 For example, if the patient was Serious side effects such as hallucinations and abnormal
started on methylphenidate but could not tolerate the side movements require discontinuation of medication.13,14
effects, switching to dextroamphetamine with or without Growth suppression or delay is a major concern for parents
amphetamine is rational. The majority of patients who fail one of children taking stimulants. However, the evidence of this
stimulant will respond to an alternative stimulant.13 If the side effect is not clear. At present, growth delay appears to be
patient fails two appropriate trials of different stimulant medica- transient and to resolve by midadolescence, but more data are
tions, a third stimulant formulation or second-line non-stimulant needed to rmly resolve this issue.10 Another concern is the
such as bupropion, imipramine, or atomoxetine can be consid- risk of substance abuse with stimulant use. A diagnosis of
ered. The diagnosis of ADHD should be revalidated as well. ADHD alone increases the risk of substance abuse in adoles-
Stimulants theoretically exert their effect by blocking the cents and adults. However, stimulant use has not been shown
reuptake of dopamine and norepinephrine, thus improving to further increase this risk but actually may decrease this risk,
academic performance and decreasing motor activity in provided ADHD is treated adequately.15
ADHD patients. Stimulants have been shown to decrease dg- The choice of ADHD medication should be made based on
eting and nger tapping, increase on-task classroom behavior the patients condition, the prescribers familiarity with the
and positive interactions at home and in social environments, medications, the ease of administration, and cost. Stimulants
and ameliorate conduct and anxiety disorders.14 should be used rst line in most ADHD patients, although
Stimulants should be initiated at recommended starting doses there is no clear advantage of using one stimulant over
and titrated up with a consistent dosing schedule to the appro- another in managing symptoms of ADHD.16
priate response while minimizing side effects (Table 392).
Generally, stimulants should not be used in patients who have Non-stimulants
glaucoma, severe hypertension or cardiovascular disease,
hyperthyroidism, severe anxiety, or previous illicit or stimulant Atomoxetine
drug abuse. Further, stimulants can be used, albeit cautiously, Atomoxetine is the most recent addition to the ADHD arma-
in patients with seizure disorders, Tourettes syndrome, and mentarium in both children and adults. In clinical studies,
motor tics.14 atomoxetine has demonstrated superior efcacy over placebo
Initial response to short-acting stimulant formulations and equivalent efcacy when compared with a suboptimal
(e.g., methylphenidate and dextroamphetamine) is seen immediate-release methylphenidate dose.1720 However, it is
within 30 minutes and can last for 4 to 6 hours.13,14 This short not clear whether atomoxetine is superior to typical
duration of effect frequently requires that short-acting stimu- methylphenidate doses or other stimulant formulations.
lant formulations be dosed at least twice daily, thus increasing Atomoxetine may be used as a second- or third-line medica-
the chance of missed doses and non-compliance. Further, tion for ADHD.
patients using any stimulant formulation but especially short- Atomoxetine selectively inhibits the reuptake of adrenergic
acting formulations can experience a rebound effect of neurotransmitters, principally norepinepherine.1720 Atomoxetine
ADHD symptoms as the stimulant wears off.14 is metabolized through the cytochrome P-450 CYP2D6 pathway.
To minimize rebound problems associated with short- Approximately 5% to 10% of the population are CYP2D6 poor
acting formulations and still maintain early stimulant release, metabolizers, and atomoxetines half-life is increased signicantly
once-daily products (Adderall XR, Concerta, Metadate in this population.21 The recommended dosing for atomoxetine
CD, and Ritalin LA) have been developed. Stimulant drug depends on the weight of the patient and is given daily in either
formulations can be divided into short-, intermediate-, and a single or two divided doses21 (Table 392). In poor metaboliz-
extended-acting preparations (Table 392). Most intermediate- ers, atomoxetine should be dosed once daily at 25% to 50% of the
acting agents release the medication in a slow, continuous dose typically used in normal metabolizers.21 The maximum
fashion without any early release (except Dexedrine Spansules). therapeutic effect of atomoxetine may take up to 4 weeks to be
All extended-acting formulations have early release of med- seen, which is signicantly longer than what is required with
ication and deliver a delayed release of stimulant in either a stimulants. Common side effects of atomoxetine are similar to
pulsed or continuous manner. Most of the extended-acting those of stimulants: dyspepsia, nausea, vomiting, somnolence,
stimulants are capsules containing coated beads that can be and decreased appetite. Some studies have reported an increase
opened and sprinkled on semisolid food. The exception, in blood pressure and heart rate.1820 There is evidence that
Concerta tablets, uses an oral osmotic controlled-release atomoxetine can slow growth rate and cause weight loss; thus,
delivery system (the empty tablet shell can be detected in height and weight should be monitored routinely in pediatric
the stool). patients1820 (Table 393). Further, atomoxetine labeling includes
Adverse effects of stimulants can be generalized to the strong warnings about severe hepatotoxicity and increased asso-
whole class (Table 393). Most of these side effects can be ciation with suicidal thinking.
TABLE 392. Selected Medications in Treating ADHDa
Typical Dosing
Drug, Generic (Brand) Initial Dose Titration Schedule Range (Maximum Dose)
Stimulants
Short-acting
Methylphenidateb 5 mg two times daily 510 mg/day in weekly intervals 520 mg two to three times
(Methylin, Ritalin) daily (60 mg/day)
Dexmethylphenidateb (Focalin) 2.5 mg two times daily 2.55 mg/day in weekly intervals 510 mg twice daily (20 mg/day)
Dextroamphetamineb 2.55 mg every morning 2.55 mg/day in weekly intervals 520 mg twice daily (40 mg/day)
(Dexedrine)
Intermediate-acting
Methylphenidateb (Ritalin SR, 10 mg once daily 10 mg/day in weekly intervals 2040 mg daily in the
Metadate ER, Methylin ER) morning (60 mg/day)
Dextroamphetamine/ 2.55 mg once to twice daily 2.55 mg in weekly intervals 1030 mg every morning or
amphetamineb 520 mg twice daily
(Adderall) (40 mg/day)
Dextroamphetamineb 5 mg every morning 5 mg/day in weekly intervals 530 mg daily or 515 mg
(Dexedrine Spansule) twice daily (40 mg/day)
Extended-acting
Methylphenidateb
(Concerta) 18 mg every morning 918 mg/day in weekly intervals 1854 mg every morning (54 mg/day)
(Metadate CD) 20 mg every morning 1020 mg/day in weekly 2040 mg daily in the morning
intervals (60 mg/day)
(Ritalin LA) 20 mg every morning 10 mg/day in 2040 mg daily in the morning
weekly intervals (60 mg/day)
Dextroamphetamine/ 510 mg every morning 510 mg/day in weekly 1030 mg every morning or
amphetamineb (children) intervals 515 mg twice daily
(Adderall XR) 20 mg once daily (adults) (30 mg/day, children)
(60 mg/day, adult)
Dexmethylphenidateb 5 mg every morning (children) 5 mg/day in weekly 1020 mg daily in the morning
(Focalin XR) 10 mg every morning (adults) intervals (20 mg/day)
Non-stimulants
Atomoxetineb (Strattera) Less than or equal to 70 kg: to target dose of 1.2 mg/kg 4060 mg/day (1.4 mg/kg or
0.5 mg/kg per day divided per day after 3 days 100 mg/day, whichever is less)
once to twice daily
Greater than 70 kg: 40 mg 40 mg/day after 3 days 4080 mg/day divided once to twice
once daily (may to total of 100 mg/day daily (100 mg/day)
after 23 weeks)
Imipramine (Tofranil) 1.5 mg/kg per day in one or 1 mg/kg per day every 3 1.53 mg/kg per day in one or
two divided doses to 4 days two divided doses (5 mg/kg per
day, child)
100300 mg/day in one or two
divided doses (300 mg/day, adult)
Clonidine (Catapres) 0.05 mg once daily 0.05 mg/day every 3 to 7 days 0.1 mg once to four times daily
(0.4 mg/day)
Guanfacine (Tenex) 0.5 mg at bedtime 0.5 mg every 3 to 14 days 1.53 mg/day divided into two or
three times daily (4 mg/day)
Bupropion (Wellbutrin, 3 mg/kg per day for 7 days 3 mg/kg per day in weekly 6 mg/kg per day or 400 mg/day
Wellbutrin SR, (children); 150 mg once intervals (children); whichever is smaller (children);
Wellbutrin XL) daily of SR or XL (adults) 150300 mg/day in weekly 150450 mg/day (400 mg/day
intervals (adults) SR; 450 mg/day XL - adults)
a
Pediatric dosing except where adult dosing specied.
b
FDA approved for treatment of ADHD.
Atomoxetine is similar to extended-acting stimulants in advocated only if the patient has failed or is intolerant to the
that it can be given once daily in many patients. Atomoxetine standard stimulant therapy (Fig. 391).
appears to lack any abuse potential and is not a controlled
substance.22 One big disadvantage of atomoxetine is cost com- Bupropion
pared with other ADHD medications (Table 394). Bupropion is a monocyclic antidepressant that inhibits the
Due to the high cost and lack of long-term efcacy and reuptake of norepinephrine and dopamine. Bupropion is
comparison studies with stimulants, atomoxetine should be effective for relieving symptoms of ADHD in children but is
TABLE 393. ADHD Medication Side-Effect Proles, Management, and Monitoring
Drug Side Effects Management Monitoring

Stimulants
Methylphenidate, GI upset, nausea, Administer after meals Height, weight, blood pressure, pulse
dextroamphetamine, decreased appetite, Encourage high-calorie meals Eating and sleeping patterns
mixed-salts potential growth Divide dose Evaluate every 2 to 4 weeks until
amphetamine delay Give snacks in the evening stable dose is achieved; then
Change to shorter-acting stimulant evaluate every 3 months
Use drug holiday or different medication
if severe growth delay
Sleep disturbance Give dose earlier in the day
Give clonidine or guanfacine at bedtime
Discontinue all doses given afternoon
Change to a shorter-acting stimulant
Rebound symptoms Change to longer-acting stimulant
Overlap stimulant dosing
Moodiness Dose or change to longer-acting
stimulant
Verify diagnosis/comorbidity
Irritability Evaluate time of occurrence
Early onset: dose or change to longer-
acting stimulant
Late onset: Switch to longer-acting
stimulant
Evaluate for comorbidity
Blood pressure Dose or change to longer-acting
and pulse stimulant
Tics Discountinue or change to a different
stimulant
Give clonidine or guanfacine
Non-stimulants
Atomoxetine Blood pressure and Dose or change to another medication Same as above but with baseline and
pulse, nausea, routine liver function tests for
vomiting, fatigue, hepatotoxicity
and insomnia
Hepatotoxicity, suicidal Discountinue or change to a another
thoughts medication
Tricyclic antidepressants Sedation Administer later in the day Blood pressure, pulse, sleeping pattern
(imipramine)
Cardiac conduction Dose or change medication Evaluate every 3 days until stable
delay, dizziness, dose is achieved; then evaluate
pulse every 3 months
Anticholinergic effects Dose or change medication
(constipation, dry
mouth, difculty
urinating, blurry
vision)
Clonidine and guanfacine Sedation, arrthymias, Sedation: administer later in the day Same as above but with
constipation, Dose or change medication electrocardiogram (ECG)
dizziness
( blood pressure)
Bupropion GI upset, restlessness, Dose or change medication Height, weight, blood pressure, pulse
sleep disturbances, Tics, rash, and seizures: discontinue every month
rash, tics, risk of medication Eating and sleeping patterns
seizures
TABLE 394. 30-Day Costa of Selected ADHD Medication Regimens
Generic Regimen (Brand) Costa

Short-Acting Stimulants
Methylphenidate
Generic 5-, 10-, or 20-mg tab twice daily $
Methylin 5 mg/5 mL soln twice daily $$
Dexmethylphenidate
Focalin 2.5-mg tab twice daily $
5- or 10-mg tab twice daily $$
Dextroamphetamine
Generic 5- or 10-mg tab twice daily $
Intermediate-Acting Stimulants
Methylphenidate
Methylin ER 10- or 20-mg ER tab daily $
Dextroamphetaminec
Dexedrine Spansule 5-, 10-, or 15-mg cap daily $$
Dextroamphetamine/amphetamine
Generic 5-, 7.5-, 10-, 12.5-, 15-, 20-, or $
30-mg tab daily
Extended-Acting Stimulants
Methylphenidate
Concertac 18-, 27-, 36-, or 54-mg tab daily $$$
Metadate CDb 10-, 20-, or 30-mg cap daily $$$
Ritalin LAb 10-, 20-, 30-, or 40-mg cap daily $$$
Dextroamphetamine/amphetamine
Adderall XRb 5-, 10-, 15-, 20-, 25-, or 30-mg cap daily $$$
Dexmethylphenidate
Focalin XRb 5-, 10-, or 20-mg cap daily $$$
Non-stimulants
Atomoxetine
Strattera 10-, 18-, 25-, 40-, 60-, 80-, or $$$$
100-mg cap daily
Imipramine
Generic 10-, 25-, or 50-mg tab twice daily $
Clonidine
Generic 0.1-, 0.2-, or 0.3-mg tab twice daily $
Guanfacine
Generic 1-mg tab twice daily $
2-mg tab twice daily $$
Bupropion
Generic 75- or 100-mg tab twice daily $$
Wellbutrin SR 100- or 150-mg SR tab twice daily $$$
200-mg SR tab twice daily $$$$
Wellbutrin XL 150- or 300-mg XL tab daily $$$$
a
Cost based on brand regimen specied without a dispensing fee or discount for a 1-month supply. Costs
are current as of November 2006.
b
Bimodal release (early then late; mimics twice daily dosing of shorter-acting stimulant counterpart).
c
Ascending release (early then gradual/continuous).
$, less than $40; $$, $40 to $79; $$$, $80 to $120; $$$$, greater than $120.
tab, tablet; cap, capsule; chew tab, chewable tablet; soln, solution; SR, sustain release; ER, extended
release; XL, extended release; LA, long-acting; CD, extended release (biphasic immediate release with
extended release).
not as effective as stimulants.23,24 Similar results have been of ADHD can be attributed to the direct cost of pharma-
shown in adults.23 Specic dosing recommendations are out- cotherapy, ofce visits, diagnostic measurements, therapy
lined in Table 392. Bupropion is well tolerated with minimal monitoring, and indirect costs (e.g., lost work time and
side effects (e.g., insomnia, headache, and nausea). Side effects productivity). It is estimated that children with ADHD are up
typically disappear with continuation of therapy and are min- to nine times more likely than other children to have pre-
imized with slow titration of dose. Bupropion can worsen tics scriptions lled and incur ofce visits.
and movement disorders. Bupropion is a rational choice in an When selecting a treatment for an ADHD patient, the
ADHD patient with comorbid depression.23 However, seizures cost burden to the patients family should be considered.
have been associated with bupropion doses greater than Immediate-release stimulants may be more cost-effective in
6 mg/kg per day.25 Seizures related to high doses can be min- many patients compared with longer-acting stimulant formu-
imized by reducing the dose or switching to a longer-acting lations (Table 394), but in certain circumstances, longer-acting
formulation. Owing to the propensity of seizures with bupro- stimulant formulations may provide a cost benet owing to
pion, its use is contraindicated in patients with seizure and increased adherence to the medication and prolonged control of
eating disorders. symptoms of ADHD. Some non-stimulant ADHD medications
(e.g., TCAs, 2-adrenergic agonists, and bupropion) appear to
Tricyclic Antidepressants be less costly than many stimulant formulations; however, these
The tricyclic antidepressants (TCAs), such as imipramine, can agents have not been proven to have superior efcacy over stim-
alleviate symptoms of ADHD. Like bupropion, TCAs likely ulants in treating ADHD. Decisions on selection of specic
will improve symptoms associated with comorbid anxiety and ADHD medications should not be based solely on cost, but ef-
depression. The mechanism of action of TCAs is in blocking cacy and safety, along with adherence to the prescribed regimen,
norepinephrine transporters, thus increasing norepinephrine should be considered foremost.
concentrations in the synapse; the increase in norepinephrine
is believed to alleviate the symptoms of ADHD. TCAs have
been demonstrated to be an effective non-stimulant option
for ADHD but less effective than stimulants. However, their OUTCOME EVALUATION
use in ADHD has declined owing to case reports of sudden
death and anticholinergic side effects6,13 (Table 393). Further, It is important to carefully document core ADHD symptoms at
TCAs may lower seizure threshold and increase the risk of car- baseline to provide a reference point from which to evaluate
diotoxicity, (e.g., arrythmias). Patients starting on TCAs effectiveness of treatment. Improvement in individualized
should have a baseline and routine electrocardiograms. patient outcomes are desired, such as (1) family and social
relationships, (2) disruptive behavior, (3) completing required
Clonidine and Guanfacine tasks, (4) self-motivation, (5) appearance, and (6) self-esteem. It
Clonidine and guanfacine are central 2-adrenergic agonists is very important to elicit evaluations of the patients behavior
that inhibit the release of norepinephrine presynaptically. from family, school, and social environments in order to assess
Both these agents are less effective than stimulants in treating the preceding. Using standardized rating scales (e.g., Conners
symptoms of ADHD but typically are used as adjuncts to Rating ScalesRevised, Brown Attention-Decit Disorder Scale,
stimulants to control disruptive or aggressive behavior and and IOWA Conners Scale) in both children and adults with
alleviate insomnia.26 Guanfacine will last 3 to 4 hours longer ADHD helps to minimize variability in evaluation.29 After initi-
than clonidine and requires less frequent dosing. Common ation of therapy, evaluations should be done every 2 to 4 weeks
side effects with clonidine and guanfacine are low blood pres- to determine efcacy of treatment, height, weight, pulse, and
sure and sedation. Sedation is transient and should subside blood pressure. Physical examination or liver function tests may
after 2 to 3 weeks of therapy.26 Rarely, severe side effects such be used to monitor for adverse effects.
as bradycardia, rebound hypertension, irregular heart beats, Typically, therapeutic benets will be seen within days of
and sudden death have been reported. initiating stimulants and within a month or two with atom-
oxetine and bupropion. Once a maintenance dosing has been
achieved, schedule follow-up visits every 3 months. At these
Pharmacoeconomic and Treatment Adherence visits, assess height and weight, and screen for possible
Considerations adverse drug effects. If a patient has failed to respond to
Proper ADHD treatment is a substantial nancial burden.27,28 multiple agents, re-evaluate for other possible causes of
Annual health care costs of patients with ADHD are more behavior dysfunction. Counsel patients and their families
than double those of patients without ADHD ($1343 versus that treatment is generally long term. Typically, appropri-
$503, respectively).27 Further, the total cost of ADHD in the ately treated patients learn to better control their ADHD
United States in 2000 was $31.6 billion.28 The nancial burden symptoms as adults.
ABBREVIATIONS
ADHD: attention-decit hyperactivity disorder
DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders,
4th edition, Text Revision
1. Assess the patients symptoms and parent/teacher evalua-
tions to determine whether they meet the DSM-IV-TR Reference lists and self-assessment questions and answers are
diagnostic criteria for ADHD. Evaluate whether the available at www.ChisholmPharmacotherapy.com.
symptoms can be explained by another disorder.
2. Interview the patient and/or caregivers to obtain a com- Log into the website: www.pharmacotherapyprinciples.com
plete medical history, which should include family for information on obtaining continuing education credit for
medical history, current and past prescription and non- this chapter.
prescription medications, and dietary intake. Determine
whether the patient is taking medication/supplements
that could interfere with the therapy. KEY REFERENCES AND READINGS
3. Educate the patients parents and/or caregivers that
behavioral therapy is not as effective as stimulant therapy. American Academy of Pediatrics: Subcommittee on Attention-
Educate parents regarding the issues of growth delay and Decit/Hyperactivity Disorder and Committee on Quality
substance abuse risks with stimulants. Improvement. Clinical practice guideline: Treatment of the
4. Perform a baseline physical examination before starting school-aged child with attention-decit/hyperactivity disorder.
stimulant therapy. Include blood pressure, pulse, and Pediatrics 2001;108:10331044.
height and weight measurements. In patients taking stim- Herrerias CT, Perrin JM, Stein MT. The child with ADHD: Using the
ulants, perform a general physical examination yearly, AAP clinical practice guideline. Am Fam Physician 2001;63(9):
and monitor blood pressure quarterly in adults. 18031810.
5. Start patients on a low initial dose of a stimulant and Rappley MD. Attention decit-hyperactivity disorder. N Engl J Med
titrate up to the desired response in order to minimize 2005;352:165173.
side effects and costs. Voeller KKS. Attention-decit hyperactivity disorder (ADHD). J Child
Neurol 2004;19:798814.
6. If the patient is not responding to therapy after an ade- Wolraich ML, Wibbelsman CJ, Brown TE, et al. Attention-
quate trial, assess compliance with the prescribed decit/hyperactivity disorder among adolescents: A review of
regimen. If the patient is not compliant, counsel the the diagnosis, treatment, and clinical implications. Pediatrics
patient and caregivers and explore reasons for 2005;115(6):17341746.
non-compliance. In some cases, switching to another
stimulant formulation may improve compliance.
7. Important counseling points to convey to the patient
and/or caregiver:
What is ADHD?
What are the complications of untreated ADHD?
When to take medications and what to expect with
therapy.
What side effects to expect and what to do if these
occur.
Controversy over substance abuse and growth delay
with stimulant therapy.
What medications, prescription and non-prescription,
to avoid.
Section 7. Endocrinologic Disorders
40 DIABETES MELLITUS
Christopher L. Cook, John T. Johnson, and William E. Wade
LEARNING OBJECTIVES
1. Discuss the incidence and economic impact of diabetes.

2. List screening and diagnostic criteria for diabetes.
3. Distinguish clinical differences in type 1, type 2, and gestational diabetes mellitus.
4. Discuss therapeutic goals for blood glucose, blood pressure, and lipids for a patient with
diabetes.
5. Recommend nonpharmacologic therapies, including meal planning and physical activity,
for patients with diabetes.
6. Compare oral agents used in treating diabetes by their mechanisms of action, time of
action, side effects, contraindications, and effectiveness.
7. Select appropriate insulin therapy based on onset, peak, and duration of action.
8. Develop a comprehensive therapeutic patient monitoring plan for a patient with diabetes
based on patient-specic factors.
KEY CONCEPTS Several classes of oral agents are available to treat patients with
type 2 DM who are unable to achieve glycemic control
Diabetes mellitus (DM) describes a group of chronic meta- through diet and exercise.
bolic disorders that are characterized by hyperglycemia and Insulin is the essential treatment for patients with type 1
are associated with long-term microvascular, macrovascular, DM and can overcome insulin resistance in patients with
and neuropathic complications. type 2 DM.
Glycemic control remains the primary objective in managing Diabetes mellitus (DM) describes a group of chronic
diabetes and its complications.
metabolic disorders characterized by hyperglycemia that may
Type 2 DM is the most prevalent form of diabetes and result in long-term microvascular, macrovascular, and neuro-
accounts for approximately 90% to 95% of all diagnosed
pathic complications. These complications contribute to dia-
cases. Type 2 DM is usually slow and progressive in its devel-
betes being the leading cause of (1) new cases of blindness
opment and often is preceded by pre-diabetes. Rising blood
among adults, (2) end-stage renal disease, and (3) non-traumatic
glucose levels result from increasing insulin resistance and
lower limb amputations. In addition, the increased cardiovas-
impaired insulin secretion leading to a situation of relative
cular risk associated with DM contributes to it being the sixth
insulin deciency.
leading cause of death in the United States. The nancial
Although type 1 DM may appear at any age, it is encoun- impact of DM in 2002 was approximately $132 billion, or 1 of
tered most commonly in individuals younger than 30 years
every 10 dollars spent on health care in the United States. This
of age. Type 1 DM is characterized by an absolute deciency
averages to an annual health care cost of $13,243 for patients
in insulin resulting from pancreatic -cell destruction.
with diabetes versus $2560 for those without diabetes.1
Patients and clinicians can evaluate blood glucose control While prevention and treatment of DM remain a challenge,
through a combination of self-monitoring of blood glucose
several landmark studies have shown that complications asso-
data and hemoglobin HbA1c testing.
ciated with DM can be delayed or prevented through proper
643
644 SECTION 7 / ENDOCRINOLOGIC DISORDERS
blood glucose management.2,3 Thus, glycemic control remains Risk factors for type 2 diabetes include:
the primary objective in diabetes management.
First-degree family history of DM (i.e., parents or siblings)
Overweight or obese
EPIDEMIOLOGY AND ETIOLOGY Habitual physical inactivity
Race or ethnicity (Native American, Latino/Hispanic-American,
DM is characterized by a complete lack of insulin, a relative Asian-American, African-American, and Pacic Islanders)
lack of insulin, or insulin resistance. These defects result in Pre-diabetes (i.e., previously identied with impaired glu-
an inability to properly use glucose for energy. DM affects an cose tolerance or impaired fasting glucose)
estimated 20.8 million persons in the United States, or 7% Hypertension (Greater than or equal to 140/90 mm Hg)
of the population. While an estimated 14.6 million persons High-density lipoprotein (HDL) less than 35 mg/dL (0.91
have been diagnosed, another 6.2 million people who have mmol/L) and/or a triglyceride level greater than 250 mg/dL
DM are unaware they have the disease. Worldwide, the (2.83 mmol/L)
number of people with DM is expected to rise to 35% by History of gestational diabetes or delivery of a baby weigh-
the year 2025.1 ing greater than 9 pounds (4.09 kg)
The increasing prevalence of DM is due in part to three History of vascular disease
inuences: lifestyle, ethnicity, and age. Sedentary lifestyle cou- History of polycystic ovary disease
pled with greater consumption of high-fat foods and larger Other conditions associated with insulin resistance (e.g.,
portion sizes has resulted in increasing rates of persons being acanthosis nigricans)5
overweight or obese. Current estimates indicate that 65% of
the United States population is overweight and 30% is obese. Type 1 DM, previously referred to as insulin-dependent or
Overweight is dened as body mass index (BMI) of greater juvenile-onset DM, constitutes 5% to 10% of all diagnosed cases
than 25 kg/m2, whereas a BMI of greater than 30 kg/m2 consti- of DM. Type 1 DM usually is diagnosed in children and adults
tutes obesity. The Centers for Disease Control and Prevention younger than 30 years of age, although the disease can present at
(CDC) estimates that 25% to 33% of Americans do not engage any age. This form of the disease is characterized by an absolute
in an adequate amount of daily activity.4 Compounding this deciency in insulin resulting from pancreatic b-cell destruction.
lifestyle trend, certain ethnic groups are at a disproportionately Latent autoimmune diabetes in adults (LADA), slow-onset type
high risk of DM. Individuals of Native American and Alaskan 1 or type 1.5 DM, is a form of autoimmune type 1 diabetes that
native, African-American, and Hispanic/Latino-American occurs in individuals older than the usual age of onset. Patients
descent have a 1.7 to 2.2 times greater risk of developing DM often are mistakenly thought to have type 2 diabetes because
compared with non-Hispanic whites.1 In addition, African- the person is older and may respond initially to treatment with
American and Hispanic/Latino-American populations are oral hypoglycemic agents. However, these patients do not have
growing at a faster rate than the general United States popu- insulin resistance, but antibodies are present in the blood that
lation. The third contributing factor is increasing age. The are known to destroy pancreatic -cells.
prevalence of DM increases with age from approximately 2% It has been suggested that the easiest way to differentiate
of individuals 20 to 39 years of age to 20.9% of individuals between type 1 and type 2 DM is by measuring C-peptide lev-
older than 60 years of age.1 As the population ages, the inci- els. Type 1 diabetics have C-peptide levels below 1 ng/mL
dence of DM is expected to increase. (0.33 nmol/L), whereas those with type 2 disease will have val-
ues greater than 1 ng/mL (0.33 nmol/L).
Type 2 DM, previously referred to as adult-onset or non- Glucose intolerance diagnosed in women during pregnancy
insulin-dependent DM, is the most prevalent form of the disease is called gestational diabetes mellitus (GDM) and occurs in
and accounts for approximately 90% to 95% of all diagnosed approximately 7% of all pregnancies. Women who have GDM
cases.1 Type 2 DM is characterized by a relative insulin de- have a 20% to 50% chance of developing diabetes within 5 to
ciency and insulin resistance. 10 years. Risk factors for GDM include obesity, glycosuria,
Type 2 DM is usually slow and progressive in its develop- strong family history of DM, age greater than 35 years of age,
ment and often is preceded by pre-diabetes. The development pre-diabetes detected before pregnancy, previous delivery of
of pre-diabetes places the individual at high risk of eventually babies with birth weights greater than 9 pounds (4.09 kg), and
developing diabetes. It is currently estimated that 41 million ethnicity (African-American, Hispanic/Latino-American, or
persons in the United States have pre-diabetes. Pre-diabetes is Native American). Clinical detection of and therapy for GDM
dened as having either a fasting and/or a postprandial blood are important because blood sugar control produces signi-
glucose level higher than normal but not high enough to be cant reductions in perinatal morbidity and mortality.
classied as DM. Because progression from pre-diabetes to Rare forms of DM have been reported and account for 1% to
diabetes is not inevitable, interventions during pre-diabetes 5% of all diagnosed cases. Causes of these rare forms of DM
are gaining popularity. include specic genetic conditions, surgery, drugs, malnutrition,
CHAPTER 40 / DIABETES MELLITUS 645
TABLE 401. Medications That May Affect Glycemic Controla
Drug Effect on Glucose Mechanism/Comment

Angiotensin-converting enzyme inhibitors Slight reduction Improves insulin sensitivity
Alcohol Reduction Reduces hepatic glucose production
-Interferon Increase Unclear
Diazoxide Increase Decreases insulin secretion, decreases
peripheral glucose use
Diuretics Increase May increase insulin resistance
Glucocorticoids Increase Impairs insulin action
Nicotinic acid Increase Impairs insulin action, increases insulin
resistance
Oral contraceptives Increase Unclear
Pentamidine Decrease, then Toxic to b-cells; initial release of stored
increase insulin, then depletion
Phenytoin Increase Decreases insulin secretion
b-Blockers May increase Decreases insulin secretion
Salicylates Decrease Inhibition of I-kappa-B kinase-beta (IKK-beta)
(only high doses, e.g., 46 g/day)
Sympathomimetics Slight increase Increased glycogenolysis and gluconeogenesis
Clozapine and olanzapine Increase Unclear; weight gain
a
This list is not inclusive of all medications reported to cause glucose changes.
Reproduced, with permission, from DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiological Approach.
6th ed. New York: McGraw-Hill; 2005, Table 7210, p. 1346.
infections, and other illnesses. Table 40-1 contains a list of hormones, such as growth factor, cortisol, and epinephrine,
medications that may affect glycemic control. While the use of increase blood glucose levels. While blood glucose levels vary, the
these medications is not contraindicated in persons with DM, opposing actions of insulin and glucagon, along with the coun-
caution and awareness of the effects on blood glucose should terregulatory hormones, maintain these values between 70 and
be taken into account when managing patient care. 120 mg/dL (3.89 and 6.66 mmol/L).
Type 1 Diabetes
PATHOPHYSIOLOGY
The primary defect in type 1 DM is an absolute insulin de-
ciency resulting from pancreatic b-cell destruction. -Cell destruc-
Normal Carbohydrate Metabolism
tion is most commonly the result of an autoimmune process
The bodys main energy source is the metabolism of glucose. usually precipitated through genetic susceptibility and/or an
Cells metabolize glucose completely through glycolysis and environmental trigger. Certain genetic markers can be measured
the Kreb cycle, producing water and carbon dioxide as waste to determine if a person is at risk of diabetes. The presence of
products. Glucose not immediately needed for energy is human leukocyte antigens (HLAs), especially HLA-DR, is
stored in the liver and muscles as glycogen. Later, when energy strongly associated with the development of type 1 diabetes.
is needed, glycogenolysis converts stored glycogen back to Over 95% of people with type 1 DM have HLA-DR3 and HLA-
glucose. Excess glucose also can be converted to triglycerides DR4 present. In addition, persons with DM often develop islet-
and stored in fat cells. Triglycerides subsequently undergo cell antibodies, insulin autoantibodies, or glutamic acid decar-
lipolysis, yielding glycerol and free fatty acids. While usually boxylase autoantibodies. More than 90% of persons with type 1
reserved for other functions, proteins also can be converted to DM have at least one diabetes-related antibody present. As more
glucose through a process called gluconeogenesis. Normal -cells are destroyed, glucose metabolism becomes compro-
homeostasis is achieved through a balance of the metabolism of mised due to reduced insulin release following a glucose load.
glucose, free fatty acids, and amino acids to maintain a blood At the time of diagnosis, most patients have a 90% loss of -
glucose level sufcient to provide an uninterrupted supply of cell function. The remaining 10% of -cell function at diag-
glucose to the brain.6 nosis creates a honeymoon period during which blood glu-
Insulin and glucagon are produced in the pancreas by cells cose levels are easier to control and smaller amounts of insulin
known as islets of Langerhans. -Cells make up 70% to 90% of are required. Once this remaining -cell function is lost,
the islets and produce insulin, whereas -cells produce glucagon. patients become completely insulin-decient and require
The main function of insulin is to decrease blood glucose more exogenous insulin. Figure 401 describes the progres-
levels, whereas glucagon, along with other counterregulatory sion of type 1 DM.
Hyperinsulinemia, or high blood levels of insulin, is an early

Genetic predisposition
Immunologic abnormalities nding in the development of type 2 DM. More insulin is
Normal insulin secreted to maintain normal blood glucose levels until even-
-cell mass (% of max)
release
tually the pancreas can no longer produce sufcient insulin.
Progressive impairment
100 in insulin release The resulting hyperglycemia is enhanced by extremely high
Overt diabetes insulin resistance, pancreatic burnout in which -cells lose
functional capacity, or both. Patients with type 2 DM typically
Honeymoon
50 period have approximately 40% -cell function at diagnosis.
Decreasing -cell function also results in a reduced ability to
produce a rst-phase insulin response sufcient to signal the
0 liver to stop producing glucose during the fed state. As DM
0 progresses, large numbers of patients with type 2 disease even-
Birth Time (yr)
tually lose all -cell function and require exogenous insulin to
maintain blood glucose control.
FIGURE 401 Scheme of the natural history of the -cell defect
in type 1 diabetes mellitus. (Used, with permission, from DiPiro
JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Insulin Resistance
Pathophysiological Approach. 6th ed. New York: McGraw-Hill; Insulin resistance is the primary factor that differentiates type 2
2005, Fig. 724, p. 1339.) yr, year. DM from other forms of diabetes. Insulin resistance may be
present up to 10 years prior to the diagnosis of DM and can con-
tinue to progress throughout the course of the disease.
Type 2 Diabetes Resistance to insulin occurs most signicantly in skeletal muscle
and the liver. Insulin resistance in the liver poses a double
Type 2 DM is characterized by a slow, gradual onset of hyper-
threat because the liver becomes non-responsive to insulin for
glycemia that often is asymptomatic. The underlying metabolic
glucose uptake, and hepatic production of glucose during the
dysfunction contributing to this disease is thought to be a com-
fed state does not cease. Hyperglycemia results because
bination of both genetic and environmental factors. Rising
ingested glucose and continued hepatic glucose production
blood glucose levels result from increasing insulin resistance
combine to raise blood glucose levels.
and impaired insulin secretion leading to relative insulin de-
ciency. Prior to describing these two insulin defects, it is nec-
Metabolic Syndrome
essary to understand normal insulin action and its role in
Insulin resistance has been associated with a number of other
glucose control.
cardiovascular risks, including abdominal obesity, hyperten-
sion, dyslipidemia, hypercoagulation, and hyperinsulinemia. The
Normal Insulin Action
clustering of these risk factors has been termed metabolic syn-
During periods of fasting, most circulating glucose is produced
drome. It is estimated that 50% of the United States population
in the liver by glycogenolysis. This endogenous production of
older than 60 years of age have metabolic syndrome. The most
glucose serves to ensure the brain a constant glucose supply.
widely used criteria to dene metabolic syndrome were estab-
Insulin secretion during fasting periods is a low, steady basal
lished by the National Cholesterol Education Program Adult
rate of 0.5 to 1 units/hour.6 On eating, blood glucose levels rise,
Treatment Panel III Guidelines (summarized in Table 402).
and the insulin-secretion response occurs in two phases. An
initial burst, known as rst phase insulin response, lasts approx-
imately 10 minutes and serves to suppress hepatic glucose pro- TABLE 402. Five Components of Metabolic Syndrome20
duction. This bolus of insulin minimizes hyperglycemia during Risk Factor Dening Level
meals and during the postprandial period. The loss of this rst
1. Abdominal obesity
phase insulin response is an early event in the progression from
Men Waist circumference greater than
glucose intolerance to DM. The second phase of insulin response 102 centimeters (40 inches)
is characterized by a gradual increase in insulin secretion, which Women Waist circumference greater than
stimulates glucose uptake by peripheral insulin-dependent 88 centimeters (35 inches)
tissues. Approximately 80% to 85% of glucose metabolism 2. Triglycerides Greater than 150 mg/dL (1.70 mmol/L)
3. HDL cholesterol
during this time occurs in muscle. The slower release of insulin
Men Less than 40 mg/dL (1.04 mmol/L)
allows the body to respond to the new glucose entering from Women Less than 50 mg/dL (1.3 mmol/L)
digestion while maintaining blood glucose levels. 4. Blood pressure Greater than or equal to 130/85 mm Hg
5. Fasting glucose Greater than or equal to 100 mg/dL
Impaired Insulin Secretion (5.55 mmol/L)
A pancreas with normal -cell function is able to adjust Note: Individuals having at least three of the ve above meet the diagnostic
insulin production to maintain normal blood glucose levels. criteria for metabolic syndrome.
Patients having this convergence of factors have been found to

be at a much higher cardiovascular risk than would be Patient Encounter, Part 1
expected from the individual components of the syndrome.
Therefore, it is important to assume a more aggressive treat-
ment plan for each of the individual abnormal components.
MF is a large-framed 32-year-old Caucasian man who is 5 ft,
Since pre-diabetes and DM are one of the component risk fac-
10 in (178 cm) tall and weighs 295 lb (134 kg). He has not
tors in the diagnostic criteria, a patient with pre-diabetes or
been to the doctor in 5 years. He is diagnosed with irritable
DM having the convergence of factors may be treated more bowel syndrome today. He visits the local free clinic, and
aggressively than a patient having pre-diabetes or DM alone. the following is discovered when labs and physical assess-
ment are performed:
Fasting glucose: 189 mg/dL (10.49 mmol/L)

CLINICAL PRESENTATION AND DIAGNOSIS BUN: 13 mg/dL (4.64 mmol/L)
Creatinine: 1.2 mg/dL (106 mol/L)
Screening AST/SGOT: 26 IU/L (0.43 Kat/L)
Currently, the American Diabetes Association (ADA) recom- ALT/SGPT: 26 IU/L (0.43 Kat/L)
TSH: 1.264 microunits/mL (1.26 mU/L)
mends routine screening for type 2 DM every 3 years in all
Total cholesterol: 277 mg/dL (7.17 mmol/L)
adults starting at 45 years of age. Earlier and more frequent
LDL: 187 mg/dL (4.84 mmol/L)
screening should be reserved for patients who are at higher HDL: 29 mg/dL (0.75 mmol/L)
risk. The ADA does not recommend screening for type 1 dia- Triglycerides: 305 mg/dL (3.45 mmol/L)
betes owing to the low incidence and acute presentation of Hemoglobin A1c: 11%
symptoms.7 See Table 403 for complete screening guidelines. BP (blood pressure): 167/98 mm Hg
What information is suggestive of diabetes?

Gestational Diabetes What criteria must be met before a diagnosis of diabetes
Risk assessment for GDM should be performed early in preg- can be made?
nancy with a random glucose test. If the normal diagnostic What type of diabetes do you think MF has based on his
threshold for diabetes is exceeded during the rst test and clinical characteristics?
What challenges can you identify for optimal clinical out-
conrmed on a subsequent day, a diagnosis of GDM can be
comes through the initial assessments for MF?
made. Otherwise, all women should be screened with an oral
glucose tolerance test (OGTT) between weeks 24 and 28 of ges- creating a treatment plan for this patient?
tation unless they are in the low-risk category. The diagnostic
Typical Clinical Presentation of Diabetes Mellitus
Characteristic Type 1 DM Type 2 DM

Age of onset Childhood or adolescence Greater than 40 years of age
Speed of onset Abrupt Gradual
Family history Negative Positive
Body type Thin Obese or history of obesity
Metabolic syndrome No Often
Autoantibodies Present Rare
Symptoms Polyuria, polydipsia, Asymptomatic
polyphagia, rapid weight
loss
Ketones at diagnosis Present Uncommon
Acute complications Diabetic Rare
ketoacidosis (DKA)
Microvascular Rare Common
complications at diagnosis
Macrovascular complications Rare Common
at or before diagnosis
TABLE 403. American Diabetes Association Screening Recommendations for Diabetes Mellitus5
Asymptomatic Type 1
The American Diabetes Association does not recommend screening for type 1 diabetes due to the low incidence in the general population
and to the acute presentation of symptoms.
Asymptomatic Type 2
1. The American Diabetes Association recommends screening for type 2 diabetes every 3 years in all adults beginning at 45 years of age,
particularly in those with a body mass index greater than or equal to 25 kg/m2.
2. Testing should be considered for persons younger than 45 years of age or more frequently in individuals who are overweight
(body mass index greater than or equal to 25 kg/m2) and have additional risk factors:
Habitually inactive
First-degree relative with diabetes
Member of a high-risk ethnic population (e.g., African-American, Latino, Native American, Asian-American, Pacic Islander)
Delivered a baby weighing greater than 9 lb (4.09 kg) or previous diagnosis of gestational diabetes mellitus
Hypertensive (greater than or equal to 140/90 mm Hg)
High density lipoprotein (HDL) cholesterol level less than 35 mg/dL (0.91 mmol/L) and/or a triglyceride level greater than 250 mg/dL
(2.83 mmol/L)
Polycystic ovary syndrome
Previous impaired glucose tolerance or impaired fasting glucose
Other clinical conditions associated with insulin resistance (e.g., acanthosis nigricans)
History of vascular disease
Type 2 in Children and Adolescents
Criteria:
Overweight (body mass index greater than 85th percentile for age and sex, weight for height greater than 85th percentile, or weight
greater than 120% of ideal for height)
Plus any two of the following risk factors:
Family history of type 2 diabetes in rst- or second-degree relatives
Race/ethnicity (Native American, African-American, Latino/Hispanic-American, Asian-American, Pacic Islander)
Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, or poly-
cystic ovary disease)
Age of initiation: Age 10 or at onset of puberty, if puberty occurs at a younger age
Frequency of testing: Every 2 years
Test method: Fasting plasma glucose preferred
Clinical judgment should be used to test for diabetes in high-risk patients who do not meet these criteria.
Gestational Diabetes
1. Risk assessment performed at rst prenatal visit with random glucose screen.
2. All women should be screened with an oral glucose tolerance test between weeks 24 and 28 of gestation unless they are in the low-risk category.
criteria for OGTT are listed in Table 404. Women considered TABLE 404. Diagnosis of Gestational Diabetes with a 100 or
low risk include those of normal weight before pregnancy; 75 g Glucose Load8
younger than 25 years of age; without rst-degree relatives
Plasma Glucose
with diabetes; non-Hispanic, African-American, or Native
American ethnicity; and no prior history of glucose intoler- Time mg/dL mmol/L
ance or poor obstetric outcome.5 100 g Glucose Load
Any woman diagnosed with GDM should be retested at Fasting 95 5.3
6 weeks postpartum. If the fasting plasma glucose (FPG) level 1 hour 180 10.0
2 hours 155 8.6
is normal, then reassessment for DM should occur every 3 3 hours 140 7.8
years. Family planning for subsequent pregnancies should be 75 g Glucose Load
discussed, and monitoring for the development of symptoms Fasting 95 5.3
of DM should be undertaken. 1 hour 180 10.0
2 hours 155 8.6
Diagnostic Criteria Note: Two or more venous plasma concentrations must be met or
exceeded for a positive diagnosis of diabetes to be made. The test
Diagnosis of DM includes glycemic outcomes exceeding should be done in the morning after an 8- to 14-hour fast and after
at least 3 days of unrestricted diet and unlimited physical activity.
threshold values with one of three testing options (Table 405). The patient should remain seated and should not smoke during the
Conrmation of abnormal values must be made on a subsequent test.
TABLE 405. Criteria for the Diagnosis of Diabetes Mellitus5 production during the fasting state, whereas postprandial glu-
cose levels in the OGTT may reect glucose uptake in peripheral
1. Symptoms of diabetes plus a casual plasma glucose concentra- tissues, insulin sensitivity, or a decreased rst-phase insulin
tion greater than or equal to 200 mg/dL (11.1 mmol/L). Casual
response.
is dened as any time of day without regard to time since last
meal. The classic symptoms of diabetes include polyuria, poly-
dipsia, and unexplained weight loss.
or
2. Fasting plasma glucose greater than or equal to 126 mg/dL TREATMENT
(7.0 mmol/L). Fasting is dened as no caloric intake for at least
8 hours.
or Goals of Therapy
3. Two-hour postload glucose greater than or equal to 200 mg/dL
DM treatment goals include reducing long-term microvascular
(11.1 mmol/L) during an oral glucose tolerance test. The test
should be performed as described by the World Health and macrovascular complications, preventing acute compli-
Organization, using a glucose load containing the equivalent of cations from high blood glucose levels, minimizing hypo-
75 g anhydrous glucose dissolved in water. glycemic episodes, and maintaining the patients overall
Note: In the absence of unequivocal hyperglycemia, these criteria
quality of life. To achieve these goals, near-normal blood
should be conrmed by repeat testing on a different day. The oral glu- glucose levels are fundamental. Two landmark trials, the
cose tolerance test is not recommended for routine clinical use. Diabetes Control and Complications Trial2 and the United
Kingdom Prospective Diabetes Study,3 showed that lowering
blood glucose levels decreased the risk of developing chronic
day for diagnosis unless unequivocal symptoms of hyper- complications. A near-normal blood glucose level can be
glycemia exist, such as polydipsia, polyuria, and polyphagia. achieved with appropriate patient education. Proper care of
The ADA recommends FPG determination as the principal DM requires goal setting and assessment for glycemic control,
tool for diagnosis of DM in non-pregnant adults owing to self-monitoring of blood glucose (SMBG) level, monitoring of
ease of use, acceptability to patients, and lower cost.7 While blood pressure and lipid levels, regular monitoring for the
the OGTT is more sensitive and modestly more specic than development of complications, dietary and exercise lifestyle
FPG determination, it is difcult to reproduce the results and modication, and proper medication use. The complexity of
is rarely performed in practice today. proper DM self-care principles has a dramatic impact on a
The ADA categorizes patients demonstrating impaired patients lifestyle and requires a highly disciplined and dedi-
fasting glucose (IFG) or impaired glucose tolerance (IGT) as cated person to maintain long-term control.
having pre-diabetes.8 The categorization thresholds of glucose
status for FPG determination and the OGTT are listed in
Table 406. These two conditions may co-exist or may be Setting and Assessing Glycemic Targets
identied independently. FPG level represents hepatic glucose Patients and clinicians can evaluate blood glucose control
through the combination of the self-monitoring of blood glucose
data and the hemoglobin A1c (HbA1c) test. Self-monitoring of
blood glucose enables patients to obtain their current blood
TABLE 406. Categorization of Glucose Status8 glucose level at any time easily and relatively inexpensively.
mg/dL mmol/L
The HbA1c test provides a weighted-mean blood glucose level
from the previous 3 months.
Fasting Plasma Glucose
(FPG)
Normal Less than 100 Less than 5.6 Self-Monitoring of Blood Glucose
Impaired fasting 100125 5.66.9 Self-monitoring of blood glucose is the standard method for
glucose (IFG) routinely checking blood glucose levels. Each reading provides a
Diabetes mellitusa Greater than or 7.0
equal to 126 point-in-time evaluation of glucose control that can vary widely
2-Hour Postload depending on numerous factors, including food, exercise, stress,
Plasma Glucose and time of day. By examining multiple individual points of
(Oral glucose tolerance data, patterns of control can be established. Therapy can be eval-
test) uated from these patterns, and adjustments can be made to
Normal Less than 140 7.8
Impaired glucose 140199 improve overall blood glucose control. The ADA pre-meal
tolerance (IGT) 7.811.0 plasma glucose goals are 90 to 130 mg/dL (57.22 mmol/L), and
Diabetes mellitusa Greater than or 11.1 peak postprandial plasma glucose goals are less than 180 mg/dL
equal to 200 (10 mmol/L).5 The American Association of Clinical
a
Provisional diagnosis of diabetes (diagnosis must be conrmed; see Endocrinologists (AACE) supports tighter SMBG controls, with
Table 405). pre-meal goals of less than 110 mg/dL (6.11 mmol/L) and peak
post-meal goals of less than 140 mg/dL (7.77 mmol/L).9 For Blood Pressure, Lipids, and Monitoring for
patients with type 1 DM, the ADA recommends that SMBG Complications
be performed at least three times daily. The frequency of The ADA standards of medical care address many of the com-
testing in patients with type 2 DM is still controversial. The mon comorbid conditions, as well as complications that result
ADA recommends testing frequently enough to gain and from the progression of DM. Table 407 presents goals for
maintain blood glucose control. While the majority of practi- blood pressure measurements, lipids values, and monitoring
tioners recommend SMBG to their patients with type 1 DM, parameters for complications associated with diabetes.
the role of SMBG in improving glucose control in type 2 DM is
unproven.10 General Approach to Therapy
Typically, in SMBG, a drop of blood is placed on a test
strip that is then read by a glucometer. Recent technological Type 1 DM
advancements have decreased the blood sample size required Treatment of type 1 DM requires providing exogenous insulin to
to as small as 0.3 microliters, provided the capability of alter- replace the endogenous loss of insulin from the non-functional
nate site testing, and provided readings in as few as 5 seconds. pancreas. Ideal insulin therapy mimics normal insulin physiology.
Many SMBG devices can download or transfer information
to a computer program that can summarize and produce
graphs of the data. Identifying patterns in the patients blood Patient Encounter, Part 2: The Follow-up
glucose data can aid practitioners in modifying treatment Visit
for better glucose control. Specic therapy adjustment can
be made for patterns found at certain times of the day, on
MF comes back 1 week later for you to review the labora-
certain days, or with large day-to-day variances. While most tory results with him and to determine if medications are
testing occurs by lancing the ngertip to produce a blood necessary. When you check his FBG level today, the result
droplet, alternate-site testing has been approved for testing is 210 mg/dL (11.7 mmol/L). A diagnosis of DM is made,
the palm, arm, leg, and abdomen. Alternate-site testing was but you have no other blood glucose records. The following
developed as a means to decrease the pain encountered with information is gained from MF during the visit:
repeated ngersticks by using body locations that have a PMH
lower concentration of nerve endings. Occasional sinus infections over the last several years
In choosing a glucose meter for a patient, several addi- Reports last eye examination about 6 years ago; believes
tional factors may aid in the best selection for the patient. he could use new glasses
Larger display areas or units with audible instructions and No other problems reported
results may be better suited for older individuals and those FH
with visual impairment. Patients with arthritis or other con- Father: 64 years of age; history of alcohol abuse, hyper-
ditions that decrease dexterity may prefer larger meters with tension, and myocardial infarction
little or no handling of glucose strips. Younger patients or Mother: 62 years of age; history of type 2 DM, hyperten-
busy professionals, on the other hand, may prefer the smaller sion, and obesity
meters with features such as faster results, larger memories, Sister: 34 years of age; history of hypothyroid and obesity
reminder alarms, and downloading capabilities that facilitate SH
individuals checking their blood glucose levels. Drinks 3 to 4 times per week and smokes cigarettes 1 to
2 packs per day for 20 years
No steady employment
Hemoglobin A1c
Hemoglobin A1c (HbA1c) is the gold standard for evaluating Meal history
Usually has a donut and large coffee in the mornings, fast-
long-term glycemic control.11 Glucose interacts sponta-
food value meal for lunch, and a diner meal for supper
neously with hemoglobin in red blood cells to form glycosy-
(meat and two vegetables)
lated derivatives. The most prevalent derivative is HbA1c.
Greater amounts of glycosylation occur when blood glucose Physical activity
levels increase. Because hemoglobin has a life span of approx- No regular physical activity routine but does walk around
about 30 minutes a day
imately 120 days, levels of HbA1c provide a marker reecting
the average glucose levels over this timeframe. The ADA
What are your treatment goals for MF regarding blood
goal for persons with DM is less than 7%, whereas the glucose, blood pressure, and lipids?
AACE supports a goal of less than 6.5%. Testing HbA1c levels What nonpharmacologic and pharmacologic approaches
should occur at least twice a year for patients who are are available for MF?
meeting treatment goals and four times per year for patients Are there any specialist care providers you would refer
not meeting goals or those who have had recent changes in MF to?
therapy.5
TABLE 407. American Diabetes Association Recommended Goals of Therapy
Area Goals
Glycemia
HbA1c Less than 7%
Every 3 months until in goal; then every 6 months
Preprandial plasma glucose 90130 mg/dL (5.07.2 mmol/L)
Peak postprandial plasma glucosea Less than 180 mg/dL (less than 10 mmol/L)
Blood Pressure Less than 130/80 mm Hg
Evaluate at every visit
Lipids Evaluate at least yearly
Low-density lipoprotein (LDL) Less than 100 mg/dL (2.59 mmol/L)
or less than 70 mg/dL (1.81 mmol/L) if high risk
High-density lipoprotein (HDL) Greater than 40 mg/dL (1.04 mmol/L) for males;
greater than 50 mg/dL (1.3 mmol/L) for females
Triglycerides Less than 150 mg/dL (1.70 mmol/L)
Monitoring for Complications
Eyes Dilated eye exam yearly
Feet Feet should be examined at every visit
Urinary microalbumin Yearly
a
Peak postprandial glucose measurements should be made 1 to 2 hours after the beginning of the meal.
The basal-bolus approach attempts to reproduce basal insulin Gestational Diabetes

response through the use of intermediate- or long-acting An individualized meal plan consisting of three meals and
insulin, whereas short- or rapid-acting insulin replicates bolus three snacks per day is recommended commonly in GDM.
release of insulin physiologically seen around a meal in non- Preventing ketosis, promoting adequate growth of the fetus,
diabetics. A number of different regimens have been used maintaining satisfactory blood glucose levels, and preventing
through the years to more closely follow natural insulin pat- nausea and other undesired gastrointestinal side effects are
terns. As a general rule, basal insulin makes up approximately desired goals in these patients. Controlling blood sugar levels
50% of the total daily dose. The remaining half is provided is important to prevent harm to the baby. An abundance of
with bolus doses around three daily meals. Exact doses are glucose causes excessive insulin production by the fetus,
individualized to the patient and the amount of food con- which, if left uncontrolled, can lead to the development of an
sumed. Type 1 DM patients frequently are started on about abnormally large fetus. Infant hypoglycemia at delivery,
0.6 units/kg per day, and then doses are titrated until glycemic hyperbilirubinemia, and complications associated with deliv-
goals are reached. Most type 1 DM patients use between 0.6 ery of a large baby also may occur when blood glucose levels
and 1 unit/kg per day. are not controlled adequately.
Currently, the most advanced form of insulin therapy is the Insulin should be used when blood glucose levels are not
insulin pump, also referred to as continuous subcutaneous maintained adequately at target levels by diet and physical
insulin infusion (CSII). Using the short- or rapid-acting activity. Only human insulin should be used for treating
insulins only, these pumps are programmed to provide a slow GDM to prevent the transfer of anti-insulin antibodies. Oral
release of small amounts of insulin as the basal portion of glucose-lowering agents are not recommended during preg-
therapy, and then larger bolus doses are injected by the patient nancy. Additionally, women with pre-pregnancy hyperten-
to account for the consumption of food. sion and dyslipidemia should have their medications reeval-
uated at conception.
Type 2 DM
Treatment of type 2 DM has changed dramatically over the Nonpharmacologic Therapy
past decade with the addition of a number of new drugs and
the ADA recommendations to maintain tighter glycemic con- Diet
trol. Figure 402 details an algorithm for type 2 diabetes. Despite the popular notion, there is not a diabetic diet. The
Lifestyle modications, including education, nutrition, and recommended diet for patients with diabetes is a meal plan
exercise, are paramount to managing the disease successfully. low in fat, high in ber, low to moderate in calories, and
Many patients assume that once pharmacologic therapy is ini- achieving a balance of the various components and nutrients
tiated, lifestyle modications are no longer necessary. needed.12 Medical nutrition therapy (MNT) is considered an
Practitioners should educate patients regarding this miscon- integral component of diabetes management and diabetes
ception. Since type 2 diabetes is a progressive disease, blood self-management education. People with DM should receive
glucose levels will eventually increase making insulin therapy individualized MNT, preferably by a registered dietitian. As
and lifestyle modications the eventual required therapy. part of the diabetes management plan, MNT is not a single
Targets
Diagnosis and initial intervention23
HbA1c less than or equal to 6.57.0% (less
than 0.51.0% above reference range)
FPG/SMBG less than 110130 mg/dL (less
than 6.17.2 mmol/L)
2 hour PPG/SMBG less than 140180 Education/nutrition/exercise
mg/dL (less than 7.810 mmol/L)
Targets met FPG/SMBG/PPG targets not met after 1 month
HbA1c every 36 months Consider initial monotherapy Other initial monotherapy options:
(or early dual therapy4) Pioglitazone/rosiglitazone
Sulfonylurea and/or metformin1,5 Nateglinide
Repaglinide
Acarbose/miglitol
Insulin or insulin analog
Targets met Targets not met after 3 months Other combination options:
Continue therapy Metformin or a sulfonylurea plus
HbA1c every 36 months Combine sulfonylurea-metformin pioglitazone/rosiglitazone
or acarbose/miglitol
Metformin plus
Nateglinide or repaglinide; or
insulin or insulin analog (as
mono-or combination therapy)
Targets met Targets not met after 36 months

Continue combination therapy Add bedtime intermediate-acting insulin or once-daily glargine;
HbA1c every 36 months before supper intermediate-regular insulin or lispro/
aspart mix; add third oral agent; or switch to split dose
insulin or insulin analog therapy; consider referral to
endocrinologist
1. Metformin is the only Food and Drug Administration (FDA) approved oral diabetic agent in children (greater than or equal to age 10); other oral agents
may be used at the discretion of the clinician
2. If initial presentation with Fasting Plasma Glucose (FPG) greater than or equal to 260 mg/dL (14.11 mmol/L) in a symptomatic patient, consider insulin or
insulin analog as initial intervention.
3. If initial FPG greater than or equal to 210 mg/dL (11.7 mmol/L) or, Hemoglobin A1c (HbA1c) greater than or equal to 9.0%, consider dual oral agent therapy
(metformin-sulfonylurea or other options) at presentation.
4. If initial dual oral therapy is initiated, decide on add-on therapy options within 36 months if glycemic targets are not met.
5. Preferred in overweight/obese or dyslipidemic patients.
FIGURE 402 Glycemic control algorithm for type 2 DM in children and adults. (Adapted with permission, from DiPiro
JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A Pathophysiological Approach. 6th ed. New York: McGraw-Hill;
2005, Fig. 728, p. 1356. Also refer to Nathan DM, Buse JB, Davidson MB, et al. Management of Hyperglycerin in type 2
diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006; 29:19631972.)
PPG, postprandial glucose; SMBG, self-monitoring of glucose.
visit to a dietitian but rather an ongoing continuing dialog to The ADA does not recommend low-carbohydrate diets in
assist the patient to integrate healthier choices into his or her diabetes management. Although carbohydrates are a primary
daily lifestyle decisions. As such, MNT should be customized contributor to post-meal glucose levels, they are also an
to take into account cultural, lifestyle, and nancial consider- important source of energy, water-soluble vitamins, minerals,
ations. MNT plans should integrate a variety of foods that the and ber. Thus, the ADA recommends that carbohydrate
patient enjoys and allow for exibility to encourage patient intake consists of 45% to 65% of total calories.
empowerment and improve patient adherence.
During these MNT educational and planning sessions, Weight Management
patients receive instructions on appropriate food selection, Moderate weight loss has been shown to reduce cardiovascu-
preparation, and proper portion control. The primary focus lar risk, as well as delay or prevent the onset of DM in those
of MNT for patients with type 1 DM is matching optimal with pre-diabetes. The recommended primary approach to
insulin dosing to carbohydrate consumption. In type 2 DM, weight loss is therapeutic lifestyle change (TLC), which inte-
the primary focus is calorie reduction to achieve weight loss. grates a 500 to 1000 kcal/day reduction in calorie intake and
an increase in physical activity.12 A slow but progressive

weight loss of 1 to 2 lb (0.450.91 kg) per week is preferred. Patient Encounter, Part 3: Creating a
While individual target caloric goals should be set, a general Care Plan
rule for weight-loss diets is that they should supply at least
1000 to 1200 kcal/day for women and 1200 to 1600 kcal/day Create a care plan for MFs DM, including:
for men. Since 80% of patients with type 2 diabetes are over- Statement of drug-related needs and/or problems
weight, this strategy works best for these patients. Goals for therapy
Detailed plan with nonpharmacologic and pharmaco-
Physical Activity logic therapy
Physical activity is also an important component of a compre- Follow-up plan to evaluate whether MFs goals for therapy
hensive DM management program. Regular physical activity have been achieved and adverse effects avoided
has been shown to improve blood glucose control and reduce
cardiovascular risk factors, such as hypertension and elevated
serum lipid levels. Physical activity is also a primary factor Immunizations
associated with long-term maintenance of weight loss and Inuenza and pneumonia are common preventable infectious
overall weight control. Regular physical activity also may pre- diseases that increase mortality and morbidity in persons with
vent the onset of type 2 DM in high-risk persons. chronic diseases including DM.5 Yearly inuenza vaccinations,
Prior to initiating a physical activity program, several con- commonly called u shots, are recommended for patients
siderations should be made. Patients should undergo a with DM. Pneumococcal vaccination also is recommended for
detailed physical examination, including screening for patients with DM as a one-time vaccination for most patients.
microvascular or macrovascular complications that may be
worsened by a particular activity. Initiation of physical activi- Pharmacologic Therapy
ties in an individual with a history of a sedentary lifestyle
A number of therapeutic advancements and new options for
should begin with a modest increase in activity. Walking,
managing patients with DM have become available over the
swimming, and cycling are examples of low-impact exercises
past decade, including -glucosidase inhibitors, biguanides, non-
that could be encouraged. At the same time, gardening and
sulfonylurea secretagogues, and thiazolidinediones (TZD).15 In
usual house-cleaning tasks are good exercises as well. Long-
addition, a number of new insulin formulations have been
term goals are to perform at least 30 minutes of aerobic activ-
added to the armamentarium, including rapid-acting insulins,
ity as many days a week as possible.13
combination mixtures, and basal insulins.16 Finally, a number
of emerging therapies have been approved recently, including
Preventing Diabetes
pramlintide, exanatide, inhaled insulin and the dipeptidyl
The Diabetes Prevention Program was a 3-year study that
peptidase-4 (DPP-IV) inhibitors. The following section
showed that lifestyle modications, including exercise (30
describes the current oral agents available to treat type 2 DM.
minutes/day, 5 days/week) and moderate (5%10%) weight
Later in this section, the insulins and other injectible medica-
loss, reduce the probability of developing DM by 58% in
tions for type 1 and type 2 DM will be addressed.17, 18
patients with pre-diabetes. Results from this study suggest that
diet, exercise, and behavior modication are effective in pre- Oral agents currently available are indicated in patients
venting type 2 DM in high-risk patients.14 with type 2 DM who are unable to achieve glycemic control
through diet and exercise. Oral agents commonly used in the
Psychological Assessment and Care management of type 2 DM typically are classied according to
Mental health and social state have been shown to have an their mechanism of action. Insulin secretagogues include sul-
impact on a patients ability to carry out DM management fonylureas and non-sulfonylurea secretagogues. These agents
care tasks. Approximately one in four patients with DM expe- stimulate and enhance endogenous insulin release. Insulin sensi-
rience episodes of major depression. Therefore, clinicians tizers include the thiazolidinediones that decrease insulin resist-
should incorporate psychological assessment and treatment ance in the periphery. The biguanides decrease hepatic glucose
into routine care. The ADA guidelines recommend psycho- output and the DPP-IV inhibitors enhance the incretin system.
logical screening, which includes determining the patients Each of these agents may be used as monotherapy (Table 408)
attitudes regarding DM, expectations of medical manage- or in combination with other medications for synergistic effects.
ment and outcomes, mood and affect, general and diabetes-
related quality of life, and nancial, social, and emotional Sulfonylureas
resources. Patients demonstrating non-compliance, depres- Sulfonylureas represent the rst class of oral antidiabetes
sion, an eating disorder, and/or cognitive functioning that agents approved for use in the United States. These drugs are
impairs judgment should be referred to a mental health spe- classied as being either rst- or second-generation agents.
cialist familiar with DM.5 Both classes of sulfonylureas are equally effective when given at
654
TABLE 408. Oral Agents for the Treatment of Type 2 Diabetes Mellitus
Generic Dosage Starting Titration Maximum

Generic Name Brand Available Strengths (mg) Dosage (mg/day) Doses/Day Intervals Dose (mg) Effect (hour) Comments/Cautions
SulfonylureasFirst Generation
Major adverse events: Hypoglycemia, weight gain
Acetohexamide Dymelor Y 250, 500 250 12 57 days 1500 Up to 16 Metabolized in liver,
excreted in kidneys
Chlorpropamide Diabinese Y 100, 250 250 1 35 days 500 Up to 72 Caution in elderly and kidney
disease, disulram-like reaction
with alcohol
Tolazamide Tolinase Y 100, 250, 500 100250 12 Weekly 1000 Up to 24 Excreted via kidney, less side
effects than tolbutamide
Tolbutamide Orinase Y 250, 500 10002000 23 35 days 3000 Up to 12 Excreted via kidney, but can
be useful in kidney disease
SulfonylureasSecond Generation
Major adverse event: Hypopglycemia
Glipizide Glucotrol, Y 5, 10 5 12 35 days 40 Up to 20 Take immediate release
Slow release Glucotrol XL N 2.5, 5, 10, 20 5 1 35 days 20 24 tablets on an empty stomach;
caution in elderly
Glyburide Diaeta, Y 1.25, 2.5, 5 5 12 Weekly 20 Up to 24 Metabolized in liver and excreted
Micronase, Y in kidneys and bile, caution in
Micronized Glynase N 1.5, 3, 6 3 12 Weekly 12 Up to 24 elderly
Glimepiride Amaryl N 1, 2, 4 12 1 35 days 8 24 60% renal and 40% liver
elimination, take with rst
main meal
Non-sulfonylurea Secretagogues
Hypoglycemia and weight gain are at a reduced risk due to short duration of action
Nateglinide Starlix N 60, 120 120 3 with Not 120 per meal Up to 4 Frequency of dosing
meals applicable dependent on frequency
of meals
Repaglinide Prandin N 0.5, 1, 2 0.51 3 with Weekly 4 per meal; Up to 4 Frequency of dosing dependent
meals 16 daily on frequency of meals
Biguanides
Major adverse events: GI symptoms, nausea, diarrhea, lactic acidosis
Metformin Glucophage Y 500, 850, 1000 500 2 12 weeks 2550 Up to 24 Renally excreted unmetabolized
Extended release Glucophage XR N 500, 750 5001000 1 Weekly 2000 Up to 24 Discontinue if serum creatinine
greater than 1.4 mg/dL (females)
or 1.5 mg/dL (males)
Thiazolidinediones
Major adverse events: Edema, weight gain; discontinue use if alanine aminotranferase (ALT) greater than 3 times normal; monitor liver function tests at baseline and periodically thereafter
Pioglitazone Actos N 15, 30, 45 15 1 812 weeks 45 24 Metabolism by cytochrome
P-450 2C8 and 3A4 pathways,
days for onset of action
Rosiglitazone Avandia N 2,4, 8 24 12 812 weeks 8 mg/day or Up to 24 Metabolism by cytochrome
4 mg twice P-450 2C8 and 2C9 pathways,
daily days for onset of action
a-Glucosidase Inhibitors
Major adverse events: GI symptoms including atulence, cramps, and abdominal distension
Acarbose Precose N 25, 50, 100 25 13 with 48 weeks 100 mg Up to 3 Eliminated in bile, take
meals 3 times with rst bite of meal, little
daily absorption
Miglitol Glyset N 25, 50, 100 25 13 with 48 weeks 100 mg Up to 3 Eliminated through
meals 3 times kidney and feces, take with rst
daily bite of meal
Dipeptidyl peptidase-4 inhibitors
Major adverse events: Nasopharyngitis, upper respiratory tract infection
Sitegliptin Januvia N 25, 50, 100 100 1 Not applicable 100 24 Reduce dosage for renal insufciency
Combination Products
a a a
Glyburide/ Glucovance N 1.25/250 2.55/500 2 with 2 weeks
Metformin 2.5/500 meals
a
5/500
a a
Glipizide/ Metaglip N 2.5/250, 2.55/500 2 with 2 weeks
Metformin 2.5/500, meals
5/500
a a a a
Rosiglitazone/ Avandamet N 1/500, 12/500 2 with
Metformin 2/500, 4/500, meals
2/1000,
4/1000
a a a a
Pioglitazone/ Actosplus N 15/500, 15/500 12
Metformin Met 15/850 or 15/850
a
Refer to information for individual products in the combination.
GI, gastrointestinal; N, no; Y, yes
655
equipotent doses. Today, the vast majority of patients receiving glucose by increasing insulin sensitivity in both hepatic and
a sulfonylurea are prescribed a second-generation agent. peripheral muscle tissues; however, the exact mechanism of
Sulfonylureas enhance insulin secretion by blocking ATP- action remains unknown. Metformin has been shown to reduce
sensitive potassium channels in the cell membranes of pancre- HbA1c levels by 1.5% to 2% and FPG levels by 60 to 80 mg/dL
atic -cells. This action results in membrane depolarization, (3.334.44 mmol/L) when used as monotherapy. The response
allowing an inux of calcium to cause the translocation of to metformin can vary according to the starting point of the
secretory granules of insulin to the cell surface, and enhances patient. Larger effects can be seen in patients with a higher ini-
insulin secretion. The extent of insulin secretion depends on tial HbA1c level (e.g., greater than 10%) than in patients begin-
the blood glucose level. More insulin is released in response to ning therapy with a relatively lower value (e.g., less than 8%). It
higher blood glucose levels, whereas the additional insulin is effective in reducing fasting as well as post-meal blood glucose
secretion from sulfonylureas is less at near-normal glucose lev- levels. Metformin does not affect insulin release from -cells of
els. Insulin is then transported through the portal vein to the the pancreas, so hypoglycemia is not a common side effect.
liver, suppressing hepatic glucose production.6 While the onset of action begins within days, the maximum
All sulfonylureas undergo hepatic biotransformation, with therapeutic effect of this agent may not be observed until after
most agents being metabolized by the cytochrome P-450 2C9 2 weeks of therapy.
pathway. First-generation sulfonylureas are more likely to Metformin also has been shown to produce benecial effects
cause drug interactions than second-generation agents. All on serum lipid levels and thus has become a rst-line agent for
sulfonylureas except tolbutamide require a dosage adjustment type 2 DM patients with metabolic syndrome. Triglyceride and
or are not recommended in renal impairment. In elderly low-density lipoprotein (LDL) cholesterol levels often are
patients or those with compromised renal or hepatic function, reduced by 8% to 15%, whereas high-density lipoprotein (HDL)
lower starting dosages are necessary. cholesterol improves by approximately 2%. A modest weight
Monotherapy with sulfonylureas generally produce a 1.5% loss of 2 to 3 kg (4.46.6 lb) also has been reported with met-
to 2% decline in HbA1c concentrations and a 60 to 70 mg/dL formin therapy. Metformin often is used in combination with a
(3.333.89 mmol/L) reduction in FBG levels. Secondary failure sulfonylurea or a thiazolidinedione for synergistic effects.
with these drugs occurs at a rate of 5% to 7% per year as a Metformin does not undergo signicant protein binding
result of continued pancreatic -cell destruction. One limita- and is eliminated from the body unchanged in the urine.
tion of sulfonylurea therapy is the inability of these products to Elderly patients with a calculated creatinine clearance of less
stimulate insulin release from -cells at extremely high glucose than 70 to 80 mL/minute should not receive this product. It is
levels, a phenomenon called glucose toxicity. contraindicated in patients with a serum creatinine level
greater than or equal to 1.4 mg/dL (124 mol/L) in women
Non-sulfonylurea Secretagogues and 1.5 mg/dL (133 mol/L) in men. Additionally, therapy
While producing the same effect as sulfonylureas, non- with metformin should be withheld in patients undergoing
sulfonylurea secretagogues, also referred to as meglitinides, radiographic procedures in which a nephrotoxic dye is used.
have a much shorter onset and duration of action. Non- Therapy should be withheld the day of the procedure, as well
sulfonylurea secretagogues also produce a pharmacologic as for the following 2 to 3 days.
effect by interacting with ATP-sensitive potassium channels Primary side effects associated with metformin therapy are
on the -cells; however, this binding is to a receptor adjacent gastrointestinal in nature, including decreased appetite, nausea,
to those to which sulfonylureas bind. and diarrhea. These side effects can be minimized through slow
The primary benet of non-sulfonylurea secretagogues is titration of the dose and often subside within 2 weeks.
in reducing post-meal glucose levels by about 40 mg/dL Discontinuation because of side effects occurs in only 3% to 5%
(2.22 mmol/L). These agents have demonstrated a reduction in of patients.
HbA1c levels between 0.6% and 1%. Owing to the rapid onset Biguanides such as metformin are thought to inhibit mito-
and short duration of action of these agents, non-sulfonylurea chondrial oxidation of lactic acid, thereby increasing the
secretagogues are to be taken within 15 minutes of a meal. They chance of lactic acidosis occurring. Fortunately, the incidence
also may be used in combination therapy with other drugs to of lactic acidosis in clinical practice is rare. Patients at greatest
achieve synergistic effects. Combining a non-sulfonylurea secret- risk for developing lactic acidosis include those with liver dis-
agogue with a sulfonylurea usually improves glucose control. ease or heavy alcohol use, severe infection, heart failure, and
shock. Thus, it is common practice to evaluate liver function
prior to initiation of metformin.
Biguanides
The only biguanide approved by the Food and Drug
Administration (FDA) and currently available in the United Thiazolidinediones
States is metformin. Metformin was approved in the United Commonly referred to as TZDs or glitazones, thiazolidine-
States in 1995, although it has been used extensively in Canada diones have established a signicant role in type 2 DM therapy.
and Europe since 1959. This agent is thought to lower blood As monotherapy, both rosiglitazone and pioglitazone reduce
FPG levels by 30 to 50 mg/dL (1.672.78 mmol/L), and the

overall effect on HbA1c is a 1% to 1.5% reduction. Onset of Patient Encounter, Part 4: Oral to
action for thiazolidinediones is delayed for several weeks and Insulin Therapy
may require up to 12 weeks before maximum effects are
observed. Combining a sulfonylurea, non-sulfonylurea secret-
Several years have passed since you have been following
agogue, metformin, or insulin with a thiazolidinedione can MFs therapy. His weight is down to 230 lb (104.6 kg), and
improve HbA1c reductions to 2% to 2.5%. he tries to maintain his diet and exercise. His recent HbA1c
Additional effects of thiazolidinediones are seen in the lipid levels have increased up to 8.4% from 7.2% despite combi-
prole. Both pioglitazone and rosiglitazone increase HDL cho- nation therapy with sulfonylureas and metformin. The physi-
lesterol by 3 to 9 mg/dL (0.080.23 mmol/L). Pioglitazone has cian believes that it is time to start insulin therapy for MF
been shown to decrease serum triglycerides by 10% to 20%, and asks you to initiate therapy and follow his regimen.
whereas no substantial effect is observed with rosiglitazone.
LDL cholesterol concentrations increase by 5% to 15% with What insulin therapy would you choose for MF?
rosiglitazone, whereas no signicant increase has been How would you transition MF to insulin?
reported for pioglitazone.
Thiazolidinediones are known to increase insulin sensitivity
by stimulating peroxisome proliferator-activated receptor -Glucosidase is an enzyme along the brush border of intes-
gamma (PPAR-). Stimulation of PPAR- results in a number of tinal cells that breaks down complex carbohydrates into simple
intracellular and extracellular changes, including an increased sugars, resulting in absorption. -Glucosidase inhibitors work
number of insulin receptors, increased insulin receptor sensitiv- by delaying the absorption of carbohydrates from the intestinal
ity, decreased plasma fatty acid levels, and an increase in a host tract, which reduces the rise in postprandial blood glucose
of intracellular signaling proteins that enhance glucose uptake. concentrations. Gastrointestinal side effects occur as the result
Thiazolidinediones may produce uid retention and edema; of intestinal bacteria in the distal gut metabolizing undigested
however, the mechanism by which this occurs is not com- carbohydrates and producing carbon dioxide and methane
pletely understood. It is known that blood volume increases gas. -Glucosidase inhibitors are contraindicated in patients
approximately 10% with these agents, resulting in approxi- with short-bowel syndrome or inammatory bowel disease. In
mately 6% of patients developing edema. Thus, these drugs addition, neither drug in this class is recommended for
are contraindicated in situations in which an increased uid patients with a creatinine clearance of less than 25 mL/minute.
volume is detrimental, such as heart failure. Fluid retention
appears to be dose-related and increases when combined with Dipeptidyl peptidase-4 inhibitors
insulin therapy. The newest therapeutic class of oral agents for DM is the dipep-
A few cases of hepatotoxicity have been reported with tidyl peptidase-4 (DPP-IV) inhibitors. Sitagliptin is the rst and
rosiglitazone and pioglitazone, but no serious complications only agent in this class to be FDA approved, but vildagliptin and
have been reported, and symptoms typically reverse within saxagliptin are currently in clinical trials and may soon join this
several weeks of discontinuing therapy. Therefore, periodic class as therapeutic options. Sitagliptin is indicated for patients
liver function tests should be performed at baseline and dur- with type 2 DM as monotherapy or in combination therapy
ing thiazolidinedione therapy. Patients with a baseline alanine with metformin or a thiazolidinedione. The DPP-IV inhibitors
aminotransferase (ALT) level greater than 2.5 times the upper slow the inactivation of incretin hormones within the gut. The
limit of normal should not receive a TZD. If ALT levels rise to incretin hormones are released throughout the day by the intes-
greater than 3 times the upper limit of normal in patients tines and increased levels are produced in response to a meal.
receiving a TZD, the medication should be discontinued. Normal or elevated incretin hormones, including glucagon-like
peptide-1 (GLP-1) and glucose-dependent insulinotropic
-Glucosidase Inhibitors polypeptide (GIP), increase insulin production and release by
Acarbose and miglitol are -glucosidase inhibitors currently the pancreatic beta cells. In addition, GLP-1 has been shown to
approved in the United States. As monotherapy, -glucosidase decrease glucagon secretion from the pancreatic alpha cells
inhibitors reduce FPG concentrations by between 40 and 50 which leads to a decrease in hepatic glucose production. Since
mg/dL (2.222.78 mmol/L); however, HbA1c reductions range DPP-IV inhibitors increase and prolong only active incretin
only from 0.3% to 1%. While these agents have been popular levels, the resulting increase in insulin release and glucagon
in Europe and other parts of the world, they have failed to gain reduction occur in a glucose dependent manner.
widespread use in the United States. High incidences of gas- Reductions in HbA1c of 0.7%0.8% were found in clinical
trointestinal side effects, including atulence (41.5%), abdom- trials verses placebo in both monotherapy and combination
inal discomfort (11.7%), and diarrhea (28.7%), have limited therapy using the recommended dose of sitagliptin 100 mg
their use. Low initial doses followed by gradual titration may daily taken with or without food. Dosage adjustments to 50 mg
minimize gastrointestinal side effects. and 25 mg daily are recommended for patients with moderate
(CrCl greater than or equal to 30 to less than 50 mL/minute) regular insulin, rendering a product with a delayed onset but
and severe (CrCl less than 30 mL/minute) renal impairment extended duration of action. With the advent of the long-acting
respectively. Renal function monitoring is recommended insulins, NPH insulin use has declined due to: (1) an inability to
prior to initiation and periodically thereafter. Adverse events predict accurately when peak effects occur, and (2) a duration of
in clinical trials included nasopharyngitis (5.2%), upper res- action of less than 24 hours. Additionally, protamine is a foreign
piratory tract infection (6.3%), and headache (5.1%). protein that may increase the possibility of an allergic reaction.
Currently, no signicant drug interactions are known. NPH insulin can be mixed with regular insulin and used
immediately or stored for future use up to 1 month at room
Insulins temperature or 3 months in refrigeration. NPH insulin can be
Insulin is the one agent that can be used in all forms of DM for mixed with either aspart or lispro insulins, but it must be
blood sugar control. Insulin is the essential treatment for injected immediately after mixing. Whenever mixing insulin
patients with type 1 DM and can overcome insulin resistance in products with NPH insulin, the shorter-acting insulin should
patients with type 2 DM. Insulin is available commercially in var- be drawn into the syringe rst.
ious formulations that vary markedly in terms of onset and dura-
tion of action and the source from which a product is obtained. Long-Duration Insulin
Insulins can be divided into four separate classes based on their Two long-duration insulin preparations are approved for use
length of action. Most formulations are available as U-100, indi- in the United States. Glargine and detemir are designed as
cating a concentration of 100 units/mL. Insulin is typically refrig- once-daily-dosing basal insulins. Insulin glargine differs from
erated, and most vials are good for 28 days at room temperature. regular insulin by three amino acids, resulting in a low solu-
Specic details of insulin products are listed in Table 409. bility at physiologic pH. The clear solution is supplied at a pH
The most common route of administration for insulin is of 4, which precipitates on subcutaneous administration.
subcutaneous injection using a syringe or pen device. Insulin Given this property, glargine cannot be administered intra-
syringes are distinguished according to the syringe capacity, venously or mixed with other insulin products. Both glargine
syringe markings, and needle gauge and length. The most and detemir do not produce peak serum concentrations and
common insulin syringe capacities are 30, 50, and 100 units. can be administered irrespective of meals or time of day.
The 30- and 50-unit syringes are marked at 1-unit increments,
whereas the 100-unit syringe is marked at 2-unit intervals. Combination Insulin Products
Syringe needles range from 28 to 31 gauge and 5/16- to 1/2-in A number of combination insulin products are available com-
length. The insulin pens are self-contained systems of insulin mercially. NPH is available in combinations of 70/30 and 50/50
delivery. The primary advantage of the pen system is that the with regular insulin. Two short-acting insulin analog mixtures
patient does not have to draw up the dose from the insulin vial. are also available. Humalog Mix 75/25 contains 75% insulin
lispro protamine suspension and 25% insulin lispro. Novolog
Regular Insulin Mix 70/30 contains 70% insulin aspart protamine suspension
Regular insulin is unmodied crystalline insulin commonly and 30% insulin aspart. The lispro and aspart insulin prota-
referred to as natural insulin. It is a clear solution that has a rel- mine suspensions were developed specically for these mixture
atively rapid onset and short duration of action. On subcuta- products and will not be commercially available separately.
neous injection, regular insulin forms small aggregates called
hexamers that undergo conversion to dimers followed by Oral Inhalation Insulin
monomers before systemic absorption can occur. Therefore, The rst inhaled insulin product was approved in early 2006.
patients should be counseled to inject regular insulin subcuta- Exubera, recombinant human insulin, is an alternative to meal-
neously 30 minutes prior to consuming a meal. Regular insulin time injectible insulin available in the United States. It has an
is the only insulin that can be administered intravenously. onset of action of between 10 to 20 minutes, which is similar to
rapid-acting insulin, and a duration of action of around 6
Rapid-Acting Insulin hours, which is similar to regular insulin. Inhaled insulin will
Three rapid-acting insulins have been approved in the United not totally replace injectible insulin because long-acting insulin
States: lispro, aspart, and glulisine. Substitution of one or two injections are necessary for basal control. This product is avail-
amino acids in regular insulin results in the unique pharmaco- able in 1 and 3 mg blister packs, which are equivalent to about
kinetic properties characteristic of these agents. Onset of action 3 to 8 units of injectible insulin. Some patients may need mul-
of rapid-acting insulins varies from 15 to 30 minutes, with peak tiple inhalations to attain their mealtime dose. Exubra is not
effects occurring 1 to 2 hours following administration. recommended for patients with chronic lung disease such as
asthma or chronic obstructive pulmonary disease, patients
Intermediate-Duration Insulin who smoke, or patients who have stopped smoking within the
Neutral Protamine Hagedorn, better known as NPH insulin, is past 6 months. Monitoring of lung function should be per-
prepared by a process in which protamine is conjugated with formed at baseline and 6 months post initiation of therapy.
TABLE 409. Insulin Agents for the Treatment of Type 1 and Type 2 Diabetes Mellitus
Generic Name (Insulin) Brand Manufacturer Strength Onset (minutes) Peak (hours) Duration (hours) Administration Options
Rapid-Acting Insulin
Lispro Humalog Eli Lilly U-100 1530 0.52.5 34 10 mL vial, 3 mL cartridge and
disposable pen
Aspart Novolog Novo-Nordisk U-100 1530 13 35 10 mL vial, 3 mL cartridge and
disposable pen
Glulisine Apidra Aventis U-100 1530 12 34 10 mL vial, 3 mL cartridge and
disposable pen
Short-Acting Insulin
Regular Humulin R Eli Lilly U-100, 3060 23 36 U-100 10 mL vial; U-500
U-500 20 mL vial
Novolin R Novo-Nordisk U-100 10 mL vial, 3 mL cartridge, 3 mL Innolet
Intermediate-Acting Insulin
Neutral protamine Humulin N Eli Lilly U-100 24 hours 46 812 10 mL vial, 3 mL cartridge
Hagedorn Novolin N Novo-Nordisk U-100 10 mL vial, 3 mL cartridge, 3 mL InnoLet
Long-Acting Insulin
Glargine Lantus Aventis U-100 45 hours Flat 2224 10 mL vial, 3 mL cartridge for Opticlik
Detemir Levmir Novo-Nordisk U-100 34 hours Flat Up to 24 10 mL vial, 3 mL cartridge, 3 mL
Innolet, 3 mL disposable FlexPen
Combination Insulin Products
Neutral protamine Humulin Eli Lilly U-100 3060 1.516 1016 10 mL vial, 3 mL disposable pen
Hagedorn and regular 70/30
Novolin 70/30 Novo Nordisk U-100 3060 212 1016 10 mL vial, 3 mL cartridge, 3 mL Innolet
Humulin 50/50 Eli Lilly U-100 3060 25.5 1016 10 mL vial
Neutral protamine Humalog Mix Eli Lilly U-100 1530 16.5 1518 10 mL vial, 3 mL disposable pen
lispro and lispro 75/25
Neutral protamine Novolog Mix Novo Nordisk U-100 1530 14 Up to 24 10 mL vial, 3 mL cartridge, 3 mL
aspart and aspart 70/30 disposable FlexPen
Oral Inhalation Insulin
Recombinant human Exubera Pzer 1 mg = 1020 0.51.5 6 1 mg, 3 mg blister packs
insulin ~3 units
injectible
insulin
659
Skin
Catheter
Fat
Insulin
Dosage instructions are entered

into the pumps small computer
and the appropriate amount of
insulin is then injected into the
body in a calculated, controlled
manner
Insulin pump
FIGURE 403 Insulin pump.
Insulin Pump Therapy have more exibility in timing and content of meals and exer-
Insulin pump therapy consists of a programmable infusion cise schedules. Nonetheless, insulin pump therapy is not for
device that allows for basal infusion of insulin 24 hours daily, as everyone. The complexity associated with its use, cost, increased
well as bolus administration following meals. As seen in Fig. 403, need for blood glucose monitoring, and psychological factors
an insulin pump consists of a programmable infusion may prevent individuals from using this technology optimally.
device with an insulin reservoir. This pump is attached to an
infusion set with a small needle that is inserted in subcuta- Incretin Mimetics
neous tissue in the patients abdomen, thigh, or arm. Most Incretin mimetics are agents with biologic activities similar to
patients prefer insertion in abdominal tissue because this site incretin hormones but have longer durations of action.
provides optimal insulin absorption. Patients should avoid Incretin hormones are substances produced by the gastroin-
insertion sites along belt lines or in other areas where clothing testinal tract in response to food that act to stimulate insulin
may cause undue irritation. Infusion sets should be changed secretion. Obese, insulin-resistant patients with type 2 diabetes
every 2 to 3 days to reduce the possibility of infection. have lower levels of incretin hormones. Exanatide is the rst
Patients use a carbohydrate-to-insulin ratio to determine incretin mimetic approved by the FDA and is indicated as
how many units of insulin are required. To determine an indi- adjunct therapy in type 2 DM in which adequate blood glucose
viduals ratio, the 450 rule is used for patients using regular control has not been achieved with sulfonylureas, metformin, or
insulin, whereas the 500 rule is used for lispro or aspart pump both (Table 4010). HbA1c reductions ranging from 0.5% to 1%
users. To calculate the ratio using the 500 rule, the patient have been observed with this agent, whereas FPG concentrations
would divide 500 by his or her total daily dose of insulin. For decrease by 8 to 10 mg/dL (0.440.56 mmol/L). Postprandial
example, if a patient were using 25 units of insulin daily, his or glucose values decline by 60 to 70 mg/dL (3.333.89 mmol/L).
her carbohydrate-to-insulin ratio would be 500:25, or 20:1. Exanatide lowers blood glucose levels by producing glucose-
This ratio theoretically means that 1 unit of lispro or aspart dependent insulin secretion; reducing post-meal glucagon
insulin should cover 20 g of carbohydrate. If blood sugar lev- secretion, which decreases post-meal glucose output;
els are below or above the desired blood glucose target, the increasing satiety, which decreases food intake; and regulat-
amount of insulin can be adjusted. Once this ratio is deter- ing gastric emptying, which allows nutrients to be absorbed
mined, patients can eat more or fewer carbohydrates at a given into the circulation more smoothly. Serum levels peak
meal and adjust the bolus dose accordingly. approximately 2 hours after subcutaneous administration.
Insulin pump therapy may be used to lower blood glucose Exanatide is eliminated renally and is not recommended in
levels in any type of DM; however, patients with type 1 DM are patients with a creatinine clearance of less than 30 mL/minute.
the most likely candidates for this form of treatment. Use of an An increased risk of hypoglycemia occurs when exanatide
insulin pump may improve blood glucose control, reduce wide is used in combination with a sulfonylurea; however, this is
uctuations in blood glucose levels, and allow individuals to not encountered in exanatide monotherapy or in conjunction
with metformin and/or thiazolidinedione therapy. Side effects HbA1c by an additional 0.4% to 0.5%. Pramlintide slows gastric
include nausea (44%), vomiting (13%), and diarrhea (13%). emptying without altering absorption of nutrients, suppresses
No major drug interactions have been found with exanatide. glucagon secretion, and leads to a reduction in food intake by
The extent and rate of absorption of orally administered increasing satiety. By slowing gastric emptying, the normal ini-
drugs may be affected with concomitant use of exanatide; tial post-meal spike in blood glucose is reduced.
however, no clinical signicance has been established to date. Hypoglycemia, nausea, and vomiting are the most common
Exanatide is available in 5 and 10 mcg injectible prelled dis- side effects encountered with pramlintide therapy, although
posable pens. Initial therapy is 5 mcg twice daily, injected before pramlintide itself does not produce hypoglycemia. To decrease
the two largest meals of the day. Meals should be separated by the risk of hypoglycemia, doses of short-acting, rapid-acting, or
at least 5 to 6 hours. Doses then are increased after a month to premixed insulins should be reduced by 50% before pramlintide
10 mcg if the patients blood glucose is improving and nausea is is initiated. Pramlintide is metabolized primarily by the kidneys,
limited. Exanatide can be given up to 60 minutes before a meal, but dosage adjustments in liver or kidney impairment are not
but practical use indicates that injection just before a meal may required. Pramlintide has the potential to delay the absorption of
decrease nausea. An average weight loss of 3 to 5 pounds orally administered medications. When rapid absorption is
(1.362.27 kg) commonly occurs with the 5 mcg dose, whereas needed for efcacy of an agent, pramlintide should be adminis-
a weight loss of 5 to 10 pounds (2.274.55 kg) is observed with tered 2 hours before or 1 hour after this drug. Pramlintide should
the 10 mcg dose. not be used in patients receiving medications that alter gastroin-
testinal motility, such as anticholinergic agents, or drugs that slow
Amylin the absorption of nutrients, such as -glucosidase inhibitors.
Pramlintide acetate was approved for use in the United States
in March 2005 (Table 40-10). This agent is a synthetic analog Treatment of Concomitant Conditions
of human amylin, which is a naturally occurring neuroen-
docrine peptide that is co-secreted by the -cells of the pan- Coronary Heart Disease
creas in response to food. Amylin secretion is completely or Nearly two-thirds of patients with DM will die of coronary
relatively decient in patients with diabetes. Pramlintide is heart disease (CHD). Interventions targeting smoking cessa-
given by subcutaneous injection before meals to lower post- tion, glycemic control, blood pressure control, lipid manage-
prandial blood glucose elevations. However, unlike insulin, it ment, antiplatelet therapy, and lifestyle changes, including diet
does not cause weight gain. Use of pramlintide actually results and exercise, can reduce the risk of cardiovascular events.
in an average weight loss of 2.2 to 4.4 lb (12 kg). Patients with diabetes should receive at least an aspirin daily
Pramlintide is indicated as combination therapy with insulin unless contraindicated. Refer to appropriate chapters in the
in patients with type 1 or 2 DM. It has been shown to decrease text concerning CHD.
TABLE 4010. Non-insulin Injectible Agents for the Treatment of Diabetes Mellitus
Generic Type of Dosage

Name Diabetes Strengths Starting Titration Maximum Time to Effect
(Brand) Mellitus (mcg)b,c Dosage Doses/Day Interval Dose (mcg) (minute) Comments/Cautions
a
Pramlintide 1 15, 30, 15 3 37 days 60 20 Take just before major meals;
(Symlin) 45, 60 reduce insulin by 50%
Maintenance dose
3060 mcg
2 60, 120 60 3 37 days 120 20 Side effects: Hypoglycemia,
nausea, vomiting
May delay oral drug
absorption
Exanatidea 2 5, 10 5 2 1 month 10 1530 Take just before
(Byetta) morning and evening
meal; prelled disposable
pen; may delay absorption
of oral drugs; separate
doses by 1 hour
Side effects: Nausea,
vomiting, diarrhea,
increased hypoglycemia
with sulfonylureas
a
Generic not available in United States.
b
Pramlintide supplied as 0.6 mg/mL in 5 mL vials.
c
Exanatide supplied as 250 mcg/mL, 1.2 mL for the 5 mcg prelled pen and 2.4 mL for the 10 mcg per dose prelled pen.
Hyperlipidemia reaching peak effect, or inadequately adjusted drug therapy in

The National Cholesterol Education Program Adult Treatment renally or hepatically impaired patients. Patients experiencing
Panel III guidelines classify the presence of DM to be of the same symptoms of hypoglycemia should check their blood glucose
risk equivalence as CHD. The primary target for lipid-lowering level, consume 15 g of carbohydrate, and wait 10 to 15 minutes
treatment of LDL cholesterol is less than 100 mg/dL (2.59 for symptom resolution. Examples of acceptable treatments may
mmol/L). For patients at high cardiovascular risk, LDL target is include a small box of raisins, 4 oz (approximately 120 mL) of
70 mg/dL (1.81 mmol/L). Treatment with an HMG-CoA reduc- orange juice, 8 oz (approximately 240 mL) of skim milk, or
tase inhibitor, commonly called a statin, often is required to three to six glucose tablets. In patients receiving an -glucosidase
achieve these goals. After LDL cholesterol goals are reached, inhibitor in combination with a sulfonylurea or insulin, hypo-
triglyceride and HDL goals also should be achieved. Treatments glycemia should be treated with glucose tablets or skim milk
including niacin or brate therapy may be used to reach these owing to the mechanism of action of the -glucosidase
secondary goals. However, caution should be used with statin- inhibitors. If the blood glucose level has dropped below 50 mg/dL
brate combination therapy because a higher risk of adverse (2.78 mmol/L), as much as 30 g of carbohydrate may be neces-
events has been reported (see Chapter 9). sary to raise blood glucose levels adequately. For patients with
hypoglycemia experiencing a loss of consciousness, a glucagon
Hypertension emergency kit should be administered by intramuscular or sub-
Uncontrolled blood pressure plays a major role in the devel- cutaneous route, and emergency medical personnel should be
opment of macrovascular events and nephropathy in patients contacted. The patient should be rolled onto his or her side to pre-
with DM. The ADA recommends that blood pressure goals for vent aspiration since many patients receiving the glucagon injec-
patients with DM be less than 130/80 mm Hg. In addition, tion will vomit.
there are several general principles regarding the treatment of
hypertension in diabetes patients. Angiotensin-converting
Diabetic Ketoacidosis
enzyme (ACE) inhibitors, angiotensin II receptor blockers,
Diabetic ketoacidosis (DKA) is a reversible but potentially life-
and calcium channel blockers are recommended as initial
threatening medical emergency that results from a relative or
therapy because of their benecial effects on renal function.
absolute deciency in insulin. Without insulin, the body cannot
Low-dose thiazide diuretics also can be used as either rst- or
use glucose as an energy source and must obtain energy via
second-line therapy. The most common use of thiazide
lipolysis. This process produces ketones and leads to acidosis.
diuretics for patients with DM is in synergistic combination
While DKA occurs frequently in young patients with type 1 DM
with other agents. -Blockers also can be used as either rst-
on initial presentation, it can occur in adults as well as with
or second-line therapies. While -blockers may mask the
patients who have type 2 DM. Often precipitating factors such as
symptoms of hypoglycemia, it is generally believed that the
infection or errors in administration of insulin or oral diabetes
benet of -blockers outweighs the low risk of hypoglycemia
medications can cause DKA. Signs and symptoms develop rap-
in the patient with type 2 DM. In order to achieve blood pres-
idly over a few hours and commonly include fruity or acetone
sure goals, most patients require combination therapy with
breath, nausea, vomiting, dehydration, polydipsia, polyuria, and
two or three antihypertensive agents (see Chapter 2).
deep, rapid breathing. Non-specic symptoms include lethargy,
headache, and weakness. Hallmark diagnostic criteria for DKA
Treatment of Acute Complications include hyperglycemia (greater than 250 mg/dL, 13.9 mmol/L),
ketosis (anion gap greater than 10), and acidosis (arterial pH less
Hypoglycemia than or equal to 7.25). Typical uid decit is 6 L or more, with
Hypoglycemia, or low blood sugar, can be dened clinically as a major decits of serum sodium and potassium common. The
blood glucose level of less than 50 mg/dL (2.78 mmol/L). severity of DKA depends on the magnitude of the decrease in
Individuals with DM can experience symptoms of hypo- arterial pH, serum bicarbonate levels, and the mental state
glycemia at varying blood glucose levels. Patients who have reg- rather than the magnitude of the hyperglycemia.
ular blood glucose levels as high as 300 to 400 mg/dL Treatment goals of DKA consist of reversing the underlying
(16.6522.2 mmol/L) may experience symptoms of hypo- metabolic abnormalities, rehydrating the patient, and normal-
glycemia once blood glucose levels are lowered to the middle to izing the serum glucose. Fluid replacement with normal saline
upper 100 mg/dL (5.55 mmol/L) range. Most people whose at 1 L/hour is recommended to rehydrate the patient and to
blood glucose levels are controlled adequately may experience ensure that the kidneys are perfused. Potassium and other elec-
symptoms when levels fall below 70 mg/dL (3.89 mmol/L). trolytes are supplemented as indicated by laboratory assessment.
Symptoms of hypoglycemia include shakiness, sweating, fatigue, The use of sodium bicarbonate in DKA is controversial and gen-
hunger, headaches, and confusion. Common causes of hypo- erally is not recommended when the pH is greater than or equal
glycemia include delayed or inadequate amounts of food intake, to 7.1. Regular insulin at 0.1 to 0.2 unit/kg per hour by con-
especially carbohydrates, excessive doses of medications (e.g., tinuous intravenous infusion is the preferred treatment in DKA
sulfonylureas and insulin), exercising when insulin doses are to regain metabolic control rapidly. Once plasma glucose values
TABLE 4011. Management of Diabetic Ketoacidosis ketonemia, and acidosis associated with DKA. Patients with
hyperglycemia and dehydration lasting several days to weeks
1. Conrm diagnosis ( plasma glucose, positive serum ketones,
are at the greatest risk of developing HHS. Illness and infection
metabolic acidosis).
2. Admit to hospital; intensive-care setting may be necessary for are common precipitating causes of HHS. Two main diagnos-
frequent monitoring or if pH less than 7.0 or unconscious. tic criteria for HHS are a plasma glucose value of greater than
3. Assess: Serum electrolytes (K+, Na+, Mg2+, Cl, bicarbonate, 600 mg/dL (33.3 mmol/L) and a serum osmolality of greater
phosphate) than 320 mOsm/kg. The extreme hyperglycemia and large
Acid-base statuspH, HCO3, PCO2, b-hydroxybutyrate
uid decits resulting from osmotic diuresis are major chal-
Renal function (creatinine, urine output)
4. Replace uids: 23 L of 0.9% saline over rst 13 hours lenges to overcome with this condition. Similar to DKA, the
(510 mL/kg per hour); subsequently, 0.45% saline at 150300 treatment of HHS consists of aggressive rehydration, correc-
mL/hour; change to 5% glucose and 0.45% saline at 100200 tion of electrolyte imbalances, and continuous insulin infu-
mL/hour when plasma glucose reaches 250 mg/dL (14 mmol/L). sion to normalize serum glucose. However, in patients with
5. Administer regular insulin: IV (0.1 units/kg) or IM (0.4 units/kg),
HHS, blood glucose levels should be reduced gradually to
then 0.1 units/kg per hour by continuous IV infusion; increase
2- to 10-fold if no response by 24 hours. If initial serum potas- minimize the risk of cerebral edema.
sium is less than 3.3 mmol/L (3.3 mEq/L), do not administer
insulin until the potassium is corrected to greater than
3.3 mmol/L (3.3 meq/L). Treatment of Long-Term Complications
6. Assess patient: What precipitated the episode (non-compliance,
infection, trauma, infarction, cocaine)? Initiate appropriate
work-up for precipitating event (cultures, CXR, ECG). Retinopathy
7. Measure capillary glucose every 12 hours; measure elec- Diabetic retinopathy occurs when the microvasculature that
trolytes (especially K+, bicarbonate, phosphate) and anion gap supplies blood to the retina becomes damaged. This damage
every 4 hours for rst 24 hours. permits leakage of blood components through the vessel walls.
8. Monitor blood pressure, pulse, respirations, mental status, and
Diabetic retinopathy is the leading cause of blindness in adults
uid intake and output every 14 hours.
9. Replace K+: 10 mEq/hour when plasma K+ less than 5.5 mEq/L, 20 to 74 years of age in the United States. Retinopathy is staged
ECG normal, urine ow and normal creatinine documented; as either non-proliferative or proliferative. Non-proliferative
administer 4080 mEq/hour when plasma K+ less than 3.5 mEq/L retinopathy often causes no visual disturbances and may
or if bicarbonate is given. remain asymptomatic for years. Proliferative retinopathy
10. Continue above until patient is stable, glucose goal is 150250
occurs when new retinal vessels form as a result of retinal
mg/dL, and acidosis is resolved. Insulin infusion may be
decreased to 0.050.1 units/kg per hour. ischemia in a process called neovascularization. Vision loss
11. Administer intermediate or long-acting insulin as soon as from proliferative retinopathy may range from mild blur-
patient is eating. Allow for overlap in insulin infusion and sub- ring, to obstruction of vision, to complete blindness. Blurred
cutaneous insulin injection. vision is the presenting symptom for many patients who are
CXR, chest x-ray; ECG, electrocardiogram; IM, intramuscularly; diagnosed with diabetes. The ADA recommends that
IV, intravenous. patients with DM receive a dilated eye examination annually
Source: Adapted from M Sperling, in Therapy for Diabetes Mellitus and by an ophthalmologist or optometrist. Glycemic control is
Related Disorders, American Diabetes Association, Alexandria, VA,
1998; and AE Kitabchi et al: Diabetes Care 24:131, 2001. the best prevention for slowing the progression of retino-
pathy. Early retinopathy may be reversed with improved glu-
cose control.
drop below 250 mg/dL (13.9 mmol/L), the insulin infusion may
be decreased, and dextrose 5% to 10% can be added to the Neuropathy
intravenous uids. During the recovery period, it is recom- Peripheral neuropathy is the most common complication
mended to continue administering insulin and to allow reported in type 2 DM. This complication generally presents
patients to eat as soon as possible. Dietary carbohydrates com- as pain, tingling, or numbness in the extremities. The feet are
bined with insulin assist in the clearance of ketones. Resolution affected more often than the hands and ngers. A number of
of DKA is indicated by a blood glucose level of less than 200 treatment options have been tried with mixed success.
mg/dL (11.1 mmol/L), a bicarbonate level of greater than or Current options include pregabalin, gabapentin, low-dose tri-
equal to 10 mEq/L (10 mmol/L), and a venous pH of greater cyclic antidepressants, duloxetine, venlafaxine, topiramate,
than 7.3. See Table 4011 for the management of DKA.19 non-steroidal anti-inammatory drugs, and topical capsaicin.
Autonomic neuropathy is also a common complication as
Hyperosmolar Hyperglycemic State DM progresses. Clinical presentation of autonomic neuropa-
Hyperosmolar hyperglycemic state (HHS) is a life-threatening thy may include gastroparesis, resting tachycardia, orthostatic
condition similar to DKA that also arises from inadequate hypotension, impotence, constipation, and hypoglycemic auto-
insulin, but HHS occurs primarily in older patients with type 2 nomic failure. Therapy for each individual autonomic compli-
DM. DKA and HHS also differ in that HHS lacks the lipolysis, cation is addressed separately.
Microalbuminuria and Nephropathy dressings, treating edema, and limiting ambulation. Untreated
DM is the leading contributor to end-stage renal disease. Early foot problems may develop gangrene, necessitating surgical
evidence of nephropathy is the presence of albumin in the intervention.
urine. Therefore, as the disease progresses, larger amounts of
protein spill into the urine. The ADA recommends urine protein Special Situations
tests annually in type 2 DM patients. For children with type 1
DM, annual urine protein testing should begin with the onset of Hospitalized Care
puberty or 5 years after the diagnosis of diabetes. The most com- Aggressive treatment of hyperglycemia in hospitalized patients
mon form of screening for protein in the urine is a random spot can prevent unnecessary cost to patients and health care systems.
collection for measurement of the urine albumin/creatinine When patients are either physically or emotionally stressed,
ratio. The desirable value is less than 30 mcg of albumin per counterregulatory hormones are released, increasing blood glu-
milligram of creatinine. Microalbuminuria is dened as cose levels. Insulin drip therapy for patients with blood glucose
between 30 and 300 mcg of albumin per milligram of creati- levels greater than 140 mg/dL (7.77 mmol/L) is considered supe-
nine. The presence of microalbuminuria is a strong risk factor rior to sliding-scale insulin. Sliding-scale insulin therapy typi-
for future kidney disease in type 1 DM patients. In type 2 DM cally lags the blood glucose level instead of proactively
patients, microalbuminuria has been found to be a strong risk addressing the increased blood glucose levels. Blood glucose lev-
factor for macrovascular disease. Glycemic control and blood els can be measured by several methods. Arterial samples are
pressure control are primary measures for the prevention of usually 5 mg/dL (0.28 mmol/L) higher than capillary values and
progression of nephropathy. ACE inhibitors and angiotensin 10 mg/dL (0.56 mmol/L) greater than venous values.
II receptor blockers prevent the progression of renal disease in When preparing an insulin infusion for a patient, several fac-
type 2 DM patients. Treatment of advanced nephropathy tors must be considered. Insulin will absorb to glass and plastic,
includes dialysis and kidney transplantation. reducing the amount of insulin actually delivered by 20% to
30%. Priming the tubing will decrease variability of insulin
infused. Therefore, when patients can be converted safely from
Foot Ulcers
infusion to needle and syringe therapy, the total daily dose
Lower extremity amputations are one of the most feared and
should be reduced by 20% to 50% of the daily infusion amount.
disabling sequelae of long-term uncontrolled DM. A foot
ulcer is an open sore that develops and penetrates to the sub-
Sick Days
cutaneous tissues. Complications of the feet develop prima-
Patients should monitor their blood glucose levels more closely
rily as a result of peripheral vascular disease, neuropathies,
during sick days because it is common for illness to increase val-
and foot deformations. Peripheral vascular disease causes
ues. Additional insulin coverage may be necessary to prevent
ischemia to the lower limbs. This decreased blood ow
DKA. Patients should monitor for the presence of urine ketones
deprives the tissues of oxygen and nutrients and impairs the
by a urine dipstick test that changes color in the presence of
ability of the immune system to function adequately.
ketones. Sugar and electrolyte solutions such as sports drinks
Symptoms of peripheral vascular disease include intermit-
may be used by type 1 DM patients to prevent dehydration, elec-
tent claudication, cold feet, pain at rest, and loss of hair on
trolyte depletion, and hypoglycemia. However, patients with type
the feet and toes. Smoking cessation is the single most
2 DM may require sugar-free products if blood glucose levels are
important treatment for peripheral vascular disease. In addi-
elevated consistently. With proper management, patients can
tion, exercising by walking to the point of pain and then rest-
decrease their chance of illness-induced hospitalization.
ing and resuming can be a vital therapy to maintain or
improve the symptoms of peripheral vascular disease.
Outcome Evaluation
Pharmacologic intervention with pentoxifylline or cilostazol
also may be useful to improve blood ow and reduce the The success of therapy for DM is measured by the ability of
symptoms of peripheral vascular disease. the patient to manage his or her disease appropriately
Neuropathies play a large part in the development of foot between health care provider visits.
ulcers. Loss of sensation in the feet allows trauma to go unno- Appropriate therapy necessitates adequate patient education
ticed. Autonomic neuropathy can cause changes in the blood about the disease, development of a meal plan to which
ow, perspiration, skin hydration, and possibly bone composi- patients can comply, and integration of a regular exercise
tion of the foot. Motor neuropathy can lead to muscle atrophy, program.
resulting in weakness and changes in the shape of the foot. To Patient care plans should include a number of daily evalua-
prevent foot complications, the ADA recommends daily visual tions to be performed by the patient, such as examination of
examination of the feet and a foot check performed at every the feet for any sores, cuts, or abrasions; checking the skin for
physician visit. Sensory testing with a 10-gauge monolament dryness to prevent cracking and chang; and monitoring
can detect areas of neuropathy. Treatment consists of glycemic blood glucose values as directed. Weekly appraisals of weight
control, preventing infection, debriding dead tissues, applying and blood pressure are also advised.
Until HbA1c levels are at goal, quarterly visits with the ABBREVIATIONS
patients primary health care provider are recommended.
Table 407 summarizes the specic ADA goals for therapy. AACE: American Association of Clinical Endocrinologists
The practitioner should review SMBG data and a current ACE: angiotensin-converting enzyme inhibitors
HbA1c level for progress and address any therapeutic or edu- ADA: American Diabetes Association
cational issues. ALT: alanine aminotransferase
At minimum, yearly laboratory evaluation of serum lipids, AST: aspartate aminotransferase
BMI: body mass index
urinary microalbumin, and serum creatinine should be per-
BP: blood pressure
formed. If the patient is on a thiazolidinedione, liver func-
tion tests should be performed at least once a year. CDC: Centers for Disease Control and Prevention
CHD: Coronary Heart Disease
CSII: continuous subcutaneous insulin infusion
DKA: diabetic ketoacidosis
DM: diabetes mellitus
Patient Care and Monitoring DPP-IV: dipeptidyl peptidase-4
FDA: Food and Drug Administration
FPG: fasting plasma glucose
GDM: gestational diabetes mellitus
1. Assess the patient for development or progression of DM
GIP: glucose-dependent insulinotropic polypeptide
and DM-related complications.
GLP-1: glucagon-like peptide-1
2. Evaluate SMBG for glycemic control, including FPG and HbA1c: hemoglobin A1c
postprandial levels. HDL: high-density lipoprotein cholesterol
Are the blood glucose values too high or low? HHS: hyperosmolar hyperglycemic state
Are there specic times of day or specic days not in HLA: human leukocyte antigen
control? IFG: impaired fasting glucose
Is hypoglycemia occurring? IGT: impaired glucose tolerance
3. Assess the patient for changes in quality-of-life measures, IKK-beta: I-kappa-B kinase beta
such as physical, psychological, and social functioning LADA: latent autoimmune diabetes in adults
and well-being. LDL: low-density lipoprotein cholesterol
MNT: medical nutrition therapy
4. Perform a thorough medication history of prescription, NPH: neutral protamine Hagedorn
over-the-counter, and herbal product use. OGTT: oral glucose tolerance test
Are there any medication problems, including pres- PPAR-: peroxisome proliferator activator receptor gamma
ence of adverse drug reactions, drug allergies, and PPG: postprandial glucose
drug interactions? SGOT: serum glutamic oxolacetic transaminase
Is the patient taking any medications that may affect SGPT: serum glutamic pyruvic transaminase
blood glucose control? SMBG: self-monitoring of blood glucose
5. Review all available laboratory data (some settings may TLC: therapeutic lifestyle change
have only patient-reported values) for attainment of ADA TSH: thyroid-stimulating hormone
goals (Table 407). What therapy goals are not being TZDs: thiazolidinediones
met, and what tests or referrals to other members of the
health care team are needed? Reference lists and self-assessment questions and answers are
6. Recommend appropriate therapy, and develop a plan to available at www.ChisholmPharmacotherapy.com.
assess effectiveness.
7. Stress adherence to prescribed lifestyle and medication Log into the website: www.pharmacotherapyprinciples.com
regimen. for information on obtaining continuing education credit for
8. Provide patient education on diabetes, lifestyle modica-
this chapter.
tions, appropriate monitoring, and drug therapy:
Causes of DM complications and how to prevent them.
How lifestyle changes including diet and exercise can KEY REFERENCES AND READINGS
affect diabetes.
How to perform SMBG and what to do with the results. American Association of Clinical Endocrinologists. Medical guidelines
When to take medications and what to expect. for the management of diabetes mellitus: The AACE system of
What adverse effects may occur? intensive diabetes self-management2002 update. Endocr Pract
What warning sign(s) should be reported to the 2002; 8(suppl 1):4082.
physician? American Diabetes Association. Diabetes Facts and Figures. Available at:
www.diabetes.org/diabetes-statistics.jsp; accessed March 28, 2006.
American Diabetes Association. Standards of medical care in dia- of the National Cholesterol Education Program (NCEP) Expert
betes. Diabetes Care 2006; 29(suppl 1):S4S42. Panel on Detection, Evaluation, and Treatment of High Blood
Centers for Disease Control and Prevention. Overweight and Obesity Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;
Trends. CDC. Available at: www.cdc.gov/nccdphp/dnpa/obesity/ 285:24862497.
index.htm; accessed March 28, 2006. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes:
DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 Scientic review. JAMA 2002; 287:360372.
diabetes mellitus: Scientific review. JAMA 2003; 289: Triplett CL, Reasner CA, Isley WL. Diabetes mellitus. In: DiPiro JT,
22542264. Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysio-
The Diabetes Control and Complications Trial Research Group. The logical Approach. 6th ed. New York: McGraw-Hill; 2005.
effect of intensive treatment of diabetes on the development and UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-
progression of long-term complications in insulin-dependent glucose control with sulphonylureas or insulin compared
diabetes mellitus. N Engl J Med 1993; 329:977986. with conventional treatment and risk of complications in
Expert Panel on Detection, Evaluation, and Treatment of High Blood patients with type 2 diabetes (UKPDS 33). Lancet 1998;
Cholesterol in Adults. Executive Summary of the Third Report 352:837853.
41 THYROID DISORDERS
Michael D. Katz
LEARNING OBJECTIVES
1. Explain the major components of the hypothalamic-pituitary-thyroid axis and the

interaction among these components.
2. Discuss the prevalence of thyroid disorders, including subclinical (mild) and overt (typical
signs and/or symptoms present) hypothyroidism and hyperthyroidism.
3. Discuss the relationship between serum thyroid-stimulating hormone (TSH) levels and
primary thyroid disease and the advantages for the use of TSH levels over other tests such as
serum T4 (thyroxine) and T3 (triiodothyroinine) levels.
4. Identify the typical signs and symptoms of hypothyroidism and the consequences of
inadequate treatment.
5. Describe the clinical use of levothyroxine in the treatment of hypothyroidism, including
initial dose and dose titration, and patient monitoring.
6. Discuss the issues regarding levothyroxine product bioequivalence and the advantages of
maintaining patients on the same product.
7. Identify the typical signs and symptoms of Graves disease and the consequences of
inadequate treatment.
8. Describe the management of hypothyroidism and hyperthyroidism in pregnant women.
9. Discuss the pharmacotherapy of Graves disease, including the advantages and disadvantages
of antithyroid drugs versus radioactive iodine, adverse effects, and patient monitoring.
10. Describe the potential effects of amiodarone, lithium, and interferon- on thyroid function.
KEY CONCEPTS screened or seek earlier medical attention. Patients with mild
hypothyroidism may have subtle symptoms that progress so
In most patients with thyroid hormone disorders, the mea- slowly that they are not noticed easily by the patient or family.
surement of a serum thyroid-stimulating hormone (TSH) The lack of overt or specic signs and symptoms emphasizes
level is adequate for the diagnosis of hypothyroidism and the importance of using the serum TSH level to identify
hyperthyroidism. The target TSH for most patients being patients with hypothyroidism.
treated for thyroid disorders should be the mean normal There are three major goals in the treatment of hypothy-
value of 1.4 milliunits/L or 1.4 microunits/mL (target range roidism: replace the missing hormones, relieve symptoms,
0.52.5 milliunits/L or 0.52.5 microunits/mL). and achieve a stable biochemical euthyroid state.
Hypothyroidism can affect virtually any tissue or organ in the Despite the availability of a wide array of thyroid hormone
body. However, the most common symptoms, such as fatigue, products, it is clear that synthetic levothyroxine (LT4) is the
lethargy, sleepiness, cold intolerance, and dry skin, are non- treatment of choice for almost all patients with hypothyroidism.
specic and are seen with many other disorders. The classic LT4 mimics the normal physiology of the thyroid gland, which
overt signs, such as myxedema and delayed deep tendon secretes mostly T4 as a prohormone. As needed, based on
reexes, are seen uncommonly now because more patients are metabolic demands, peripheral tissues convert thyroxine (T4)
667
to triiodothyronine (T3). If T3 is used to treat hypothyroidism, proper fetal growth and development, particularly development
the peripheral tissues lose their ability to control local meta- of the central nervous system (CNS). After delivery, the primary
bolic rates. LT4 also has distinct pharmacokinetic advantages role of thyroid hormone is in the regulation of energy metabo-
over T3. With a 7-day half-life, LT4 provides a very smooth dose- lism. These hormones can affect the function of virtually every
response curve with little peak and trough effect. organ in the body. The parafollicular C cells of the thyroid gland
There is no evidence that one LT4 product is better than produce calcitonin. The function of calcitonin and its therapeu-
another. However, given the likelihood that these products do tic use are discussed in other chapters in this book.
have different bioavailabilities, patients should be maintained T4 and T3 are produced by the organication (binding of
on the same LT4 product. Given the generic substitution reg- iodine to tyrosine residues of thyroglobulin) of iodine in the
ulations of most states, this is best accomplished by prescrib- thyroid gland. Iodine is actively transported into the thyroid
ing a brand-name product. The prescriber should not allow follicular cells. This inorganic iodine is oxidized by thyroid
substitution in the way mandated by state regulations. peroxidase and covalently bound to tyrosine residues of thy-
The goals of treating hyperthyroidism are to relieve symp- roglobulin. The iodinated tyrosine residues monoiodotyro-
toms, to reduce thyroid hormone production to normal levels sine and diiodotyrosine couple to form T4 and T3. Eighty per-
and achieve biochemical euthyroidism, and to prevent long- cent of thyroid hormone is synthesized as T4 and is stored in
term adverse sequelae. the thyroid bound to thyroglobulin. Thyroid hormones are
Agranulocytosis is one of the most serious adverse effects of released from the gland when needed, primarily under the
antithyroid drug therapy. inuence of thyroid-stimulating hormone (TSH) from the
The growth and spread of thyroid carcinoma are stimulated anterior pituitary. T4 and T3 are transported in the blood by
by TSH. An important component of thyroid carcinoma man- three proteins, 70% to thyroid-binding globulin (TBG), 15%
agement is the use of LT4 to suppress TSH secretion. Early in to transthyretin (thyroid-binding prealbumin), and 15% to
therapy, patients receive the lowest LT4 dose sufcient to fully albumin. T4 is 99.97% protein-bound, and T3 is 99.7% protein-
suppress TSH to undetectable levels. Controlled trials show bound, with only the unbound or free fractions physiologically
that suppressive LT4 therapy reduces tumor growth and active. The high degree of protein binding results in a long
improves survival. half-life of these hormones: approximately 7 days for T4 and
Patients receiving amiodarone must receive monitoring for 24 hours for T3.
thyroid abnormalities. Baseline measurements of serum TSH, Most of the physiologic activity of thyroid hormones is
FT4, FT3, antithyroid peroxidase antibody (anti-TPOAb) and from the actions of T3. T4 can be thought of primarily as a pro-
TSH receptor-stimulating antibodies (TSHR-SAb) should be hormone. Eighty percent of needed T3 is derived from the con-
performed. TSH, FT4, and FT3 should be checked 3 months version of T4 to T3 in peripheral tissue under the inuence of
after initiation of amiodarone and then every 3 to 6 months. tissue deiodinases. These deiodinases allow end organs to pro-
duce the amount of T3 needed to control local metabolic func-
Thyroid disorders are common. Over 2 billion people, or 38% tions. These enzymes also catabolize T3 and T4 to biologically
of the worlds population, have iodine deciency, resulting in inactive metabolites. Thyroid hormones bind to intracellular
74 million people with goiters. While iodine deciency is not receptors and regulate the transcription of various genes.
a signicant problem in developed countries, a number of The production and release of thyroid hormones are regu-
common thyroid problems exist. The most common prob- lated by the hypothalamic-pituitary-thyroid axis (Fig. 411).
lems related to thyroid function, hypothyroidism and hyper- Hypothalamic thyrotropin-releasing hormone (TRH) stimu-
thyroidism, often require long-term pharmacotherapy. lates the release of TSH (thyrotropin) when there are physio-
Undetected or improperly treated thyroid disease can result in logically inadequate levels of thyroid hormones. TSH promotes
long-term adverse sequelae, including increased mortality. It the production and release of thyroid hormones from the
is important that clinicians are aware of the prevalence of thy- gland. As circulating thyroid hormone levels rise to needed
roid disorders, methods of identifying thyroid disorders, and levels, negative feedback results in decreased release of TSH and
appropriate therapy. This chapter focuses on the most com- TRH. The release of TRH is inhibited by somatostatin and its
mon pharmacologically treated thyroid disorders. analogs, and the release of TSH can be inhibited by dopamine,
dopamine agonists, and high levels of glucocorticoids.
THYROID HORMONE PHYSIOLOGY AND

BIOSYNTHESIS SPECTRUM OF THYROID DISEASE
The thyroid gland is the largest endocrine gland in the body, There are two general modes of presentation for thyroid
residing in the neck, anterior to the trachea, between the disorders: changes in the size or shape of the gland and
cricoid cartilage and the suprasternal notch. The thyroid gland changes in secretion of hormone from the gland. In some
produces two biologically active hormones, thyroxine (T4) and cases, structural changes can result in changes in hormone
triiodothyronine (T3). Thyroid hormones are essential for secretion. Thyroid nodules and goiters in euthyroid patients
CHAPTER 41 / THYROID DISORDERS 669
Epidemiology of Thyroid Disease

A number of studies have assessed the epidemiology of thyroid
hormone abnormalities. The Third National Health and
Hypothalamus Nutrition Examination Survey (NHANES III)1 reported the
prevalence of thyroid hormone disorders in 17,353 people
TRH
12 years and over in a sample representing the geographic and
(+) ethnic distribution of the United States population. Hypo-
thyroidism was found in 4.6% (4.3% subclinical) and hyperthy-
(?) roidism in 1.3% (0.7% subclinical) of the sample. Antithyroid
Pituitary peroxidase antibodies (anti-TPOAb) were found in 11.3% of
()
this population. The prevalence of hypothyroidism was higher
in older age groups and in whites and Hispanics, whereas blacks
had a lower prevalence of antithyroid antibodies and hypothy-
roidism. The Colorado Thyroid Health Survey2 assessed thyroid
T3 + T4 function in 25,862 subjects attending a health fair. The overall
TSH
prevalence of an abnormal TSH level was 11.7% of the study
population, with 9.4% hypothyroid (9% subclinical) and 2.2%
hyperthyroid (2.1% subclinical). Of the 916 subjects taking thy-
(+) roid medication, 60% were euthyroid, with an equal distribution
between subclinical hypothyroidism and hyperthyroidism.
Thyroid These ndings imply that many patients who are receiving thy-
FIGURE 411. Hypothalamic-pituitary-thyroid axis. Thyrotropin- roid medications are not being managed successfully.
releasing hormone (TRH) is synthesized in the neurons within the
paraventricular nucleus of the hypothalamus. TRH is released into
the hypothalamic-pituitary portal circulation and carried to the PATIENT ASSESSMENT AND MONITORING
pituitary, where it activates the pituitary to synthesize and release
thyrotropin (TSH). TSH activates the thyroid to stimulate the syn- The assessment of patients for thyroid disorders entails a history
thesis and secretion of thyroxine (T4) and triiodothyronine (T3). T4 and physical examination. In many patients with subclinical or
and T3 inhibit TRH and TSH secretion, closing the feedback loop. mild thyroid disease, there may be an absence of specic signs
and symptoms, and the physical examination may be normal.
Various diagnostic tests can be used, including serum thyroid
hormone(s), TSH, and thyroid antibody levels and imaging
are common problems. Patients with a goiter often require techniques to evaluate patients for thyroid disorders. Normal
no specic pharmacotherapy, unless the goiter is due to values for selected laboratory tests are given in Table 411.
iodine deciency. In developing countries, iodized salt is the
TABLE 411. Selected Thyroid Tests for Adults
primary therapy in treating goiter. Thyroid nodules, seen in
4% to 7% of adults, may be malignant or autonomously Test Normal Range Comments
secrete thyroid hormones. A discussion of thyroid nodules
TSH 0.52.5 milliunits/L Gold standard; may be
is beyond the scope of this chapter. However, thyroid cancer (0.52.5 lowered by dopamine,
will be discussed briey in the context of levothyroxine microunits/mL)a dopamine agonists,
(LT4) suppressive therapy. The reader is referred to other glucocorticoids,
resources for a more extensive review of thyroid cancer octreotide, recovery
from severe
management.
nonthyroidal illness
Changes in hormone secretion can result in hormone de-
Free T4 0.71.9 ng/dL May be normal in mild
ciency or excess. While patients with overt hypothyroidism and (9.024.5 pmol/L) thyroid disease
hyperthyroidism may have dramatic signs and symptoms, Anti-TPOAb Less than 100 units/mL Present in autoimmune
most patients have subtle signs and symptoms that progress hypothyroidism;
slowly over time. The availability of sensitive and specic bio- predicts more rapid
chemical tests for the diagnosis of thyroid hormone disorders progression from
has facilitated screening and earlier diagnosis, including those subclinical to overt
hypothyroidism
with subclinical thyroid disorders. Screening of newborns for
TSHR-SAb Undetectable Conrms Graves disease
congenital hypothyroidism has reduced the incidence of men-
a
tal retardation and cretinism dramatically in the United States. milliunits/L = microunits/mL; clinical laboratories use either unit of meas-
urement. Anti-TPOAb, antithyroid peroxidase antibody; T4, thyroxine;
However, congenital hypothyroidism owing to iodine de- TSH, thyroid-stimulating hormone; TSH-SAb, TSH receptor-stimulating
ciency remains a signicant worldwide public health problem. antibodies.
TSH Levels Serum Hormone Levels

In most patients with thyroid hormone disorders, the Serum T4 and T3 levels were used commonly to assess thyroid
measurement of a serum TSH level is adequate for the diagno- function. Screening thyroid function tests measure total serum
sis of hypothyroidism and hyperthyroidism. TSH is a highly T4 or T3 levels. Because of the high degree of protein binding
sensitive bioassay of the thyroid axis. A two-fold change in of these hormones, the free fraction can be altered by changes
serum free T4 levels will result in a 100-fold change in TSH in the levels of binding proteins or the degree of protein bind-
levels. This biologic magnication by TSH allows the TSH ing. Since a number of factors can alter protein binding, the
to be used in early diagnosis as well as in closely titrating older assays are very insensitive and should no longer be used,
therapy in hypothyroidism and hyperthyroidism. 3 In even with protein-binding adjustment factors such as the free
patients with hypothyroidism or hyperthyroidism resulting thyroxine index. Free or unbound T4 (FT4) and T3 (FT3) assays
from gland dysfunction (primary thyroid disease), there is are readily available and are more sensitive in identifying thy-
an inverse relationship between the TSH level and thyroid roid dysfunction than the older total assays.5 However, patients
function. High TSH signies hypothyroidism (or iatrogenic with mild hypothyroidism or hyperthyroidism will have a nor-
underreplacement), and low TSH signies hyperthyroidism mal FT4 level despite an abnormal TSH level.
(or iatrogenic overreplacement). There is controversy The laboratory assessment of patients with suspected thy-
regarding the normal or laboratory reference ranges for roid disorders must be based on the continuum of disease
TSH. NHANES III1 showed that the mean TSH level in a from subclinical or mild to overt (Fig. 412).
normal population was 1.4 milliunits/L (milliunits/L =
microunits/mL; clinical laboratories use either unit of meas-
urement), but the values were not normally distributed.
While most laboratories quote the upper limit of normal Global tests of thyroid gland function can be performed to assess
for TSH as 4.5 milliunits/L based on the NHANES III data, the rate of hormone synthesis. The radioactive iodine uptake
95% of subjects had a TSH level of between 0.5 and (RAIU) will be elevated in hyperthyroidism and can aid in iden-
2.5 milliunits/L. The population of subjects whose TSH level tifying thyrotoxicosis owing to non-thyroid gland sources.
was 2.5 to 4.5 milliunits/L probably had mild hypothy- Radionuclide thyroid scans are used in the evaluation of thyroid
roidism and should not have been included as part of the nodules. Since many thyroid disorders are autoimmune, meas-
normal reference range for TSH. It has been proposed that urement of various serum antithyroid antibodies can be per-
the reference TSH range be redened with an upper limit of formed. Antithyroid peroxidase (anti-TPOAb) and antithy-
normal of 2.5 or 3 milliunits/L.4 The target TSH for most roglobulin antibodies (anti-TGAb) are present in many patients
patients being treated for thyroid disorders should be the mean with hypothyroidism. Most patients with Graves disease will
normal value of 1.4 milliunits/L or 1.4 microunits/mL (target have TSH stimulating receptor antibodies (TSHR-SAb) as well
range 0.52.5 milliunits/L or 0.52.5 microunits/mL). as elevated anti-TPOAb and antimicrosomal antibodies.
0.5 2.0 FIGURE 412. TSH

and the continuum
of thyroid disorders.
FT3, free T3; FT4, free
LT4 Rx T4; LT4, levothyroxine;
? mild therapeutic ? mild
(subclinical) (subclinical) TPOAb, thyroid pero-
target xidase antibody; TSH,
Overt hypothyroidism hypothyroidism
Overt thyroid-stimulating
hypothyroidism hypothyroidism hormone. (Reprinted,
New with permission,
Elevated
FT4 and/or FT3 TSH Low FT4 from reference 4.)
FT4 & FT3 FT4 within +
+ within range reference range
Low TSH Elevated TSH
reference ranges + TPOAb
TSH mU/L 0.01 0.1 1.0 10 100

2.5
~0.4 ~4.0
Current laboratory
TSH reference limits
Milliunits/L (mU/L) = microunits/mL (U/L); clinical laboratories use either unit of measurement.
HYPOTHYROIDISM TABLE 412. Common Causes of Hypothyroidism10,12
Primary Hypothyroidism
Hypothyroidism is the most common clinical disorder of thyroid
Autoimmune thyroiditis (Hashimotos disease)
function. It is the clinical syndrome that results from inadequate Iatrogenic (irradiation, surgery)
secretion of thyroid hormones from the thyroid gland. The vast Drugs (amiodarone, radiocontrast media, lithium, -interferon)
majority of hypothyroid patients have primary gland failure, Silent thyroiditis (including postpartum)
whereas rare patients have pituitary or hypothalamic failure. Secondary Hypothyroidism
Most studies dene hypothyroidism based on a serum TSH level Pituitary disease
above the upper limit of the laboratory reference range. In adults, Hypothalamic disease
1.4% of women and 0.1% of men are biochemically hypothy-
roid. However, the incidence is highly age-dependent. In the Signs and Symptoms of Hypothyroidism
Colorado Thyroid Health study,2 by age 64, 12% of women and
Hypothyroidism can affect virtually any tissue or organ in
5% of men were hypothyroid, and in the over 74 years age group,
the body. The most common symptoms, such as fatigue, lethargy,
the incidence in men approached that of women. Most epi-
sleepiness, cold intolerance, and dry skin, are non-specic and can
demiologic studies of hypothyroidism in the elderly show a
prevalence of 6% to 12%. There is a strong correlation between
the presence of anti-TPOAb or anti-TGAb and the risk of devel- Clinical Presentation and Diagnosis of
oping hypothyroidism. In patients with subclinical hypothy- Hypothyroidism10
roidism and positive anti-TPOAb, 5% per year will progress to
overt hypothyroidism.6 Other risk factors for the development of
hypothyroidism include postpartum state, family history of Symptoms
autoimmune thyroid disorders, a previous history of head and Fatigue
neck or thyroid surgery, head and neck irradiation, other autoim- Lethargy
mune endocrine disorders such as type 1 diabetes and Addisons Sleepiness
disease, other non-endocrine autoimmune diseases such as celiac Mental impairment
Depression
disease and pernicious anemia, prior history of treatment for
Cold intolerance
thyrotoxicosis, and treatment with amiodarone or lithium. Hoarseness
Dry skin
Screening for Hypothyroidism Decreased perspiration
Because the prevalence of hypothyroidism is high in certain Weight gain
Decreased appetite
populations, screening may be useful. Screening for hypothy-
Constipation
roidism in women over age 35 is as cost-effective as screening Menstrual disturbances
for breast cancer and hypertension,7 although some organiza- Arthralgia
tions recommend screening of adults over the ages of 50 or 60. Paresthesia
Others advocate a case-nding approach, i.e., to perform a
Signs
TSH determination in patients based on risk factors or the
Slow movements
presence of signs and symptoms.8,9 Slow speech
Hoarseness
Causes of Hypothyroidism Bradycardia
The most common causes of hypothyroidism are listed in Dry skin
Non-pitting edema (myxedema)
Table 412. Up to 90% of patients with autoimmune thy-
Hyporeexia
roiditis have circulating anti-TPOAbs. The autoimmune Delayed relaxation of reexes
inammatory response results in a lymphocytic inltration of
the thyroid gland and its eventual destruction. Screening/Diagnosis
A TSH level of 4.5 to 10 milliunits/L constitutes mild or sub-
Iatrogenic hypothyroidism can follow thyroid irradiation
clinical hypothyroidism, and some patients with a TSH level
or surgery and excessive doses of antithyroid drugs. Several
of 2.5 to 4.5 milliunits/L also may be mildly hypothyroid. A
drugs can cause hypothyroidism, including iodine-containing TSH level greater than 10 milliunits/L signies overt hypo-
drugs such as amiodarone and radiocontrast media, lithium, thyroidism. The free T4 level will be normal (0.71.9 ng/dL
interferon-, p-aminosalicylic acid, and aminoglutethimide.5 or 9.024.5 pmol/L) in mild or subclinical hypothyroidism
Iodine deciency is a common worldwide cause of hypothy- and low (less than 0.7 ng/dL or 9.0 pmol/L) in patients with
roidism, including congenital hypothyroidism in newborns. obvious signs and/or symptoms.
Patients with hypothalamic or pituitary disease often have

other signs of pituitary disease, such as hypogonadism, and Milliunits/L (mU/L) = microunits/mL (U/L); clinical laborato-
ries use either unit of measurement.
the TSH level will be low.
be seen with many other disorders. The classic overt signs, such as hypothyroidism, the peripheral tissues lose their ability to control
myxedema and delayed deep tendon reexes, are seen uncom- local metabolic rates. LT4 also has distinct pharmacokinetic advan-
monly now because more patients are screened or seek medical tages over T3. With a 7-day half-life, LT4 provides a very smooth dose-
attention earlier. Patients with mild hypothyroidism may have response curve with little peak and trough effect. T3, with a 24-hour
subtle symptoms that progress so slowly that they are not noticed half-life, provides a signicant peak and trough effect, and many
easily by the patient or family. The lack of overt or specic signs and patients will have symptoms of thyrotoxicosis after each dose is
symptoms emphasizes the importance of using the serum TSH level administered. For patients who have difculty adhering to a once-
to identify patients with hypothyroidism. daily regimen, a once-weekly LT4 regimen is safe and effective.
Animal-derived products such as desiccated thyroid and
Sequelae of Hypothyroidism thyroglobulin are derived from cow and pig thyroid and have
various degrees of purity. These products contain both LT4
Hypothyroidism is a chronic disease that may result in signif-
and T3, but the amount of T3 is much higher (T4:T3 = 4:1)
icant long-term sequelae. Hypercholesterolemia is associated
than what would be found in the human thyroid gland
with hypothyroidism, increasing the long-term risk of cardio-
(T4:T3 = 14:1). With the desiccated thyroid products, there are
vascular disease. Between 4% and 14% of patients with hyper-
cholesterolemia are found to be hypothyroid. The Colorado concerns about standardizing the amount of hormone and
Thyroid Health Study2 showed a direct correlation between lot-to-lot variability. While some patients want to use these
the degree of TSH elevation and the rise in serum cholesterol. agents because they are natural, they are not natural for
Hypothyroidism also may result in increased systemic vascu- humans. With the strong evidence supporting the safety and
lar resistance, decreased cardiac output, and increased dias- efcacy of LT4 in the treatment of hypothyroidism, there is no
tolic blood pressure. Hypothyroidism can cause signicant rationale for the use of these animal-derived products. Patients
neuropsychiatric problems, including a dementia-like state in who are being treated with these agents should be strongly
the elderly that is reversible with levothyroxine (LT4) therapy. encouraged to switch to synthetic LT4. Also, patients should be
Maternal hypothyroidism can have dire consequences for the encouraged not to purchase thyroid-containing products from
developing fetus. The fetus is almost completely dependent on health food stores or from questionable Internet sites.
maternal thyroid hormones during the rst trimester, a time Liotrix is a xed-ratio LT4/T3 product, although the LT4:T3
crucial for development of the CNS. Inadequately treated ratio is not physiologic for humans. Several studies have been
maternal hypothyroidism results in increased risk of miscar- published that evaluate the use of LT4 and T3 combinations in
riage and developmental impairment in the child.11 ratios that mimic human physiology. While early studies with
Myxedema coma is seen in advanced hypothyroidism. these combinations showed improved neuropsychiatric and
These patients develop CNS depression, respiratory depression, quality-of-life outcomes compared with LT4 monotherapy,
cardiovascular instability, and uid and electrolyte distur- subsequent randomized, controlled trials have shown no out-
bances. Myxedema coma often is triggered by an underlying come benet.13 Except in rare circumstances (such as patients
acute medical condition such as infection, stroke, trauma, or with impaired T4-to-T3 conversion), there is no rationale for
administration of CNS depressant drugs. using combinations of LT4 and T3 to treat hypothyroidism.
TREATMENT Bioequivalence and LT4 Product Selection

LT4 products have a long history of bioavailability problems.14
Pharmacotherapy of Hypothyroidism Over the years, LT4 bioavailability has increased, so maintenance
There are three major goals in the treatment of hypothy- doses today are signicantly lower than those seen in the 1970s
roidism: replace the missing hormones, relieve symptoms, and and early 1980s. Currently, the average bioavailability of LT4
achieve a stable biochemical euthyroid state. While these goals products is about 80%. Because of long-standing concerns about
should not be difcult to achieve, 20% to 40% of treated LT4 bioequivalence, and because LT4 products had never under-
patients are not receiving optimal pharmacotherapy. gone formal approval by the Food and Drug Administration
(FDA) under the 1938 Food, Drug, and Cosmetics Act, the FDA
Thyroid Hormone Products mandated that all manufacturers of LT4 products submit an
A number of thyroid hormone products are marketed in the Abbreviated New Drug Application (ANDA) to keep their prod-
United States (Table 413). These products include synthetic LT4 ucts on the United States market after 2001.15 Products approved
and T3, combinations of synthetic LT4 and T3, and animal- under this process would have to comply with FDA manufactur-
derived products. Despite the availability of a wide array of thy- ing and bioequivalence standards. This FDA action has resulted
roid hormone products, it is clear that synthetic LT4 is the treatment in many changes in the United States LT4 market, as well as
of choice for almost all patients with hypothyroidism.12 Using LT4 renewed interest in LT4 bioequivalence. By 2006, several brand
mimics the normal physiology of the thyroid gland, which secretes and generic products had been approved by the FDA. Some of
mostly T4 as a prohormone. Peripheral tissues convert T4 to T3 as the generic products carry AB ratings (bioequivalence) to certain
needed, based on metabolic demands. If T3 is used to treat brand products.16
TABLE 413. Thyroid Preparations
Drug/Dosage
Form Content Relative Dose Comments
Levothyroxine Synthetic LT4; 60 mcg Gold standard for treating hypothyroidism;
(Synthroid , 25, 50, 75, products not therapeutically equivalent;
Levoxyl, 88, 100, 112, full replacement dose 11.6 mcg/kg per
Unithroid), other 125, 137, 150, day; when switching from animal product,
brands, and generics 175, 200, and lower calculated daily dose by 2550 mcg;
300 mcg tablets; intravenous form rarely needed
500 mcg vial for injection
Liothyronine (Cytomel) Synthetic T3; 5, 25, 15 mcg Rarely needed in treatment of hypothyroidism;
and 50 mcg tablets rapid absorption and pharmacologic effect;
increased toxicity versus LT4; no outcome
benet to combining with LT4
Thyroid (desiccated) Desiccated pork or beef 1 grain (65 mg) Non-physiologic for humans; unpredictable
USP (Armour, thyroid glands; contains hormone content and stability; T3 content
others) T3 and T4; 0.25, 0.5, may cause toxicity
1, 1.5, 2, 3, 4, and
5-grain tablets
Thyroglobulin (Proloid) Partially puried pork 65 mg Non-physiologic T4: T3 ratio; T3 content may
thyroglobulin; cause toxicity; removed from United States
32, 65, 100, 130, market
and 200 mg tablets
Liotrix (Thyrolar) Synthetic T4, T3 in xed 4:1 12.5/50 mcg T3: T4 Non-physiologic T4: T3 ratio; T3 content
ratio; 1/4, 1/2, 1, 2, 3 (1 strength) may cause toxicity
strength tablets
LT4, levothyroxine; T3, triiodothyronine; T4, thyroxine.
For many years, there have been concerns regarding the FDA and colleagues19 helps to answer this question. Twenty-two well-
bioequivalence methodology for LT4 products. FDA bioequiva- controlled hypothyroid women were randomly switched to the
lence standards allow a 20% to +25% variance in pharmacoki- same dose of four different products every 6 weeks. Non-baseline
netic parameters between the test and reference products. Many corrected bioequivalence data showed these products to be bio-
people feel that this degree of allowed variance is not appropri- equivalent. However, as each product switch occurred, more of
ate for a narrow-therapeutic-index (NTI) drug such as LT4.17 the subjects had an abnormal TSH level.20 By the end of the
Also, there are unique challenges to performing bioequivalence third product switch, 52% had an abnormal TSH level. This is
studies in an endogenous hormone such as LT4. Since these strong evidence that LT4 products are not therapeutically equiv-
single-dose pharmacokinetic studies are done in healthy vol- alent even if they are rated as bioequivalent by the FDA.
unteers, the pharmacokinetic data are a combination of endoge- Evidence does exist that small differences in the LT4 dose
nous and exogenous LT4. Seventy percent of the area under the can result in large changes in TSH. The impact on TSH of
curve (AUC) in these studies consists of the subjects endoge- small changes in LT4 dose was assessed in 21 adult hypothyroid
nous T4. Thus, it is doubtful that bioavailability differences patients.21 When the daily dose was reduced by 25 mcg, 78%
among products could be detected. Blakesley and colleagues18 had an elevated TSH level. When the daily dose was increased
showed that the standard FDA bioequivalence methodology by 25 mcg, 55% had a low TSH level. Clearly, differences in the
would rate 600, 450, and 400 mcg LT4 doses as bioequivalent. LT4 dose or bioavailability within the FDA-allowed variance for
This study also showed that mathematically removing the sub- bioequivalent products can cause signicant changes in TSH.
jects endogenous T4 level (baseline correction) improves the There is no evidence that one LT4 product is better than
sensitivity of the analysis, allowing a distinction between 33% another. However, given the likelihood that these products do have
and 25% but not 12.5% dose differences. Based on these data, different bioavailabilities, patients should be maintained on the
the FDA, since 2003, has required that LT4 bioequivalence data same LT4 product. Given the generic substitution regulations of
undergo baseline correction. While this method has improved most states, this is best accomplished by prescribing a brand-name
the ability to identify large differences in LT4 bioequivalence, product and not allowing substitution in the way mandated by
small but clinically signicant differences will not be identied. state regulations. While practitioners are pressured by managed-
More important than bioequivalence is the therapeutic care organizations and employers to substitute LT4 products as
equivalence of LT4 products. Will patients have the same out- a cost-saving measure, such switching is not in the best interest
comes if bioequivalent products are used? The study by Dong of the patient and should not be allowed. If patients are
switched to a different product, a TSH determination should be full replacement dose. In patients with ischemic heart disease,
done in 6 to 8 weeks to allow retitration. The economic impact start with 12.5 to 25 mcg/day and slowly titrate to the full
of retitration must be considered when formularies are changed replacement dose. If the patient develops angina or other forms
to reduce the drug acquisition cost. of myocardial ischemia, lower the dose and titrate more slowly.
At the start of therapy and with each change in dose, recheck the
Therapeutic Use of LT4 TSH in 6- to 8-week intervals. If the TSH is not in the target range
LT4 is indicated for patients with overt hypothyroidism.22 (0.52.5 milliunits/L), change the dose by 10% to 20% and then
However, the need for treatment is controversial in patients recheck the TSH 6 to 8 weeks later. As the dose is titrated, assess
with mild or subclinical disease (TSH less than 10 milli- the patients symptoms. Many patients will improve quickly, and
units/L). There are no large clinical trials that show an outcome many patients will feel the best if the TSH is titrated to low-
benet with treating these patients, and the therapeutic decision normal to middle-normal levels (0.51.5 milliunits/L).
must be individualized.1,23 Many patients with subclinical Patients with mild or subclinical hypothyroidism do not
hypothyroidism do, in fact, have subtle symptoms that need to be started on the full replacement dose because they
improve with LT4 replacement. If the patients serum choles- still have some endogenous hormone production. Start these
terol is elevated,24 or if serum anti-TPOAbs are present, many patients on 25 to 50 mcg/day, and titrate every 6 to 8 weeks
clinicians recommend LT4 therapy. based on TSH levels. Over time, it is likely that the LT4 dose
In patients younger than age 65 with overt hypothyroidism, will need to be increased slowly as the patients thyroid gland
the average LT4 replacement dose is 1.6 mcg/kg per day (use loses residual function.
ideal body weight in obese patients25). If there is no history of
cardiac disease, these patients may be started on the full Risks of Over- and Undertreatment
replacement dose. The full replacement dose in patients over Patients receiving LT4 therapy who are not maintained in a
age 75 is lower, about 1 mcg/kg per day.26 In the elderly, the euthyroid state are at risk for long-term adverse sequelae. In
starting dose is 25 to 50 mcg/day, and the dose is titrated to the general, overtreatment and a suppressed TSH is more common
than undertreatment27 with an elevated TSH. Patients with
long-term overtreatment may be at higher risk for atrial bril-
Patient Encounter 1, Part 1 lation and other cardiovascular morbidities, depression, and
post-menopausal osteoporosis. Patients who are undertreated
are at higher risk for hypercholesterolemia and other cardiovas-
cular problems, depression, and obstetric complications.
HT, a 34-year-old woman, comes to the clinic complaining
of fatigue, lethargy, and having a fuzzy head for the past Alterations in LT4 Dose Requirements
6 months. She thought it was because she was working too A number of factors can alter LT4 dose requirements (Table 414).
hard, but the symptoms have not improved despite a better
The most common cause of increased dose requirement is
work schedule. She has noticed a 5-lb (2.3-kg) weight gain,
her menses have become heavier, she feels cold all the
the co-administration of LT4 with calcium or iron supple-
time, and her skin is drier. She takes no medications other ments. Counsel patients that they should take the LT4 dose at
than occasional acetaminophen for headache and milk of least 2 hours before or 6 hours after the calcium or iron dose.
magnesia for constipation. Her vital signs and physical
examination, including pelvic examination are normal. Patient Monitoring
Labs Patients on stable LT4 therapy do not need frequent monitor-
Serum cholesterol: 220 mg/dL (5.7 mmol/L; normal less than ing. In most patients, measuring a TSH every 6 to 12 months,
200 mg/dL, or 5.2 mmol/L) along with an assessment of clinical status, is adequate
TSH: 9.7 milliunits/L (normal 0.52.5 milliunits/L) (Table 415). If the patients clinical status changes (e.g.,
Free T4: 0.6 ng/dL (7.7 pmol/L; normal 0.71.9 ng/dL, or pregnancy, etc.), more frequent monitoring may be neces-
924.5 pmol/L) sary. LT4 prescriptions should be written as microgram doses
She weighs 66 kg (145 lb), and she is 5 ft, 7 in (170 cm) tall. to avoid potential errors when written as milligram doses (e.g.,
250 mcg dispensed when 0.025 mg is ordered).
Why should HT receive LT4 therapy? Patient education is an important component of care.
What dose would you initiate?
Educate patients about the benets of proper therapy, the
How would you monitor and titrate her therapy?
What would you tell HT regarding the signicance of her
importance of adherence, and the importance of receiving a
symptoms, elevated TSH level, and risk versus benets of consistent LT4 product. Some patients will take excessive
LT4 therapy? amounts of LT4 in an effort to feel better or as a weight-
loss treatment. Explain to patients that excessive amounts of
LT4 will not improve symptoms more than therapeutic
Milliunits/L (mU/L) = microunits/mL (U/L); clinical laborato-
ries use either unit of measurement. doses and that this drug is not an effective treatment for
obesity.
TABLE 414. Factors That Alter LT4 Dose Requirements

Increased Dose Decreased Dose
Requirement Requirement
Decreased LT4 absorption Aging
Malabsorption syndromes Delivery of pregnancy One year later, HT comes to you and excitedly states that she
Withdrawal of interacting is pregnant. She just saw her obstetrician, who started her on
substance a prenatal vitamin. She states that she has felt very well since
Drugs/Diet: her LT4 was started and that she is amazed at how much bet-
Calcium ter she feels (I didnt know how bad I felt until I started the
Iron thyroid medicine). The most recent TSH determination,
Aluminum obtained 6 months ago, was 1.5 milliunits/L (normal 0.52.5
Fiber milliunits/L). Her current LT4 dose is 88 mcg/day.
Soy
Cholestyramine/colestipol
Sucralfate
How will pregnancy affect HTs LT4 dose requirement?
Sodium polystyrene sulfonate What would you recommend regarding her LT4 dose and
monitoring?
Increased TBG:
Pregnancy
What would you tell HT regarding the potential impact of
Cirrhosis her pregnancy on her LT4 therapy and the potential risks
Estrogen therapy to her baby if she is not given an adequate dose of LT4
Tamoxifen, raloxifene therapy during her pregnancy?
Hereditary

Increased clearance: Milliunits/L (mU/L) = microunits/mL (U/L); clinical laborato-
Rifampin ries use either unit of measurement.
Carbamazepine
Phenytoin
Phenobarbital
hypothyroid women who become pregnant will quickly
Impaired deiodination:
need an increased dose of LT4, averaging 50% above the pre-
Amiodarone
pregnancy dose.28 The increased dose should be maintained
Mechanism unknown:
Sertraline
throughout the pregnancy, with monthly TSH monitoring to
Lovastatin keep the TSH in the middle- to low-normal range. After deliv-
ery, the LT4 dose can be reduced to pre-pregnancy levels. Since
LT4, levothyroxine; TBG, thyroxine-binding globulin.
prenatal vitamins contain signicant amounts of calcium and
iron, remind these patients to take the LT4 dose at least 2 hours
Special Populations and Conditions before or 6 hours after the vitamin.
Hypothyroidism and Pregnancy
Children
Hypothyroidism during pregnancy has a variety of maternal
Congenital hypothyroidism is still seen in the United States, and
and fetal adverse effects.11 During pregnancy, -human chori-
all newborns in the United States undergo screening with a
onic gonadotropin (-hCG) acts as a TSH receptor agonist,
TSH level. As soon as the hypothyroid state is identied, the
increasing the amount of thyroid hormone available for fetal
newborn should receive the full LT4 replacement dose. The
growth and development. Maternal hypothyroidism results in
replacement dose of LT4 in children is age-dependent. In new-
an increased rate of miscarriage and decreased intellectual
borns, the usual dose is 10 to 17 mcg/kg per day. LT4 tablets may
capacity of the child. Endocrinologists recommend a TSH
be crushed and mixed with breast milk or formula. Serum FT4
measurement as soon as the pregnancy is conrmed. Most
levels (target 1.62.2 ng/dL or 20.5928.31 pmol/L) are used for
dose titration in infants because the TSH level may not respond
TABLE 415. Monitoring LT4 Therapy
to treatment as it does in older children and adults. By 6 months
Serum TSH: of age, the required dose is reduced to 5 to 7 mcg/kg per day,
Every 612 months or if change in clinical status and from ages 1 to 10 years, the dose is 3 to 6 mcg/kg per day.
68 weeks after any dose or product change After age 12, adult doses can be given.
In rst trimester pregnancy, then monthly
Same product prescribed/dispensed with every rell.
Watch for mg/mcg dosing errors. Myxedema Coma
Assess patients understanding of disease, therapy, and need for This is a life-threatening condition owing to severe, long-
adherence and tight control. standing hypothyroidism and has a mortality rate of 60% to
Assess for signs/symptoms of over- and undertreatment. 70%. These patients are given 300 to 500 mcg intravenous LT4
Identify potential interactions between LT4 and foods and/or drugs.
initially, using caution in patients with underlying cardiac
LT4, levothyroxine; TSH, thyroid-stimulating hormone. disease. While administration of T3 would provide a more
rapid onset of action, there is no evidence that T3 improves

Hypothyroidism Patient Care and outcomes in myxedema coma. Historically, glucocorticoids,
Monitoring such as hydrocortisone 50 to 100 mg every 6 hours, are admin-
istered owing to concern about simultaneous adrenal insuf-
ciency. While there is no strong evidence for an outcome benet,
1. Use serum TSH to identify patients with hypothyroidism
the use of glucocorticoids is reasonable because such treatment
and to monitor LT4 replacement therapy.
may be lifesaving, and the risks of a short course of cortico-
2. Use synthetic LT4 as the treatment of choice for
steroids at this dose are low. As patients improve, the LT4 dose
hypothyroidism.
can be given orally in a typical full replacement dose.
3. Provide LT4 replacement to patients with overt
hypothyroidism.
4. Consider replacement therapy in patients with a TSH HYPERTHYROIDISM/THYROTOXICOSIS
level of greater than 2.5 but less than 10 milliunits/L
who have subtle symptoms (e.g., mild fatigue, Hyperthyroidism is much less common than hypothyroidism.
lethargy, etc.), elevated cholesterol, or positive anti- In NHANES III,1 1.3% of the population was hyperthyroid
TPOAbs. (0.5% overt, 0.8% subclinical), with the highest incidences in
5. Provide the calculated full replacement LT4 dose women overall and in men and women in the 20 to 39 and over
(1.6 mcg/kg per day based on ideal body weight if 80 years of age groups. The Colorado Thyroid Health Study2
obese) to patients with overt hypothyroidism who are showed a hyperthyroid incidence of 2.2% (2.1% subclinical).
older than 12 and younger than 65 years of age and
who do not have cardiac disease. Causes of Thyrotoxicosis
6. Patients with mild hypothyroidism may be started at 25
to 50 mcg/day of LT4. The common causes of thyrotoxicosis are shown in Table 416.29,30
Thyrotoxicosis can be related to the presence or absence of excess
7. Elderly patients or those with cardiac disease should be
hormone production (hyperthyroidism). Graves disease is the
started at a lower LT4 dose (e.g., 12.525 mcg/day).
most common cause of hyperthyroidism. Thyrotoxicosis in the
8. Measure serum TSH 6 to 8 weeks after starting or any
elderly is more likely due to toxic thyroid nodules or multi-
dose change. If the TSH level is not in the target range,
nodular goiter than to Graves disease. Excessive intake of thy-
alter the dose by 10% to 20% increments.
roid hormone may be due to overtreatment with prescribed
9. The target TSH for patients on LT4 replacement therapy
therapy. Surreptitious use of thyroid hormones also may occur,
for hypothyroidism is 0.5 to 2.5 milliunits/L. Most
especially in health professionals or as a self-remedy for obesity.
patients feel best at a TSH level in the low- to middle-
normal range (i.e., 0.51.5 milliunits/L). Thyroid hormones can be obtained easily without a prescription
from health food stores or Internet sources.
10. Provide a brand-name LT4 product, and do not allow the
patient to be switched to different products. If the product
is switched, check a TSH in 6 weeks and retitrate the dose. Clinical Manifestations of Thyrotoxicosis
11. Write LT4 prescriptions as microgram not milligram Many of the signs and symptoms seem to be related to auto-
doses to avoid errors. nomic hyperactivity. As with hypothyroidism, the clinical
12. Check a TSH every 6 to 12 months in stable patients
receiving LT4 replacement. TABLE 416. Causes of Thyrotoxicosis29
13. Make sure that patients understand the importance of
adherence and the risks of over- and underuse of LT4. Primary hyperthyroidism
Graves disease
14. At each visit, assess the patient for signs and symptoms Toxic multinodular goiter
of over- and undertreatment. Toxic adenoma
15. Monitor for drug interactions, such as LT4 absorption Thyroid cancer
problems caused by calcium and iron. Struma ovarii
Iodine excess (including radiocontrast, amiodarone)
16. Check a TSH in pregnant women as soon as the preg-
Thyrotoxicosis without hyperthyroidism
nancy is diagnosed. In hypothyroid pregnant women,
Subacute thyroiditis
check the TSH monthly, and expect to raise the LT4 dose Silent (painless) thyroiditis
during the rst trimester. Maintain the TSH in the low- to Excess thyroid hormone intake (thyrotoxicosis factitia)
middle-normal range. After delivery, reduce the LT4 dose
Secondary hyperthyroidism
to the pre-pregnancy dose. TSH-secreting pituitary tumors
Trophoblastic (hCG-secreting) tumors

Milliunits/L (mU/L) = microunits/mL (U/L); clinical laborato- Gestational thyrotoxicosis
Adapted, with permission. hCG, human chorionic gonadotropin; TSH,
thyroid-stimulating hormone.
1191 patients over age 60, patients with a suppressed TSH had a
Clinical Presentation and Diagnosis of 2.1-fold increased risk of all-cause mortality and a 3.3-fold
Hyperthyroidism29,30 increased risk of cardiovascular mortality versus patients with a
normal TSH. Recent studies have shown that prolonged sub-
clinical thyrotoxicosis speeds the loss of bone mineral density
Symptoms
Nervousness and increases fracture rates in postmenopausal women.35,36
Fatigue
Weakness Graves Disease
Increased perspiration
Heat intolerance Graves disease30 is an autoimmune syndrome that includes
Tremor hyperthyroidism, diffuse thyroid enlargement, exophthal-
Hyperactivity, irritability mos and other eye ndings, and skin ndings. The prevalence
Palpitations of Graves disease in the United States is approximately 0.4%
Appetite change (usually increased) in women and 0.1% in men. The peak age of incidence is
Weight change (usually weight loss) 20 to 49 years, with a second peak after 80 years of age.
Menstrual disturbances (often oligomenorrhea) Hyperthyroidism results from the production of TSHR-SAbs
Diarrhea in at least 80% of patients. These antibodies have TSH agonist
Signs activity, thereby stimulating hormone synthesis and release.
Hyperactivity These antibodies cross-react with orbital and broblastic tis-
Tachycardia sue, resulting in ophthalmopathy and dermopathy. While the
Atrial brillation (especially in elderly) underlying cause of Graves disease is not known, heredity
Hyperreexia seems to play a role. Subclinical Graves disease may become
Warm, moist skin
acutely overt in the presence of iodine excess, infection, stress,
Ophthalmopathy, dermopathy (Graves disease)
parturition, smoking, and lithium and cytokine therapy.
Goiter
Muscle weakness There are several features of Graves disease that are dis-
tinct from other forms of thyrotoxicosis. Clinically apparent
Screening/Diagnosis ophthalmopathic changes are seen in 20% to 40% of patients
Low TSH level (less than 0.5 milliunit/L) will signify
and include exophthalmos, proptosis, chemosis, conjuncti-
thyrotoxicosis.
val injection, and periorbital edema. Lid retraction causes a
Free T4 is elevated in overt hyperthyroidism.
Increased radioiodine uptake in the thyroid indicates typical staring or startled appearance (Fig. 413). Patients
increased hormone production by the thyroid gland. may complain of vague eye discomfort and excess tearing. In
Almost all patients with Graves disease will have positive severe cases, the eyelids are unable to close completely, result-
TSHR-SAbs and positive anti-TPOAbs. ing in corneal damage. In very severe cases, the optic nerve
can be compressed, resulting in permanent vision loss. All
patients with suspected or known Graves disease must be
manifestations may be subtle initially and slowly progressive. evaluated and monitored by an ophthalmologist.
Screening of patients for thyroid disease may identify patients Dermopathy occurs in 5% to 10% of patients with Graves
with subclinical or mild thyrotoxicosis. Patients may seek med- disease and usually is associated with severe ophthalmopathy.
ical attention only after a long period of thyrotoxicosis or owing Skin ndings include hyperpigmented, non-pitting indura-
to an acute complication such as atrial brillation. The clinical tion of the skin, typically over the pretibial area (pretibial
manifestations of thyrotoxicosis in the elderly may be blunted myxedema), the dorsa of the feet, and shoulder areas. Clubbing
or atypical. These patients may present only with atrial brilla- of the digits (thyroid acropachy) is associated with long-standing
tion or depression. thyrotoxicosis.
Subclinical Thyrotoxicosis Treatment of Hyperthyroidism

Subclinical or mild thyrotoxicosis is dened as a low TSH with a Treatment of thyrotoxicosis due to hyperthyroidism is similar,
normal FT4 level. While there may be few or no symptoms in regardless of the underlying cause. The goals of treating
these patients, there are several areas of concern.31,32 Many hyperthyroidism are to relieve symptoms, to reduce thyroid hor-
patients will progress to overt thyrotoxicosis. Patients with sub- mone production to normal levels and achieve biochemical
clinical hyperthyroidism have been shown to suffer long-term euthyroidism, and to prevent long-term adverse sequelae.
cardiovascular and bone sequelae. In a 10-year follow-up of 2007
patients over age 60,33 patients with an undetectable TSH level -Blockers
had a 3.1-fold increased risk of atrial brillation versus those Because many of the manifestations of hyperthyroidism appear
with a normal TSH. In a different 10-year follow-up study34 of to be mediated by the -adrenergic system, -adrenergic
FIGURE 413. Features of Graves dis-

ease. A. Facial appearance: exophthal-
mos, lid retraction, periorbital edema,
and proptosis. B. Thyroid dermopathy
over lateral aspects of shins.
C. Thyroid clubbing (acropachy).
(Reprinted, with permission, from
Jameson JL, Weetman AP. Disorders of
the thyroid gland. In: Kasper DL,
Braunwald E, Fauci AS, et al, (eds.)
Harrisons Principles of Internal
Medicine. 16th edition. New York:
McGraw-Hill; 2004: 2114.)
blockers are used to rapidly relieve palpitations, tremor, anxiety, given prior to radioactive iodine treatment because the iodide
and heat intolerance. Since -blockers do not reduce the syn- will inhibit concentration of the radioactivity in the thyroid.
thesis of thyroid hormones, they are used only until more spe- Iodides also are used to protect the thyroid from radioactive
cic antithyroid therapy is effective. Since non-selective agents iodine fallout after a nuclear accident or attack. Daily adminis-
can impair the conversion of T4 to T3, propranolol and nadolol tration of 30 to 100 mg iodide will markedly reduce thyroid
are used. An initial propranolol dose of 20 to 40 mg four times gland uptake of radioactive iodine. The most frequent toxic
daily should be titrated to relieve signs and symptoms. effects with iodide therapy are hypersensitivity reactions,
-Blockers should not be used in patients with decompen- iodism (characterized by palpitations, depression, weight
sated heart failure or asthma. When a contraindication to loss, and pustular skin eruptions), and gynecomastia.
-blockers exists, clonidine or diltiazem may be used.
Antithyroid Drugs
Methods to Reduce Thyroid Hormone Synthesis The thionamide agents propylthiouracil and methimazole are
Excess production of thyroid hormone can be reduced in used in the United States to treat hyperthyroidism.39 Carbimazole,
four ways: iodides, antithyroid drugs, radioactive iodine, and a methimazole analog, is available in Europe. These drugs
surgery.30,37,38 inhibit thyroid hormone synthesis by interfering with thyroid
peroxidasemediated iodination of tyrosine residues in thy-
Iodide roglobulin. Propylthiouracil has the added effect of inhibiting
Large doses of iodide inhibit the synthesis and release of the conversion of T4 to T3. The thionamides also have immuno-
thyroid hormones. Serum T4 levels may be reduced within suppressant effects. In patients with Graves disease treated
24 hours, and the effects may last for 2 to 3 weeks. Iodides are with thionamides, TSHR-SAb levels and other immune medi-
used most commonly in Graves disease patients prior to sur- ators decrease over time. Both drugs are well absorbed from
gery and to quickly reduce hormone release in patients with the gastrointestinal tract. Propylthiouracil has a half-life of 1
thyroid storm. Potassium iodide is administered either as a to 2.5 hours, whereas the half-life of methimazole is 6 to
saturated solution (SSKI) that contains 38 mg iodide per drop 9 hours.
or as Lugols solution, which contains 6.3 mg iodide per drop. Antithyroid drugs are used as primary therapy for Graves dis-
The typical starting dose is 120 to 400 mg/day. Iodide therapy ease or as preparative therapy before surgery or radioactive
should start 7 to 14 days prior to surgery. Iodide should not be iodine administration. The decision to use antithyroid drugs as
primary therapy must be weighed against the risks and benets propylthiouracil) to maintain the euthyroid state. Excessive
of radioiodine or surgery. Patient preference must be considered. doses of antithyroid drugs will result in hypothyroidism.
In most patients, there is no clear advantage of one thion- Methimazole is preferred to normalize thyroid function prior
amide over the other. While propylthiouracil has the advantage to radioactive iodine therapy because propylthiouracil
of inhibiting T4- to T3-conversion, methimazole can be given increases the failure rate of radioactive iodine therapy.
as a single daily dose. The usual starting dose of methimazole Remission of Graves disease occurs in 40% to 60% of
is 15 to 30 mg/day, and the usual starting dose of propyl- patients after 1 to 2 years of therapy. Levels of TSHR-SAb after a
thiouracil is 100 mg three times daily. Thyroid hormone levels course of treatment may have predictive value in that antibody-
drop in 2 to 3 weeks, and after 6 weeks, 90% of patients with positive patients almost always will relapse. However, antibody-
Graves disease will be euthyroid. Thyroid function testing negative patients also may relapse after therapy is stopped.
should be performed every 4 to 6 weeks until stable. After the Antithyroid therapy may be stopped or tapered after 12 to
patient becomes euthyroid, the antithyroid drug dose often can 24 months. Relapse usually occurs in the rst 3 to 6 months
be decreased (510 mg/day methimazole, 100200 mg/day after stopping antithyroid therapy. About 75% of women in
remission who become pregnant will have a postpartum relapse.
When therapy is discontinued, a therapeutic strategy should be
in place in the event of relapse. Many patients will opt for
Patient Encounter 2, Part 1 radioactive iodine as a long-term solution.
Antithyroid drugs are associated with a low rate of adverse
effects. Skin rash, arthralgias, and gastrointestinal upset are seen
in 5% of patients. While the drug can be continued in the pres-
GD is a 24-year-old woman who comes to the clinic stat-
ing, Im so nervous and hungry, and Im losing weight.
ence of a minor skin rash, the development of arthralgia warrants
What is wrong with me? She rst noticed these symptoms discontinuation. Hepatotoxicity is an uncommon but potentially
2 months ago, and they have worsened steadily. She feels serious adverse effect, occurring in 0.1% to 0.2% of patients.
anxious for no reason and has trouble sleeping. She has However, transient rises in aminotransferase enzyme levels are
noticed that her appetite has increased, although she has seen in up to 30% of patients treated with propylthiouracil.
lost about 5 lb (2.3 kg). Sometimes she can feel her heart Severe hepatocellular damage can occur from propylthiouracil,
beating in her chest, but she denies chest pain or syncope. whereas methimazole can cause cholestatic jaundice. Vasculitis is
She also has noticed that she is always sweaty and that her another potentially serious but uncommon reaction that is more
menses have become very light. Her only medications are a common with propylthiouracil. Patients may develop a drug-
hormonal oral contraceptive and occasional naproxen for induced lupus syndrome, and some, particularly Asians, can
dysmenorrhea. She thinks that her mother had some kind of
develop antineutrophil cytoplasmic antibody-positive vasculitis.
thyroid problem when she was pregnant.
PE Agranulocytosis is the most feared side effect of antithyroid
VS: Pulse 112 beats per minute, blood pressure 108/72, drug therapy. Agranulocytosis must be distinguished from a
RR 12, temperature 37.4C (99.32F) transient decrease in white blood cell count seen in up to
HEENT: Diffusely enlarged thyroid; mild exophthalmos 12% of adults and 25% of children with Graves disease.
CV: Tachycardic, RRR Agranulocytosis occurs in 0.3% of patients, and the incidence
Exts: Fine tremor is the same with propylthiouracil and methimazole.
Skin: Warm and moist Agranulocytosis almost always occurs within the rst 3 months
ECG: Sinus tachycardia of therapy, and it occurs suddenly and unpredictably. Patients
Labs will present with fever, malaise, and sore throat, and the
Electrolytes, complete blood count normal. Urine hCG absolute neutrophil count will be less than 1000/mm3. Patients
negative. TSH less than 0.5 milliunit/L (normal may develop sepsis and die rapidly. Agranulocytosis is thought
0.52.5 milliunits/L); FT4 3.1 ng/dL (39.9 pmol/L; normal to be autoimmune-mediated. If agranulocytosis occurs, dis-
0.71.9 ng/dL, or 9.024.5 pmol/L); +TSHR-SAbs continue the antithyroid drug immediately, administer broad-
spectrum antibiotics if the patient is febrile, and consider
What therapeutic options exist for GDs Graves disease?
the administration of granulocyte colony-stimulating factor.
What would you recommend?
How would you initiate and titrate therapy?
The white blood cell count should recover in a week or two.
What would you tell GD regarding the cause of her signs Patients who develop agranulocytosis should not be switched
and symptoms, signicance of her abnormal thyroid func- to another thionamide drug. Monitoring for agranulocyto-
tion tests, and therapeutic options? sis is controversial owing to its sudden and predictable
nature. Most practitioners do not recommend routine

Milliunits/L (mU/L) = microunits/mL (U/L); clinical laborato- monitoring of the complete blood count, although early
ries use either unit of measurement. detection could improve patient outcomes. Patients initi-
ating thionamide therapy must be informed about the signs
and symptoms of agranulocytosis and other serious side

effects. Patients should be asked to report signs and symptoms Patient Encounter 2, Part 2
suggestive of infection such as fever and sore throat lasting
more than 2 or 3 days or any bruising.
One month later, GD is back for a follow-up visit. She
Radioactive Iodine notes that her thyrotoxic symptoms are gone, and overall,
Radioactive iodine, typically 131I, produces thyroid ablation she feels great. She is receiving propylthiouracil 100 mg
without surgery. 131I is well absorbed after oral administration. three times daily. Her most recent TSH was 0.9 milliunit/L
The iodine is concentrated in the thyroid gland and has a half- (normal 0.52.5 milliunits/L), and her free T4 was 1.6 ng/dL
life of 8 days. Over a period of weeks, thyroid cells that have (20.6 pmol/L; normal 0.71.9 ng/dL, or 9.024.5 pmol/L).
taken up the 131I begin to develop abnormalities and necrosis. However, over the past few days she has developed a sore
Eventually, thyroid cells are destroyed, and hormone produc- throat and feels achy. She wonders if she has the u. Her
tion is reduced. After a single dose, 40% to 70% of patients will vital signs show a pulse of 92 beats/minute and a tempera-
be euthyroid in 6 to 8 weeks, and 80% will be cured. In most ture of 38.3C (101F). A complete blood count reveals a
total white blood cell count of 100/mm3 or 0.1 109/L
patients, hypothyroidism will develop, and long-term LT4
(normal 400010,000/mm3 or 410 109/L) with
replacement will be necessary. Because 131I has a slow onset of
15 neutrophils (absolute neutrophil count 150).
action, most patients are treated initially with -blockers and
antithyroid drugs. Thionamide drugs must be withdrawn for What has happened to GD?
at least 4 to 6 days prior to 131I administration to allow ade- What are you concerned about?
quate accumulation of the radioactive iodine in the gland. How will you manage this problem?
-Blockers can be continued during 131I therapy. The dose of What will you tell GD regarding the possible cause of her
131 new symptoms, the signicance of her low white blood
I is based on the estimated weight of the patients thyroid
gland. Radioactive iodine therapy is contraindicated during cell count, and recommended actions?
pregnancy and breastfeeding. Radioactive iodine therapy may

acutely worsen Graves ophthalmopathy. Patients with promi- Milliunits/L (mU/L) = microunits/mL (U/L); clinical laborato-
nent eye disease may be started on prednisone 40 mg/day, with
the dose tapered over 2 to 3 months. Radioactive iodine also
may cause a painful thyroiditis, which may necessitate anti-
inammatory therapy. Any long-term carcinogenic effect of 131I maintain maternal euthyroidism should be used. Antithyroid
has not been demonstrated in long-term clinical trials. therapy in excessive doses may suppress fetal thyroid function.
Surgery Neonatal and Pediatric Hyperthyroidism

Subtotal thyroidectomy is indicated in patients with very large Some neonates born to mothers with Graves disease will be
goiters and thyroid malignancies and those who do not hyperthyroid at delivery. Antithyroid drug therapy (propylthi-
respond or cannot tolerate other therapies. Patients must be ouracil 510 mg/kg per day or methimazole 0.51 mg/kg per
euthyroid prior to surgery, and patients often are administered day) may be required for up to 12 weeks. One drop per day of
iodide preoperatively to reduce gland vascularity. The overall SSKI may be used in the rst few days to rapidly reduce thy-
surgical complication rate is 2.7%. Postoperative hypothyroid hormone synthesis and release.
roidism occurs in 10% of patients who undergo subtotal
thyroidectomy. Thyroid Storm
Thyroid storm is a life-threatening condition caused by severe
Special Conditions and Populations thyrotoxicosis. Signs and symptoms include high fever, tachycar-
dia, tachypnea, dehydration, delirium, coma, and gastrointestinal
Graves Disease and Pregnancy disturbances. Thyroid storm is precipitated in a previously
Pregnancy may worsen or precipitate thyrotoxicosis in women hyperthyroid patient by infection, trauma, surgery, radioactive
with underlying Graves disease owing to the TSH agonist iodine treatment, and sudden withdrawal from antithyroid
effect of hCG. Untreated maternal thyrotoxicosis may result in drugs. Patients are treated with a short-acting -blocker such as
increased rates of miscarriage, premature delivery, eclampsia, intravenous esmolol, intravenous or oral iodide, and large doses
and low-birth-weight infants. Fetal and neonatal hyperthy- of propylthiouracil (9001200 mg/day in three to four divided
roidism may occur as a result of transplacental passage of doses). Supportive care with acetaminophen to suppress fever,
TSHR-SAbs. Because radioactive iodine is contraindicated uid and electrolyte management, and antiarrhythmic agents are
and surgery is best avoided during pregnancy, most patients important components of therapy. Intravenous hydrocortisone
are treated with antithyroid drugs. Propylthiouracil is consid- 100 mg every 8 hours is used often due to the potential presence
ered the treatment of choice, and the lowest possible dose to of adrenal insufciency.
those in the intensive-care unit, frequently have reduced total

Hyperthyroidism Patient Care and T4 levels, although FT4 levels usually are normal. In the criti-
Monitoring cally ill, there is a correlation between the degree of serum T4
reduction and mortality. In most acutely ill patients who are
euthyroid, the TSH level is normal. However, administration of
1. A low or undetectable TSH level identies thyrotoxicosis.
dopamine, octreotide, or high doses of glucocorticoids can
2. Refer the patient for a diagnostic assessment to identify reduce TSH levels. During recovery from acute illness, the TSH
the underlying cause. Identify Graves disease by the
level may become modestly elevated to renormalize serum T4
presence of eye and/or skin ndings and the presence
levels. During this time, thyroid function tests may be misin-
of TSHR-SAbs.
terpreted to indicate hypothyroidism. Despite the sometimes
3. Refer patients with Graves disease to an ophthalmolo-
very low T4 levels, there is no evidence that LT4 administration
gist for assessment and monitoring.
has any benet. Patients with possible thyroid abnormalities
4. Treat severe or troublesome autonomic signs and symp- during acute illness should be evaluated by an endocrinologist.
toms with a non-selective -blocker such as propranolol
20 to 40 mg four times daily. Titrate the -blocker dose
based on signs and symptoms.
THYROID CANCER AND LT4 SUPPRESSION
5. In patients with excess thyroid hormone production,
reduce hormone production with an antithyroid drug
The growth and spread of thyroid carcinoma is stimulated
and/or radioactive iodine. Choose therapy based on
by TSH. An important component of thyroid carcinoma manage-
patient-specic factors and preference.
ment is the use of LT4 to suppress TSH secretion. Early in therapy,
6. Antithyroid drugs have a delayed effect. After 2 to 4 weeks
patients receive the lowest LT4 dose sufcient to fully suppress TSH
of therapy, adjust the dose if the TSH is not in the target
to undetectable levels. Controlled trials show that suppressive
range (0.52.5 milliunits/L). Once the patient is euthyroid,
consider reducing the dose of antithyroid drug to avoid LT4 therapy reduces tumor growth and improves survival. These
hypothyroidism. patients are purposefully overtreated with LT4 and rendered
subclinically hyperthyroid. Postmenopausal women should
7. Consider stopping antithyroid therapy in Graves disease
after 12 to 18 months to see if remission has occurred. receive aggressive osteoporosis therapy to prevent LT4-induced
bone loss. Other thyrotoxic complications, such as atrial brilla-
8. Monitor patients on antithyroid drugs for signs and
tion, should be monitored and managed appropriately.
symptoms of adverse effects.
9. Monitor for symptoms of neutropenia (e.g., fever or sore
throat), and check white blood cell count if symptoms
occur.
DRUG-INDUCED THYROID ABNORMALITIES
10. If radioactive iodine is given, make sure that antithyroid
Drugs can affect thyroid function in a number of ways.41 Effects
drugs are stopped 4 to 6 days prior to treatment.
of drugs on thyroid hormone protein binding, LT4 absorption,
11. Several months after radioactive iodine, expect that the and metabolism have been discussed previously. Several com-
patient will require permanent LT4 replacement.
monly used medications can alter thyroid hormone secretion.
12. Treat pregnant hyperthyroid women with propylthiouracil.

Amiodarone
Milliunits/L (mU/L) = microunits/mL (U/L); clinical laborato-
ries use either unit of measurement. Amiodarone42 is a commonly prescribed antiarrhythmic drug
that contains two iodide atoms, constituting 38% of its mass.
Each 200 mg dose of amiodarone provides 75 mg iodide.
Amiodarone deiodination releases about 6 mg of free iodine
NON-THYROIDAL ILLNESS (EUTHYROID SICK daily, 20 to 40 times more than the average daily intake of
SYNDROME) iodine in the United States. Amiodarone blocks conversion of
T4 to T3, inhibits entry of T3 into cells, and decreases T3 recep-
A number of changes in the hypothalamic-pituitary-thyroid tor binding. Amiodarone will cause thyroid abnormalities in
axis occur during acute illness.40 These changes are termed 11% of previously euthyroid patients. Amiodarone causes
nonthyroidal illness or euthyroid sick syndrome. The type rapid reduction in serum T3 levels, increases free and total T4
and degree of abnormalities depend on the severity of illness. levels, and increases TSH level. After 3 months of therapy,
Mild to moderate medical illness, surgery, or starvation causes TSH levels usually return to normal, although the serum T3
a decrease in serum T3 levels owing to decreased peripheral and T4 level changes may remain. Most of these patients are
conversion of T4 to T3. The reduced T3 levels do not correlate euthyroid because the free T3 levels are in the low-normal
with ultimate mortality and are thought to be an adaptive range. Amiodarone-induced hypothyroidism is more com-
response to stress. Patients with more severe illness, especially mon in iodine-sufcient areas of the world. Patients with
underlying autoimmune thyroiditis are much more likely to Success of therapy for thyroid disorders must be based not
develop amiodarone-induced hypothyroidism. Amiodarone- only on short-term improvement of the patients clinical sta-
induced hypothyroidism occurs most commonly within the tus and abnormal laboratory values but also on achievement
first year of therapy. If amiodarone cannot be discontinued, LT4 of a long-term euthyroid state. Maintaining the TSH level in
therapy will be effective in most patients. If amiodarone can be the normal range improves symptoms and reduces the risk of
stopped, thyroid function will return to normal in 2 to 4 months. long-term complications.
Amiodarone is more likely to cause thyrotoxicosis in Because pharmacotherapy often is lifelong, especially in
iodine-decient areas. Type 1 amiodarone-induced thyrotoxi- patients with hypothyroidism, patients must undergo periodic
cosis is caused by iodine excess and typically occurs in patients monitoring to avoid the long-term complications of hypothy-
with preexisting multinodular goiter or subclinical Graves roidism and hyperthyroidism. In the hypothyroid patient, such
disease. Type 2 amiodarone-induced thyrotoxicosis is a monitoring may involve simply asking the patient about signs
destructive thyroiditis that occurs in patients with no under- and symptoms and a yearly measurement of the TSH level.
lying thyroid disease. Amiodarone-induced thyrotoxicosis is Any change in the patients clinical status, such as a new
more common in men. Because amiodarone has -blocking pregnancy or a major change in body weight, necessitates a
activity, palpitations and tachycardia may be absent. In type 1 reevaluation of therapy. Patients at high risk for complica-
thyrotoxicosis, amiodarone should be discontinued. If amio- tions, such as pregnant women, the elderly, and patients with
darone therapy cannot be stopped, larger doses of antithyroid underlying cardiac disease, must be monitored more closely.
drugs may be needed to control thyrotoxicosis. In type 2 thy- Patients should be educated and periodically reminded
roiditis, stopping amiodarone may not be necessary because about the importance of adherence and long-term tight con-
spontaneous resolution may occur. Prednisone 40 to 60 mg/day trol, the need for periodic clinical and laboratory monitor-
will quickly improve thyrotoxic symptoms. Prednisone may be ing, and the importance of staying on one LT4 product.
tapered after 1 to 2 months of therapy. In the hyperthyroid patient, relieving signs and symptoms and
achieving a euthyroid state are the desired outcomes. The
Patients receiving amiodarone must receive monitoring method of achieving these outcomes may change over time
for thyroid abnormalities. Baseline measurements of serum with the use of antithyroid drugs versus radioactive iodine.
TSH, FT4, FT3, anti-TPOAbs, and TSHR-SAbs should be per- Patients with hyperthyroidism also must undergo periodic
formed. TSH, FT4, and FT3 should be checked 3 months after clinical and laboratory monitoring, with more frequent mon-
initiation of amiodarone and then every 3 to 6 months. itoring if there is a change in the patients clinical status.
Patients who receive antithyroid drugs must be monitored
Lithium for adverse drug events such as agranulocytosis.
Patients who receive radioactive iodine must be monitored
Lithium is associated with hypothyroidism in up to 34% for the development of hypothyroidism.
of patients, and hypothyroidism may occur after years of In patients with thyroid cancer, the desired outcomes with
therapy. Lithium appears to inhibit thyroid hormone syn- LT4 therapy often are different from those in the hypothyroid
thesis and secretion. Patients with underlying autoimmune patient.
thyroiditis are more likely to develop lithium-induced LT4 doses sufcient to suppress tumor growth may result in
hypothyroidism. Patients may require LT4 replacement a suppressed TSH and mild hyperthyroidism. These patients
even if lithium is discontinued. must be monitored closely for complications of the mild
hyperthyroid state, such as bone mineral loss and develop-
ment of atrial brillation.
Interferon-
Interferon- causes hypothyroidism in up to 39% of patients
being treated for hepatitis C infection. Patients may develop a ABBREVIATIONS
transient thyroiditis with hyperthyroidism prior to becoming
hypothyroid. The hypothyroidism may be transient as well. ANDA: Abbreviated New Drug Application
Asians and patients with preexisting anti-TPOAbs are more anti-TGAb: antithyroglobulin antibody
likely to develop interferon-induced hypothyroidism. The anti-TPOAb: antithyroid peroxidase antibody
mechanism of interferon-induced hypothyroidism is not AUC: area under the (time-concentration) curve
-hCG: beta-human chorionic gonadotropin
known. If LT4 replacement is initiated, it should be stopped
after 6 months to re-evaluate the need for replacement therapy.
FDA: Food and Drug Administration (United States)
FT3: free T3
Outcome Evaluation FT4: free T4
hCG: human chorionic gonadotropin
Desired outcomes include relieving signs and symptoms and LT4: levothyroxine
achieving a euthyroid state. NHANES: National Health and Nutrition Examination Survey
NTI: narrow therapeutic index Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: a
RAIU: radioactive iodine uptake Fundamental and Clinical Text. 9th ed. Philadelphia: Lippincott
SSKI: saturated solution of potassium iodide Williams & Wilkins; 2005.
T3: triiodothyronine Cooper DS. Drug therapy: Antithyroid drugs. N Engl J Med 2005;
T4: thyroxine 352:905917.
TBG: thyroxine-binding globulin Cooper DS. Hyperthyroidism. Lancet 2003; 362:459468.
TPOAb: thyroid peroxidase antibody Farwell BP, Braverman LE. Thyroid and antithyroid drugs. In:
TRH: thyrotropin-releasing hormone Brunton L, Lazo J, Parker K, eds. Goodman & Gilmans The
TSH: thyroid-stimulating hormone Pharmacological Basis of Therapeutics. 11th ed. New York:
TSHR-SAb: TSH receptor-stimulating antibodies McGraw-Hill; 2006: 15111540.
Langton JE, Brent GA. Nonthyroidal illness syndrome: Evaluation of
Reference lists and self-assessment questions and answers are thyroid function in sick patients. Endocrinol Metab Clin North
available at www.ChisholmPharmacotherapy.com. Am 2002; 31:159172.
Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams
Textbook of Endocrinology. 10th ed, Philadelphia: Saunders; 2002.
Roberts CGP, Ladenson PW. Hypothyroidism. Lancet 2004;
for information on obtaining continuing education credit for 363:793803.
this chapter.
American Association of Clinical Endocrinologists Thyroid Task

Force. Evaluation and Treatment of Hyperthyroidism and
Hypothyroidism, 2002; www.aace.com/clin/guidelines/hypo_
hyper.pdf; accessed October 30, 2005.
Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005;
118:706714.
42 ADRENAL GLAND DISORDERS
Devra K. Dang, Judy T. Chen, Frank Pucino, Jr., and Karim Anton Calis
LEARNING OBJECTIVES
1. Explain the regulation and physiologic roles of hormones produced by the adrenal glands.
2. Recognize the clinical presentation of patients with adrenal insufciency.
3. Describe the pharmacologic management of patients with acute and chronic adrenal
insufciency.
4. Recommend therapy monitoring parameters for patients with adrenal insufciency.
5. Recognize the clinical presentation of Cushings syndrome and the physiologic
consequences of cortisol excess.
6. Recommend strategies to prevent the development of Cushings syndrome associated with
exogenous glucocorticoid administration.
7. Describe the pharmacologic and nonpharmacologic management of patients with Cushings
syndrome.
8. Recommend therapy monitoring parameters for patients with Cushings syndrome.
KEY CONCEPTS Pharmacotherapy generally is reserved for patients: (1) in

whom the ectopic adrenocorticotropic hormonesecreting
Signs and symptoms of adrenal insufciency reect the dis- tumor cannot be localized; (2) who are not surgical candi-
turbance of normal physiologic carbohydrate, fat, and protein dates; (3) who have failed surgery; (4) who have had a relapse
homeostasis caused by inadequate cortisol production and after surgery; or (5) in whom adjunctive therapy is required to
inadequate cortisol action. achieve complete remission.
Lifelong glucocorticoid replacement therapy may be neces- In drug-induced Cushings syndrome, discontinuation of the
sary for patients with adrenal insufciency, and mineralocor- offending agent is the best management option. However,
ticoid replacement therapy usually is required for those with abrupt withdrawal of the glucocorticoid can result in adrenal
Addisons disease. insufciency or exacerbation of the underlying disease.
During an acute adrenal crisis, the immediate treatment goals Glucocorticoid doses of less than 7.5 mg/day of prednisone
are to correct volume depletion, manage hypoglycemia, and (or its equivalent) for fewer than 3 weeks generally would not
provide glucocorticoid replacement. be expected to lead to suppression of the hypothalamic-
Patients who experience excessive stress should be educated pituitary-adrenal axis.
regarding the need for additional glucocorticoid replacement
and prompt medical attention. The adrenal glands are important in the synthesis and regula-
Patients with Cushings syndrome owing to endogenous or tion of key hormones. They play a crucial role in water and
exogenous glucocorticoid excess typically present with similar electrolyte homeostatsis, as well as regulation of blood pres-
clinical manifestations. sure, carbohydrate and fat metabolism, physiologic response
Surgical resection is considered the treatment of choice for to stress, and sexual development and differentiation. This
Cushings syndrome from endogenous causes if the tumor chapter focuses on pharmacologic and nonpharmacologic
can be localized and if there are no contraindications. management of the two most common conditions associated
685
with adrenal gland dysfunction: glucocorticoid insufciency Adrenal artery

(e.g., Addisons disease) and glucocorticoid excess (Cushings Phrenic
artery
syndrome). Other adrenal disorders such as congenital adrenal Right adrenal
Inferior phrenic vein
hyperplasia, pheochromocytoma, hypoaldosteronism, and Left adrenal
Right adrenal
hyperaldosteronism are beyond the scope of this chapter. vein Left adrenal vein
Renal
artery Renal artery
PHYSIOLOGY, ANATOMY, AND BIOCHEMISTRY Right Left

OF THE ADRENAL GLAND kidney kidney
Renal Renal
The adrenal gland is located on the upper segment of the kidney vein vein
(Fig. 421). It consists of an outer cortex and an inner medulla.
Inferior
The adrenal medulla secretes the catecholamines epinephrine vena cava
Abdominal
aorta
(also called adrenaline) and norepineprhine (also called nora-
drenaline), which are involved in regulation of the sympathetic FIGURE 421. Anatomy of the adrenal gland. (Reprinted, with
nervous system. The adrenal cortex consists of three histologi- permission, from Gums JG, Tovar JM. Adrenal gland disorders.
cally distinct zones: zona glomerulosa, zona fasciculata, and an In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy:
A Pathophysiologic Approach. New York: McGraw-Hill; 2005:
innermost layer called the zona reticularis. Each zone is respon- 13911406.)
sible for production of different hormones (Fig. 422).
FIGURE 422.
Adrenal steroid
Cholesterol synthesis. The
adrenal cortex
consists of three
Zona Zona Zona histologically dis-
reticularis fasciculata glomerulosa tinct zones: the
zona glomerulosa,
Pregnenolone
zona fasciculata,
and an innermost
17 3B-HSD layer called the
zona reticularis.
Each zone is
17-hydroxy- responsible for pro-
DHEA-S DHEA 17, 20 Progesterone
pregnenolone
duction of different
hormones. (17 =
3B-HSD 3B-HSD 17 21 17-hydroxylase;
3B-HSD = 3-
Androstene- 17-hydroxy- 11-deoxy-
hydroxysteroid
17, 20 dehydrogenase;
dione progesterone corticosterone
21 = 21-hydroxy-
lase; 17,20 =
17, 20 21 11B
17,20-lyase; 11B =
11-hydroxylase;
11-deoxy- AS = aldosterone
Estrone Testosterone Corticosterone
cortisol synthase; DHEA =
dehydroepiandro-
11B sterone; DHEA-S =
sulfated form of
dehydroepiandro-
Dihydro- 18-OH- sterone.)
Estradiol Cortisol
testosterone corticosterone
AS
Aldosterone
CHAPTER 42 / ADRENAL GLAND DISORDERS 687
The zona glomerulosa is responsible for the production of condition is usually classied as primary, secondary, or terti-
the mineralocorticoids aldosterone, deoxycorticosterone, and ary depending on the etiology (Table 421). Chronic adrenal
18-hydroxy-deoxycorticosterone. Aldosterone promotes renal insufciency is rare. The estimated prevalences of primary
sodium retention and excretion of potassium. Its synthesis and secondary adrenal insufciency are approximately 60 to
and release are regulated by renin in response to decreased 143 and 150 to 280 cases per 1 million persons, respectively.
vascular volume and renal perfusion. Adrenal aldosterone Primary adrenal insufciency usually is diagnosed in the
production is regulated by the renin-angiotensin- third to fth decades of life, whereas secondary adrenal
aldosterone system. insufficiency is commonly detected during the sixth
The zona fasciculata produces the glucocorticoid hormone
cortisol. Cortisol is responsible for maintaining homeostasis of
carbohydrate, protein, and fat metabolism. Its secretion follows
a circadian rhythm, with the highest secretion occurring in the
early-morning hours (peaking around 8 A.M.). Thereafter, cor- TABLE 421. Etiologies of Adrenal Insufciency1,46,21,22
tisol levels decrease throughout the day, approach 50% of the
Primary Adrenal Insufciency (Addisons Disease)
peak value by 4 P.M., and reach their nadir around midnight.1 Autoimmuneaccounts for 70%90% of all cases of primary
The normal rate of cortisol production is approximately 8 to adrenal insufciency
15 mg/day.2 Cortisol plays a key role in the bodys response to Infectious or granulomatous diseases
stress. Its production increases markedly during physiologic Tuberculosis
stress, such as during acute illness, surgery, or trauma. In addi- Sarcoidosis
tion, certain conditions, such as alcoholism, depression, anxiety Cytomegalovirus
Fungal (histoplasmosis, coccidioidomycosis, cryptococcosis,
disorder, obsessive-compulsive disorder, poorly controlled dia- Blastomyces dermatitidis infection)
betes, morbid obesity, starvation, anorexia nervosa, and chronic Human immunodeciency virus, AIDS
renal failure, are associated with increased cortisol levels. High Mycobacterial, cytomegaloviral, and Pneumocystis carinii
total cortisol levels are also observed in the presence of increased (P. jiroveci ) infection
Medicationsinhibitors of steroidogenesis (aminoglutethimide,
cortisol-binding globulin (the carrier protein for 80% of circu- etomidate, ketoconazole, metyrapone, mitotane)
lating cortisol molecules), which is seen in pregnancy or other Hemorrhagic
high-estrogen states (e.g., exogenous estrogen administration).1 Bilateral adrenal hemorrhage or infarctionusually due to
Cortisol is converted in the liver to an inactive metabolite anticoagulant therapy, coagulopathy, thromboembolic disease,
known as cortisone. or meningococcal infection. Causes acute adrenal insufciency.
Adrenalectomy
The zona reticularis produces the androgens androstene- Adrenoleukodystrophy (in males)
dione, dehydroepiandrosterone (DHEA), and the sulfated Adrenomyeloneuropathy
form of dehydroepiandrosterone (DHEA-S). Only small Inltrative disordersamyloidosis, hemochromatosis
amounts of testosterone and estrogen are produced in the Genetic causes
adrenal glands. Androstenedione and DHEA are converted in Congenital adrenal hyperplasia
the periphery, largely to testosterone and estrogen. Familial glucocorticoid deciency and hypoplasia
Metastatic malignancy
Adrenal hormone production is controlled by the hypo-
Secondary Adrenal Insufciency
thalamus and pituitary gland. Corticotropin-releasing hor- Drug-induced (most common cause of secondary adrenal
mone (CRH) is secreted by the hypothalamus and stimulates insufciency)
secretion of adrenocorticotropic hormone (ACTH), also Chronic glucocorticoid administration at supraphysiologic
known as corticotropin from the anterior pituitary. ACTH, in doses
turn, stimulates the adrenal cortex to produce cortisol. When Megestrol acetatehas glucocorticoid-like activity
sufcient or excessive cortisol levels are reached, a negative Mifepristone (RU 486)antagonizes glucocorticoid receptors
Post-cure of Cushings syndrome
feedback is exerted on the secretion of CRH and ACTH, Panhypopituitarism
thereby decreasing overall cortisol production. The control of Pituitary tumor
adrenal androgen synthesis also follows a similar negative- Transsphenoidal pituitary microsurgery
feedback mechanism. Pituitary irradiation
Traumatic brain injury
Tertiary Adrenal Insufciency
Hypothalamic failure
ADRENAL INSUFFICIENCY Drug-inducedchronic glucocorticoid administration at
supraphysiologic doses
AIDS, acquired immunodeciency syndrome
Adrenal insufciency generally refers to the inability of the Partially adapted, with permission, from Aron DC, Findling JW, Tyrrell
JB. Glucocorticoids and adrenal androgens. In: Greenspan FS, Gardner
adrenal glands to produce adequate amounts of cortisol for DG, (eds.) Basic and Clinical Endocrinology. New York: Lange Medical
normal physiologic functioning or in times of stress. The Books/McGraw-Hill; 2004: 362413.
decade.1,3 Adrenal insufciency is more prevalent in women

than in men with a ratio of 2.6:1.1 Clinical Presentation and Diagnosis
of Chronic Adrenal Insufciency1,3,4,6
Pathophysiology
General
Primary adrenal insufciency (also known as Addisons The symptoms, especially in the early stages, may be
disease) occurs when the adrenal glands are unable to pro- vague and mimic those of other medical conditions.
duce cortisol. It occurs from destruction of the adrenal The cardinal symptoms and signs are weakness and
cortex, usually from an autoimmune process. In general, the fatigue requiring rest periods, gastrointestinal symptoms,
clinical manifestations are observed when destruction of the weight loss, and hypotension.
cortex exceeds 90%.4 Signs and symptoms of adrenal Patients with autoimmune adrenal insufciency may have
insufciency reect the disturbance of normal physiologic car- other autoimmune disorders such as type 1 diabetes mel-
bohydrate, fat, and protein homeostasis caused by inadequate litus and autoimmune thyroiditis.
cortisol production and inadequate cortisol action. Primary Symptoms
adrenal insufciency usually develops gradually. Patients may Weakness and fatigue are the most common.
remain asymptomatic in the early stages, with signs and symp- Anorexia, nausea, and diarrhea (these may range from
toms present only during times of physiologic stress. Persistent mild to severe with vomiting and abdominal pain).
signs and symptoms of hypocortisolism typically occur with Hypoglycemia may occur in some patients.
disease progression. Additionally, adrenal insufciency may Amenorrhea
Salt craving may occur in some patients with primary
be accompanied by a reduction in aldosterone and androgen
adrenal insufciency.
production.
Secondary adrenal insufciency occurs as a result of a pitu- Signs
itary gland dysfunction whereby decreased production and Weight loss
secretion of ACTH leads to a decrease in cortisol synthesis. Hypotension (less than 110/70 mm Hg) and orthostasis
Dehydration, hypovolemia, and hyperkalemia (in primary
Tertiary adrenal insufciency is a disorder of the hypothala-
adrenal insufciency only)
mus that results in decreased production and release of CRH,
Decreased serum sodium and chloride levels
which, in turn, decreases pituitary ACTH production and Increased serum blood urea nitrogen (BUN) and creati-
release. In contrast to Addisons disease (i.e., primary adrenal nine owing to dehydration
insufciency), aldosterone production is unaffected in the Hyperpigmentation of skin (usually around creases,
secondary and tertiary forms of the disease. Chronic adrenal pressure areas, areolas, genitalia, and new scars) and
insufciency often has a good prognosis if diagnosed early mucous membranes. Dark freckles and patches of
and treated appropriately. vitiligo may be present. Hyperpigmentation, owing to
Acute adrenal insufciency (i.e., adrenal crisis) results from increased ACTH levels, occurs in primary adrenal
the bodys inability to increase endogenous cortisol sufciently insufciency.
during periods of excessive physiologic stress. Adrenal crisis Personality changes (irritability and restlessness)
Loss of axillary and pubic hair in women owing to
can occur when patients with chronic adrenal insufciency do
decreased androgen production
not receive adequate glucocorticoid replacement during
Blood count abnormalities (e.g., normocytic, nor-
stressful conditions (such as those experienced during sur- mochromic anemia, relative lymphocytosis, neutrophilia,
gery, infection, acute illness, invasive medical procedures, or eosinophilia)
trauma). Acute adrenal insufciency also can result from
Laboratory Tests (Table 422)
bilateral adrenal infarction owing to hemorrhage, embolus,
Decreased basal and stress-induced cortisol levels
sepsis, or adrenal vein thrombosis. Additionally, abrupt discon-
Decreased aldosterone level (in primary adrenal insuf-
tinuation or rapid tapering of glucocorticoids (given chroni- ciency only)
cally in supraphysiologic doses) may lead to adrenal crisis. This Lack of increase in cortisol and aldosterone level after
condition results from prolonged suppression of the hypothal- ACTH stimulation
amic-pituitary-adrenal (HPA) axis and subsequent adrenal
Other Diagnostic Tests (Table 422)
gland atrophy and hypocortisolemia. Other drugs associated
Computed tomography (CT) or magnetic resonance
with adrenal insufciency include those that inhibit produc- imaging (MRI) of the adrenal glands, pituitary,
tion (e.g., ketoconazole) or increase metabolism [e.g., the and/or hypothalamus can aid in determining the
cytochrome P-450 subfamily IIIA polypeptide 4 (CYP450 etiology.
3A4) inducer rifampin] of cortisol.4 Regardless of etiology, The presence of anti-adrenal antibodies is suggestive of
patients experiencing an adrenal crisis require immediate glu- an autoimmune etiology.
cocorticoid treatment because manifestations (such as circu-
latory collapse) can lead to life-threatening sequelae.
TABLE 422. Tests for Diagnosing Adrenal Insufciency4,6
Test Procedure and

Measurement Typical Finding in
Test Rationale Adrenal Insufciency Comments
Screening Tests to Conrm Diagnosis of Adrenal Insufciency

Rapid ACTH Measure serum cortisol Serum cortisol concentration False negative results occur if the ACTH
stimulation 3060 minutes after less than 18 mcg/dL deciency is of recent onset.
test (also administering cosyntropin (497 nmol/L) To differentiate between primary and secondary
called 1 mcg IV or 250 mcg IVa or tertiary adrenal insufciency, use same
cosyntropin Increased cortisol secretion blood samples to measure plasma aldosterone
stimulation in normal individuals in level (see below).
test) response to ACTH
stimulation but not
in adrenal insufciency
Unstimulated Measure serum cortisol Serum cortisol greater than
serum at 68 A.M. 18 mcg/dL (497 nmol/L) is
cortisol Serum cortisol level peaks normal
measurement in the early morning. Serum cortisol less than
3 mcg/dL (83 nmol/L) is
indicative of adrenal
insufciency
Insulin tolerance Administer insulin IV to Serum cortisol concentration Distinguishes between normal individuals and
test (insulin- induce hypoglycemia; less than 18 mcg/dL patients with secondary adrenal insufciency
induced then measure serum (497 nmol/L) is indicative Contraindicated in patients with a seizure
hypoglycemia cortisol during sympto- of secondary adrenal history, older than 60 years, or with cardio-
test) matic hypoglycemia insufciency vascular or cerebrovascular disease
[conrm that blood Requires close medical supervision
glucose is less than Contraindicated in adrenal crisis
40 mg/dL
(2.22 mmol/L)].
Evaluates ability of entire
HPA axis to respond
to stress (hypoglycemia)
Overnight Administer metyrapone at Normal response is a Distinguishes between normal individuals and
metyrapone midnight then measure decrease in serum cortisol patients with secondary adrenal insufciency
test serum cortisol at 8 A.M. to less than 5 mcg/dL Contraindicated in adrenal crisis
(rarely used) the next day. (138 nmol/L) and an
Metyrapone inhibits increase in the cortisol
cortisol synthesis. Its precursor to more than
administration leads to 7 mcg/dL (193 nmol/L).
rise in levels of ACTH Response not seen in
and the precursor of secondary adrenal
cortisol. Patients with insufciency.
adrenal insufciency
do not exhibit this.
Tests to Determine Diagnosis of Primary, Secondary, and Tertiary Adrenal Insufciency

Test Procedure and
Test Measurement Rationale to Distinguish Between Etiologies
Plasma Measure plasma Primary adrenal insufciency: low plasma aldosterone level.
aldosterone aldosterone from same Secondary or tertiary adrenal insufciency: aldosterone level is normal
concentration blood samples as those [greater than or equal to 5 ng/dL (139 pmol/L)]
used in ACTH
stimulation test.
Plasma ACTH Measure plasma ACTH Primary adrenal insufciency: hypocortisolism leads to elevated plasma
concentration ACTH (via positive HPA axis feedback).
Secondary or tertiary adrenal insufciency: plasma ACTH low or
inappropriately normal.
ACTH, adrenocorticotropic hormone or corticotropin; FDA, Food and Drug Administration; HPA, hypothalamic-pituitary-adrenal; IV, intravenously.
a
The 250 mcg dose has also been administered intramuscularly in an outpatient setting. The 1 mcg dose is not FDA-approved.
TABLE 423. Pharmacologic Characteristics of Commonly Used Glucocorticoids4
Estimated Potency Relative to Hydrocortisone

Glucocorticoid Mineralocorticoid Equivalent Dose
(Anti-Inammatory) (Sodium-Retaining) Expressed in
Glucocorticoid Activity Activity Milligrams
Short-Acting (Half-Life Less than 12 Hours)
Hydrocortisone 1 1 20
Cortisone 0.8 0.8 25
Intermediate-Acting (Half-Life 1236 Hours)
Prednisone 4 0.25 5
Prednisolone 4 0.25 5
Methylprednisolone 5 Less than 0.01 4
Triamcinolone 5 Less than 0.01 4
Long-Acting (Half-Life Greater than 48 Hours)
Betamethasone 25 Less than 0.01 0.60.75
Dexamethasone 3040 Less than 0.01 0.75
Modied, with permission, from Williams GH, Dluhy RG. Disorders of the adrenal cortex. In: Kasper DL,
Braunwald E, Fauci A, et al, (eds.) Harrisons Principles of Internal Medicine. New York: McGraw-Hill;
2005: 21272148.
Treatment and Outcome Evaluation

Patient Encounter 1, Part 1:
Chronic Adrenal Insufciency Presentation and Medical History
The general goals of treatment are to manage symptoms and
prevent development of adrenal crisis. Lifelong glucocorticoid
AB is a 60-year-old woman presenting to the clinic with a
replacement therapy may be necessary for patients with adrenal chief complaint of fatigue and weakness. She has noticed a
insufciency, and mineralocorticoid replacement therapy usually is gradual increase in symptoms over the past year but attributed
required for those with Addisons disease. Glucocorticoids with this to old age. Recently, she has required more frequent rest
sufcient mineralocorticoid activity generally are required. breaks than before. On further questioning, she complained of
However, the addition of a potent mineralocorticoid such as intermittent nausea leading to decreased appetite and a 10 lb
udrocortisone (along with adequate salt intake) sometimes (4.55 kg) weight loss over the past year. She also reported
is needed to prevent sodium loss, hyperkalemia, and intravas- darkening of a recent scar.
cular volume depletion. Mineralocorticoid supplementation PMH
typically is not indicated for the treatment of secondary or Type 1 diabetes mellitus since age 5, currently controlled
tertiary adrenal insufciency because aldosterone production Hypothyroidism, currently controlled
often is unaffected. Moreover, patients with secondary or ter- Osteoarthritis (knees) for 5 years
tiary adrenal insufciency may require only replacement FH
therapy until the HPA axis recovers. Hydrocortisone often is Unknown
prescribed because it most closely resembles endogenous
SH
cortisol (with its relatively high mineralocorticoid activity and
Retired secretary; denies smoking, alcohol use, or illicit
short half-life) and allows the design of regimens that simu- drug use
late the normal circadian cycle.6 Other glucocorticoids, how-
ever, can be used. The pharmacologic characteristics of com- Current meds
Insulin glargine 30 units at bedtime
monly used glucocorticoids are presented in Table 423. Since
Lispro insulin three times daily with mealspractices car-
patients with primary adrenal insufciency can experience
bohydrate counting
DHEA deciency, DHEA replacement also has been tried. Levothyroxine 75 mcg once daily
Several small clinical studies, consisting mostly of women, sug- Acetaminophen 1000 mg every 8 hours as needed for
gest that treatment with DHEA can improve mood and fatigue joint pain
and provide a general sense of well-being.79 Nonetheless, use Capsaicin 0.075% cream three times a day for joint
of DHEA remains controversial and requires further study. pain
Table 424 lists the treatment guidelines and monitoring (Continued)
parameters for chronic adrenal insufciency.
TABLE 424. Management Strategies for Chronic Adrenal

PE Insufciency1,3,6
VS: Sitting BP: 108/70 mm Hg; P: 74 beats/minute; standing
BP: 96/68 mm Hg; P: 86; RR: 14 breaths/minute; weight: Primary Adrenal Insufciency (Addisons Disease)
150 lb (68.18 kg); height: 5 ft, 5 in (165.1 cm) Give oral hydrocortisone 1215 mg/m2 divided into two doses,
Skin: Hyperpigmentation on creases of palms and around with two-thirds of the dose given in the morning upon awakening
nipples, darkening of scar on left leg (to mimic the early-morning rise in endogenous cortisol) and
the remaining one-third of the dose given in the late afternoon
CV: RRR, normal S1, S2; no murmurs, rubs, or gallops
(to avoid insomnia).
Labs Monitor weight, blood pressure, and serum electrolytes and
Serum electrolytes: sodium 132 mEq/L (132 mmol/L), assess resolution of clinical features and patients feeling of
potassium 5.2 mEq/L (5.2 mmol/L), chloride 98 mEq/L general well-being. Adjust dosages accordingly.
(98 mmol/L), bicarbonate 30 mEq/L (30 mmol/L), blood Monitor for adverse reactions from hydrocortisone administra-
tion. Glucocorticoid therapy at physiologic replacement doses
urea nitrogen (BUN) 25 mg/dL (8.9 mmol/L), creatinine should not lead to the development of Cushings syndrome.
1.3 mg/dL (115 mol/L), glucose 120 mg/dL (6.66 mmol/L) However, careful monitoring should still be performed. Use
the smallest effective dose.
Which signs or symptoms of adrenal insufciency does Doses of hydrocortisone may need to be increased or decreased
AB exhibit? in patients taking CYP450 3A4 inducers (e.g., phenytoin, rifampin,
Does ABs presentation offer any clues as to the etiology barbiturates) or inhibitors (e.g., protease inhibitors), respectively.
or classication of adrenal insufciency? Educate patients regarding need for increased hydrocortisone
dosage during excessive physiologic stress.
Which tests would be most useful for determining the etio-
Give oral udrocortisone at a daily dose of approximately
logy and conrming the diagnosis of adrenal insufciency? 0.050.2 mg in the morning.
Monitor for resolution of hypotension, dizziness, dehydration,
hyponatremia, and hyperkalemia. Increase the dose as clini-
cally necessary.
Clinical Presentation and Diagnosis of Monitor for adverse reactions from mineralocorticoid adminis-
tration (e.g., hypertension, hypokalemia, uid retention) and
Acute Adrenal Insufciency (Adrenal decrease the dose if these occur. Remember that hydrocorti-
Crisis)1,3,4 sone also possesses mineralocorticoid activity.
Maintain an adequate sodium intake (about 34 g/day).
Although controversial, consider giving DHEA 50 mg/day (in the
General morning) to female patients who do not experience an improve-
Onset of symptoms is acute and precipitated by excessive ment in mood and well-being even with adequate glucocorti-
physiologic stress. coid and mineralocorticoid replacement.
Symptoms Monitor serum DHEA-S (aim for the middle range of normal
levels in healthy young people) and free testosterone level.
Severe weakness and fatigue
Secondary and Tertiary Adrenal Insufciency
Abdominal or ank pain Give 215 mg/m2 of oral hydrocortisone as described above.
Signs Patients may require a lower dose of glucocorticoid than those with
Severe dehydration leading to hypotension and shock primary adrenal insufciency. Some patients will only require gluco-
(circulatory collapse). Hypovolemia may not be respon- corticoid replacement temporarily, which can be discontinued after
recovery of the HPA axis (e.g., drug-induced adrenal insufciency,
sive to intravenous hydration and may require the use of adrenal insufciency following treatment for Cushings syndrome).
vasopressors. Fludrocortisone therapy is generally not needed.
Tachycardia Monitor for progression of the underlying etiology.
Nausea, vomiting
Fever CYP450 3A4, cytochrome P-450 subfamily IIIA polypeptide 4; DHEA,
dehydroepiandrosterone; DHEA-S, the sulfated form of dehydroepiandro-
Confusion sterone; HPA, hypothalamic-pituitary-adrenal.
Hypoglycemia
Laboratory abnormalities are similar to those observed in
chronic adrenal insufciency.
Laboratory Tests Patient Encounter 1, Part 2: Treatment
The unstimulated serum cortisol and rapid ACTH stimulation
tests are useful in the diagnosis of adrenal crisis (Table 422).
The insulin tolerance test is contraindicated owing to preex-
isting hypoglycemia. The metyrapone test is also contraindi- After appropriate laboratory and diagnostic tests are performed,
cated because metyrapone inhibits cortisol production. AB is diagnosed with Addisons disease.
Note: Given the life-threatening nature of this condition,
empirical treatment should be started before laboratory con- How should her chronic adrenal insufciency be treated?
rmation in patients who present with the clinical picture of What monitoring parameters (therapeutic and toxic) should
an acute adrenal crisis. be implemented?
TABLE 425. Treatment of Acute Adrenal Crisis

Adrenal Insufciency: Patient Care and
Monitoring General and Supportive Measures
1. Promptly correct volume depletion, dehydration, and
hypoglycemia with large volumes of intravenous normal saline
1. Evaluate patients presenting with the typical clinical and 5% dextrose (about 23 L).
2. Evaluate and correct infection or other precipitating factors.
manifestations for chronic or acute adrenal insufciency.
Glucocorticoid Replacement
2. Perform initial screening tests to conrm the presence of 1. Administer hydrocortisone sodium phosphate or hydrocortisone
adrenal insufciency. sodium succinate, 100 mg intravenously every 6 to 8 hours for
3. Once diagnosis is conrmed, perform further testing to 24 hours.
differentiate between primary, secondary, and tertiary 2. If the patient is hemodynamically stable, reduce the dosage to
adrenal insufciency. 50 mg every 6 to 8 hours.
3. Increase the dose of hydrocortisone to 200400 mg/day if
4. In patients presenting with acute adrenal crisis who have complications occur or persist.
not been diagnosed previously with adrenal insuf- 4. Taper hydrocortisone to maintenance therapy by day 4 or 5 and
ciency, immediate treatment with injectable hydrocorti- add udrocortisone as needed.
sone and intravenous saline and dextrose solutions
should be initiated prior to conrmation of the diagnosis Adapted, with permission, from Aron DC, Findling JW, Tyrrell JB.
Glucocorticoids and adrenal androgens. In: Greenspan FS, Gardner DG,
because of the life-threatening nature of this condition. (eds.) Basic and Clinical Endocrinology. New York: Lange Medical
Determine and correct the underlying cause of the acute Books/McGraw-Hill; 2004: 362413.
adrenal crisis (e.g., infection).
5. Glucocorticoid replacement therapy is necessary for patients
with adrenal insufciency, and mineralocorticoid replace- with known adrenal insufciency, additional glucocorticoid
ment therapy is required for those with Addisons disease. replacement (higher dose and parenteral route) must be
6. In patients with chronic adrenal insufciency, when given prior to major surgery to prevent adrenal crisis
excessive physiologic stress is anticipated (e.g., pending (Table 426 lists a sample protocol). Patients who experi-
surgery), devise a strategy to give supplemental doses of ence excessive stress should be educated regarding the need for
glucocorticoid during this period. Monitor the patient for additional glucocorticoid replacement and prompt medical
signs of an acute adrenal crisis, and develop a plan to attention. Although the dosage of glucocorticoid generally
treat this emergency condition. is individualized, a common recommendation is to double the
7. Monitor the patient for adequacy of treatment, as well as maintenance dose of hydrocortisone if the patient experiences
adverse reactions from glucocorticoid and/or mineralo- fever or undergoes invasive dental or diagnostic procedures.6
corticoid therapy. Patients who experience vomiting or diarrhea may not absorb
8. Determine the duration of treatment for patients with oral glucocorticoids adequately and may benet from par-
secondary and tertiary adrenal insufciency. enteral therapy until symptoms resolve.
9. Provide patient education regarding disease state and
treatment:
Causes of adrenal insufciency, including drug- TABLE 426. Glucocorticoid Treatment of Adrenal Insufciency
induced etiologies. in Patients Undergoing Surgery
How to recognize the clinical manifestations.
How to prevent an acute adrenal crisis (adhere to ther- 1. Correct electrolytes, blood pressure, and uid status as
apy, and do not stop glucocorticoid treatment necessary.
abruptly). There may be a need to increase the dose of 2. Give 100 mg of hydrocortisone sodium phosphate or
hydrocortisone sodium succinate intramuscularly (provide on
glucocorticoid during excessive physiologic stress.
call to the operating room).
Administration of parenteral glucocorticoid during an 3. Give 50 mg of hydrocortisone intramuscularly or intravenously in
acute adrenal crisis. the recovery room and then every 6 hours for the rst 24 hours.
Need to notify all health care providers of the condition. 4. If patient is hemodynamically stable, reduce dosage to 25 mg
Encourage wearing or carrying medical alert identica- every 6 hours for 24 hours and then taper to maintenance
tion (e.g., bracelet or card). dosage over 35 days.
Counsel on dietary and pharmacologic therapy, including 5. Resume previous udrocortisone dose when the patient is taking
duration of treatment and potential adverse consequences oral medications.
of glucocorticoid and mineralocorticoid replacement. 6. Maintain or increase hydrocortisone dosage to 200400 mg/day
if fever, hypotension, or other complications occur.
Adapted, with permission, from Aron DC, Findling JW, Tyrrell JB.
Acute Adrenal Insufciency Glucocorticoids and adrenal androgens. In: Greenspan FS, Gardner
During an acute adrenal crisis, the immediate treatment DG, (eds.) Basic and Clinical Endocrinology. New York: Lange Medical
Books/McGraw-Hill, 2004:362413. Originally from Miller WL, Tyrrell
goals are to correct volume depletion, manage hypoglycemia, and JB, in: Endocrinology and Metabolism. Felig P, Baxter JD, Frohman LA,
provide glucocorticoid replacement (Table 425). In patients (eds.) New York: McGraw-Hill, 1995:555711.
HYPERCORTISOLISM (CUSHINGS SYNDROME) refers specically to Cushings syndrome from an ACTH-

secreting pituitary adenoma. The plasma ACTH concentration
Epidemiology and Etiology is elevated in ACTH-dependent conditions but not in ACTH-
independent cases because elevated cortisol concentrations
Cushings syndrome refers to the pathophysiologic changes suppress pituitary ACTH secretion via negative feedback.
associated with exposure to supraphysiologic cortisol concen- Adrenocorticotropic hormone and cortisol concentrations
trations (endogenous hypercortisolism) or pharmacologic are elevated episodically in ACTH-dependent disease due to
doses of glucocorticoids (exogenous hypercortisolism). random hypersecretion of ACTH.4 Other major differences
Cushings syndrome from endogenous causes is a rare condi- among the vast etiologies of Cushings syndrome are shown
tion, with an estimated incidence of 2 to 5 cases per 1 million in Table 428.
persons per year.10 Patients receiving chronic supraphysio- Physiologic cortisol secretion follows a circadian pattern,
logic doses of glucocorticoids, such as those with rheuma- with cortisol levels rising in the early morning, peaking at
tologic disorders, are at high risk of developing Cushings approximately 8 A.M., and then declining steadily throughout
syndrome. the remainder of the day until they reach a nadir at midnight.
This circadian rhythm is lost in most patients with Cushings
syndrome. As such, detection of elevated midnight cortisol
Pathophysiology concentrations can be useful in the diagnosis of Cushings
Cushings syndrome can be classied as ACTH-dependent or syndrome.
ACTH-independent (Table 427). ACTH-dependent Cushings Cushings disease and adrenal carcinomas cause adrenal
syndrome results from ACTH-secreting (or rarely, CRH-secreting) androgen hypersecretion in high enough concentrations to
adenomas. ACTH-independent Cushings syndrome is due result in signs of androgen excess (such as acne, menstrual irreg-
either to excessive cortisol secretion by the adrenal glands (inde- ularities, and hirsutism) and cause virilization in women.4
pendent of ACTH stimulation) or to exogenous glucocorticoid Drug-induced Cushings syndrome from glucocorticoid
administration. Patients with Cushings syndrome owing to administration occurs most commonly in patients receiving oral
endogenous or exogenous glucocorticoid excess typically present therapy, but other routes (e.g., inhalation, dermal, nasal, and
with similar clinical manifestations. The term Cushings disease intra-articular) also have been implicated.11 Over-the-counter
products, including non-prescription medications and herbal
products, also should be evaluated because they may contain cor-
ticosteroids or agents that possess glucocorticoid-like activity. The
TABLE 427. Etiologies of Cushings Syndrome1,1113 risk of glucocorticoid-induced Cushings syndrome appears to
increase with higher doses and/or longer treatment durations.11
ACTH-Dependent Left untreated, patients with Cushings syndrome may
ACTH-secreting pituitary tumor (Cushings disease)70% of
cases of endogenous Cushings syndrome
experience severe complications of hypercortisolism, resulting
ACTH-secreting non-pituitary tumors (ectopic ACTH in up to a nearly four-fold increase in mortality.14 Mortality in
syndrome)15% of cases of endogenous Cushings syndrome; patients with Cushings syndrome is mostly attributed to car-
usually from small cell lung carcinoma, bronchial carcinoids, diovascular disease. Hypertension, hyperglycemia, and hyper-
pheochromocytoma, or thymus, pancreatic, ovarian, or thyroid lipidemia are common ndings and can be associated with
tumor. The tumor is usually disseminated (difcult to localize).
CRH-secreting non-pituitary tumors (ectopic CRH syndrome)
cardiac hypertrophy, atherosclerosis, and hypercoagulability.
rare Osteopenia, osteoporosis, and increased fractures also have
ACTH-Independent15% of cases of endogenous Cushings been reported.14 Children may experience linear growth retar-
syndrome dation from reduced growth hormone secretion and inhibi-
Unilateral adrenal adenoma tion of epiphyseal cartilage development in long bones.10,14
Adrenal carcinoma
Bilateral nodular adrenal hyperplasiarare (less than 1%)
Drug-Induced Cushings Syndrome (ACTH-independent)most Treatment
common cause of Cushings syndrome
Prescription glucocorticoid preparations (most routes of The goal of treatment in patients with Cushings syndrome is
administration) reversal of hypercortisolism and management of the associated
Non-prescription and herbal products with glucocorticoid comorbidities, including the potential for long-term sequelae
activity (e.g., non-prescription anti-itch products with
hydrocortisone, herbal products with magnolia bark or those such as cardiac hypertrophy. Surgical resection is considered
claiming to contain adrenal cortex extracts or other by-products) the treatment of choice for Cushings syndrome from endogenous
Other drugs with glucocorticoid activity (e.g., megestrol acetate, causes if the tumor can be localized and if there are no con-
medroxyprogesterone) traindications. The treatment of choice for Cushings syn-
ACTH, adrenocorticotropic hormone or corticotropin; CRH, corticotropin- drome from exogenous causes is gradual discontinuation of
releasing hormone. the offending agent.
Clinical Presentation and Diagnosis of Kidney stones (15% to 50%)

Cushings Syndrome1,10,11 Hypokalemic alkalosis (from mineralocorticoid effect of
cortisol)
Cardiovascular
General Hypertension (from mineralocorticoid effect of cortisol) (85%)
Patients with Cushings syndrome due to either endogenous Patients are at risk for the cardiovascular complications of
or exogenous glucocorticoid excess typically present with hypertension, hyperlipidemia, and hyperglycemia.
similar clinical manifestations. Peripheral edema
Differential diagnoses include diabetes mellitus and meta- Genitourinary
bolic syndrome because patients with these conditions Menstrual irregularities (the most typical presentation is
share several similar characteristics with Cushings syn- amenorrhea) (70%)
drome patients (e.g., obesity, hypertension, hyperlipidemia, Erectile dysfunction (85%)
hyperglycemia, and insulin resistance). In women, the Other
presentations of hirsutism, menstrual abnormalities, and Psychiatric changes such as depression, emotional lability,
insulin resistance are similar to those of polycystic ovary psychosis, euphoria, anxiety, and decreased cognition (85%)
syndrome. Cushings syndrome can be differentiated from Sleep disturbances
these conditions by identifying the classic signs and symp- Osteopenia (80%) and osteoporosis, usually affecting tra-
toms of truncal obesity, moon faces with facial plethora, becular bone
a buffalo hump and supraclavicular fat pads, red-purple Linear growth impairment in children
skin striae, and proximal muscle weakness. Proximal muscle weakness (65%)
True Cushings syndrome also must be distinguished from Avascular necrosis (more common in iatrogenic cases)
other conditions that share some clinical presentations (as Glaucoma and cataracts
well as elevated plasma cortisol concentrations), such as Impaired wound healing and susceptibility to opportunistic
depression, alcoholism, obesity, and chronic illnessthe infections
so-called pseudo-Cushings states. Hypothyroidism
Signs and Symptoms (Percent Prevalence) Laboratory Tests
General appearance The diagnosis of Cushings syndrome and its etiology often
Weight gain and obesity, manifesting as truncal obesity are complex and generally require the involvement of
(90%) endocrinologists and specialized testing centers.
A rounded and puffy face (moon face) (75%) Initial screening tests to conrm the presence of hypercorti-
Dorsocervical (buffalo hump) and supraclavicular fat solism and differentiate Cushings syndrome from condi-
accumulation tions with similar presentations include 24-hour urinary
Hirsutism (excessive hair growth) (75%) free cortisol determination and overnight low-dose dexam-
Skin changes (from atrophy of dermis and connective tissue) ethasone suppression test (DST) (Table 429).
Thin skin The midnight plasma cortisol determination and combined
Facial plethora (70%) dexamethasone suppression plus CRH test are used less
Skin striae (stretch marks that are usually red or purple in commonly.
appearance and greater than 1 cm) (50%) Typically, a combination of at least two screening tests is
Acne (35%) used to establish the preliminary diagnosis.
Easy bruising (40%) Once the diagnosis is conrmed, additional tests can be
Hyperpigmentation performed to determine the etiology.
Metabolic Other Diagnostic Tests
Hyperglycemia that can range from impaired glucose toler- Imaging studies may be used to distinguish between pituitary,
ance (75%) to diabetes mellitus (20% to 50%) ectopic, and adrenal tumors (Table 428).
Hyperlipidemia (70%)
Polyuria (30%)
Nonpharmacologic Therapy usually is reserved for patients who are not surgical candidates
Transsphenoidal pituitary microsurgery is the treatment of or for those who relapse or do not achieve complete remission
choice for Cushings disease. Removal of the pituitary tumor following pituitary surgery. Because the response to pituitary
can bring about complete remission (cure) in 78% to 97% of irradiation can be delayed (several months to years), concomi-
cases. HPA axis suppression associated with chronic hypercor- tant treatment with cortisol-lowering medication may be neces-
tisolism can result in prolonged adrenal insufciency lasting for sary. Bilateral adrenalectomy is also used for the management of
months after surgery and requiring exogenous glucocorticoid adrenal carcinoma and in patients with poorly controlled
administration. Pituitary irradiation or bilateral adrenalectomy ectopic Cushings in whom the ACTH-producing lesion cannot
TABLE 428. Differences among the Major Etiologies of Cushings Syndrome4,9,14,23
ACTH-Dependent ACTH-Independent
Exogenous
Pituitary Dependent Ectopic Glucocorticoid Adrenal Adrenal
(Cushings Disease) ACTH Syndrome Administration Adenoma Carcinoma
Onset of signs Gradual Rapid Gradual to rapid Gradual Rapid
and symptoms
Symptoms severity Mild to moderate Atypical Mild to severe Mild to moderate Severe
Dominant sex/age Female; 2040 years Male; adults Female and male; all ages Female Female; children
(range: childhood
to 70 years)
Virilization + + + + +++
Abdominal mass 0 0 0 0 ++
Plasma ACTH Slightly elevated Elevated Low Low Low
concentration
CRH stimulation Response Rare response Decreased or No response No response
test no response
High-dose Between 50% Less cortisol No cortisol No cortisol No cortisol
dexamethasone and 80% suppression suppression suppression suppression
suppression cortisol suppression
test
Pituitary MRI Tumor Normal Normal Normal Normal
Adrenal gland Normal or bilateral Normal or No change Mass(es) Mass(es)
CT or MRI hyperplasia bilateral
hyperplasia
ACTH, adrenocorticotropic hormone or corticotropin; CRH, corticotropin-releasing hormone; CT, computed tomography; MRI, magnetic resonance
imaging; 0, none; +, mild; ++, moderate; +++, pronounced.
Adapted in part, with permission, from Gums JG, Tovar JM. Adrenal gland disorders. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy: A
Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 13911406.
be localized. Bilateral laparoscopic adrenalectomy achieves an (2) who are not surgical candidates; (3) who have failed surgery;
immediate and total remission (nearly 100% cure rate), but (4) who have had a relapse after surgery; or (5) in whom adjunc-
these patients will require lifelong glucocorticoid and mineralo- tive therapy is required to achieve complete remission.17 The
corticoid supplementation.15,16 Nelsons syndrome may develop drugs used are classied according to their mechanism and
in nearly 20% to 50% of patients who undergo bilateral adrena- site of action (Table 4210). The most widely used therapeutic
lectomy without pituitary irradiation. This condition presum- class is the adrenal steroidogenesis inhibitors.17 Agents in this
ably results from persistent hypersecretion of ACTH by the class include ketoconazole, mitotane, metyrapone, and amino-
intact pituitary adenoma, which continues to grow because of glutethimide. Steroidogenesis inhibitors can improve hypercor-
the loss of feedback inhibition by cortisol. Treatment of Nelsons tisolism by inhibiting enzymes involved in the biosynthesis of
syndrome may involve pituitary irradiation or surgery.4 cortisol. Because of their potential to cause adrenal suppression,
The treatment of choice in patients with adrenal adenomas is temporary glucocorticoid replacement (and, in some cases,
unilateral laparoscopic adrenalectomy. These patients require mineralocorticoid supplementation) may be needed during
glucocorticoid supplementation during and after surgery owing and after treatment.
to atrophy of the contralateral adrenal gland and suppression
of the HPA axis. Glucocorticoid therapy is continued until
In drug-induced Cushings syndrome, discontinuation of
the offending agent is the best management option. However,
recovery of the remaining adrenal gland is achieved. Patients
abrupt withdrawal of the glucocorticoid can result in adrenal
with adrenal carcinomas have a poor prognosis (5-year survival
insufciency or exacerbation of the underlying disease.11
of 20% to 58%) due to the advanced nature of the condition
(metastatic disease). Surgical resection to reduce tumor burden Glucocorticoid doses less than 7.5 mg/day of prednisone (or its
and size, pharmacologic therapy, and bilateral laparoscopic equivalent) for fewer than 3 weeks generally would not be expected
adrenalectomy are the treatment options used commonly to to lead to suppression of the HPA axis.2,5 However, in patients
manage this condition.1,16 receiving pharmacologic doses of glucocorticoids for prolonged
periods, gradual tapering to near-physiologic levels (57.5 mg/day
Pharmacologic Therapy of prednisone or its equivalent) should precede drug discontin-
Pharmacotherapy generally is reserved for patients: (1) in uation. Administration of a short-acting glucocorticoid in the
whom the ectopic ACTH-secreting tumor cannot be localized; morning and use of alternate-day dosing may reduce the risk of
TABLE 429. First-Line Screening Tests in Patients with Characteristics of Cushings Syndrome1,10,14
Test Procedure and

Measurement Typical Finding in
Test Rationale Cushings Syndrome Comments
24-Hour urinary Collect urine over 24 Urinary free cortisol greater Easy to perform but should not be used
free cortisol hours and measure than 4 times the upper alone because sensitivity and specicity
unbound cortisol that is reference limit is depend on the assay used.
excreted by kidneys indicative of Cushings To exclude periodic hypercortisolism, three
Urinary cortisol is syndrome. Values between or more samples should be obtained
elevated in 1 and 4 times the upper (with urinary creatinine measurement to
hypercortisolic states reference limit suggest assess completeness of the collection).
either Cushings syndrome Distinguishes Cushings syndrome from obesity
or pseudo-Cushings (no elevation). However, false-positive if
syndrome other pseudo-Cushings states,
physiologic stress, or pregnancy.
False-negative if decreased renal function
or subclinical hypercortisolism.
Overnight Give 1 mg oral Plasma cortisol greater Simple to perform and inexpensive.
low-dose dexamethasone at than 14.3 mcg/dL Can be used in conjunction with or instead
dexamethasone 11 P.M., then measure (395 nmol/L) is of the urinary free cortisol test.
suppression plasma cortisol at diagnostic for Can also use the two-day 2 mg DST.
test (DST) 89 A.M. the next Cushings syndrome. False-positive if pseudo-Cushings states,
morning Plasma cortisol less physiologic stress, pregnancy, estrogen
Dexamethasone than 1.2 mcg/dL treatment, uremia, taking inducers of
administration (33 nmol/L) is not dexamethasone metabolism (phenytoin,
suppresses morning suggestive of etc.), or decreased dexamethasone
plasma cortisol in Cushings syndrome absorption.
normal individuals False-negative if subclinical hypercortisolism
or slow metabolism of dexamethasone.
Late-night salivary Collect salivary cortisol Elevated late-night Diagnostic criteria need further validation.
cortisol concentration salivary cortisol Easiest screening test to perform (sample can
at 11 P.M. be collected at home by patient).
Loss of circadian rhythm Can be used in conjunction with, or instead
of cortisol secretion of, the urinary free cortisol test.
(no nadir at night)
in Cushings syndrome
but not in pseudo-
Cushings states
DST, dexamethasone suppression test.
adrenal suppression. Testing of the HPA axis may be useful in

Patient Encounter 2 assessing adrenal reserve. In some cases, supplemental glucocor-
ticoid administration during excessive physiologic stress may be
needed for up to 1 year after glucocorticoid discontinuation.11
Table 4211 lists strategies to prevent the development of hyper-
EF is a 45-year-old woman who presents to the dermatologist
for evaluation of facial acne. She has a history of a 25 lb
cortisolism and hypocortisolism.
(11.36 kg) weight gain, irregular menses, and frequent vaginal
yeast infections over the past 2 years. She complains of Outcome Evaluation
increased facial hair growth and lower extremity muscle Monitor patients receiving surgical, medical, or radiation
weakness. Physical examination reveals facial acne, facial hir-
therapy for resolution of the clinical manifestations of
sutism, truncal obesity, thin skin, and purple abdominal striae.
Her past medical history is signicant for hypertension, type 2
hypercortisolism. Symptoms often improve immediately
diabetes mellitus, hyperlipidemia, and rheumatoid arthritis. after surgery and soon after initiation of drug therapy.
However, it may take months for symptoms to resolve fol-
Which ndings are suggestive of Cushings syndrome? lowing radiation therapy.
Is there anything in EFs history that would suggest an Monitor for normalization of serum cortisol concentrations.
exogenous cause of her presumed Cushings syndrome? The Patient Care and Monitoring text box (page 699) dis-
cusses additional evaluation strategies.
TABLE 4210. Pharmacologic Treatments for Cushings Syndrome1720
Dosage:
Initial, Common and/or
Mechanism of Usual, Major Adverse
Drug Action Maximum Reactions Comment
Inhibitors of Adrenal Steroidogenesis
Aminoglutethimide Inhibits conversion of 250 mg every High incidence of Used in ACTH-independent cases
(oral administration) cholesterol to 6 hours adverse reactions: and ectopic ACTH syndrome.
pregnenolone, Increase by lethargy, Less effective as monotherapy due
11-hydroxylase, 250 mg somnolence, to reex rise in ACTH but can be
18-hydroxylase, per day dizziness, ataxia, combined with metyrapone or
and conversion of every 12 rash, nausea, with pituitary radiation.
androstenedione weeks headache. Glucocorticoid and mineralo-
to estrone. 2 g/day Tolerance to adverse corticoid replacements needed.
reactions develops High potential for drug interactions
with continued use. due to potent induction of hepatic
Hematologic enzymes.
disturbances and
hypothyroidism
also seen.
Ketoconazole Inhibits several 200 mg twice Generally well Effective in a majority of causes;
(oral administration) cytochrome daily tolerated. rapid clinical improvement seen.
P-450 enzymes, 600800 Transaminase May be used with amino-
including mg/day in two elevations, GI glutethimide if inadequate efcacy
17,20-lyase, divided intolerance, and rash. as monotherapy.
17-hydroxylase, doses Gynecomastia, Monitor efcacy with urinary
and 1200 mg/day testicular function cortisol.
11-hydroxylase. in two impairment, and Monitor liver transaminases for
Also inhibits divided adrenal insufciency hepatotoxicity.
cholesterol doses at high doses (more Useful in women with hirsutism and
synthesis. than 600 mg/day). patients with hyperlipidemia.
Metyrapone Inhibits 11-hydroxylase. 750 mg/day Generally well tolerated. Used in Cushings disease, ectopic
(oral administration) Also suppresses 5004000 Hirsutism, acne, adrenal ACTH syndrome, and adrenal
aldosterone mg/day in four insufciency, GI carcinoma.
synthesis. divided doses intolerance, rash, Allows lower doses of
6 g/day hypokalemia, edema, aminoglutethimide if used in
hypertension. combination.
Etomidate Inhibits 17, 20-lyase, Limited clinical Injection-site pain, Intravenous route of administration
(intravenous 17-hydroxylase, experience, nausea, vomiting, limits use.
administration) and 1.64.2 mg/hour myoclonus.
11-hydroxylase. intermittently
Adrenolytic Agent
Mitotane Inhibits steroidogenesis 26 g/day in 34 GI intolerance (high Used primarily for adrenal
(oral administration) at lower doses and divided doses incidence), fatigue, carcinoma but can be used in
is adrenolytic at 910 g/day in 34 dizziness, other types of Cushings syndrome.
higher doses. Inhibits divided doses somnolence, Efcacy takes several weeks.
11-hydroxylase 16 g/day in 34 gynecomastia. Lower rate of relapse when used
and cholesterol divided doses Hyperlipidemia with pituitary radiation. Also
side-chain cleavage. requiring lipid- enables lower doses and therefore
Reduces aldosterone lowering treatment. lower rate of adverse reactions.
synthesis. Adrenal insufciency
requiring
glucocorticoid
replacement therapy.
(Continued )
TABLE 4210. Pharmacologic Treatments for Cushings Syndrome1720 (Continued )
Dosage:
Initial, Common and/or
Mechanism of Usual, Major Adverse
Drug Action Maximum Reactions Comment
Central Neuromodulators of ACTH Release
Bromocriptine Dopamine agonist 3.7530 mg/day, Postural hypotension, Low rate of efcacy in Cushings
(oral administration) also reported dizziness, nausea, disease and Nelsons syndrome.
up to 40 mg/day nasal congestion.
Cyproheptadine Antagonizes serotonin 2032 mg/day Sedation, increased Efcacy variable.
(oral administration) receptors. May also appetite, GI Slow onset of clinical improvement
inhibit histamine intolerance. (23 months).
receptors. May have Has been used in pregnant
direct inhibitory Cushings disease patients.
effect on hypo-
thalamus or pituitary.
Octreotide Long-acting 3001200 mcg/day Injection site pain, Most useful in Nelsons syndrome
(subcutaneous somatostatin analog reported nausea, diarrhea, and ectopic ACTH syndrome.
or intravenous hypoglycemia or Not effective as monotherapy in
administration) hyperglycemia, Cushings disease but may be
hypothyroidism, effective when used with
dizziness, biliary ketoconazole.
disease. Not effective in adrenal tumors.
Ritanserin Selectively antagonizes 1015 mg/day Low incidence of Few clinical experiences.
(oral administration) central serotonin-2 central nervous Published reports of efcacy in
receptors. system reactions. some cases of Cushings disease.
Sodium valproate Inhibits GABA 6001200 mg/day Neurologic disturbances, Variable efcacy seen in Cushings
(oral administration) aminotransferase. GI intolerance, disease and Nelsons syndrome.
May decrease CRH weight gain.
secretion.
Peripheral Glucocorticoid Antagonist
Mifepristone Antagonizes Up to 20 mg/kg GI intolerance, rash, Requires cautious use since few
(RU 486) glucocorticoid per day drowsiness, clinical experiences and no
(oral administration) receptors. gynecomastia, biochemical markers available
hypoadrenalism. to monitor efcacy of treatment.
Has abortifacient Increases cortisol level via
and embryotoxic antagonism of negative feedback
properties. of ACTH secretion.
ACTH, adrenocorticotropic hormone or corticotropin; CRH, corticotropin-releasing hormone; GABA, -aminobutyric acid; GI, gastrointestinal.
TABLE 4211. Principles of Glucocorticoid Administration to Avoid Hypercortisolism or Hypocortisolism
To Prevent Hypercortisolism and Development of Cushings Syndrome

Give the lowest glucocorticoid dose that will manage the disease being treated and for the shortest possible duration.
If possible, give glucocorticoid via administration routes that minimize systemic absorption (such as inhalation or dermal).
Administer glucocorticoid treatment every other day (calculate the total 48-hour dose and give as a single dose of intermediate-acting
glucocorticoid in the morning).4
Avoid concurrent administration of drugs that can inhibit glucocorticoid metabolism.
To Prevent Hypocortisolism and Development of Adrenal Insufciency or Adrenal Crisis
Assess patients at risk for adrenal insufciency with screening tests (serum cortisol, plasma ACTH stimulation, etc.)
If the patient requires discontinuation from chronic treatment with supraphysiologic doses of glucocorticoid, the following discontinuation
protocol can be used:4
Gradually taper the dose to approximately 20 mg of prednisone or equivalent per day, given in the morning, then
Change glucocorticoid to every other day administration, in the morning.
Stop the glucocorticoid when the equivalent physiologic dose is reached (20 mg/day of hydrocortisone or 57.5 mg/day of prednisone
or equivalent).
Understand that recovery of the HPA axis may take up to a year after glucocorticoid discontinuation during which the patient may
require supplementation therapy during periods of physiologic stress.
Evaluate patients at risk for adrenal insufciency as a result of treatment(s) of Cushings syndrome and initiate glucocorticoid and miner-
alocorticoid replacement therapy as appropriate.
Avoid concurrent administration of drugs that can induce glucocorticoid metabolism.
Educate patients about:
The need for replacement or supplemental glucocorticoid and mineralocorticoid therapy
How to administer parenteral glucocorticoid if unable to immediately access medical care during an emergency
Need to wear or carry medical identication regarding their condition (e.g., card, bracelet)
ACTH, adrenocorticotropic hormone or corticotropin; HPA, hypothalamic-pituitary-adrenal.
Cushings Syndrome: Patient Care and Monitor for development of pituitary hormone
Monitoring deciency.
7. If surgical resection does not achieve satisfactory disease
control or is not indicated, evaluate the patient for pitu-
1. Patient evaluation should include a thorough history of all itary radiation or bilateral adrenalectomy with concomi-
medications and herbal or dietary supplements. tant pituitary radiation.
2. Perform initial screening tests to conrm Cushings syn- Monitor patients treated with pituitary radiation for
drome and rule out those with pseudo-Cushings conditions development of pituitary hormone deciency.
(in other words, until it is determined that it is not a pseudo- 8. Evaluate patients with adrenal adenomas for unilateral
Cushings syndrome). adrenalectomy.
3. Once diagnosis is conrmed, perform further testing to 9. Give glucocorticoid and mineralocorticoid replacement
determine the etiology of Cushings syndrome. to patients who undergo adrenalectomy (permanently in
4. Attempt to taper glucocorticoid if Cushings syndrome is the case of bilateral adrenalectomy).
from exogenous administration. 10. Evaluate the patient for appropriateness of pharmaco-
5. If endogenous Cushings syndrome, determine if patient is logic therapy depending on etiology of Cushings
an appropriate candidate for surgical resection of the syndrome.
tumor. Does the patient have any conditions that con- 11. Monitor patient for response to therapy, need for dose
traindicate surgical resection, such as advanced disease adjustments, and presence of adverse drug reactions.
(metastatic adrenal carcinoma)? 12. Once disease control is achieved, continue to monitor
6. Develop a formal plan to assess the response and compli- biochemical markers and patient for development of
cations associated with surgery:15 complications of Cushings syndrome because relapse
Measure plasma cortisol after surgery to determine if the may occur.
patient displays persistent hypercortisolism (surgical 13. Provide patient education regarding disease state and
treatment failure) or hypocortisolism (adrenal insuf- treatment:
ciency requiring steroid replacement therapy).
Causes of Cushings syndrome, including drug-induced
In patients demonstrating hypocortisolism:
etiologies.
Monitor for signs and symptoms of glucocorticoid with- How to recognize the clinical manifestations of
drawal (e.g., headache, fatigue, malaise, and myalgia).
Cushings syndrome.
Monitor for signs and symptoms of adrenal insufciency. Possible sequelae of Cushings syndrome.
Monitor morning cortisol or response to ACTH stimu- How to reduce the modiable cardiovascular and
lation every 3 to 6 months to assess for HPA axis
metabolic complications.
recovery. Discontinue glucocorticoid replacement
Advantages and disadvantages of potential treatment
therapy when cortisol concentrations are greater than
options.
19 mcg/dL (524 nmol/L) on either test.
Possible adverse consequences of treatment.
Monitor cortisol, ACTH, low-dose dexamethasone Need for glucocorticoid and mineralocorticoid replace-
suppression, or other tests to assess for risk of relapse
ment after treatment, if appropriate.
of hypercortisolism.
Importance of adherence to therapy.
ABBREVIATIONS DHEA-S: sulfated form of dehydroepiandrosterone

DST: dexamethasone suppression test
3B-HSD: 3-hydroxysteroid dehydrogenase GABA: -aminobutyric acid
11B: 11-hydroxylase GI: gastrointestinal
17: 17-hydroxylase HPA: hypothalamic-pituitary-adrenal
17,20: 17,20-lyase IM: intramuscularly
21: 21-hydroxylase IV: intravenous or intravenously
ACTH: adrenocorticotropic hormone or corticotropin MRI: magnetic resonance imaging
AIDS: acquired immunodeciency syndrome
AS: aldosterone synthase Reference lists and self-assessment questions and answers are
BUN: blood urea nitrogen available at www.ChisholmPharmacotherapy.com.
CRH: corticotropin-releasing hormone
CT: computed tomography Log into the website: www.pharmacotherapyprinciples.com for
CYP450 3A4: cytochrome P-450 subfamily IIIA, polypeptide 4 information on obtaining continuing education credit for this
DHEA: dehydroepiandrosterone chapter.
KEY REFERENCES AND READINGS Findling JW, Raff H. Screening and diagnosis of Cushings syndrome.
Endocrinol Metab Clin North Am 2005; 34:385402.
Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications Hopkins RL, Leinung MC. Exogenous Cushings syndrome and glu-
of Cushings syndrome: A consensus statement. J Clin cocorticoid withdrawal. Endocrinol Metab Clin North Am
Endocrinol Metab 2003; 88:55935602. 2005; 34:371384.
Aron DC, Findling JW, Tyrrell JB. Glucocorticoids and adrenal andro- Morris D, Grossman A. The medical management of Cushings syn-
gens. In: Greenspan FS, Garden DG (eds.). Basic and Clinical drome. Ann NY Acad Sci 2002; 970:119133.
Endocrinology. New York: Lange Medical Books/McGraw-Hill; Nieman LK, Ilias I. Evaluation and treatment of Cushings syndrome.
2004: 362413. Am J Med 2005; 118:13401346.
Coursin DB, Wood KE. Corticosteroid supplementation for adrenal Salvatori R. Adrenal insufciency. JAMA 2005; 294:24812488.
insufciency. JAMA 2002; 287: 236240.
43 PITUITARY GLAND DISORDERS
Judy T. Chen, Devra K. Dang, Frank Pucino, Jr., and Karim Anton Calis
LEARNING OBJECTIVES
1. List the mediators and primary effects of the pituitary hormones.

2. Identify the clinical features of patients with acromegaly.
3. Discuss the role of surgery and radiation therapy for patients with acromegaly.
4. Select appropriate pharmacotherapy for patients with acromegaly based on patient-
specic factors.
5. Identify the clinical features of children and adults with growth hormone deciency and
select appropriate pharmacotherapy for these patients.
6. List the monitoring parameters necessary to assess therapeutic outcomes and adverse
effects in patients receiving growth hormone therapy.
7. List the common etiologies of hyperprolactinemia.
8. Identify the clinical features of patients with hyperprolactinemia.
9. Select appropriate pharmacologic and nonpharmacologic treatments for patients with
hyperprolactinemia based on patient-specic factors.
KEY CONCEPTS comorbid conditions such as hypertension, diabetes, arrhyth-

mias, coronary artery disease, and heart failure to prevent
Surgical resection of the pituitary tumor through transsphe- vascular and neuropathic complications.
noidal pituitary microsurgery is the treatment of choice for Recombinant growth hormone therapy is the main pharma-
most patients with growth hormoneproducing pituitary cologic treatment for growth hormone deciency in both
adenomas. children and adults.
Somatostatin analogs are the mainstay of pharmacotherapy Although comparative trials have not been conducted, recom-
for the treatment of acromegaly when surgery and radiation binant growth hormone products appear to have similar ef-
are contraindicated or have failed. cacy for treating growth hormone deciency.
Pegvisomant is indicated for patients who do not tolerate or Dopamine agonists are the rst-line treatment of choice for
fail other treatments or for those with extremely elevated all patients with hyperprolactinemia; transsphenoidal sur-
insulin-like growth factor I levels. gery and radiation therapy are reserved for patients who are
Dopamine agonists may be appropriate for patients with resistant to or severely intolerant of pharmacologic therapy.
mildly elevated insulin-like growth factor I levels who have Women who become pregnant while on a dopamine agonist
growth hormone and prolactin co-secreting tumors. should discontinue treatment immediately to minimize fetal
Prolonged exposure to elevated growth hormone and exposure. Because cabergoline has a long half-life, women
insulin-like growth factor I levels can lead to serious compli- who plan to become pregnant should discontinue the drug
cations in patients with acromegaly. Aggressively manage at least 1 month before planned conception.
701
PHYSIOLOGY OF THE PITUITARY GLAND insufciency or absence of all anterior pituitary hormones
(i.e., panhypopituitarism). A tumor located in the pituitary
The pituitary gland, located at the base of the brain, is a small gland may result in excess secretion of a hormone or may
endocrine gland about the size of a pea weighing approxi- physically compress the gland and suppress adequate hormone
mately 600 mg. The pituitary gland is referred to as the mas- release. The type, location, and size of a pituitary tumor often
ter gland because it is responsible for the regulation of other determine a patients clinical presentation. This chapter dis-
endocrine glands and body systems. Growth, development, cusses the pathophysiology and role of pharmacotherapy in
metabolism, reproduction, and stress homeostasis are among the treatment of acromegaly, growth hormone deciency, and
the functions inuenced by the pituitary. Functionally, the hyperprolactinemia. The following hormones are discussed
gland consists of two distinct sections: the anterior pituitary elsewhere in this book: adrenocorticotropic hormone (ACTH
lobe (adenohypophysis) and the posterior pituitary lobe or corticotropin), thyroid-stimulating hormone (TSH or thy-
(neurohypophysis). The human intermediate pituitary lobe rotropin), luteinizing hormone (LH), follicle-stimulating hor-
has minimal structure and function. The pituitary receives mone (FSH), vasopressin (antidiuretic hormone or ADH), and
neural and hormonal input from the inferior hypothalamus oxytocin.
via blood vessels and neurons contained in the pituitary stalk.
The posterior pituitary is innervated by direct nervous
stimulation from the hypothalamus, resulting in the release of GROWTH HORMONE (SOMATOTROPIN)
specic hormones. The hypothalamus synthesizes two hor-
mones, oxytocin and vasopressin. These hormones are stored Somatotropin or growth hormone (GH) is the most abun-
in and released from the posterior pituitary lobe. Oxytocin dant hormone produced by the anterior pituitary lobe. The
exerts two actions: (1) it promotes uterine contractions dur- GH-secreting somatotropes account for 50% of hormone-
ing labor, and (2) it contracts the smooth muscles in the breast secreting cells in the anterior pituitary. GH is regulated pri-
to stimulate the release of milk from the mammary gland dur- marily by the hypothalamic-pituitary axis. The hypothalamus
ing lactation. Vasopressin is an antidiuretic hormone (ADH) releases growth hormonereleasing hormone (GHRH) to
essential for proper uid and electrolyte balance in the body. stimulate GH synthesis and secretion, whereas somatostatin
Specically, vasopressin increases the permeability of the dis- inhibits it.1 On stimulation by GHRH, somatotropes release
tal convoluted tubules and collecting ducts of the nephrons to GH into the circulation, thereby stimulating the liver and
water. This causes the kidney to excrete less water in the urine. other peripheral target tissues to produce insulin-like growth
Consequently, the urine becomes more concentrated as water factors (IGFs). These IGFs, also known as somatomedins, are
is conserved. the peripheral GH targets. There are two types of IGFs: IGF-I
In contrast to the posterior pituitary lobe, the anterior and IGF-II. IGF-II is responsible primarily for regulating fetal
pituitary lobe is under the control of several releasing and growth, whereas IGF-I is the hormone responsible for growth
inhibiting hormones secreted from the hypothalamus via a of bone and other tissues. High levels of IGF-I inhibit GH
portal vein system. The anterior pituitary lobe, in turn, syn- secretion through negative feedback, thereby inhibiting
thesizes and secretes six major hormones. Figure 431 sum- GHRH secretion.1 The hypothalamus also may stimulate the
marizes the physiologic mediators and effects of each of these release of somatostatin to inhibit GH secretion. Effects of
hormones. IGF-I in peripheral tissues are both GH-dependent and GH-
independent.2 GH is an anabolic hormone with direct anti-
insulin metabolic effects. By stimulating protein synthesis
HORMONAL FEEDBACK REGULATORY SYSTEMS and shifting the bodys energy source from carbohydrates to
fats, GH promotes a diabetic state2 (Table 431). GH controls
The hypothalamus is responsible for the synthesis and somatic growth and has a critical role in the development of
release of hormones that regulate the pituitary gland. normal skeletal muscle, myocardial muscle, and bone.
Stimulation or inhibition of the pituitary hormones elicits a In healthy individuals, GH is secreted in a pulsatile pattern
specic cascade of responses in peripheral target glands. In throughout a 24-hour period, with several short bursts occur-
response, these glands secrete hormones that exert a negative ring mostly during the night. The most intense period of GH
feedback on other hormones in the hypothalamic-pituitary secretion occurs within the rst 1 to 2 hours of slow-wave sleep
axis (Fig. 431). This negative feedback serves to maintain (stage 3 or 4 deep sleep).1 In between these bursts, basal con-
body system homeostasis. High circulating hormone levels centration of GH falls to very low or undetectable levels
inhibit the release of hypothalamic and anterior pituitary because of its short half-life in the blood (19 minutes). The
hormones. amount of GH secretion uctuates throughout a persons life-
Damage and destruction of the pituitary gland may result time. Secretion of GH is lowest during infancy, increases dur-
in secondary hypothyroidism, hypogonadism, adrenal insuf- ing childhood, peaks during adolescence, and then declines
ciency, growth hormone deciency, hypoprolactinemia, or gradually during the middle years.1 These changes are parallel
CHAPTER 43 / PITUITARY GLAND DISORDERS 703
Hypothalamus
()
GHRH
PRH Water
TRH ADH
(+) CRH
(Vasopressin)
Balance
GnRH
LHRH Posterior
Dopamine
GABA Pituitary
GHIH (Somatostatin) () Anterior
Pituitary Oxytocin
Milk Uterine
(+) Let-Down Contraction
ANTERIOR GH Prolactin TSH ACTH FSH, LH FSH, LH

PITUITARY (Somatotropin) (Thyrotropin) (Corticotropin)
HORMONES
TARGET
ORGANS
Liver Mammary Thyroid Adrenal Ovaries Testes

Gland Gland Gland
Inhibin Inhibin
TROPHIC T3, T4 Cortisol Estradiol Testosterone
IGF-I
HORMONES Progesterone
PRINCIPAL
EFFECTS Linear and Milk Metabolism Cell Equilibrium Ovulation Sperm
Organ Growth Production Heat Production and Function Formation
FIGURE 431. Hypothalamic-pituitary-target-organ axis. Trophic hormones are hormones that regulate the
activity of endocrine glands. The hypothalamic hormones regulate the biosynthesis and release of eight pitu-
itary hormones. Stimulation of each of these pituitary hormones produces and releases trophic hormones
from their associated target organs to exert their principal effects. Subsequently, increased serum concentra-
tion of the trophic hormones released from the target organs can inhibit both the hypothalamus and the
anterior pituitary gland to maintain homeostasis (negative feedback). Inhibin is produced by the testes in the
male and ovaries in the female during pregnancy. Inhibin acts in direct negative feedback on pituitary pro-
duction of follicle-stimulating hormone (FSH). Melanocyte-stimulating hormone (MSH) produced by the
anterior pituitary is not illustrated in the gure.
() = inhibit; (+) = stimulate; ACTH = adrenocorticotropic hormone (corticotropin); ADH = antidiuretic
hormone (vasopressin); CRH = corticotropin-releasing hormone; FSH = follicle-stimulating hormone;
GABA = -aminobutyric acid; GH = growth hormone (somatotropin); GHIH = growth hormoneinhibiting
hormone (somatostatin); GHRH = growth hormonereleasing hormone; GnRH = gonadotropin-releasing
hormone; IGF-I = insulin-like growth factor I; LH = luteinizing hormone; LHRH = luteinizing hormone
releasing hormone; PRH = prolactin-releasing hormone; T3 = triiodothyronine; T4 = thyroxine; TRH =
thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone (thyrotropin).
to an age-related decline in lean muscle mass. In addition to 1 million population are affected, with an estimated annual
GH itself, several internal and external factors also modulate incidence of 3 to 4 cases per 1 million people.3,4 In more than
GH synthesis (e.g., serotonin, dopamine, and -adrenergic 95% of the cases, overproduction of GH is due to a benign
agonists), including low plasma glucose, exercise, stress, pituitary tumor (adenoma), whereas malignant tumors
trauma, emotional excitement, and ingestion of protein-rich occur in less than 1%.4 Most pituitary adenomas occur
meals.1 spontaneously as a result of a genetic mutation acquired
during life. Depending on the size of the tumor, pituitary
adenomas are classied as: (1) microadenomas if they are
Growth Hormone Excess 10 mm or less in diameter or (2) macroadenomas if they are
greater than 10 mm. Rarely, non-pituitary tumors may cause
Epidemiology and Etiology acromegaly. These tumors can produce GH, but more com-
Acromegaly affects both genders equally; the average age of monly they secrete GHRH and result in excessive GH and
presentation is 44 years. Approximately 50 to 70 people per IGF-I production.
TABLE 431. Effects of Growth Hormone2 Diagnosis of acromegaly is based on both clinical and bio-
chemical findings. Because secretion of GH fluctuates
Action(s) Effect(s) throughout the day, a single random measurement is never
Lipid Increases the use of fat Increases breakdown reliable for diagnosing GH excess. However, GH-mediated
metabolism by stimulating of fat (lipolysis) IGF-I production results in relatively stable serum IGF-I con-
triglyceride Increases circulating
centrations during the day, which correlate positively with
breakdown and fatty acid levels
oxidation of Increases lean body 24-hour mean GH levels.1 This makes elevated IGF-I levels an
adipocytes. mass ideal screening test for acromegaly and a reliable monitoring
Protein Stimulates protein Increases muscle biochemical marker to assess disease activity and response to
metabolism anabolism by mass therapy.5,6 Because IGF-I levels may uctuate with age and
increasing amino gender, it is important to compare IGF-I levels with age- and
acid uptake and sex-matched population values.5,6 Other conditions such as
protein synthesis
nutritional status, liver dysfunction, insulin levels, and illness
and decreasing
oxidation of also can affect IGF-I levels. Almost all IGF-I in the circula-
proteins. tion is bound to IGF-binding proteins (IGFBPs), which also
Carbohydrate Suppresses the Decreases glucose regulate IGF bioactivity. The major carrier protein for circu-
metabolism ability of insulin utilization lating IGF-I is the GH-dependent protein IGFBP-3, which
to stimulate uptake also can be used to assess therapeutic response.2 Low IGFBP-
of glucose in 3 levels are associated with GH deciency, GH insensitivity,
peripheral tissues.
and malnutrition. The measurement of serum GH secreted
Decreases insulin Insulin resistance
receptor sensitivity. by the pituitary in response to an oral glucose tolerance test
Impairs postreceptor Hyperglycemia (OGTT) is considered the primary biochemical test for diag-
insulin action. nosing acromegaly. GH is suppressed after administration of
Stimulates glucose Increases hepatic a 75 g oral glucose challenge because postprandial hyper-
synthesis in the glucose output
glycemia inhibits secretion of GH for at least 1 hour. If the
liver (gluconeogenesis)
GH level does not decline to less than 1 ng/mL (1 mcg/L)
during the test, the patient is diagnosed with acromegaly.4
Elevation of IGF-I serum concentrations and the clinical
Pathophysiology presentation help to conrm the diagnosis.
Acromegaly is a rare, insidious disorder that manifests gradu-
ally over time. It is caused by an adenoma of the pituitary that
overproduces GH and stimulates excessive production of IGF- Acromegaly Treatment Goals
I during adulthood. This typically occurs after fusion of the Patients with acromegaly experience a two- to three-fold increase
epiphyses (growth plates) of the long bones.4 The facial fea- in mortality rate.8 Normalization of GH and IGF-I levels
tures of an acromegalic patient are depicted in Fig. 432. reverses the mortality risk and alleviates signicant comorbid
Gigantism refers to GH excess that occurs during childhood complications, especially cardiovascular, pulmonary, and
before epiphyseal closure and results in excessive linear growth. metabolic abnormalities. Reduction of IGF-I levels alone does
FIGURE 432. Before and after photographs of an

acromegalic patient. Compare the photographs of an
acromegalic woman (A) before the onset of acromegaly
and (B) after approximately 20 years, when the diagnosis
was well established. Notice the coarsening of facial
features, with enlarged nose, lips, and forehead.
Clinical Presentation and Diagnosis of Acromegaly3,79
General
The patient will experience slow development of soft-tissue overgrowth affecting many
body systems. Signs and symptoms may progress gradually over 10 to 15 years.
Symptoms
Headache and compromised visual function (loss of peripheral vision and blurred
vision) caused by the actual tumor mass and its close proximity to the optic structures.
Loss of other hormonal functions (i.e., LH, FSH, TSH, and ACTH) caused by massive
tumor size compressing the anterior pituitary lobe.
Absence of regular menstrual periods (amenorrhea), impotence, and decreased libido
caused by disruption of the gonadotropin secretion.
Excessive sweating, joint pain, nerve pain, and abnormal neurologic sensations
(paresthesias) related to elevated GH and IGF-I levels.
Signs
Coarsening of facial features
Increased hand volume
Increased ring and shoe size
Increased spacing between teeth
Increased acne/oily skin
Enlarged tongue
Deepening of voice
Thick, irregular, patchy skin discoloration
Enlarged nose, lips, and forehead (frontal bossing)
Abnormal protrusion of the mandible (prognathia)
Inappropriate secretion of breast milk (galactorrhea)
Abnormal enlargement of interior organs (organomegaly)
Carpal tunnel syndrome caused by nerve compression from the swollen tissue
Laboratory Tests
GH level greater than 1 ng/mL (1 mcg/L) following an oral glucose tolerance test
(OGTT) and elevated IGF-I level compared with age- and sex-matched control
values.
Glucose intolerance may be present in up to 50% of patients.
Additional Clinical Sequelae

Cardiovascular diseases: hypertension, coronary heart disease, cardiomyopathy, left
ventricular hypertrophy, and arrhythmia.
Osteoarthritis and joint damage develop in up to 90% of patients.
Respiratory disorders and sleep apnea occur in up to 60% of patients.
Type 2 diabetes mellitus develops in up to 40% of patients.
Increase risk for the development of esophageal, colon, and stomach cancer.

Perform magnetic resonance imaging (MRI) examination and computed tomography
(CT) of the pituitary to locate the tumor and validate the diagnosis.
Without obvious pituitary tumor but proven acromegaly, measurement of GHRH may be
helpful to detect ectopic tumors.
Source: Adapted, with permission, from Heck AM, Yanovski JA, Calis KA. Pituitary Gland
Disorders. In: Dipiro JT, Talbert RL, Yee GC, et al. (eds.) Pharmacotherapy. A Pathophysiologic
Approach. 6th ed. New York: McGraw Hill; 2005: 14071423.
TABLE 432. Goals for Management of Acromegaly4,8,1113

Patient Encounter 1: The Medical
History, Physical Examination, and 1. Normalize biochemical disease markers
Diagnostic Tests a. Reduce GH to less than 1 ng/mL (1 mcg/L) after oral glucose
tolerance test (OGTT)a
EB, a 48-year-old woman, presents to a new primary care b. Normalize IGF-I levels to age- and sex-matched control values
2. Ablate or reduce tumor size to relieve tumor mass effect
clinic. EBs chief complaints are chronic pain of the knee and
3. Prevent tumor recurrence and control tumor size
pins and needles and numbness in both hands. Over the 4. Preserve normal pituitary function
past few years, she feels that her body has been changing. EB 5. Improve clinical signs and symptoms
reports increased urinary frequency, excessive sweating, 6. Alleviate signicant morbidities
worsening headaches, an increase of two shoe sizes, and 7. Reduce mortality rates to that of the general population
facial hair that she shaves once a week. She says that her a
hands have enlarged to the point that my wedding band When using the older GH assay, suppression of GH levels to less than
1 ng/mL (1 mcg/L) after OGTT is the biochemical target. When using
wont t anymore. new, highly specic and sensitive assays, GH levels less than or equal
to 0.4 ng/mL (0.4 mcg/L) are the biochemical target.1113
PMH GH, growth hormone; IGF-I, insulin-like growth factor I.
Hypertension for 12 years, currently controlled
Hyperlipidemia for 10 years, currently controlled
Osteoarthritis for 5 years not appear to be a reliable predictor of long-term outcome.6,10
The goals of therapy are presented in Table 432.4,8,1113
FH
Mother died of colon cancer at age of 58 years. Father died General Approaches to Treatment
of myocardial infarction at an unknown age. The American Association of Clinical Endocrinologists (AACE)
SH published medical guidelines for the diagnosis and treatment of
Married, a nurse practitioner, highly educated, and physi- acromegaly (Fig. 433). According to these guidelines, surgical
cally active (bikes four times per week) resection of the pituitary tumor through transsphenoidal pituitary
microsurgery is the treatment of choice for most patients with GH-
Meds
producing pituitary adenomas.4 Most microadenomas can be
Lisinopril/hydrochlorothiazide 20/12.5 mg once daily
Atorvastatin 10 mg once daily resected successfully, resulting in prompt normalization of GH
Acetaminophen 500 mg every 8 hours as needed for joint levels. Complete resection of a macroadenoma may be difcult if
pain the tumor has already invaded the surrounding nerves and tis-
sues. In such cases, debulking of the tumor, along with adjunctive
ROS radiation and/or pharmacotherapy, may improve treatment out-
(+) coarse facial hair. Deepening of voice. Ophthalmic
come. The success rate for normalization of GH levels is approx-
examination reveals normal visual acuity and elds.
imately 90% in patients with well-dened microadenomas and
PE 46% to 48% in patients with macroadenomas.14,15 Normalization
VS: 118/76 mm Hg, P 78 beats per minute, RR 18 breaths/ of GH resulted in a 10-year survival rate of 88%, which is similar
minute, T 37.5C (99.5F) to that of the general population.14 Major but infrequent surgical
ENT: (+) protruding jaw and large eshy nose complications include meningitis, serious visual impairment,
CV: RRR, normal S1, S2; no murmurs, rubs, gallops cerebrospinal uid leakage requiring surgical repair, permanent
Abd: Soft, non-tender, non-distended; (+) bowel sounds, no
hypopituitarism, and death. Minor complications include
hepatosplenomegaly, heme () stool
diabetes insipidus, local nasal complications, transient hypo-
Labs natremia, and cerebrospinal uid leakage not requiring surgical
Electrolytes and renal function are within normal limits. repair.14 Repeat surgery is rarely an option because of the high
Fasting blood glucose level is 206 mg/dL (11.43 mmol/L), risk of serious complications. The relative contraindications to
HbA1c is 8.5%, and () microalbumin. GH level following surgery include patient frailty, acromegaly-associated comorbidi-
an oral glucose tolerance test is 8 ng/mL (8 mcg/L). Elevated ties, and medically unstable conditions such as airway difculties,
IGF-I at 790 ng/mL (790 mcg/L)
severe hypertension, or uncontrolled diabetes.4
MRI and CT scan: Both reveal a pituitary tumor approxi-
mately 5 mm in diameter.
Given this information, what signs and symptoms does EB Pharmacologic therapy is often necessary for patients in
have for acromegaly? whom surgery is not an option.4 Somatostatin analogs, GH
Identify your treatment goals for EB. receptor antagonists, and dopamine agonists are the primary
What nonpharmacologic and pharmacologic treatment pharmacologic therapies used for the management of
options are available for EB? acromegaly (Table 433). Pharmacologic therapy avoids
hypopituitarism and other surgical risks.
FIGURE 433.
Recommended schema for
management of growth
hormoneproducing ade-
nomas.4 GH = growth hor-
mone; IGF-I = insulin-like
growth factor I. (Adapted,
with permission, from AACE
Medical Guidelines for
Clinical Practice for the
diagnosis and treatment of
acromegaly. Endocr Pract
2004; 10(3):213225.)
Somatostatin Analog (Growth HormoneInhibiting tumor size reduction in less than 50% of patients.18 If treat-
Hormone) ment is discontinued, monitor patients for tumor recurrence.
Somatostatin analogs are the mainstay of pharmacotherapy Use of the rst-generation somatostatin analog octreotide is
for the treatment of acromegaly when surgery and radiation are limited by its extremely short duration of action and require-
contraindicated or have failed. These agents mimic endogenous ment for subcutaneous administration at least three times a day.
somatostatins and bind to the somatostatin receptors in the If a patients GH level returns to baseline before the end of an
pituitary to cause potent inhibition of GH, insulin, and 8-hour dosing interval, the frequency of octreotide administration
glucagon secretion. Somatostatin analogs effectively control can be increased to every 4 to 6 hours. Most patients require
GH and IGF-I levels in 50% to 70% of patients, with 41% to octreotide in doses of 100 to 200 mcg three times daily.19,20 To
67% achieving normal IGF-I levels.16,17 Previous epidemiologic improve patient tolerance to gastrointestinal (GI) adverse
studies reported that a reduction of GH levels of between effects, start octreotide at 50 mcg every 8 hours.20 Assess IGF-I
2 and 5 ng/mL (2 and 5 mcg/L) resulted in a mortality rate serum concentrations every 2 weeks after initiating therapy to
similar to that of the general population.4,6 Long-term treat- further titrate dose in increments of 50 mcg per dose.
ment can sustain hormone suppression and alleviate soft-tissue Transient GI disturbances such as diarrhea, abdominal pain,
manifestations. Although somatostatin analogs can achieve atulence, constipation, and nausea are commonly associated
substantial relief of clinical symptoms, they produce modest with somatostatin analogs.19,20 These adverse GI effects usually
TABLE 433. Comparison of Various Drugs for Treatment of Acromegaly4
Drug Type Starting Maximal Monitoring Preferred

and Agent Dose Dose Side Effects Suggestions Indication
Dopamine Agonist
Cabergoline 1 mg/week 4 mg/week Nausea, GI GH, IGF-I GH and prolactin
(Dostinex) orally orally cramps, co-secreting tumors
headache
Somatostatin analog
Octreotide 50 mcg SQ 200 mcg Nausea, GI GH, IGF-I, Somatostatin
(Sandostatin) three times SQ three cramps, ultrasonography analogresponsive
daily times daily gallstones of gallbladder tumor
(if symptoms)
Octreotide LAR 10 mg IM 30 mg IM Nausea, GI GH, IGF-I, Somatostatin
(Sandostatin LAR) every every cramps, ultrasonography analogresponsive
4 weeks 4 weeks gallstones of gallbladder tumor
(if symptoms)
Lanreotidea 60 mg IM 120 mg IM Nausea, GI GH, IGF-I, Somatostatin
every every cramps, ultrasonography analogresponsive
2 weeks 7 days gallstones of gallbladder tumor
(if symptoms)
Lanreotide Autogela 60 mg deep 120 mg deep Nausea, GI GH, IGF-I, Somatostatin
SQ every SQ every cramps, ultrasonography analogresponsive
28 days 28 days gallstones of gallbladder tumor
(if symptoms)
GH Receptor Antagonist
Pegvisomant 10 mg SQ 40 mg SQ Headache, Liver function tests High IGF-I
(Somavert) daily daily fatigue, monthly for levels not
abnormal 6 months, then responsive to
liver enzymes every 6 months; somatostatin
MRI every 6 months. analogtherapy
IGF-I (not GH) after
rst year, then yearly.
a
Lanreotide is currently not available in the United States.
GH, growth hormone; GI, gastrointestinal; IGF-I, insulin-like growth factor I; IM, intramuscularly; LAR, long-acting release; MRI, magnetic resonance
imaging; SQ, subcutaneously.
Adapted from AACE Medical Guidelines for Clinical Practice for the diagnosis and treatment of acromegaly. Endocr Pract. 2004; 10(3):213225,
by permission of publisher, AACE Corp.
subside within the rst 3 months of therapy. Octreotide inhibits To increase patient compliance, the long-acting formulation
gallbladder contractility and decreases bile secretion. The major of octreotide acetate (Sandostatin LAR) is preferred in the
adverse effect of octreotide is development of biliary sludge majority of cases. Sandostatin LAR is administered as a deep
and asymptomatic gallstones (cholelithiasis). Biliary sludge intramuscular injection in doses of 10 to 30 mg every 4
occurs in 20% of patients and is felt to be a predisposing factor weeks and is as effective as short-acting octreotide.17,21,22
for the high incidence of cholelithiasis observed in 10% to 20% Typically, at least a 2-week trial of short-acting octreotide is rec-
of patients treated with octreotide.19 Development of gallstones ommended to determine efcacy and tolerance before switching
typically occurs in patients treated for 12 months or longer and to the long-acting preparation. Counsel patients to perform
is unrelated to age, gender, or dose. Octreotide may suppress alternate injections in the gluteal region and to avoid injections
pituitary release of TSH, leading to decreased thyroid hormone in the deltoid region because of signicant injection-site dis-
secretion and subsequent hypothyroidism in 12% of treated comfort. Although antibody formation to octreotide occurs in
patients. Additionally, octreotide can alter the balance of the up to 25% of patients, development of these antibodies does not
counterregulatory hormones (i.e., glucagon, insulin, and GH), cause serious adverse effects or compromise treatment efcacy.23
resulting in either hypoglycemia or hyperglycemia. Sinus
bradycardia, conduction abnormalities, and arrhythmias have Growth Hormone Receptor Antagonist
been reported with octreotide therapy. Thus, patients taking Growth hormone receptor antagonist represents a novel approach
insulin, oral hypoglycemic agents, -blockers, or calcium chan- to the treatment of acromegaly. Pegvisomant is the only genet-
nel blockers may require dose adjustment when these agents are ically engineered GH-receptor antagonist that blocks the action
used concurrently with octreotide. of GH. The effects of pegvisomant work independently of
tumor characteristics, somatostatin, and dopamine receptors.24 patients with co-existing hyperprolactinemia also had a more
Up to 97% of acromegalic patients treated with pegvisomant favorable response to cabergoline, with 50% of patients achieving
(1020 mg/day) achieved normal age-related IGF-I levels and normal IGF-I levels, 56% GH suppression, and 65% tumor shrink-
experienced signicant improvement in clinical symptoms of age.30 Although orally administered dopamine agonists are the
GH excess by 1 year of therapy.25,26 Pegvisomant therapy is not least expensive medical therapy for managing acromegaly, the
associated with deterioration in glucose tolerance (bodys ability major disadvantage is their relative lack of efcacy compared with
to metabolize glucose) or insulin sensitivity (capacity of cells to existing therapeutic options. Dopamine agonists may be appro-
respond to insulin). A preliminary study in seven acromegalic priate for patients with mildly elevated IGF-I levels who have GH and
patients suggested that insulin sensitivity and glucose tolerance prolactin (PRL) co-secreting tumors.4
improved in patients converted from octreotide to pegviso-
mant.27 However, use of pegvisomant is associated with statisti- Radiation Therapy
cally signicant dose-dependent increases in GH despite the Radiation therapy involves the use of radiation to kill rapidly
declining IGF-I levels.25,26 The dose-dependent increase in GH growing tumor cells and often results in a reduction in tumor
is troubling because it has been suggested that persistent ele- size. Radiation therapy is extremely effective but may take 10 to
vation of GH levels may be indicative of tumor growth. 20 years before the full effects become evident. A major com-
Although patients did not experience a signicant change in plication resulting from radiation therapy is hypopituitarism,
tumor volume during studies, theoretical concerns remain requiring lifelong hormone replacement.4 There is also the
because pituitary tumors are slow growing. Thus, practitioners potential for optic nerve damage if the pituitary tumor is near
should use caution when administering pegvisomant to the optic tracts. Radiation therapy is an important adjunctive
patients with large tumors extended toward the optic chiasm therapy in patients with residual GH excess after surgery or
to prevent visual damage caused by possible tumor growth. pharmacologic therapies. Owing to delay in onset of radiation
Pegvisomant is indicated for patients who do not tolerate or fail effectiveness, pharmacologic therapies often are indicated as
other treatment options or for those with extremely elevated IGF-I bridge therapy.4,19,20 Men and women who desire to have chil-
levels (greater than 900 ng/mL or 900 mcg/L).4 Long-term efcacy dren should be warned that radiation therapy may impair the
and safety proles of pegvisomant in acromegaly remain to be function of the ovaries and testes.4
established. Available data to date suggest that pegvisomant
appears well tolerated with minimal adverse effects such as self- Outcome Evaluation
limiting injection-site reactions, nausea, diarrhea, and u-like Following a baseline evaluation, monitor patients regularly
symptoms. Safety concerns about antibody development for symptom relief.
with pegvisomant do not reduce the efcacy of therapy. Rare Lifelong biochemical assessment is critical for determining
cases of hepatotoxicity have been reported in clinical trials;25,26 therapeutic outcomes. Although some patients may experi-
therefore, use caution when administering pegvisomant to ence a rapid decline in GH levels following transsphenoidal
patients with elevated baseline liver function tests. Start subcuta- microsurgery, stabilization of IGF-I levels usually occurs
neous pegvisomant at 10 mg/day, and increase at 3-month inter- 3 months following surgery but rarely may be delayed for up
vals until IGF-I levels are normalized. In a recent study, combina- to 12 months. Measure GH and IGF-I levels 3 months post-
tion of pegvisomant once weekly and long-acting somatostatin operatively to assess treatment response.6
analogs once monthly was as effective as daily pegvisomant Since up to 10% of pituitary tumors may recur within 15
monotherapy. This combination has the potential to improve years following surgery,6,14 continual postoperative monitor-
patient adherence and cost-effectiveness of therapy.28 ing is recommended.
For patients treated with somatostatin analogs, assess baseline
Dopamine Agonists fasting blood glucose, thyroid function tests, and heart rate.
Dopamine is one of the neurotransmitters that can increase GH Thereafter, periodically monitor patients for adverse reactions
secretion in healthy adults. However, dopamine agonists adminis- such as GI disturbances, glucose intolerance, signs and symp-
tered to patients with acromegaly exert the opposite effect and sup- toms of thyroid abnormalities, bradycardia, and arrhythmias
press GH release from the tumor. The rst dopamine agonist for in patients receiving long-term octreotide therapy. Reevaluate
acromegaly, bromocriptine, achieved normal IGF-I levels in fewer IGF-I and GH levels at 3-month intervals to determine thera-
than 10% of patients and was associated with signicant adverse peutic response. Since the frequency of symptomatic gallstones
effects, including nausea, dizziness, and headaches.29 The large associated with octreotide varies among studies, the need for
doses of bromocriptine required to achieve the desired response routine ultrasound evaluation remains controversial. However,
often are associated with dose-limiting toxicity, such as GI discom- ultrasonography of the gallbladder would be indicated if the
fort and orthostatic hypotension. Cabergoline, the newer, selective patient develops symptoms of biliary abnormalities.
long-acting agonist with improved tolerability, effectively can nor- For patients treated with a GH receptor antagonist, GH levels are
malize IGF-I levels in 35% of patients and reduce GH levels to less not measured because pegvisomant is a modied GH molecule
than 2 ng/mL (2 mcg/L) in 44% of treated patients.30 Acromegalic that is detected in commercial GH assays, resulting in falsely
elevated GH levels.31 Therefore, IGF-I level is the principal bio-

chemical marker used to assess response to pegvisomant ther- Acromegaly: Patient Care and
apy. After appropriate dose titration, monitor IGF-I levels every Monitoring
6 months.6 Concern for tumor growth requires careful monitor-
ing of tumor size; therefore, performing magnetic resonance
1. Assess patients clinical signs and symptoms to deter-
imaging (MRI) every 6 months during the rst year of therapy
mine severity of acromegaly.
and annually thereafter is recommended.6 Because of abnormal
2. Review the biochemical disease markers to assess
liver function associated with pegvisomant therapy, it is manda-
severity of acromegaly.
tory to monitor all patients liver function tests monthly during
the rst 6 months and every 6 months thereafter.6 3. Review the available diagnostic data to determine pitu-
itary tumor size and location. Determine if the patient
For patients receiving dopamine agonists, the maximal sup-
has a coexisting prolactin-secreting tumor. Determine if
pression of GH and IGF-I levels may take up to 3 months to
the tumor extends toward the optic chiasm or if it is
achieve. Once stable control of biochemical markers is continuous on the optic tracts.
achieved with dopamine agonists or somatostatin analogs,
4. Assess presence of acromegaly complications.
monitor GH and IGF-I levels annually.6
Identify any signicant comorbidities associated with
With conventional multidose radiation therapy, the most acromegaly that require immediate treatment or early
rapid decline in GH serum levels occurs within the rst 2 diagnosis.
years; monitor GH levels at the second year and annually
5. Determine what treatment options the patient has tried
thereafter.6 Patients who receive single-dose radiation therapy in the past.
should be evaluated at 6-month intervals because response is
6. Evaluate the patient for the presence of surgical con-
observed earlier.
traindications to transsphenoidal microsurgery. Determine
For patients receiving concurrent pharmacologic therapy if the patient is able or willing to undergo surgical
with radiation therapy, withdraw therapies every 6 to 12 intervention.
months to evaluate endogenous GH secretion and assess the
7. Develop a formal plan to assess patients response to
development of hypopituitarism.6 and complications of surgical intervention. Measure
Prolonged exposure to elevated GH and IGF-Is can lead to both GH and IGF-I levels.
serious complications in patients with acromegaly. Aggressively 8. If surgical intervention does not achieve satisfactory dis-
manage comorbid conditions such as hypertension, diabetes, ease control, select subsequent appropriate pharmaco-
arrhythmias, coronary artery disease and heart failure to prevent logic therapy based on patient-specic factors. In
vascular and neuropathic complications. It is critical to monitor selecting therapy, be sure to consider if the patient has
any contraindications or allergies to therapies.
patients indenitely for management of the comorbidities
associated with acromegaly8 (Table 434). 9. Evaluate patient for presence of adverse drug reactions,
drug allergies, and drug interactions.
10. Develop a plan to assess efcacy of pharmacologic
TABLE 434. Assessment of Acromegaly Complications at therapy. Also consider if the patients therapy requires
Diagnosis and Follow-Up8 any dose adjustments.
11. Assess biochemical markers annually once disease con-
At Diagnosis During Long-Term Follow-Up trol is achieved.
Glucose tolerance testing Fasting blood glucose, HbA1c if 12. Routinely assess acromegaly complications, including
(samples for blood diabetes present blood pressure, glucose tolerance, fasting lipid prole,
glucose and GH only) (as appropriate) cardiac evaluations (if clinically indicated),
Serum cholesterol and Annually
colonoscopy, dual-energy x-ray absorptiometry (DEXA)
lipid prole
Echocardiography Annually scan (hypogonadal only), evaluation of residual pitu-
Electrocardiogram (ECG) Annually itary function, and evaluation of sleep apnea.
Exercise ECG If angina present 13. Provide patient education with regard to disease
Colonoscopy Every 23 years state and non-drug and drug therapy. Discuss with
DEXA (hypogonadal only) Every 23 years the patient:
Sleep assessment Annually (if altered at diagnosis) Possible complications of acromegaly
Blood pressure monitoring Annually or change of treatment
How to reduce the modiable cardiovascular and
(if hypertensive)
Echo-Doppler of carotid As indicated by clinical features metabolic risk factors
artery Potential disadvantages and effectiveness of existing
treatment options
DEXA, dual-energy x-ray absorptiometry; ECG, electrocardiogram; GH,
growth hormone; HbA1c, glycosylated hemoglobin A1c.
Importance of adherence to therapy
Reprinted, with permission, from J Endocrinol Invest. 2003; 26(12): The potential for adverse effects to occur
12421247.
Growth Hormone Deciency

Epidemiology and Etiology GH Deciency in Children7,34,35
In the United States, GH deciency affects 50,000 adults, with
6,000 new cases diagnosed annually.34 Approximately 10,000 to
General
15,000 children have growth failure owing to GH deciency.
The patient will have a physical height that is greater than
Children may present with GH deciency at any time during two standard deviations below the population mean for a
their developmental stages. The evaluation for GH deciency in given age and gender.
a short child should be deferred until appropriate exclusion of
Signs
other identiable causes of growth failure, such as hypothy-
The patient will present with reduced growth velocity and
roidism, chronic illness, malnutrition, genetic syndromes, and
delayed skeletal maturation.
skeletal disorders.39 Several medications, such as methoxamine, Children with GH-decient or GH-insufcient short
isoproterenol, glucocorticoids, cimetidine, methylphenidate, stature also may present with abdominal obesity, promi-
and amphetamines, also may induce GH insufciency.32 nence of the forehead, and immaturity of the face.
Laboratory Tests
Pathophysiology The patient will exhibit a peak GH level of less than
GH deciency exists when GH is absent or produced in 10 ng/mL (10 mcg/L) following a GH stimulation test.
inadequate amounts. GH deciency may be congenital, Reduced IGF-I and IGFBP-3 concentrations also may be
acquired, or result from disruption of the hypothalamus- present.
pituitary axis. The diagnosis of GH deciency remains a clin- Because GH deciency may be accompanied by the loss
ical challenge because no gold standard currently exists. of other pituitary hormones, hypoglycemia and hypothy-
Because GH is frequently undetectable with random sampling, roidism also may be noted.
a stimulation or provocative test usually is performed to con- Other Diagnostic Tests
rm the diagnosis in both adults and children in whom GH Perform MRI or CT of the hypothalamic-pituitary region
deciency is suspected. Numerous pharmacologic agents such to detect structural or developmental anomaly.
as insulin-induced hypoglycemia, levodopa, arginine, arginine Perform x-ray of left wrist and hand for children over 1 year
plus levodopa, arginine plus GHRH, clonidine, and glucagon of age to estimate bone age (knee and ankle for children
have been used to stimulate the pituitary to produce GH. younger than 1 year of age).
However, no single test perfectly predicts GH deciency or dis- Source: Adapted, with permission, from Heck AM, Yanovski JA,
Calis KA. Pituitary Gland Disorders. In: DiPiro JT, Talbert RL, Yee GC,
plays 100% sensitivity and specicity.33 Additionally, adminis- et al. (eds.) Pharmacotherapy. A Pathophysiologic Approach. 6th ed.
tration of each of these tests is associated with adverse effects New York: McGraw-Hill, 2005: 14071423.
requiring close medical supervision. Further, current abnormal
cutoffs to determine diagnosis are arbitrarily dened and lack
universal consensus.33 With further studies, these diagnostic abnormalities associated with increased cardiovascular risks
criteria are likely to evolve and become more accurate.34 and decreased quality of life.
In children, the diagnosis of GH deciency is further sup-
ported if height is more than two standard deviations (SD) Pharmacologic Therapy
below the population mean (age- and sex-matched).35 Failure
of linear growth is an almost universal presenting feature of Growth Hormone Therapy
childhood GH deciency. Recombinant GH therapy is the main pharmacologic treat-
Childhood GH deciency may or may not continue into ment for GH deciency in both children and adults. It promotes
adulthood. Most adults with GH deciency have overt pituitary skeletal, visceral, and general body growth; stimulates protein
disease and present with nonspecic clinical disorders distinct anabolism; and affects bone, fat, and mineral metabolism2
from pediatric GH deciency, thereby making diagnosis of GH (Table 431). GH therapy requires daily subcutaneous or intra-
deciency in adults more difcult than in children. Additionally, muscular administrations. Since two-thirds of GH secretion
adult GH deciency presumably is associated with increased risk normally occurs during sleep, it is recommended to administer
of death from cardiovascular diseases.34 subcutaneous injections in the evening.37 Many preparations of
synthetic GH are available with a variety of injection devices to
Treatment Goals for GH Deciency make administration more appealing and easier. Protropin
The goal of treatment for GH deciency is to correct associated (somatrem) and Tev-TropinTM (somatropin) are approved by
clinical symptoms.34,35 In children, prompt diagnosis and early the Food and Drug Administration (FDA) for use in children,
initiation of treatment are important to maximize nal adult whereas other somatropin products such as Nutropin,
height. In adults, efforts should be made to achieve normal Nutropin AQ, Humatrope, Norditropin, Genotropin, and
physiologic GH levels in an attempt to reverse the metabolic Saizen are FDA approved in both children and adults.
Over the last four decades, evidence has suggested that GH

Clinical Presentation and Diagnosis of treatment in GH-decient children can increase short-term
GH Deciency in Adults34,36,37 growth and improve nal adult height.39 Benecial effects of GH
therapy in adults with GH deciency have been demonstrated in
subsequent studies to normalize body composition and metabolic
General
process; improve cardiac risk prole, bone mineral density,
The patient likely will have a history of childhood-onset GH
quality of life and psychological well-being; and increase muscle
deciency, hypothalamic or pituitary disorder, or the pres-
ence of three or four other pituitary hormone deciencies strength and exercise capacity.40,41 Nonetheless, long-term ef-
caused by head trauma, tumor, inltrative diseases, surgery, cacy in improving cardiovascular risks and reducing mortality
or radiation therapy. in adults treated with GH therapy remains to be established.
Begin GH therapy as soon as possible to optimize long-term
Symptoms
growth, especially for young children in whom GH deciency is
Reduced strength and exercise capacity
Defective sweating complicated by fasting hypoglycemia.35 Selection of the optimal
Psychological problems GH replacement dose will need to be individualized depending
Low self-esteem
on response, nancial resources, and product availability.
Depression Although the appropriate time to discontinue therapy remains
Fatigue/listlessness controversial in childhood GH deciency, it is reasonable to
Sleep disturbance continue GH replacement until either the child has reached sat-
Anxiety isfactory adult height, achieved documented epiphyseal closure,
Social isolation or failed to respond to therapy.34 Management of the transition
Emotional lability and impaired self-control between pediatric and adult GH replacement remains a chal-
Poor marital and socioeconomic performance lenge because there are no current data to indicate the correct
Signs approach. Starting GH therapy at a low dose and gradually
Increased fat mass (especially abdominal obesity) titrating upward may decrease the potential for adverse effects.
Reduced lean body mass The need for GH replacement therapy may be lifelong.
Reduced muscle strength Children treated with GH replacement therapy rarely expe-
Reduced exercise performance
rience signicant adverse effects, whereas adults are more sus-
Thin, dry skin; cool peripheries; poor venous access
ceptible to dose-related adverse effects. Treatment with GH may
Depressed affect, labile emotions
Impaired cardiac function mask underlying hypothyroidism. GH-induced symptoms,
such as edema, arthralgia, myalgia, and carpal tunnel syn-
Laboratory Tests drome, are common and necessitate dose reductions in up to
The patient will exhibit a peak GH level of less than 5 ng/mL
40% of adults. Benign increases in intracranial pressure may
(5 mcg/L) following a GH stimulation test.
occur with GH therapy and generally are reversible with dis-
Low or low-normal IGF-I level also may be present.
Increased low-density lipoprotein cholesterol, total cho- continuation of treatment. Often, GH therapy can be restarted
lesterol, triglycerides; decreased high-density lipoprotein with smaller doses without symptom recurrence.
cholesterol. In rapidly growing children, a slipped capital femoral epi-
Reduced bone mineral density associated with an physis may occur when the head of the femur shifts in a
increased risk of fracture. backward direction.38 There is no evidence that this problem
Increased insulin resistance and increased prevalence of is caused by GH therapy, but any child who experiences a
impaired glucose tolerance. change in gait during treatment should be evaluated by an
GH deciency may be accompanied by the loss of other orthopedic surgeon.38 Treatment with GH may induce insulin
pituitary hormones. resistance and lead to the development of glucose intolerance
in patients with preexisting risk factors. Presently, there is no
compelling evidence that GH replacement therapy is associ-
Although comparative trials have not been conducted to date, ated with an increased risk of leukemia, solid tumor, or tumor
recombinant GH products appear to have similar efcacy for recurrence.34,35,37 However, in children with a history of malig-
treating GH deciency as long as the regimen follows currently nancies, it would be prudent to wait for a 1-year tumor-free
approved guidelines. Adults with GH deciency often require period (5 years for adults) before initiating GH therapy.34 Any
substantially lower replacement doses (625 mcg/kg per day) patients treated for a prior malignancy may be at risk for a
than prepubertal children (2550 mcg/kg per day).38 The con- second malignancy and should be monitored carefully for
version of international units (IU or mU) to milligrams is a 3:1 tumor recurrence.34 Other rare ndings associated with GH
ratio.34 Selection of an injection device depends on patient pref- replacement therapy include breast development, pancreatitis,
erence because there is currently no difference in clinical out- juvenile osteochondritis (inammation of a bone and its car-
comes among the various injection systems.38 tilage), worsening of scoliosis, and increased pigmentation.38
Assess patients with scoliosis for further curvature of the spine.

Growth Hormone Deciency in Although GH and IGF-I levels do not always correlate
Children: Patient Care and Monitoring with growth response, measure IGF-I levels yearly to assess
adherence to therapy and patient response. If the IGF-I
levels are substantially above the normal range 2 years after
1. Assess the childs growth characteristics, and compare
GH replacement therapy, the dose should be reduced.38
physical height with a population standard.
IGF-I level may be used as a guide to gradually reduce replace-
2. Obtain a thorough history and physical examination that ment dose after epiphyseal closure.
may indicate the possible presence of GH deciency.
Routine monitoring of fasting lipid prole, bone mineral
Exclude other identiable causes of growth failure, such
density, and body composition in children is not typically
as hypothyroidism, chronic illness, malnutrition, genetic
syndromes, and skeletal disorders. required during GH replacement but should be done before
and after discontinuation of therapy.35
3. Perform imaging tests of the hypothalamic-pituitary
In adults, measurement of serum IGF-I, along with careful
region to detect structural or developmental anomalies.
Perform x-ray to estimate bone age. clinical evaluation, appears to be the most reliable way to
assess the appropriateness of the GH dose.
4. Perform a provocative test to measure GH, IGF-I, and/or
Continuously monitor for dose-related adverse effects such
IGFBP-3 levels.
as edema, arthralgia, myalgia, and carpal tunnel syndrome.
5. Initiate GH replacement therapy based on patient prefer-
Assess patients body composition, psychological well-being,
ence. Make sure that the child does not have any con-
fasting lipid prole, bone mineral density, and metabolic status.
traindications to GH therapy.
Patients with a history of cancer or those at risk for malig-
6. Develop a formal plan to assess response (increase in
nancy should be monitored closely.
height and change in height velocity) and adverse effects
Measure a free thyroxine serum concentration at baseline
of GH replacement therapy. Make dosage adjustments
when appropriate. and at 6- to 12-month intervals thereafter.34
Measure blood glucose levels at baseline and every 3 months
7. May continue GH replacement therapy until a child
to assess for glucose intolerance and insulin resistance.
reaches satisfactory adult height, achieves documented
epiphyseal closure, or fails to respond to treatment. Periodic measurement of glycosylated hemoglobin (HbA1c)
also may be useful.34
8. Review and retest the child using adult GH deciency
diagnostic criteria once the child reaches nal adult height.
9. Provide patient education in regard to disease state and Growth Hormone Deciency in
drug therapy. Discuss with the child and parents: Adults: Patient Care and Monitoring
GH deciency
Potential disadvantages and effectiveness of existing
GH replacement therapy 1. Assess patients clinical signs and symptoms to determine
Importance of adherence to therapy severity of GH deciency.
Potential for adverse effects or need for lifelong replacement
2. Perform a provocative test to measure GH and IGF-I levels.
3. Evaluate the patient for the presence of metabolic abnor-
malities and cardiovascular and fracture risks.
Insulin-Like Growth Factor I Therapy
4. Initiate GH replacement therapy based on patient prefer-
Mecasermin rinbate (IplexTM and IncrelexTM) is the only recom-
ence. Make sure that the patient does not have any con-
binant once-daily IGF-I replacement therapy for the treatment of
traindications to GH therapy.
growth failure in children with severe primary IGF-I deciency
5. Develop a plan to assess the efcacy and adverse effects
or with GH gene deletions who have developed neutralizing anti-
of GH therapy, and consider if the patients therapy
bodies to GH. This product has not been evaluated in patients
requires any dose adjustments based on IGF-I level,
with GH deciency aside from the genetic abnormalities. patient response, and adverse effects.
Outcome Evaluation 6. Provide patient education in regard to disease state and
drug therapy. Discuss with the patient:
Children with GH deciency should be evaluated by a pedi-
Possible complications of GH deciency
atric endocrinologist every 3 to 6 months. Monitor for an
How to reduce the modiable cardiovascular and
increase in height and change in height velocity to assess metabolic risk factors
response to GH therapy.35 Every effort should be made to Potential disadvantages and effectiveness of existing
maximize height before the onset of puberty. Once nal GH replacement therapy
adult height is reached and GH is discontinued for at least Importance of adherence to therapy
1 month, retest and reevaluate the patient using the adult Potential for adverse effects or need for lifelong replacement
GH-deciency diagnostic criteria.35
PROLACTIN TABLE 436. Medication-Induced Hyperprolactinemia7,32,43,45
Dopamine Antagonists
Prolactin is an essential hormone for normal production of
Antipsychoticsa
breast milk following childbirth. It also plays a pivotal role in Phenothiazines
a variety of reproductive functions. Prolactin is regulated Metoclopramide
primarily by the hypothalamus-pituitary axis and secreted Domperidone
solely by the lactotroph cells of the anterior pituitary gland. Dopamine-Depleting Agents
Under normal conditions, secretion of prolactin is predomi- Reserpine
nantly under inhibitory control by dopamine and acts on the -Methyldopa
D2 receptors located on the lactotroph cells. Increase of hypo- Prolactin Stimulators
Serotonin reuptake inhibitors (SSRIs)
thalamic thyrotropin-releasing hormone (TRH) in primary
Dexfenuramine
hypothyroidism can stimulate the release of prolactin. Estrogens
Progestins
Hyperprolactinemia Antiandrogens
Gonadotropin-releasing hormone analogs
Benzodiazepines
Tricyclic antidepressants (TCAs)
Hyperprolactinemia commonly affects women of reproductive Monoamine oxidase inhibitors (MAOIs)
age more than men. Although this disorder occurs in less than Protease inhibitors
1% of the general population, the estimated prevalence in Histamine2 receptor antagonists
women with reproductive disorders (e.g., amenorrhea) is as high Other
as 9% to 17%.43 Numerous etiologies of hyperprolactinemia are Isoniazid
presented in Table 435.43,44 Any medications that block Cocaine
Opioids
Verapamil
TABLE 435. Causes of Hyperprolactinemia43,44 a

Atypicals (olanzapine and clozapine) other than risperidone may cause
an early but transient elevation in prolactin.32
Physiologic Causes Adapted, with permission, from McGraw-Hill Companies.
Pregnancy
Stress (including exercise and hypoglycemia)
Orgasm dopamine or increase the release of dopamine can induce hyper-
Sleep
Meal prolactinemia7,32,43,45 (Table 436). Therefore, it is important to
exclude medication-induced hyperprolactinemia from other
Increased Prolactin Production
Ovarian: polycystic ovarian syndrome common causes such as pregnancy, primary hypothyroidism,
Pituitary tumors: benign prolactin-secreting pituitary adenoma (prolactinoma),
Adenomas and renal insufciency. Prolactinomas are the most common
Microprolactinoma (less than 10 mm diameter) pituitary tumors. They are classied as microprolactinomas if
Macroprolactinoma (greater than or equal to 10 mm
they are less than 10 mm in diameter and as macroprolactin-
diameter)
Hypothalamic stalk interruption (prevent dopamine from omas if they are 10 mm or greater in diameter.46 In general,
reaching the pituitary) microprolactinomas rarely increase in size, whereas macro-
Hypophysitis (inammation) prolactinomas have the potential to enlarge and invade the
Ectopic tumors surrounding tissues.46
Hypothalamic Prolactin Stimulation
Primary hypothyroidism Pathophysiology
Adrenal insufciency
Hyperprolactinemia is a condition of elevated serum prolactin.43
Reduced Prolactin Elimination
It is the most common endocrine disorder of the hypothalamic-
Chronic renal failure
Hepatic cirrhosis pituitary axis. High prolactin levels inhibit the release of
Neurogenic Causes gonadotropin-releasing hormone (GnRH) by the hypothala-
Breast stimulation mus and subsequently suppress secretion of LH and FSH
Breast-feeding from the anterior pituitary. High prolactin levels result in
Chest-wall injury (e.g., surgery, herpes zoster) reduced gonadal hormone levels, often leading to reproduc-
Abnormal Molecules tive dysfunction and galactorrhea (inappropriate breast milk
Macroprolactinemia production).
Medications (Table 436)7,32,43,45 In combination with clinical symptoms, at least three repeated
Seizures measures of serum prolactin levels greater than 20 ng/mL
Idiopathic (Unknown)
(20 mcg/L) are needed to conrm the diagnosis because prolactin,

Hyperprolactinemia7,43,44
General
Hyperprolactinemia most commonly affects women of reproductive age and is very rare
in men.
Signs and Symptoms
Pre-menopausal women
Headache and compromised or loss of vision caused by the prolactin-secreting tumor
and its close proximity to the optic structures.
Clinical presentation is associated with the degree of prolactin elevation:
Prolactin greater than 100 ng/mL (100 mcg/L): hypogonadism, galactorrhea, and
amenorrhea
Prolactin 51 to 75 ng/mL (5175 mcg/L): oligomenorrhea (infrequent menstruation).
Prolactin 31 to 50 ng/mL (3150 mcg/L): decreased libido and infertility.
Increased body weight may be associated with prolactin-secreting pituitary tumor.
The degree of hypogonadism generally is proportionate to the degree of prolactin
elevation.
Excessive hair growth (hirsutism) and acne also may be present owing to relative
androgen excess compared with low estrogen levels.
Men
Decreased libido, decreased energy, erectile dysfunction, impotence, decreased sperm
production, infertility, gynecomastia, and rarely, galactorrhea.
Impotence is unresponsive to treatment and is associated with reduced muscle mass,
loss of pubic hair, and osteoporosis.
Laboratory Tests
Prolactin serum concentrations at rest will be greater than 20 ng/mL (20 mcg/L) in men
or 25 ng/mL (25 mcg/L) in women with at least three measurements.
Obtain -human chorionic gonadotropin (-hCG) level to exclude pregnancy.
Obtain TSH level to exclude primary hypothyroidism.
Obtain blood urea nitrogen and serum creatinine tests to exclude renal failure.
Perform MRI to locate the tumor, exclude a pseudoprolactinoma, and validate the
diagnosis.
Consider a bone mineral density test in patients with long-term hypogonadism.
Additional Clinical Sequelae
The prolonged suppression of estrogen in pre-menopausal women with hyperpro-
lactinemia leads to decreases in bone mineral density and signicant risk for the devel-
opment of osteoporosis.
Risk for ischemic heart disease may be increased with untreated hyperprolactinemia.
Source: Adapted, with permission, from Heck AM, Yanovski JA, Calis KA. Pituitary
Gland Disorders. In: Dipiro JT, Talbert RL, Yee GC, et al (eds.) Pharmacotherapy. A
Pathophysiologic Approach. 6th ed. New York: McGraw Hill; 2005: 14071423.
similar to GH, is released in a pulsatile manner. To make an accu- than 250 ng/mL (250 mcg/L) are almost always associated with
rate diagnosis, obtain the prolactin measurements in a fasting macroprolactinoma.46
state, before breast stimulation, and at rest. If an intravenous
line is present or planned, it is prudent to wait at least 2 hours
Treatment Goals for Hyperprolactinemia
after line insertion before measuring serum prolactin to
decrease detecting transient physiologic increases in prolactin Because hyperprolactinemia is often associated with hypogo-
level43,44 (Table 435). Medication-induced hyperpro- nadism, the goals for management of hyperprolactinemia are
lactinemia typically is associated with prolactin levels of less to restore the clinical consequences of hypogonadism and
than 150 ng/mL (150 mcg/L), whereas prolactin levels greater reduce its associated risk for osteoporosis44 (Table 437).
TABLE 437. Goals for Management of Hyperprolactinemia44

Patient Encounter 2: The Medical
1. Normalize prolactin level History, Physical Examination, and
2. Improve clinical symptoms Diagnostic Tests
3. Restore normal fertility
4. Restore and maintain normal gonadal function WB, a 27-year-old woman, presents to the Womens Health
5. Protect against development of osteoporosis
Clinic. Her chief complaint is milky uid discharge from both
6. Prevent disease recurrence
breasts. WB also mentions that her menstrual periods have
If a pituitary tumor is present: stopped since she stopped taking her oral contraceptive 8
Ablate or reduce tumor size to relieve tumor mass effect. months ago with the hope of conceiving. Her menstrual
Preserve normal pituitary function. cycle was regular before starting the oral contraceptive. WB
Prevent progression of pituitary tumor or hypothalamic disease. has no recent weight change, excessive hair growth, or acne.
She does not exercise excessively and is otherwise healthy.
PMH
None
General Approaches to Treatment
Management of drug-induced hyperprolactinemia is to discon- FM
tinue the offending agent, if possible, and start an appropriate Both parents are still alive and healthy.
therapeutic alternative. In situations where the offending agent SH
cannot be discontinued, cautious use of hormone replacement, Married, a high school teacher, and physically active (walks
biphosphonate therapy, and/or dopamine agonists may be con- 3 miles twice a week)
sidered depending on the patients clinical circumstances.45 Meds
Treatment options for the management of hyperprolactinemia NuvaRing use as directed (discontinued 8 months ago)
include (1) clinical observation, (2) pharmacologic therapy with Acetaminophen 325 mg 2 tablets every 4 to 6 hours as
dopamine agonists, (3) transsphenoidal pituitary adenomec- needed for mild headaches
tomy, and (4) radiation therapy. Figure 434 demonstrates the ROS
approach to management of hyperprolactinemia.44 Clinical Ophthalmic examination reveals normal visual acuity and
observation and close monitoring are justiable in patients with elds.
asymptomatic elevation of prolactin.43 Dopamine agonists are PE
the rst-line treatment of choice for all patients with hyperpro- HEENT: () goiter
lactinemia; transsphenoidal surgery and radiation therapy are VS: 100/62 mm Hg, P 82 beats per minute, RR 18 breaths/
reserved for patients who are resistant to or severely intolerant of minute, T 37.1C (98.8F)
pharmacologic therapy.43,47,48 CV: RRR, normal S1, S2; no murmurs, rubs, or gallops
Breasts: (+) bilateral expressible galactorrhea with no other
Pharmacologic Therapy abnormality
Dopamine is the principal neurotransmitter responsible for Abd: Soft, non-tender, non-distended; (+) bowel sounds; no
hepatosplenomegaly; heme () stool
the inhibition of prolactin secretion from the anterior pitu-
itary. Thus, dopamine agonists are the main pharmacologic Labs
therapy used for management of hyperprolactinemia.47 Electrolytes, renal and thyroid function, FSH, LH, and
Treatment with dopamine agonists has proven to be testosterone are within normal limits. Elevated prolactin at
115 ng/mL (115 mcg/L). Pregnancy test is negative.
extremely effective in normalizing serum prolactin level,
restoring gonadal function, decreasing tumor size, and MRI
improving visual elds.47 Patients with macroprolactinomas Reveals a pituitary tumor approximately 9 mm in diameter.
generally require a higher dose to normalize prolactin levels
compared with patients with microprolactinomas.46 Given this information, what signs and symptoms does
WB have for hyperprolactinemia?
Three dopamine agonists are used for the management of
Identify your treatment goals for WB.
hyperprolactinemia, bromocriptine, cabergoline, and per- What nonpharmacologic and pharmacologic treatment
golide47 (Table 438). Because these three dopamine agonists options are available for WB?
are ergot derivatives, they are contraindicated in combination
with potent cytochrome P-450 subfamily IIIA polypeptide 4
(CYP3A4) inhibitors, including protease inhibitors (e.g., uncontrolled hypertension, severe ischemic heart disease, or
ritonavir and indinavir), azole antifungals (e.g., ketoconazole peripheral vascular disorders. Caution should be exercised
and itraconazole), and some macrolide antibiotics (e.g., eryth- with concomitant use of other ergot derivates and in patients
romycin and clarithromycin). Furthermore, ergot derivatives with impaired renal or hepatic function, dementia, concur-
can cause constriction of peripheral and cranial blood vessels. rent antihypertensive therapy, or a history of psychosis, peptic
These medications are also contraindicated in patients with ulcer disease, or cardiovascular disease.
MRI of pituitary
Normal and Micro and

Macro
symptomatic symptomatic
Measure other pituitary

Dopamine agonist
hormones to exclude associated
therapy
deficiency or excess
Reduced Prolactin level Stalk effect

Normal Isolated prolactin
prolactin level after still elevated after (prolactin level not high
prolactin level excess
6-month therapy 6-month therapy enough for size of tumor)
Dopamine agonist Pituitary surgery

Asymptomatic Symptomatic
therapy recommended
Measure Reduced No effect on

Consider pituitary Normal
prolactin level prolactin level after prolactin level after
surgery prolactin level
every 46 months 6 month therapy 6 month therapy
Symptomatic
Asymptomatic despite prolactin
reduction
Measure prolactin
level every 46 months Pituitary surgery
MRI every 12 years
FIGURE 434. Approach to management of hyperprolactinemia.44 MRI = magnetic resonance imaging. (Reprinted, with permission, from
Serri O, Chik CL, Ezzat S. Diagnosis and management of hyperprolactinemia. Can Med Assoc J 2003; 169(9): 575581. 2003 by CMA
Media, Inc.)
Bromocriptine (taken with a snack) to decrease adverse effects. Slowly titrate

Bromocriptine directly binds to the D2 receptors on the lac- up to the optimal therapeutic dose (2.515 mg/day) because
totroph cells to exert its effect. Bromocriptine normalizes pro- most adverse effects subside with continual treatment.46 If
lactin level, restores menstrual cycles, and reduces tumor size the adverse GI effects are not tolerable, bromocriptine can
in approximately 90% of patients.49 Adverse effects such as be administered vaginally at a reduced dose (2.5 mg/day).47
nausea, dizziness, and orthostatic hypotension often limit 5% Owing to its short half-life of only 6 hours, bromocriptine
to 10% of patients from continuing treatment. Thus, start must be administered in divided doses, which may compro-
bromocriptine at a low dose (e.g., 0.6251.25 mg) at bedtime mise patient adherence.
TABLE 438. Comparison of Dopamine Agonists for Treatment of Hyperprolactemia47
Generic Name Starting Titrating Usually Maximal Dosing Adverse

(Brand) Dose Dose Effective Dose Dose Frequency Effects Cost
Bromocriptine 0.6251.25 1.25 mg 2.515 mg/day 40 mg/day 2 to 3 divided Dizziness, $$
(Parlodel) mg/day at increments doses per day headache,
bedtime at 1-week syncope,
interval nausea,
vomiting,
GI cramps,
orthostatic
hypotension
Cabergoline 0.5 mg/week 0.5 mg 12 mg/week 4.5 mg/week Once or twice Similar but $$$
(Dostinex) or 0.25 mg increment weekly orthostatic
twice/week at 4-week hypotension
intervals less common
Pergolidea 25 mcg/day at 25 mcg 50 mcg/day at 100 mcg/day Once daily Similar but $
(Permax) bedtime increment bedtime somnolence
at 1-week and hypotension
interval more common
a
Withdrawn from United States market in 2007.
GI, gastrointestinal; $, relatively inexpensive; $$, moderately expensive; $$$, more expensive.
Cabergoline require alertness. Monitor and report daytime sedation or any

Cabergoline was developed with a higher afnity for episodes of falling asleep while engaged in the activities of daily
dopamine D2 receptors than bromocriptine. It is a long-acting living. In 2007, pergolide was withdrawn from the United States
dopamine agonist capable of inhibiting pituitary prolactin market due to reports of serious heart valve damage in patients
secretion for at least 7 days after a single oral dose.47 The pro- receiving the drug for Parkinsons disease.
longed duration of action allows for once- or twice-weekly
administration. Adverse effects of cabergoline appear to be Nonpharmacologic Therapy
signicantly better tolerated than those of bromocriptine.47 In a small number of patients who have failed or are intolerant
However, transient elevations of serum alkaline phosphatase, of dopamine agonists, transsphenoidal adenomectomy may be
bilirubin, and aminotransferases have been reported in a few necessary. Surgical treatment is also considered in patients with
patients treated with cabergoline. Cabergoline is also more non-prolactin-secreting tumors or macroprolactinomas that
effective in normalizing prolactin levels and restoring menses jeopardize the optic chiasm.43 Nonetheless, surgical intervention
than bromocriptine.47 It also may be effective in treating does not reliably lead to long-term cure and may cause perma-
hyperprolactinemia in patients who are resistant or intolerant nent complications.44 Radiation therapy is reserved for failures
to bromocriptine and in men and women with micro- and of both pharmacologic therapy and surgery.48 However, nor-
macroprolactinomas.47,50 Given the favorable safety, efcacy, malization of prolactin levels with radiation therapy may take
and administration prole of cabergoline, it has replaced 10 years to show full benet, and radiation-induced hypopitu-
bromocriptine as rst-line treatment for the management of itarism may require lifelong hormone replacement.
hyperprolactinemia.
Management of Hyperprolactinemia in Pregnancy
Pergolide Most women with hyperprolactinemia require dopamine ago-
Pergolide is a dopamine agonist with afnity for D1 and D2 recep- nist therapy to achieve regular ovulatory cycles and pregnancy.
tors. It is 10 to 1000 times more potent than bromocriptine on a Since restoration of the ovulatory cycle may occur within 1 week
milligram-per-milligram basis. This agent has a duration of of initiating therapy, caution patients regarding their potential
action longer than 24 hours and offers the advantage of once-daily to become pregnant.51
administration. Trials outside the United States have demon- Overall, there is reassuring worldwide experience that
strated pergolide to be as safe and effective as bromocriptine bromocriptine use during pregnancy does not increase fetal
for lowering prolactin level and reducing tumor size.47 Because malformations, spontaneous miscarriage, ectopic pregnancy,
pergolide has been associated with daytime sedation, carefully or multiple births.47,48 Furthermore, no teratogenic effects have
advise patients to use caution in performing activities that been reported in women who received cabergoline during the
rst and second trimesters of pregnancy.47 Despite these data,

women who become pregnant while on a dopamine agonist Hyperprolactinemia: Patient Care and
should discontinue treatment immediately to minimize fetal Monitoring
exposure. Because cabergoline has a prolonged half-life, women
who plan to become pregnant should discontinue the drug at least
1. Assess patients clinical signs and symptoms of hyperpro-
1 month before planned conception.47,48
lactinemia.
Microadenomas rarely cause complications during preg-
2. Review the available diagnostic data to determine severity
nancy. However, untreated macroprolactinomas carry about
and exclude other common causes of hyperprolactinemia.
15% to 35% risk of tumor enlargement and potentially can
jeopardize vision.46 Therefore, monitor women with macro- 3. Obtain a thorough medication history to exclude
medication-induced hyperprolactinemia.
prolactinomas closely for the development of headache and
visual impairments. Baseline and routine visual eld exami- 4. Determine patients plan regarding pregnancy because
nations are essential. Evidence of abnormal visual elds may this inuences treatment.
indicate tumor growth and should be followed by an MRI. 5. Educate patient about safety and efcacy of dopamine
Should tumors enlarge, bromocriptine is the preferred agonists. Make sure that the patient does not have any
choice over cabergoline because of greater experience with contraindications or allergies to drug therapies.
this drug during pregnancy.51 6. Develop a formal plan to assess response and adverse
effects of dopamine agonists. When appropriate, be sure
to make dose adjustments.
Outcome Evaluation
7. If the prolactin level remains normal for 2 years, reassess
Assess patients for tolerability to dopamine agonists.
the need to continue treatment. Make sure that the
Monitor clinical symptoms associated with hyperprolactine- patient is taking the lowest effective dose for manage-
mia every month for the rst 3 months to assess therapeutic ment of hyperprolactinemia.
efcacy and assist with dose titration.
8. Provide patient education in regard to disease state and
Evaluate the patient for symptoms, such as headache, visual non-drug and drug therapy. Discuss with the patient:
disturbances, menstrual cycles in women, and sexual func- Risk factors associated with hyperprolactinemia
tion in men, to assess clinical response to therapy. Potential disadvantages and effectiveness of existing
Once the prolactin level is normalized and clinical symp- dopamine agonist therapy
toms of hyperprolactinemia have resolved, monitor pro- Potential disadvantages and effectiveness of surgery
lactin level every 6 to 12 months.43,44,46 and radiation treatment
Evaluate pregnant patients every 2 months.44 Importance of adherence to therapy
If the prolactin level is well controlled with dopamine agonist Potential for adverse effects or long-term complications
therapy for 2 to 3 years, gradually taper therapy to the lowest
effective dose. Check prolactin levels after each dose reduc-
tion.46
If the prolactin levels remain unchanged for 1 year at the
ABBREVIATIONS
reduced dose, dopamine agonist therapy may be discontinued.
AACE: American Association of Clinical Endocrinologists
It is essential to monitor prolactin levels every 6 months or ACTH: adrenocorticotropic hormone or corticotropin
annually to detect the possibility of permanent remission of ADH: antidiuretic hormone
pituitary disease.43,44 -hCG: -human chorionic gonadotropin
The need to continue dopamine agonists in postmenopausal CRH: corticotropin-releasing hormone
women must be reassessed because these patients have a CT: computed tomography
higher probability of maintaining normal prolactin levels CYP3A4: cytochrome P-450 subfamily IIIA polypeptide 4
after treatment is discontinued.52 DEXA: dual energy x-ray absorptiometry
In patients with macroprolactinomas, monitor visual eld at ECG: electrocardiogram
baseline and repeat the test 1 month after initiation of a FDA: Food and Drug Administration
dopamine agonist. FSH: follicle-stimulating hormone
GABA: -aminobutyric acid
Repeat the MRI 6 months after initiating therapy or if an
GH: growth hormone or somatotropin
increase in symptoms or rise in prolactin levels suggests the GHIH: growth hormone-inhibiting hormone or somatostatin
presence of tumor growth.43,46 GHRH: growth hormone-releasing hormone
Discontinuation of therapy in patients with macropro- GI: gastrointestinal
lactinomas usually leads to tumor regrowth and recur- GnRH: gonadotropin-releasing hormone
rence of hyperprolactinemia. This decision warrants careful HbA1c: glycosylated hemoglobin A1c
consideration. IGF: insulin-like growth factor
IGFBP-3: insulin-like growth factor binding protein 3 Biochemical assessment and long-term monitoring in patients with
IGFBPs: insulin-like growth factor binding proteins acromegaly: Statement from a joint consensus conference of
IGF-I: insulin-like growth factor I the Growth Hormone Research Society and the Pituitary
IGF-II: insulin-like growth factor II Society. J Clin Endocrinol Metab 2004; 89(7):30993102.
IM: intramuscularly Giustina A, Casanueva FF, Cavagnini F, et al. Diagnosis and treatment
LAR: long-acting release of acromegaly complications. J Endocrinol Invest 2003;
LH: luteinizing hormone 26(12):12421247.
LHRH: luteinizing hormonereleasing hormone Gharib H, Cook DM, Saenger PH, et al. American Association of
MAOI: monoamine oxidase inhibitor Clinical Endocrinologists medical guidelines for clinical prac-
MRI: magnetic resonance imaging tice for growth hormone use in adults and children2003
MSH: melanocyte-stimulating hormone update. Endocr Pract 2003; 9(1):6476.
OGTT: oral glucose tolerance test GH Research Society. Consensus guidelines for the diagnosis and
PIH: prolactin-inhibiting hormone treatment of growth hormone (GH) deciency in childhood and
PRH: prolactin-releasing hormone adolescence: summary statement of the GH Research Society.
PRL: prolactin J Clin Endocrinol Metab 2000; 85(11):39903993.
SD: standard deviation Wilson TA, Rose SR, Cohen P, et al. Update of guidelines for the use
SQ: subcutaneously of growth hormone in children: The Lawson Wilkins
SSRI: selective serotonin reuptake inhibitor Pediatric Endocrinology Society Drug and Therapeutics
T3: triiodothyronine Committee. J Pediatr 2003; 143(4):415421.
T4: thyroxine Simpson H, Savine R, Sonksen P, et al. Growth hormone replacement
TCA: tricyclic antidepressant therapy for adults: into the new millennium. Growth Horm IGF
TRH: thyrotropin-releasing hormone Res 2002; 12(1):133.
TSH: thyroid-stimulating hormone or thyrotropin Verhelst J, Abs R. Hyperprolactinemia: pathophysiology and man-
agement. Treat Endocrinol 2003; 2(1):2332.
Reference lists and self-assessment questions and answers are Biller BM, Luciano A, Crosignani PG, et al. Guidelines for the diag-
available at www.ChisholmPharmacotherapy.com. nosis and treatment of hyperprolactinemia. J Reprod Med 1999;
44(12 suppl):10751084.
Log into the website: www.pharmacotherapyprinciples.com Smith JC. Hormone replacement therapy in hypopituitarism. Expert
Opin Pharmacother 2004; 5(5):10231031.
this chapter.
AACE Medical guidelines for clinical practice for the diagnosis and
treatment of acromegaly. Endocr Pract 2004; 10(3):213225.
Section 8. Gynecologic and Obstetric Disorders
44 PREGNANCY AND LACTATION:

THERAPEUTIC CONSIDERATIONS
Deborah Sturpe and Kari Alperovitz-Bichell
LEARNING OBJECTIVES
1. Identify the stages of fetal development when birth defects are most likely to occur.
2. Describe hormonal regulation of lactation.
3. Determine trimesters and a due date for a pregnancy based on the last menstrual period.
4. List routine pregnancy care and screenings that should be provided for women with
uncomplicated pregnancies.
5. Discuss characteristics that affect drug transfer across the placental barrier and into breast milk.
6. Discuss general methods by which teratogenic risk and drug exposure during pregnancy
and lactation can be minimized.
7. Identify drugs whose use should be strictly avoided in pregnancy or lactation.
8. Recommend nonpharmacologic therapy for the following disorders when they occur
during pregnancy or lactation: nausea and vomiting, constipation, heartburn, pain, and
cough and cold.
9. Recommend an appropriate dose and formulation of folic acid to a woman desiring to
become pregnant.
10. Recommend a pharmacotherapy regimen that is likely to minimize risk to the fetus or baby
for the following disorders that are commonly experienced during pregnancy: nausea and
vomiting, constipation, hemorrhoids, heartburn, pain, and upper respiratory symptoms.
11. Recommend a pharmacotherapy regimen for asymptomatic bacteriuria in a pregnant
female that is likely to be safe and effective.
12. Recommend treatment (including drug selection, dosing, monitoring, and alternative
treatments) for bacterial vaginosis, vulvovaginal candidiasis, and sexually transmitted
diseases in a pregnant female based on guidelines from the Centers for Disease Control
and Prevention.
13. Recommend a pharmacotherapy regimen for preterm labor that will prolong time to
delivery and enhance fetal lung development while minimizing maternal side effects.
treatments) for group B Streptococcus based on guidelines of the Centers for Disease
Control and Prevention.
treatments) for induction of labor.
16. Recommend a pharmacotherapy regimen that is likely to minimize risk to the infant for
the following disorders experienced during lactation: acute mastitis, nipple candidiasis,
and insufcient milk production.
721
722 SECTION 8 / GYNECOLOGIC AND OBSTETRIC DISORDERS
KEY CONCEPTS There are fewer data on the frequency of medication use
during lactation. Use does appear to be common. A recent
Although the risk of drug-induced teratogenicity is of con- Dutch study reported that 53% of all breast-feeding mothers
cern, actual risk of birth defects from most drug exposures is had taken a medication, herb, or supplement (exclusive of
small. Choose agents with the longest safety record in preg- iron, vitamins, and homeopathic remedies).5 Furthermore,
nancy or lactation rst. more women in the United States are now abiding by the rec-
The critical time for organogenesis is during the rst eight ommendation to breast-feed. It is now estimated that up to 50%
weeks of pregnancy; thus, the risk for birth defects is high- of United States women breast-feed for at least a short time.6
est during the rst trimester.
While unnecessary medication clearly should be avoided
during pregnancy or lactation, clinicians also should avoid
PATHOPHYSIOLOGY
undertreating conditions that can lead to adverse mater-
Teratogenic risk is determined largely by timing of drug expo-
nal, fetal, or neonatal outcomes.
sure. Establishment of full implantation of the fertilized egg
Treat most benign pregnancy conditions with non-
takes 1 to 2 weeks. Thus, negative effects of drug exposure
pharmacologic therapy prior to using drug therapy.
during this time typically result in spontaneous abortion.3,7
Advise most women of childbearing potential to take a
multivitamin containing 400 mcg folic acid.
The critical time for organogenesis is during the rst 8 weeks
of pregnancy; thus, the risk for birth defects is highest during the
rst trimester3,7 (Fig. 441). After 8 weeks, most teratogenic
Clinicians often must weigh the risks and benets of drug
effects are related to fetal growth restriction or functional
therapy during pregnancy or lactation. Owing to fear of
decits such as mental retardation.3
adverse effects on the developing fetus or newborn infant, a
common solution is avoidance of therapy. However, many Multiple physical and hormonal changes take place during
chronic medical conditions, acute medical conditions, and pregnancy that may cause related problems. Anemia is common
pregnancy- and lactation-related disorders necessitate therapy due to a 30% to 50% increase in plasma volume with a dis-
to preserve the health of the mother or the baby. Since few proportionate increase in red blood cell mass.3 Increased levels
prospective clinical trials enroll pregnant or lactating women, of progesterone slow gastrointestinal motility, relax esophageal
clinicians must make decisions based largely on case reports sphincter pressure, and increase mucosal edema.8 This leads to
and surveillance data. This chapter discusses available constipation, heartburn, and rhinitis. Increased venous pressure
resources that help to guide therapy choices, general strategies and constipation often result in hemorrhoids.9 Human chori-
that reduce risks of drug use in this population, and specic onic gonadotropin produced by the placenta is thought to
treatment recommendations for some conditions commonly induce nausea and vomiting of pregnancy (commonly termed
experienced during pregnancy and lactation. morning sickness).10 Increasing abdominal girth and posture
changes commonly cause back pain.11 Finally, preterm labor
and fetal growth restriction often are caused by infection during
EPIDEMIOLOGY AND ETIOLOGY pregnancy (e.g., chlamydia, bacterial vaginosis, and bacteriuria) or
untreated maternal chronic disease (e.g., diabetes mellitus).
Medication use in pregnancy is a common phenomenon. In After birth, a rapid drop in progesterone level initially trig-
North America, up to 50% of pregnancies are unplanned,1 gers lactation through reversal of inhibitory effects on pro-
and up to 82% of women of childbearing age use a medication lactin (Fig. 442). Nipple stimulation then enables lactation to
on a routine basis.2 Consequently, many women unknowingly continue once established. During lactation, ineffective
expose the fetus to a medication before discovering the preg- removal of milk from the breast, trauma, and skin breaks may
nancy. Some pregnant women may be unaware of their con- lead to problems such as milk stasis, nipple pain, and mastitis.12
dition and will continue use of medications for acute and Additionally, some women have difcultly initiating lactation
chronic conditions. Overall, up to 86% of women are reported due to improper technique and/or activity of inhibitors such
to use some type of prescription medication during preg- as dopamine (Fig. 442).
nancy at an average of 2.9 medications per patient.3
Based on these usage patterns, it may be inevitable that some
TREATMENT
drugs will act as teratogens. But actual risk of birth defects
from most drug exposures is small. Congenital defects are found in
Desired Outcomes
approximately 5% of all live births, but only 10% of these events
are due to external factors (e.g., chemical, physical, or biologic).4 The primary goal for drug use during pregnancy and lactation
Of this 10%, only 1% is estimated to be due to medication use.4 is to treat maternal or fetal conditions as necessary while min-
Despite this low risk, many women unnecessarily terminate imizing risk to the developing fetus or neonate. Numerous sit-
pregnancies due to fear of drug-induced malformations.1 uations may necessitate drug therapy, including maternal
CHAPTER 44 / PREGNANCY AND LACTATION: THERAPEUTIC CONSIDERATIONS 723
Embryonic period (wk) Fetal period (wk) Full term
1 2 3 4 5 6 7 8 9 16 2036 38
Period of dividing Indicates common site of action teralogen Brain
zygote, implantation
and blamhar embryo CNS Palate Ear
Eye Ear
Heart Eye Heart
Teeth
Arm
Leg
External genitalia
Central nervous system
Heart
Upper limbs
Eyes
Lower limbs
Teeth
Palate
Usually not External genitalia

susceptible to
terelogens
Ear
Prenatal death Major morphological abnormalities Physiological defects and minor morphological abnormalities
FIGURE 441. Embryonic development. (Reprinted, with permission, from Moore KL, The Developing Human. New York: Elsevier, 1874;
p 96; copyright 1974.) The horizontal bars represent potential sensitivity to teratogens. The pink areas represent the more critical times.
chronic disease, symptomatic conditions associated with preg- regarding safety of drug use during pregnancy (Table 441).
nancy or lactation, and conditions associated with adverse fetal This system has several faults that include lack of data
or neonatal outcomes. regarding drug use in lactation, reliance on animal studies
for categorization, and lack of consideration for altered
General Approach to Treatment maternal pharmacokinetics and timing of exposure. 13
Furthermore, many older drugs have no FDA pregnancy cat-
Sources of Information for Drug Use during Pregnancy egory, and categorization may not be updated when new
or Lactation data prove that a medication is safer than originally believed.
The Food and Drug Administration (FDA) pregnancy label- Consequently, the FDA pregnancy labeling system is cur-
ing system is the most commonly used source for information rently under review.
FIGURE 442. A simplistic schematic of the hor-

Nipple stimulation monal control of lactation. During pregnancy,
high levels of progesterone block the effect of
(+) prolactin. After delivery, nipple stimulation
enhances prolactin and oxytocin release from
Dopamine Anterior pituitary Posterior pituitary
the pituitary gland, allowing for milk production
and letdown in the mammary glands.
() Prolactin (+) Oxytocin (+)
Data from references 48 and 50.
Progesterone
Breast milk
Milk letdown in
production in
mammary glands
mammary glands
Clinical Presentation and Diagnosis Bacteriuria. Often asymptomatic in pregnancy. Diagnosed by
positive urine culture.
Bacterial vaginosis. Clinically diagnosed by presence of three
of the following:
Conrmation of Pregnancy
Positive urine human chorionic gonadotropin followed by White, non-inammatory discharge
positive ultrasound, fetal heart sounds, and/or fetal movement. Clue cells on microscopic examination
Vaginal pH greater than 4.5
Pregnancy Dating and Gestational Age
A shy odor before or after addition of 10% potassium
Calculated from the rst day of the last menstrual period.
hydroxide (i.e., whiff test)
Due dates typically are estimated at 40 weeks gestation;
however, infants delivered at between 38 and 42 weeks are
Vulvovaginal candidiasis. Typical symptoms include vaginal
considered full term.
itching and discharge. Clinical characteristics include:
Pregnancy Symptoms
First trimester: Menstrual spotting, missed menses, fatigue, Vaginal pH less than 4.5
breast tenderness, increased urination, mood swings, nau- Observation of yeast on Gram stain or wet preparation
sea/vomiting, headache, heartburn, constipation Thick, white, cottage cheeselike discharge
Second trimester: Frequent urination, heartburn, constipa-
tion, dry skin, edema, linea nigra, melasma Chlamydia and gonorrhea. Typically asymptomatic.
Third trimester: Backache, edema, shortness of breath Diagnosed by positive culture.
Routine Pregnancy Visits Genital herpes simplex virus. Characterized by vesicular or
In a normal, uncomplicated pregnancy, visits should occur ulcerative lesions. Diagnosis conrmed by virologic or sero-
monthly until 28 weeks gestation, every 2 to 3 weeks from logic testing. Prodrome manifests as pain, burning, or itching
28 to 36 weeks gestation, and then weekly until birth. at the site where lesions will develop.
Examination for each of the following is performed at each visit: Pelvic inammatory disease. Difcult to diagnose in preg-
nancy. Symptoms may include:
Blood pressure
Weight Uterine/ovarian tenderness
Urine for protein and glucose Cervical motion tenderness
Uterine size Fever
Fetal heart rate Abnormal cervical or vaginal discharge
Fetal movement Presence of white blood cells in vaginal secretions
Routine Lab Testing for Normal Pregnancies (First Trimester Elevated erythrocyte sedimentation rate
Unless Otherwise Indicated) Elevated C-reactive protein
Human immunodeciency virus
Syphilis. Early disease may be characterized by a single geni-
Puried protein derivative (PPD) test for tuberculosis
tal lesion. Diagnosed by positive serologic testing [e.g., VDRL
Venereal Disease Research Laboratory slide test (VDRL) for
or rapid plasma reagin (RPR) test].
syphilis
Trichomoniasis. Symptoms may include vulvar irritation and
Rubella immunity
yellow-green discharge. Diagnosed after microscopic visuali-
Cervical cytology
zation of the organism.
Blood and Rh type
Hepatitis B surface antigen Preterm labor. Onset of labor prior to 37 weeks gestation.
Hepatitis C antibodies (if high risk) Group B Streptococcus. Diagnosed by positive culture on
Bacterial vaginosis testing if symptomatic or at high risk vaginal or rectal swab.
(previous preterm labor) Mastitis. Characterized by localized redness, tenderness, and
Antibody screen for Rh antibodies warmth on one breast accompanied by fever and ulike symp-
Hemoglobin and hematocrit for anemia (repeated at 2632 toms. Although uncommon, symptoms also may be bilateral.
weeks) Nipple candidiasis. Typical symptoms include nipple pain,
Urinalysis with culture for asymptomatic bacteriuria itching, burning, and/or breast pain that persist after feeding.
Gonorrhea and chlamydia Gestational diabetes. See Chapter 40.
Screens for Downs syndrome and neural tube defects Hypertension in pregnancy. Categorized as one of the following:
(at 1520 weeks) Chronic hypertension (blood pressure greater than or equal
Gestational diabetes screening (at 2428 weeks) to 140/90 mm Hg prior to pregnancy or prior to 20 weeks
Group B Streptococcus screening (at 3537 weeks) gestation that lasts more than 12 weeks postpartum)
Assessing Suitability of the Cervix for Labor Induction Preeclampsia (blood pressure greater than or equal to 140/90
Suitability is based on cervical dilation, length, consistency, and mm Hg after 20 weeks gestation accompanied by proteinuria)
position. These ndings are translated to a numerical rating called Chronic hypertension with superimposed preeclampsia
the Bishop score. A Bishop score of less than 6 indicates that phar- (onset of proteinuria after 20 weeks gestation in a woman
macologic therapy is needed to ripen the cervix prior to delivery. with chronic hypertension)
Select Problems Experienced During Pregnancy or Lactation Gestational hypertension (hypertension without proteinuria
Hyperemesis gravidarum. Severe, persistent nausea and vom- after 20 weeks gestation)
iting during pregnancy accompanied by dehydration, elec- Transient hypertension (diagnosis made retrospectively when
trolyte disturbance, ketonuria, and/or weight loss. blood pressure returns to normal before 12 weeks postpartum)
TABLE 442. Sources of Information for Drug Use in

Patient Encounter, Part 1 Pregnancy and Lactation
Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and

Lactation. 7th ed. Philadelphia: Lippincott Williams & Wilkins,
LC is a 28-year-old woman who comes to your practice 2005. (Considered an authoritative text; contains alphabetical
list of drugs with monographs and references.)
because she thinks that she is pregnant. She reports that she
Hale TW. Medications and Mothers Milk. 11th ed. Amarillo,
has not had a period in 9 weeks. When she rst missed her TX: Pharmacoft, 2004. (Provides alphabetical list of drugs with
period just over 1 month ago, she was not concerned references; calculates theoretical infant dose received after
because her cycle had become very light. However, when maternal use.)
she missed her cycle again, she took a home pregnancy American Academy of Pediatrics Committee on Drugs. The
test. That test was positive. In your practice, a repeat urine transfer of drugs and other chemicals into breast milk. Pediatrics.
pregnancy test conrms that the patient is pregnant. 2001; 108(3):776789. (Lists drugs that are considered
compatible with breast-feeding; list is periodically updated.)
What additional medical history do you need to gather Motherisk (www.motherisk.org) (Includes online information,
from this patient? fact-sheets, and has a warm-line phone number for advice for
What is the estimated gestational age of the fetus? patients and clinicians during normal business hours.)
What physical examination, laboratory testing, or other Organization of Teratology Information Services
testing would you perform at this time? (www.otispregnancy.org) (Lists and links to teratology
information services by locale; many have telephone warm-lines.)
Data regarding safety of drug use during lactation are also

lacking. Most resources list only milk to plasma ratios for General Principles of Drug Use in Pregnancy and
drugs secreted into breast milk. Unfortunately, this ratio gives Lactation
no information regarding the amount of drug ingested by an While unnecessary medications clearly should be avoided
infant or the effects of that drug on the infant. during pregnancy or lactation, clinicians also should avoid
Sources of information other than FDA pregnancy labeling undertreating conditions that can lead to adverse maternal,
exist that may provide more useful information to the clini- fetal, or infant outcomes. Additionally, clinicians should avoid
cian (Table 442). It still should be noted that these resources unnecessarily discouraging breast-feeding because breast milk
share the limitation of deriving recommendations largely provides nutritional and immunologic benet to the infant.
from data from case reports and surveillance data. Several general strategies may be employed to minimize drug
Consequently, clinicians often are forced to advise patients exposure to the fetus or neonate. First, avoid drugs with known
based on limited evidence. teratogenic effects and infant complications (Tables 443 and
444). Second, choose single-drug, short-acting therapy with
agents having the longest safety record in pregnancy or lacta-
tion. Third, choose drugs with characteristics such as high
molecular weights, strong ionization, high protein binding, and
TABLE 441. FDA Pregnancy Categories
high water solubility to limit entry into the placental circulation
or breast milk through passive diffusion.3 Finally, counsel
Category A: Adequate, well-controlled studies in pregnant women women to take agents immediately after breast-feeding to allow
have not shown an increased risk of fetal abnormalities. milk concentrations to fall prior to the next feeding.14
Category B: Animal studies have revealed no evidence of harm to
the fetus, however, there are no adequate and well-controlled
Preconception Planning
studies in pregnant women, or animal studies have shown an
adverse effect, but adequate and well-controlled studies in Planning prior to pregnancy is an important strategy for
pregnant women have failed to demonstrate a risk to the fetus. reducing the risks of birth defects and fetal or neonatal com-
Category C: Animal studies have shown an adverse effect and plications. Clinicians should consider childbearing potential
there are no adequate and well-controlled studies in pregnant when selecting therapy for chronic medical conditions and fol-
women, or no animal studies have been conducted and there
are no adequate and well-controlled studies in pregnant
low the same general principles of drug selection described
women. earlier. This is especially important for the treatment of condi-
Category D: Studies, adequate well-controlled or observational, tions such as hypertension or epilepsy because many medica-
in pregnant women have demonstrated a risk to the fetus. tions used for these conditions are known teratogens. Engage
However, the benets of therapy may outweigh the potential women in discussions regarding the potential risks to an
risk.
Category X: Studies, adequate well-controlled or observational, in
exposed fetus prior to starting therapy.1 Further information
animals or pregnant women have demonstrated positive regarding treatment of chronic medical conditions such as
evidence of fetal abnormalities. The use of the product is hypertension, human immunodeciency virus, epilepsy and
contraindicated in women who are or may become pregnant. diabetes may be found in Chapters 2, 84, 27, and 40.
TABLE 443. Drugs with Known Teratogenic Effects1,3,4 TABLE 444. Contraindicated Drugs and Drugs of Concern
During Lactation3,14,25
Drug or Class Teratogenic Effect
Drug or Class Effect
Angiotensin-converting Renal damage, growth restriction
enzyme inhibitors Contraindicated Drugs and Drug Classes
Barbiturates Neonatal withdrawal syndrome Amiodarone Neonatal hypothyroidism and
Benzodiazepines Neonatal withdrawal syndrome pulmonary toxicity
Carbamazepine Neural tube defects Bromocriptine Lactation suppression
Chemotherapeutic agents Multiple malformations (including Chemotherapeutics Neonatal immune suppression and
central nervous system, facial, neutropenia
and limb) Ergotamine Neonatal diarrhea, vomiting,
Isotretinoin Central nervous system, ear, and convulsions; lactation suppression
heart malformations Isotretinoin Possible neonatal tumors
Lithium Cardiovascular malformations Lithium Neonatal central nervous system and
Misoprostol Limb and central nervous system cardiovascular disturbances
malformations Drugs and Drug Classes of Concern
Non-steroidal Premature closing of the patent Acebutolol Neonatal hypotension, bradycardia,
anti-inammatory ductus arteriosus (late second tachypnea
agents and third trimesters), Aluminum-containing Developmental retardation
hemorrhage, necrotizing antacids
enterocolitis Antidepressants Unknown, but possibly of concern
Opioids Neonatal withdrawal syndrome Antipsychotics Unknown, but possibly of concern
Phenytoin Central nervous system Atenolol Neonatal bradycardia, cyanosis
malformations, fetal growth Benzodiazepines Unknown, but possibly of concern
restriction Clemastine Neonatal drowsiness, irritability
Tetracyclines Tooth and bone malformations Metronidazole In vitro mutagen
Thalidomide Limb and internal organ Phenobarbital Infantile spasms, neonatal sedation
malformations Primodone Neonatal sedation
Valproic acid Neural tube defects Radioactive drugs Transfer of radioactivity
Warfarin Growth restriction, fetal
hemorrhage, skeletal and
central nervous system
malformations
crackers, water, or ginger ale (small sips only) at the bedside so
that they can ingest a small snack immediately before getting out
Counsel all women of childbearing potential regarding of bed. If nausea occurs, advise the patient to lie down because
lifestyle modications that may improve pregnancy outcome. this strategy has been shown to relieve symptoms.10
These include healthy eating habits, multivitamin use, cessa- Effectiveness of acupuncture and acupressure for nausea
tion of tobacco use, cessation of illicit substance use, and and vomiting of pregnancy has not been clearly proven in clin-
moderation of alcohol intake.15 ical studies, but both methods are safe to recommend.10,16
Benets may include a reduction in nausea and dry heaving but
not in vomiting.10
Treat most benign pregnancy conditions with non- Constipation and Hemorrhoids
pharmacologic therapy prior to using drug therapy. These Nonpharmacologic treatment is the mainstay of treatment for
conditions include nausea and vomiting of pregnancy, con- constipation and hemorrhoids in pregnant patients.9,17 Advise
stipation, hemorrhoids, heartburn, pain, and upper respira- women to eat a high-ber diet, drink plenty of uids, and avoid
tory symptoms. foods such as white rice and cheese that often exacerbate consti-
pation. Patients should avoid prolonged time on the toilet, which
Nausea and Vomiting increases pressure within hemorrhoids. Soaking in warm sitz
Nonpharmacologic measures recommended for nausea and baths also may help hemorrhoids by relaxing the anal sphincter.
vomiting of pregnancy (e.g., morning sickness) include lifestyle Icing the area may decrease pain and inammation. If hemor-
and dietary changes, acupuncture, and acupressure. Counsel rhoids are severe, surgical resection or banding can be per-
women to avoid or minimize nausea triggers such as objection- formed. However, it is generally preferable to delay even minor
able odors and food textures, rapid positional changes, and car surgery until after delivery.
rides.10 Advise administration of the prenatal vitamin at bedtime
because the iron content often triggers nausea. Counsel women Heartburn
to eat small, frequent meals that are bland, high in carbohydrates, Nonpharmacologic recommendations for the treatment of
and low in fat.10 Clinicians also may advise women to keep saltine heartburn in a pregnant patient do not differ from those given
to non-pregnant patients. Primary recommendations include Data also support that ginger is safe and effective when
eating small, frequent meals, remaining upright after eating, used as an antinausea agent in pregnancy16 (Table 445).
elevating the head of the bed, and avoiding foods known to However, it may be difcult for most women to reproduce the
decrease lower esophageal sphincter tone (such as chocolate, type and dose of ginger used in clinical trials.
coffee, fatty foods, and peppermint). Second-line agents for nausea and vomiting include rst-
generation antihistamines such as diphenhydramine, dopamine
Pain agonists such as metoclopramide, and the serotonin agent
Women often experience pelvic and back pain during preg- ondansetron10 (Table 445). Limited data address their safety,
nancy. Systematic review suggests that water aerobics, pillows and maternal side effects may be experienced more commonly
that support the abdomen, physiotherapy, and acupuncture with these drugs than with rst-line agents. Antihistamine use
offer back-pain relief.18 often is associated with drowsiness, and metoclopramide may
cause extrapyramidal symptoms. Hyperemesis gravidarum
Common Cold often requires hospitalization and administration of intravenous
Rest, uids, humidied air, and nasal saline are the mainstays therapy with 5-hydroxytryptamine type 3 receptor antagonists
of nonpharmacologic therapy for the common cold. Pregnant such as ondansetron.
women experiencing cold symptoms should be advised of
these strategies and reminded that cold symptoms typically Constipation
last only 7 to 10 days. Bulk-forming laxatives such as psyllium and calcium polycar-
bophil are safe for use in pregnancy and lactation17 (Table 445).
Pharmacologic Therapy If these methods fail, then stimulant laxatives such as
bisacodyl and senna are acceptable second-line agents for
Preconception Care short-term or intermittent use, but side effects of diarrhea and
Advise most women of childbearing potential to take a abdominal pain may limit use17 (Table 445). Stool softeners
multivitamin containing 400 mcg folic acid. Folic acid deciency such as docusate are recommended commonly but have shown
is a major cause of neural tube defects because dietary little efcacy for the treatment of chronic constipation.9 Avoid
intake alone is seldom sufcient to prevent the occurrence.19 magnesium-containing laxatives or phosphosoda owing to
Neural tube defects are the second most common major the potential for electrolyte disturbances and uid retention.
congenital defect and occur in approximately 1.4 to 2 per During lactation, bulk-forming laxatives and the stimulant
1000 pregnancies.19 Defects usually develop during the rst laxative senna are likely safe for use.14
2 weeks of pregnancy, prior to the woman knowing she has
conceived; thus, preconception counseling regarding folic acid Hemorrhoids
intake is especially important. For most women, over-the- Studies are lacking regarding the safety and efcacy of hemor-
counter multivitamins provide an adequate amount of supple- rhoid treatment during pregnancy.20 At this time, recommend
mentation (Table 445). Women at increased risk of delivering a only topical anti-inammatory agents such as witch hazel
child with neural tube defects, e.g., those with a personal or fam- (Tucks pads). Although prospective studies in pregnancy are
ily history of neural tube defects and/or women taking medica- lacking, witch hazel is used commonly during pregnancy and
tions known to cause neural tube defects, require higher doses lactation without adverse incidence.
(Table 445). In such instances, clinicians should recommend
specic folic acid supplementation rather than extra doses of mul- Heartburn
tivitamins because increasing the number of multivitamins may A recent consensus panel recommends calcium- or magnesium-
cause vitamin A toxicity.19 Additional benets of multivitamin containing antacids as rst-line therapies for heartburn in
intake include the calcium and iron components (Table 445). pregnancy.21 This recommendation was based on the added
benet of calcium and magnesium supplementation. Avoid
Gastrointestinal Disturbances antacids containing aluminum hydroxide owing to associa-
tions with fetal neurotoxicity.22
Nausea and Vomiting If antacids fail to improve symptoms, recommend ranitidine
The combination of pyridoxine (vitamin B6) and doxy- (Table 445). Although most H2 blockers are thought to be safe
lamine appears to offer the most favorable benet-to-risk ratio in pregnancy, ranitidine is the only agent with double-blind,
for the treatment of nausea and vomiting in pregnancy10,16 randomized trials evaluating its use in this population.23
(Table 445). Long-term usage data show no fetal risk with the Other agents that appear to be safe for use in pregnancy
regimen.10 The combination was once marketed in the United include the proton pump inhibitors, sucralfate, and meto-
States under the brand name Bendectin, but the drug was with- clopromide (Table 445). The proton pump inhibitor with
drawn from the United States market in 1984. Women can the largest body of human safety data during pregnancy is
approximate the dosage by taking each component separately. omeprazole.24
TABLE 445. Summary of Medication Dosing Recommendations9,10,12,14,23,27,38,41,43,44, 48
Drug Dose Comments

Preconception and Routine Pregnancy Care
Calcium (Tums, Os-cal, 1300 mg orally per day (age 1418)
Maalox, Citracal) 1000 mg orally per day (age 1950)
Folic acid 400 mcg orally daily High risk = personal or family history of neural tube defects
4 mg orally daily if high risk or on medication known to cause neural tube defects
Iron (Feosol, FeroSul) 27 mg elemental iron daily Increase to 60120 mg daily if iron-deciency anemia
present
Nausea and Vomiting of Pregnancy
Diphenhydramine 12.525 mg orally four times daily Second-line agent
(Benadryl, Genahist)
Ginger 250 mg orally four times daily First-line agent
Metoclopramide (Reglan) 510 mg orally three to four times daily Second-line agent
Ondansetron (Zofran) 20 mg intravenously every 8 hours Second-line agent, may be preferred for hyperemesis
Pyridoxine/doxylamine 25 mg/12.5 mg orally three times daily First-line agent
(Vitamin B6/Unisom)
Constipation
Bisacodyl (Dulcolax, 510 mg orally (tabs) or rectally Second-line agent after bulk laxatives
Correctol) (suppositories) as needed
Polycarbophil 2 tabs one to four times daily First-line agent
(Fiberlax, Fibercon)
Psyllium (Metamucil, Product specic dosing, usually First-line agent
Genber) 1 packet/scoopful in water
up to three times daily
Senna (ExLax, Senokot) 17.2 mg orally as needed Second-line agent after bulk laxatives
Heartburn
Antacids (various) 1530 mL or 250 mg1.5 g First-line agent (avoid aluminum-containing preparations)
(Tums, Maalox, up to four times daily
Rolaids, GasEx)
Metoclopramide (Reglan) 510 mg orally three to four times Third-line agent
daily
Omeprazole (Prilosex) 20 mg orally daily Third-line agent
Ranitidine (Zantac) 150 mg orally twice daily Second-line agent after antacids
Sucralfate (Carafate) 1 g orally four times daily Third-line agent (pregnancy); rst-line agent (lactation)
Pain
Acetaminophen (Tylenol) 500650 mg orally four times daily First-line agent
Codeine 15 mg every 4 to 6 hours Third-line agent
Ibuprofen (Advil, Motrin) 200400 mg orally four times daily Second-line agent in rst trimester only. Do not use in
second or third trimester.
Naproxen (Aleve) 200400 mg orally twice daily Second-line agent in rst trimester only. Do not use in
second or third trimester.
Upper Respiratory Symptoms
Budesonide (Rhinocort) 32 mcg spray, 14 sprays in each Preferred corticosteroid for allergic rhinitis.
nostril daily
Cetirizine (Zyrtec) 10 mg orally daily Second-line agent for allergic rhinitis during second and
third trimesters only.
Chlorpheniramine 4 mg every 46 hours Preferred agent if rst-generation antihistamines are to
(Chlortrimeton) be used for allergic rhinitis.
Dextromethorphan 30 mg orally every 68 hours First-line agent for cough/cold.
(Robitussin Cough
Gels, Vicks 44, Simply
Cough, Delsym)
Guaifenesin (Hytuss, 200400 mg orally every 4 hours First-line agent for cough/cold.
Mucinex, Robitussin)
Loratadine 10 mg orally daily Second-line agent for allergic rhinitis during second and
(Claritin, Alavert) third trimesters only.
Oxymetazoline (Afrin, 0.05% spray, 23 sprays in each First-line agent for cough/cold. Limit use to 3 to 5 days to
Neo-Synephrine nostril twice daily for 3 to 5 days avoid rebound congestion.
12-hour)
Pseudoephedrine (Sudafed) 60 mg every 46 hours Second and third trimesters only.
TABLE 445. Summary of Medication Dosing Recommendations9,10,12,14,23,27,38,41,43,44, 48 (Continued )
Drug Dose Comments

Bacteriuria
Amoxicillin 500 mg three times daily for 3 days
(Trimox, Amoxil)
Cephalexin (Keex) 250500 mg four times daily for 3 days
Nitrofurantoin 100 mg twice daily for 3 days
macrocrystals (Macrobid)
Bacterial Vaginosis
Clindamycin (Cleocin) 300 mg orally twice daily for 7 days Oral administration is second-line agent in pregnancy;
100 mg cream or suppository vaginal administration is rst-line agent in lactation, but
intravaginally at bedtime for 3 days contraindicated in pregnancy
Metronidazole (Flagyl) 250 mg three times daily for 7 days First-line agent in pregnancy; avoid during lactation
Vulvovaginal Candidiasis
Clotrimazole (Mycelex, 1% cream, 5 g intravaginally for 7 days
Gyne-Lotrimin) 100-mg vaginal tablet daily for 7 days
Miconazole (Monistat) 2% cream, 5 g intravaginally for 7 days
100-mg vaginal suppository daily for 7 days
Terconazole (Terazol) 0.4% cream, 5 g intravaginally for 7 days
Chlamydia
Amoxicillin (Trimox, Amoxil) 500 mg orally three times daily for 7 days First-line agent in pregnancy; third-line agent in lactation
Azithromycin (Zithromax) 1 g orally once Third-line agent in pregnancy; rst-line agent in lactation
Doxycycline (Vibramycin) 100 mg orally twice daily for 7 days Avoid during pregnancy; rst-line agent in lactation
Erythromycin base (Ery-tab) 500 mg orally four times daily for 7 days Second-line agent in pregnancy
Gonorrhea
Cexime (Suprax) 400 mg orally once First-line agent in pregnancy or lactation
Ceftriaxone (Rocephin) 125 mg intramuscularly once First-line agent in pregnancy or lactation
Ciprooxacin (Cipro) 500 mg orally once Contraindicated in pregnancy; rst-line agent in lactation,
except for residents of California or Hawaii.
Ooxacin (Floxin) 400 mg orally once Both ooxacin: levooxacin should have description given for
Levooxacin (Levaquin) 250 mg orally once cipro.
Spectinomycin (Trobicin) 2 g intramuscularly once Second-line agent in pregnancy for cephalosporin-allergic patients
Herpes Simplex Virus
Acyclovir (Zovirax) 400 mg orally three times daily 710-day therapy for initial episode; 5-day therapy for
for 710 days, or 800 mg recurrent episodes
orally twice daily for 5 days
Pelvic Inammatory Disease
Clindamycin plus Clindamycin 900 mg intravenously
gentamicin every 8 hours; gentamicin
(Cleocin/Garamycin) dosed based on
pharmacokinetics 14 days
Syphilis
Benzathine penicillin 2.4 million units intramuscularly Desensitize penicillin-allergic patients during pregnancy;
G (Bicillin) once also rst-line agent during lactation.
Doxycycline (Vibramycin) 100 mg twice daily for 14 days Alternative during lactation (but not pregnancy) for
penicillin-allergic patients
Tetracycline (Sumycin) 500 mg four times daily for 14 days Alternative during lactation (but not pregnancy) for
penicillin-allergic patients
Trichomoniasis
Metronidazole (Flagyl) 2 g orally once Safe during pregnancy. During lactation, temporarily stop
breast-feeding for 1224 hours.
Antenatal Steroids
Betamethasone 12 mg intramuscularly every
(Celestone) 24 hours for two doses
Dexamethasone (Decadron, 6 mg intramuscularly every
Dexasone, Cortastat) 12 hours for two doses
Tocolytics
Indomethacin (Indocin) 50100 mg oral load, then
2550 mg orally every
6 hours 48 hours
Magnesium sulfate 46 mg intravenous bolus over Generally not favored
20 minutes, then 23 g per
hour intravenous drip
(Continued)
TABLE 445. Summary of Medication Dosing Recommendations9,10,12,14,23,27,38,41,43,44, 48 (Continued)
Drug Dose Comments

Nifedipine (immediate 30 mg oral load, then 1020 mg First-line agent
release) (Procardia) every 46 hours
Terbutaline (Brethine) 0.25 mg subcutaneously every
20 minutes to 3 hours
Group B Streptococcus
Ampicillin (Principen) 2 g intravenously initially, then See Fig. 443
1 g intravenously every
4 hours until delivery
Cefazolin (Ancef) 2 g intravenously initially, then
1 g intravenously every
Clindamycin (Cleocin) 900 mg intravenously every
Erythromycin (Erythocin) 500 mg intravenously every
Penicillin G (Pzerpen) 5 million units intravenously
initially, then 2.5 million
units intravenously every
Vancomycin (Vancocin, 1 g intravenously every 12 hours
Vancoled) until delivery
Labor Induction
Oxytocin 26 milliunits per minute intravenous
infusion (high dose)
12 milliunits per minute
intravenous infusion (low dose)
Cervical Ripening
Dinoprostone gel (Prepidil) 1 application (0.5 mg) every 6 hours Store in refrigerator and bring to room temperature
to maximum of 3 doses in 24 hours before use
Dinoprostone vaginal insert Insert once (releases 0.3 mg per hour)
(Cervidil) for up to 12 hours
Misoprostol (Cytotec) 25 mcg intravaginally every 36 hours Contraindicated if previous cesarean section
Mastitis
Cephalexin (Keex) 250 mg orally four times daily 1014 days First-line agent
Dicloxacillin 125 mg orally four times daily 1014 days First-line agent
Erythromycin (Ery-tab) 333 mg orally three times daily 1014 Second-line agent in penicillin-allergic patients
days
Nipple Candidiasis
Fluconazole (Diucan) 100 mg orally daily Second-line agent when topical azoles fail
Ketoconazole (Nizoral) 2% creamapply to affected areas First-line agent
after each feeding
Miconazole (Micatin, 2% creamapply to affected areas First-line agent
Monistat-Derm) after each feeding
Nystatin drops (Mycostatin) 200,000 units (2 mL) orally four For concurrent treatment of the neonate/infant regardless of
times daily maternal drug choice
Nystatin topical (Mycostatin) 100,000 units/gapply to affected
areas after each feeding
Enhancement of Lactation
Metoclopramide 10 mg orally three times daily for 710 days
During lactation, sucralfate may be the best choice for treat- acetaminophen does not relieve pain, non-steroidal anti-
ment of heartburn because it is not absorbed systemically.25 If inammatory drugs (NSAIDs) may be used cautiously during
symptoms are not controlled, the H2 blockers are acceptable the rst trimester only in women who do not have a history
alternatives.14,25 Avoid aluminum-containing antacids during of gastrointestinal bleed, peptic ulcer, or aspirin allergy
lactation owing to reports of aluminum toxicity in otherwise (Table 445). Also avoid NSAID use in women who have had
healthy infants.22 difculty conceiving or have experienced miscarriage.26 Use of
NSAIDs in the late second or third trimester has been associated
Pain with multiple fetal and neonatal complications (Table 443).
Acetaminophen generally is considered the drug of choice Avoid opioid use during pregnancy owing to reports of
for the treatment of pain during pregnancy (Table 445). If fetal growth restriction, neonatal dependence, and neonatal
patients using oxymetazoline to limit use to 3 to 5 days in order

Patient Encounter, Part 2 to minimize the incidence of rebound congestion. Oral pseu-
doephedrine is also acceptable for treatment of congestion dur-
ing the second and third trimesters, but avoid use in the rst
trimester owing to the risk of fetal gastroschisis (incidence 20 per
During your rst encounter with LC, you collect the following
10,000 treated women).28 Codeine is not a preferred therapy for
data:
cough in this population.27
PMH Treat allergy symptoms with nasal corticosteroids during
Seasonal allergic rhinitis pregnancy.28 Budesonide has extensive safety data in preg-
FH nant women and may be the drug of choice in the treatment
Mother delivered two preterm infants. of naive patients. If antihistamines are indicated, chlorpheni-
SH ramine is preferred owing to its record of safe use during
Works as a librarian. Denies use of alcohol, tobacco, or pregnancy. Fewer data are available regarding the safety of
illicit substances. second-generation antihistamines during pregnancy. Animal
and human studies seem to suggest overall safety for cetirizine
Meds
Loratadine 10 mg daily and loratadine.2830 However, guidelines recommend their use
Ibuprofen 400 mg prn headache (uses approximately only in women on topical corticosteroid therapy who are
once weekly) unable to tolerate chlorpheniramine.28 Avoid fexofenadine
Ortho-Tri-Cyclen Lo daily owing to reports of teratogenic effects in animals.28
Multivitamin (generic for Centrum) daily During lactation, oral or nasal decongestants, nasal
ROS steroids, and loratadine are acceptable for treatment of upper
(+) Nausea with occasional vomiting on awakening each respiratory symptoms.14 However, one case of adverse neo-
morning 2 weeks. Lasts for 1 to 2 hours. Has missed natal outcome has been reported with the rst-generation
3 days of work owing to symptoms. Remainder of ROS antihistamine clemastine.14 Few data are available regarding
within normal limits. the safety of other rst-generation antihistamines during lac-
VS: Blood pressure 118/62, pulse 72 beats per minute, tation. Therefore, avoid use of this drug class during lactation.
respiratory rate 12, temperature 37C (98.6F)
The patient states that she wants to have this baby but Bacteriuria
expresses concern over the medications she has been Bacteriuria during pregnancy, including asymptomatic dis-
using over the last 9 weeks. She states that neither she ease, is associated with pyelonephritis, low birth weight, and
nor her husband could handle having a deformed baby, preterm delivery. Treatment improves these risks; thus, treat all
and she asks you if she should consider terminating the women testing positive for bacteriuria empirically with antimi-
pregnancy.
crobial therapy targeted at Escherichia coli infection.31 Safe
agents for empirical therapy include amoxicillin, cephalexin,
What resources can you use to help determine the risk of
her drug exposures? and nitrofurantoin32,33 (Table 445). Sulfonamides and ampi-
Based on that information, what advice would you give cillin also have been used, but increasing bacterial resistance
her regarding the risk to her baby? to these agents renders them second-line choices.32 Avoid
What do you recommended for her morning sickness? quinolones owing to the possible risk of bone and cartilage mal-
formations. Once culture and sensitivity results are available,
change the antimicrobial regimen if necessary. Recommend
standard 3-day antimicrobial therapy because there is insuf-
cient evidence among pregnant women to support 1-day
respiratory depression. However, brief treatment with small
regimens.32,34
doses of codeine is acceptable for severe pain unresponsive
to acetaminophen or NSAIDs.1 For lactating women, aceta-
minophen, NSAIDs, and most opioids are considered com- Bacterial Vaginosis
patible with breast-feeding by the American Academy of Bacterial vaginosis is associated with preterm delivery, but
Pediatrics.14 treating asymptomatic disease does not appear to decrease
this risk.3537 Consequently, treat only symptomatic disease
(Table 445).
Upper Respiratory Symptoms The Centers for Disease Control and Prevention (CDC) rec-
For common cold symptoms such as congestion and cough, recommend oral metronidazole for the treatment of bacterial vagi-
ommend nasal oxymetazoline, oral guaifenesin, and dextromethor- nosis in pregnant women.38 Metronidazole is deemed safe for use
phan according to joint guidelines from the American College of by the CDC during all stages of pregnancy despite package label-
Obstetricians and Gynecologists and the American College of ing listing a contraindication in the rst trimester.38 Oral clin-
Allergy, Asthma, and Immunology27 (Table 445). Counsel damycin is an option for women not tolerating metronidazole.38
It is not a rst-line agent owing to lower efcacy compared Gonorrhea

with oral metronidazole in non-pregnant populations.38 Avoid Treat gonorrheal infections during pregnancy, including those
clindamycin vaginal cream due to associations with prema- that are asymptomatic, with cexime or ceftriaxone in order to
ture labor and neonatal infection.38 reduce the risk of preterm labor38 (Table 445). Spectinomycin is
Counsel women taking metronidazole regarding potential an alternative choice for penicillin- or cephalosporin-allergic
for nausea, vomiting, and abdominal pain. Counsel patients to women.38 Avoid tetracyclines during pregnancy owing to known
avoid alcohol or alcohol-containing substances during ther- teratogenic effects (Table 443). Also avoid quinolones owing to
apy with metronidazole owing to the risk of disulfuram-like the possible risk of bone or cartilage malformations.
reactions. During lactation, all CDC rst-line recommended thera-
Clindamycin vaginal cream is the preferred therapy for pies for gonorrhea (Table 445) are deemed compatible
bacterial vaginosis during lactation because metronidazole is with breast-feeding by the AAP.14 Quinolone therapy is not
listed as a drug of concern by the American Academy of recommended for women residing in California or Hawaii
Pediatrics (AAP)14 (Tables 444 and 445). Counsel patients due to the increasing numbers of quinolone-resistant
that clindamycin cream weakens latex condoms and species.38
diaphragms, potentially rendering them ineffective.
Herpes Simplex
Herpes simplex virus may be transmitted to the neonate if
Vulvovaginal Candidiasis active vaginal lesions or the prodrome is present at the time of
Treat symptomatic vulvovaginal candidiasis in pregnant women birth. Consequently, cesarean section often is recommended
with topical azole therapy according to CDC guidelines.38 Oral for these women. Vaginal delivery is indicated if vaginal
uconazole is not recommended. Asymptomatic disease does lesions or the prodrome are not present.
not require treatment. Vulvovaginal candidiasis during Recommend oral acyclovir for treatment of genital herpes
pregnancy is considered a complicated case; thus, 7-day simplex episodes during pregnancy in order to help reduce the
therapy (instead of 1- to 3-day therapy) is recommended38 need for cesarean section38 (Table 445). Intravenous therapy
(Table 445). may be indicated for very severe episodes. Safety of acyclovir
During lactation, topical azoles remain the drug of choice has not been rmly established, but surveillance data do not
for vulvovaginal candidiasis.38 Oral uconazole is not recom- suggest an increased risk of teratogenic effects. Acyclovir is
mended in order to minimize the development of uconazole- preferred over valacyclovir or famcyclovir because experience
resistant Candida species in the general population. Counsel with the latter agents in pregnancy is limited.
women using topical azoles that the medication weakens latex During lactation, acyclovir is deemed compatible with
condoms and diaphragms, potentially rendering them inef- breast-feeding by the AAP even though the drug does con-
fective for preventing pregnancy and transmission of sexually centrate in milk.14 No recommendation has been made
transmitted infections. regarding the safety of valacyclovir or famcyclovir during
lactation.
Sexually Transmitted Infections Pelvic Inammatory Disease
Treat pelvic inammatory disease during pregnancy with
Chlamydia intravenous clindamycin plus gentamicin in order to reduce mater-
Treat chlamydia infections during pregnancy, including nal morbidity, preterm delivery, and fetal death38 (Table 445).
those that are asymptomatic, with erythromycin or amoxicillin Avoid regimens using doxycycline owing to known teratogenic
in order to reduce risk of preterm labor38 (Table 445). effects (Table 443), and avoid quinolones owing to the possi-
Systematic review suggests that amoxicillin is better tolerated ble risk of bone and cartilage malformations.
than erythromycin and has fewer discontinuations owing to
adverse drug reactions than erythromycin.39 Azithromycin Syphilis
may be a safe alternative in women unable to take, tolerate, or Treat syphilis during pregnancy with benzathine peni-
adhere to these rst-line recommendations.38 However, cillin G in order to prevent transmission of syphilis to the fetus
azithromycin is a third-line therapy because there are longer and to cure the disease in the fetus38 (Table 445). Penicillin-
safety records for erythromycin and amoxicillin in pregnancy. allergic women must undergo desensitization to the drug.38
Avoid doxycycline in pregnant women owing to known terato- Alternative therapies used in non-pregnant patients are either
genic effects (Table 443). teratogenic (e.g., tetracycline and doxycycline) or will not cure
During lactation, azithromycin and doxycycline are rst- disease in the fetus (e.g., erythromycin).38
line choices for chlamydia38 (Table 445). Both are deemed Treat syphilis during lactation with benzathine penicillin G or
compatible with breast-feeding by the AAP and generally are any of the CDC-recommended alternatives for penicillin-allergic
more effective and better tolerated than erythromycin or patients (Table 445). All choices are deemed compatible with
amoxicillin.14,38 breast-feeding by the AAP.14
Trichomoniasis impairment, aspirin allergy, or a history of peptic ulcer disease

Treat symptomatic trichomoniasis with oral metronidazole in or other bleeding disorders. Although typically well tolerated
order to alleviate maternal symptoms (Table 445). Do not by the mother, reports of increased risk of postpartum hem-
treat asymptomatic disease. There is no evidence suggesting orrhage and patent ductus arteriosus is worrisome.36
that treatment of asymptomatic disease will reduce the inci- The calcium channel blockers have been associated with
dence of preterm labor or low birth weight, and systematic both prolonged pregnancy and decreased neonatal morbid-
review suggests that this practice may even increase the inci- ity.36,42 When compared with -mimetics (e.g., terbutaline)
dence of preterm birth.40 and magnesium, they show better neonatal outcome and a
Advise women requiring treatment for trichomoniasis dur- lower incidence of serious maternal side effects.42 Potential
ing lactation to discontinue breast-feeding for 12 to 24 hours minor maternal adverse effects include headache, ushing,
after receiving single-dose metronidazole therapy in order to dizziness, and transient hypotension.41
minimize risk to the infant.14 During this time, advise women to
pump and discard breast milk in order to avoid engorgement. Group B Streptococcus
Counsel women taking metronidazole to avoid drinking Maternal transmission of group B Streptococcus during the
alcohol or using alcohol-containing substances during therapy. intrapartum period is a cause of neonatal sepsis and death. All
pregnant women should be screened for group B Streptococcus
disease using vaginal and rectal swabs between 35 and 37 weeks
Preterm Labor
gestation. Antibiotic therapy has been proven to reduce the inci-
Administration of antenatal corticosteroids during preterm dence of early-onset neonatal disease in high-risk groups of
labor having an onset prior to 34 weeks gestation has been proven
women43 (Table 446). Start treatment at the time of membrane
to decrease the risk of neonatal respiratory distress, intraventricular
rupture and continue until delivery. If women receive therapy
hemorrhage, necrotizing enterocolitis, and death15,41 (Table 445).
owing to unknown group B Streptococcus status and no growth
No benet from antenatal corticosteroids is gained if labor starts
is seen 48 hours after culture, discontinue therapy. Therapy is
after 34 weeks gestation. In order to allow for administration of
not required in women undergoing planned cesarean section
antenatal steroids, tocolytic therapy often is used to prolong time
who have not experienced membrane rupture.
to delivery by 2 to 7 days.36 Agents commonly used as tocolytics
The antibiotic of choice for group B streptococcal disease is
in the United States include magnesium sulfate, terbutaline,
penicillin G, although ampicillin is an alternative.43 No resistance
indomethacin, and nidepine (Table 445).
to either agent has been reported, and their narrow spectrum of
Systemic review concludes that tocolytic therapy with the
activity makes them ideal choices.43 Resistance has developed
calcium channel blockers offers the best benet-to-risk ratio.42
with the use of alternative choices for penicillin-allergic patients.
However, few head-to-head comparisons have been made
A treatment algorithm for group B Streptococcus is shown in
between agents. Guidelines from the American College of
Fig. 443, and dosing recommendations are shown in Table 445.
Obstetricians and Gynecologists (ACOG) therefore recom-
mend selecting an agent based on maternal status and poten- Labor Induction
tial adverse drug reactions.41 Do not recommend combination Up to 33.7% of pregnancies are delivered through labor
tocolytic therapy, maintenance tocolytic therapy, or repeated induction.44 Prior to pharmacologically inducing contrac-
courses of acute tocolytic therapy owing to increased fetal risk tions, the cervix must be favorable for labor. Two drugs have
and lack of efcacy.41 proven efcacy for cervical ripening: the prostaglandin E
Data proving that magnesium sulfate prolongs pregnancy analog dinoprostone (available as a gel or a vaginal insert)
is lacking.36 It is contraindicated for use in women with myas- and misoprostol (Table 445). Guidelines from the ACOG
thenia gravis, and serious complications such as maternal pul- recommend using either drug and give no clear guidance on
monary edema and cardiac arrest have been reported.41 More choosing one over the other.45
benign side effects such as ushing, headache, and nausea
often cause discontinuation of therapy.36 TABLE 446. Characteristics of Women Who Should Receive
Terbutaline has been shown to prolong pregnancy but has Intrapartum Treatment for Group B
not been associated with decreased neonatal morbidity.36 It is Streptococcus per CDC Guidelines43
contraindicated for use in women with preexisting cardiac
arrhythmia. Potentially serious adverse effects include pul- Previous delivery of a group B Streptococcuspositive infant
monary edema, cardiac arrhythmia, or myocardial ischemia Positive group B Streptococcus screen
Group B Streptococcus bacteriuria
in the mother. Reported fetal and neonatal adverse effects Unknown group B Streptococcus status plus one or more of
include tachycardia, hyperglycemia, and hyperinsulinemia.41 the following:
Indomethacin prolongs pregnancy but has not been inde- Less than 37 weeks gestation
pendently associated with decreased neonatal morbidity.36 It Membrane rupture of greater than 18 hours
may be of particular benet in women with hydramnios.36 Intrapartum body temperature greater than or equal to 38C
(100.4F)
Avoid use in women with a history of severe renal or hepatic
FIGURE 443.
No
Penicillin G or Ampicillin Penicillin allergy? Algorithm for
intrapartum antibiotic
Yes therapy against
group B
No Anaphylaxis, angioedema, Streptococcus.43
Cefazolin
urticaria, or asthma?
Yes
Base therapy on Group B

Streptococcus culture and
sensitivity
Erythromycin sensitive Unknown sensitivity OR Clindamycin sensitive

erythromycin/clindamycin resistant
Erythromycin Vancomycin Clindamycin
Systematic review concludes that misoprostol shows greater Nipple Candidiasis

efcacy versus dinoprostone, but this benet is offset by a Treat nipple candidiasis by applying topical ketoconazole, nys-
greater incidence of side effects.46 Compared with dinoprostone, tatin, or miconazole to the nipples after each feeding and by
misoprostol is associated with a higher incidence of uterine administering oral nystatin drops to the breast-feeding
hyperstimulation, alterations in fetal heart rate, and fetal infant12 (Table 445). In severe or recurrent cases, the mother
distress.46 Misoprostol also has been associated with uterine may be treated with oral uconazole.12,14 Although messy,
rupture in patients with previous delivery by cesarean sec- gentian violet applied topically to both the nipples and the
tion and should be avoided in this population.44 infants mouth is also effective for resistant cases.12
Despite these limitations to misoprostols use, it is much
cheaper than the dinoprostone products. The average cost of Enhancement of Lactation
misoprostol is less than $1 per dose versus a cost of $65 to $75 Metoclopramide is the drug of choice for enhancement of lac-
for dinoprostone gel.45 At $165, the dinoprostone insert is more tation when improved feeding technique fails to increase milk
expensive than the dinoprostone gel but offers the advantage of ow48 (Table 445). Metoclopramide exerts its effect through
quick removal should adverse events occur.45 dopamine antagonism. Increases in milk production should be
Pharmacologic agents used for cervical ripening often induce noted within 2 to 5 days of metoclopramide initiation. Monitor
contractions. However, if contractions do not begin within 6 to patients for extrapyrimidal symptoms.
12 hours of dinoprostone use or within 3 hours of misoprostol Other agents used for lactation enhancement include dom-
use, oxytocin may be administered.44 Both high- and low-dose peridone and fenugreek. Like metoclopramide, domperidone is a
oxytocin regimens have been studied (Table 445). Both regi- dopamine antagonist. Risk of extrapyramidal effects is lower with
mens appear to have equal efcacy and are recommended by the domperidone because it does not cross the blood-brain barrier.
ACOG.44,45 High-dose oxytocin may shorten the time to deliv- However, the FDA issued a warning against domperidone use
ery, but this advantage is offset by a higher incidence of uterine owing to reports of cardiac arrhythmia, myocardial infarction,
hyperstimulation and fetal heart rate changes.47 and sudden death associated with the intravenous formulation.49
Data regarding fenugreeks efcacy are anecdotal, and the herb
Breast Infections should not be recommended unless other efforts fail.48
Acute Mastitis
Treat acute mastitis with antistaphylococcal antibiotics such Patient Encounter, Part 3
as dicloxacillin or cephalexin for 10 to 14 days in order to pre-
vent recurrent disease and breast abscess12 (Table 445).
Penicillin-allergic women alternatively may be treated with LC had an uneventful pregnancy before arriving at the hos-
erythromycin.12 Occasionally, intravenous antibiotics are pital in labor at 31 weeks gestation.
needed for resistant, recurrent, or chronic cases. Encourage
women to continue breast-feeding through acute mastitis and What do you recommend at this time?
to empty all leftover milk from the affected breast.12
OUTCOME EVALUATION examination and pain relief. Improvement should be noted

within 1 week of initiating therapy.
Report birth defects that are believed to be teratogenic effects.
At a minimum, complete an FDA Medwatch Form (available at Preterm Labor
www.fda.gov/medwatch). Additionally, clinicians may report Many tocolytic drugs require special monitoring of both mother
events to local teratology information services (links available and fetus. Monitor cardiac status by electrocardiogram and pul-
at www.otispregnancy.org). Some pharmaceutical companies monary status by physical examination in mothers receiving
have developed pregnancy registries for their drugs. In such terbutaline or magnesium sulfate owing to the risk of cardiac
instances, report both positive and negative outcomes of drug arrhythmia, cardiac ischemia, and pulmonary edema. Monitor
exposure during pregnancy to those companies. blood pressure and heart rate in mothers receiving terbutaline,
Monitor the mother for efcacy and adverse effects of drug magnesium sulfate, or nifedipine owing to the risk of hypoten-
therapy used during pregnancy or lactation. Monitor all param- sion. Check fetal heart rate during therapy and neonatal heart
eters that would be followed in a non-pregnant or lactating rate, respiratory rate, and oxygen saturations after delivery.
population. At times, additional monitoring is required owing
to pregnancy, and these exceptions are discussed below. Some Labor Induction
conditions also require monitoring of the fetus or neonate.
Continuously monitor uterine activity and fetal heart rate
Conditions Requiring Only Monitoring for when giving drug therapy for cervical ripening or oxytocin.
Symptomatic Improvement Total duration of monitoring depends on the agent used, and
current guidelines recommend the following44,45:
Little special monitoring is required for the treatment of gas-
trointestinal disturbances, upper respiratory symptoms, and Dinoprostone gel. Start monitoring 15 minutes prior to gel inser-
pain experienced during pregnancy or lactation. Response to tion and continue for 30 to 120 minutes after administration.
therapy is judged by maternal symptomatic relief. Change Dinoprostone insert. Start monitoring 15 minutes prior to
therapy if no relief is obtained within 1 to 2 weeks after initiat- insertion and continue for 15 minutes after removal.
ing therapy. In the case of severe, persistent nausea and vomit- Misoprostol. Start monitoring 15 minutes prior to insertion
ing, monitor maternal weight, orthostatic blood pressure, and and continue for 3 hours after administration.
electrolytes to diagnose possible hyperemesis gravidarum. Oxytocin. Monitor until delivery.
Infections during Pregnancy

Owing to the risk of preterm labor that is associated with
gynecologic infections during pregnancy, pregnant women
require follow-up objective testing for most of these infec-
tions. This includes:38 1. Provide prenatal counseling regarding appropriate
medication use during pregnancy. If possible, alter the
drug regimen for chronic medical conditions to one
Repeat urine culture 10 days after completion of therapy for that is least likely to cause fetal harm. Obtain good
bacteriuria control of maternal conditions prior to conception.
Repeat culture for bacterial vaginosis 1 month after comple- 2. Recommend appropriate folic acid, calcium, and iron
tion of therapy intake prior to conception.
Repeat culture for gonorrhea or chlamydia 3 weeks after 3. After pregnancy is achieved, encourage routine pregnancy
completion of therapy monitoring and care.
4. Treat conditions during pregnancy that pose a risk to the
Some pregnancy infections can be passed to the neonate. In fetus or neonate. Choose therapy as recommended by
such instances, monitor the baby for signs and symptoms of guidelines or those with the longest history of safe use in
disease. This includes the following: pregnancy.
5. Treat conditions that cause bothersome maternal symp-
Group B Streptococcus. Observe the neonate for signs and toms during pregnancy with drug therapy only after non-
symptoms of sepsis until 48 hours after birth. If present, start pharmacologic methods fail. Choose therapy with the
longest history of safe use in pregnancy.
a full diagnostic work-up (including complete blood cell
6. Encourage breast-feeding. If drug therapy is required dur-
count and blood culture) and empirical antibiotic therapy.43
ing breast-feeding, try to choose short-acting agents with
Genital herpes simplex virus. Infants born to mothers with active the longest history of safe use in lactation and administer
disease at birth should be monitored for signs and symptoms of immediately after feedings.
disease. Surveillance culture of mucosal surfaces is optional.38 7. Monitor infants for birth defects and/or unusual reactions that
may be due to maternal drug use. Report suspected drug-
Monitor mothers suffering from breast infections during related reactions to the FDA and other appropriate registries.
lactation for clinical improvement as judged by physical
AAP: American Academy of Pediatrics American Academy of Pediatrics Committee on Drugs. Transfer of
ACOG: American College of Obstetricians and Gynecologists drugs and other chemicals into human milk. Pediatrics 2001;
CDC: Centers for Disease Control and Prevention 108:776789.
FDA: Food and Drug Administration Briggs GC, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation.
NSAID: non-steroidal anti-inammatory drug 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005.
PPD: puried protein derivative Gilstrap LC, Oh W, Green MF, Lemons JA. Guidelines for Perinatal
RPR: rapid plasma reagin Care. 5th ed. American Academy of Pediatrics, The American
VDRL: Venereal Disease Research Laboratory slide test College of Obstetricians and Gynecologists; 2002.
Hale TW. Medications and Mothers Milk. 11th ed. Amarillo, TX:
Reference lists and self-assessment questions and answers are Pharmacoft; 2004.
available at www.ChisholmPharmacotherapy.com. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of peri-
natal group B streptococcal disease: revised guidelines from
Log into the website: www.pharmacotherapyprinciples.com CDC. Morb Mortal Wkly Rep (MMWR) 2002; 51(RR-11):122.
Sexually transmitted diseases treatment guidelines 2002. Centers for
Disease Control and Prevention. Morbid Mortal Wkly Rep
this chapter. (MMWR) 2002; 51(RR-6):178.
45 CONTRACEPTION
Julie M. Koehler and Kathleen B. Haynes
LEARNING OBJECTIVES
1. Discuss the physiology of the normal female reproductive system.

2. Compare the efcacy of oral contraceptives with that of other methods of contraception.
3. State the mechanism of action of hormonal contraceptives.
4. Discuss the risks associated with the use of contraceptives, and state absolute and relative
contraindications to their use.
5. List side effects associated with the use of various contraceptives, and recommend
strategies for minimizing or eliminating such side effects.
6. Describe advantages and disadvantages of various contraceptives, including both oral and
non-oral formulations.
7. Cite important drug interactions with oral contraceptives.
8. Provide appropriate patient education regarding the important differences between various
barrier contraceptives.
9. Discuss how emergency contraception may be employed to prevent accidental pregnancy.
10. Provide appropriate patient education regarding the use of oral contraceptives, and
recommend and discuss the use of non-oral contraceptives when appropriate.
KEY CONCEPTS When a contraceptive dose is missed, the risk of accidental

pregnancy may be increased. Depending on how many doses
Heavy smokers (greater than or equal to 15 cigarettes per day) were missed, the contraceptive formulation being used, and
over the age of 35, as well as patients with a history of throm- the phase of the cycle during which doses were missed, coun-
boembolic disease, stroke, coronary artery disease, any estrogen- seling regarding the use of additional methods of contracep-
dependent neoplasm, or undiagnosed abnormal uterine tion may be warranted.
bleeding, should not take estrogen-containing contraceptives.
Side effects associated with the use of combined oral contra- Historically, the 1950s represented an important time in the
ceptives may be minimized by appropriately adjusting either control of human fertility. It was during that decade that the rst
the total estrogen or progestin content. combined oral contraceptives were developed. Shortly after the
Antibiotic administration during contraceptive use may discovery that the exogenous administration of hormones such
decrease the efcacy of many combined contraceptives. as progesterone successfully blocked ovulation, the use of hor-
Non-oral forms of contraceptives, such as the transdermal monal steroids quickly became the most popular method of con-
patch and the transvaginal ring, avoid the need for daily traception worldwide. Specically, combined oral contraceptives
administration and, as such, may enhance convenience of use represent the most commonly used reversible form of contra-
for the patient. ception today, and it is estimated that nearly 100 million
Oral, transdermal, and transvaginal contraceptives, as well as women worldwide take oral contraceptives.1 Further, in the
intrauterine devices and most barrier contraceptives, do not United States, it is estimated that at some time during their
protect against sexually transmitted diseases. lives, more than 80% of women born since 1945 have used oral
737
contraceptives.1,2 Since the introduction of oral contraceptives, attachment of the early embryo to the lining of the uterine
many newer forms of contraceptives have been developed and cavity, or implantation, occurs.
are available for use in the United States. New hormone delivery
systems, such as transdermal systems, transvaginal systems, and
intrauterine devices (IUDs), offer women effective and more PREVENTION OF PREGNANCY:
convenient alternatives to oral contraceptives. CONTRACEPTIVES AND DEVICES
Goals of Contraception/Desired Outcome

EPIDEMIOLOGY
As to be expected, the most common goal of contraception is
According to the National Survey of Family Growth, approxi- the prevention of pregnancy. However, some patients may use
mately 6.3 million pregnancies occur annually in the United contraceptive methods for other benets, such as menstrual
States.3 Of these pregnancies, it is estimated that nearly 3.15 mil- cycle regulation, reduction of premenstrual symptoms, or
lion are unintended.3,4 Contributing to the risk of unintended treatment of acne.
pregnancy is the fact that approximately 7.5% of all women who
are at risk of becoming pregnant do not use any form of contra- Choice of Contraceptives: Important Considerations
ception.3,4 In addition, many women who do use contraceptives
use their chosen method of contraception imperfectly, and this When helping a patient decide on a contraceptive, the most
also increases the risk of undesired pregnancy. Given these statis- important goal is to nd an option that the patient is com-
tics, the provision of appropriate and adequate instruction to fortable with and that the clinician feels will be benecial for
patients regarding how to use contraceptive methods effectively the patient. It is imperative to explain the side effects, safety
is essential in order to reduce the risk of unwanted pregnancy. concerns, and non-contraceptive benets of each alternative
Exposure to sexually transmitted diseases (STDs) is also a to the patient so that she may make an informed decision.
concern for women who are sexually active. It is estimated Fertility goals can be different for each patient. It must be
that 15 million people in the United States become newly determined if the goal is to postpone contraception, space out
infected annually with an STD.5 Given that not all methods of the next pregnancy, or avoid further pregnancy altogether.
contraception protect the user adequately against STDs, the Also, a clinician must understand the patients desire to have
provision of proper patient education by health care profes- or not have a regular bleeding pattern because many contra-
sionals regarding this risk is absolutely essential. ceptives will affect menses.
As discussed later in this chapter, contraindications exist for
various forms of contraception. Patients must be evaluated
PHYSIOLOGY completely by a health care professional to rule out any medical
contraindications to certain contraceptives. The physical exami-
The female menstrual cycle is divided into four functional nation also will allow health care professionals to determine if
phases: follicular, ovulatory, luteal, and menstrual.6 The folli- there are other medical concerns, such as hypertension, diabetes,
cular phase starts the cycle, and ovulation generally occurs on or liver disease, that need to be considered when determining
day 14. The luteal phase then begins and continues until the appropriate contraceptive agent. Clinicians also should
menstruation occurs.6 The menstrual cycle is regulated by a review family history for potential risks with certain forms of
negative-feedback hormone loop between the hypothalamus, birth control.
anterior pituitary gland, and ovaries6 (Fig. 451). Sexual behavior of the female must be determined to
Initially, the hypothalamus releases gonadotropin-releasing understand the risk for STDs. Women who are not in a
hormone (GnRH), which stimulates the anterior pituitary to monogamous relationship must consider their risk of STDs as
produce follicle-stimulating hormone (FSH) and luteinizing a factor in their contraceptive decision. Some barrier methods
hormone (LH). The levels of FSH and LH released vary depending protect against STDs, but agents such as hormonal contracep-
on the phase of the menstrual cycle. Just prior to ovulation, FSH tives are not capable of preventing STDs if used alone.
and LH both are at their peak levels. The FSH helps to promote Personal preference plays a large role when determining the
growth of the follicle in preparation for ovulation by causing best contraceptive option. For instance, if a woman is not inter-
granulose cells lining the follicle to grow and produce estrogen. ested in using a method that will interrupt sexual activity, then
The LH promotes androgen production by theca cells in the fol- a diaphragm would not be appropriate. Preference of the sexual
licle, promotes ovulation and oocyte maturation, and converts partner may be important as well. Certain agents such as male
granulose cells to cells that secrete progesterone after ovulation. condoms require the male partner to play an active role in con-
Conception is most likely to occur when viable sperm are traception.
present in the upper region of the reproductive tract at the Cost is also another related issue for patients. Insurance
time of ovulation. Fertilization occurs when a spermatozoan may not cover all forms of contraception, and patients may
penetrates an ovum. Approximately 6 to 8 days after ovulation, have to bear the entire cost for certain options.
CHAPTER 45 / CONTRACEPTION 739
FIGURE 451. Menstrual cycle

gonadotropin levels
events.6 (Reprinted, with permission,

FSH 50100 mlU
from Hatcher RA, Namnoum AB.
Pituitary
LH The menstrual cycle. In: Hatcher RA,

15 mlU
Trussel J, Stewart F, et al, (eds.)
1012 mlU 25 mlU Contraceptive Technology. 18th
revised ed. New York: Ardent Media;
2004: 6372.)
hormone levels
250400 pg 125250 pg
Ovary
Progesterone
1ng Estrogen
40 pg
1015 ng
Follicular phase Luteal phase
Implantation HCG detectable
endometrial
3040 cc
growth
Uterus
Ovulation
blood lost 4 mm
2 mm
Menstrual Proliferative phase Secretory phase

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Cervical mucus
Low volume High volume Low volume

Thick Thin Thick
Cloudy Clear Cloudy
No ferning Ferning No ferning
Maximal cellularity Minimal cellularity Maximal cellularity
Low elasticity High elasticity (Spinnbarkeit) Low elasticity
99
temperature
Basal body
98 Ovulation
97
Irritability Secretions Weight gain
Anxiety Nausea Bloating
Depression Sharp or dull pain Eyes swollen
Bleeding Spotting Ankles swollen
Lower abdominal pain Breast fullness
Possible symptoms
Back and leg pain Libido Breast tenderness

Migraine headaches Anxiety
Other headaches Depression
Nauses Follicle Headaches
Dizziness Nausea
Diarrhea Acne
Libido or Spotting
Infection Ovary Discharge
Nosebleeds Actual size at ovulation Pain
Seizures Constipation
Arthritis
Yeast infection
Changed insulin requirements
FSH = Follicle Stimulating Hormone LH = Luteinizing Hormone
HCG = Human Chorionic Gonadotropin
Efcacy of Contraceptives active, or mestranol, which must be converted by the liver

to ethinyl estradiol. Many different progestins are found in
The accidental pregnancy rate for women who do not use any
the various oral contraceptives. These include norethin-
form of contraception is unknown. Therefore, it is difcult to
drone, norethindrone acetate, ethynodiol diacetate,
determine the true efcacy of contraceptives in preventing
norgestrel, levonorgestrel, desogestrel, norgestimate, and
unwanted pregnancy. Table 451 shows the percentage of
drospirenone.
women who experience unintended pregnancy within 1 year
The primary mechanism by which combined oral contra-
of use of a contraceptive.7
ceptives prevent pregnancy is through inhibition of ovulation.
FSH and LH regulate the production of estrogen and proges-
Oral Contraceptives (Combined)
terone by the ovaries. Secretion of estrogen and progesterone
Combined oral contraceptives contain a combination of a by the ovaries occurs in a cyclic manner, which, in turn, deter-
synthetic estrogen and one of several steroids with progesta- mines the regular hormonal changes that occur in the uterus,
tional activity. Most oral contraceptives contain one of two vagina, and cervix associated with the menstrual cycle. Cyclic
types of estrogen: ethinyl estradiol, which is pharmacologically changes in the levels of estrogen and progesterone in the
TABLE 451. Unintended Pregnancy Rates7
Percent of Women Experiencing

an Unintended Pregnancy Percent of Women
within the First Year of Use Continuing Use
Method Typical Usea Perfect Useb at 1 Yearc
No method 85 85
Spermicides 29 18 42
Withdrawal 27 4 43
Periodic abstinence 25 51
Calendar 9
Ovulation method 3
Symptothermal 2
Postovulation 1
Cap
Parous women 32 20 46
Nulliparous women 16 9 57
Diaphragm 16 6 57
Condom
Female (Reality) 21 5 49
Male 15 2 53
Combined pill and minipill 8 0.3 68
Ortho Evra patch 8 0.3 68
NuvaRing 8 0.3 68
Depo-Provera 3 0.3 56
IUD
ParaGard (copper T) 0.8 0.6 78
Mirena (LNG-IUS) 0.1 0.1 81
Female sterilization 0.5 0.5 100
Male sterilization 0.15 0.1 100
a
Among typical couples who initiate use of a method (not necessarily for the rst time), the percentage
who experience an accidental pregnancy during the rst year if they do not stop use for any other reason.
Estimates of the probability of pregnancy during the rst year of typical use for spermicides, withdrawal,
periodic abstinence, the diaphragm, the male condom, the pill, and Depo-Provera are taken from the
1995 National Survey of Family Growth corrected for underreporting of abortion.
b
Among couples who initiate use of a method (not necessarily for the rst time) and who use it perfectly
(both consistently and correctly), the percentage who experience an accidental pregnancy during the rst
year if they do not stop use for any other reason.
c
Among couples attempting to avoid pregnancy, the percentage who continue to use a method for 1 year.
Adapted with permission.
blood, together with FSH and LH, modulate the development addition to inhibition of ovulation, combined oral contracep-
of ova and the occurrence of ovulation. The estrogen compo- tives induce changes in the cervical mucus and endometrium
nent of combined oral contraceptives is most active in inhibit- that make sperm transport and implantation of the embryo
ing FSH release.1 However, at high enough doses, estrogens unlikely.1
also may cause inhibition of LH release. In low-dose combi- Table 452 contains a partial listing of the many oral con-
nation oral contraceptives, the progestin component causes traceptives available today.8 Although the efcacy of com-
suppression of LH.1 Ovulation is prevented by suppression of bined oral contraceptives was quickly demonstrated following
the mid-cycle surge of both FSH and LH,1 and this suppression, their introduction into the market, it took longer to determine
which is induced by combined oral contraceptives, mimics the their safety and acceptability for patients. Since the mid-
physiologic changes that occur during pregnancy. 1960s, ethinyl estradiol has been the primary estrogen used in
Although suppression of FSH and LH is the primary most combined oral contraceptives. However, the amount of
mechanism by which combined oral contraceptives prevent ethinyl estradiol used in combined oral contraceptives has
ovulation, there are other mechanisms by which these hor- decreased progressively since that time, and most pills now
mones work to prevent pregnancy. Other mechanisms include contain 35 mcg of ethinyl estradiol or less. In addition, to
reduced penetration of the egg by sperm, reduced implanta- reduce side effects and improve tolerability associated with
tion of fertilized eggs, thickening of cervical mucus to prevent oral contraceptive use, new progestins and different routes of
sperm penetration into the upper genital tract, and slowed administration have been explored. In an attempt to mini-
tubal motility, which may delay transport of sperm.1 Thus, in mize the undesirable androgenic side effects associated with
TABLE 452. Some Available Oral Contraceptives8 Combined oral contraceptives are available in monophasic,
biphasic, and triphasic preparations. Monophasic preparations
Estrogen Progestin contain xed doses of estrogen and progestin in each active
Brand Name (mcg/Tablet) (mg/Tablet)
pill. Although all three preparations contain both estrogens
Monophasic Preparations and progestins, biphasic and triphasic preparations differ from
Loestrin 21 1/20 EE (20) Norethindrone (1)
monophasic preparations in that they contain varying propor-
Loestrin Fe 1/20 EE (20) Norethindrone (1)
Alesse EE (20) Levonorgestrel (0.1) tions of one or both hormones during the pill cycle. These
Desogen EE (30) Desogestrel (0.15) preparations were introduced to reduce the amount and total
Ortho-Cept EE (30) Desogestrel (0.15) monthly dose of progestins, as well as to mimic more closely
Levlen EE (30) Levonorgestrel (0.15) the hormonal changes of the menstrual cycle. However, there
Nordette EE (30) Levonorgestrel (0.15)
is no evidence to suggest that the biphasic and triphasic prepa-
Yasmin EE (30) Drospirenone (3)
Lo/Ovral EE (30) Norgestrel (0.3) rations offer any clinical advantage over the monophasic pills.8
Loestrin 21 1.5/30 EE (30) Norethindrone (1.5)
Loestrin Fe 1.5/30 EE (30) Norethindrone (1.5) Non-contraceptive Benets of Combined Oral
Ortho-Cyclen EE (35) Norgestimate (0.25)
Ovcon-35 EE (35) Norethindrone (0.4)
Contraceptives
Brevicon EE (35) Norethindrone (0.5) In addition to preventing pregnancy, there are several non-
Necon 0.5/35 EE (35) Norethindrone (0.5) contraceptive benets associated with the use of combined oral
Necon 1/35 EE (35) Norethindrone (1) contraceptive pills. Many of the potential non-contraceptive
Ortho-Novum 1/35 EE (35) Norethindrone (1) benets are highlighted below.
Demulen 1/35 EE (35) Ethynodiol diacetate (1)
Zovia 1/35E EE (35) Ethynodiol diacetate (1)
Ovral EE (50) Norgestrel (0.5) Reduction in the Risk of Endometrial Cancer
Ovcon-50 EE (50) Norethindrone (1) The risk of endometrial cancer among women who have used
Demulen 1/50 EE (50) Ethynodiol diacetate (1) oral contraceptives for at least 1 year is approximately 40%
Zovia 1/50E EE (50) Ethynodiol diacetate (1) less than the risk in women who have never used oral contra-
Necon 1/50 Mestranol (50) Norethindrone (1)
Norinyl 1 + 50 Mestranol (50) Norethindrone (1) ceptives.9 There is additional evidence to suggest that the ben-
Ortho-Novum 1/50 Mestranol (50) Norethindrone (1) et of reduced risk for endometrial cancer is detectable within
Biphasic Preparations 1 year of use1012 and that the benet may persist for years fol-
Mircette EE (20, 0,10) Desogestrel (0.15) lowing discontinuation of oral contraceptives.9
Kariva EE (20, 0, 10) Desogestrel (0.15)
Ortho-Novum 10/11 EE (35) Norethindrone (0.5,1) Reduction in the Risk of Ovarian Cancer
Necon 10/11 EE (35) Norethindrone (0.5,1)
When compared with women who have never used oral
Triphasic Preparations
contraceptives, women who have used oral contraceptives
Estrostep Fe EE (20, 30, 35) Norethindrone (1)
Tri-Levlen EE (30, 40, 30) Levonorgestrel for 4 years or less are 30% less likely to develop ovarian can-
(0.05, 0.075, 0.125) cer. There is also additional evidence to suggest that the longer
Triphasil EE (30, 40, 30) Levonorgestrel the duration of oral contraceptive use, the greater the reduc-
(0.05, 0.075, 0.125) tion in the risk of ovarian cancer. Women who have taken oral
Ortho Tri-Cyclen EE (35) Noregestimate
contraceptives for 5 to 11 years are 60% less likely to develop
(0.18, 0.215, 0.25)
Tri-Norinyl EE (35) Norethindrone ovarian cancer, and women who have taken oral contracep-
(0.5, 1, 0.5) tives for more than 12 years are 80% less likely to develop
Ortho-Novum 7/7/7 EE (35) Norethindrone ovarian cancer. As with the reduced risk of endometrial can-
(0.5, 0.75, 1) cer, there is evidence to suggest that the benet of the reduced
Ortho Tri-Cyclen Lo EE (25) Norgestimate
risk of ovarian cancer may persist for years following discon-
(0.18, 0.215, 0.25)
Velivet EE (25) Desogestrel tinuation of oral contraceptives.1012
(0.1, 0.125, 0.15)
Cyclessa EE (25) Desogestrel Improved Regulation of Menstruation
(0.1, 0.125, 0.15) Women who take oral contraceptives typically experience
EE, ethinyl estradiol. more regular menstrual cycles. In general, oral contraceptive
use is associated with less cramping and dysmenorrhea.1,8
Also, women who take oral contraceptives experience fewer
the progestins of combined oral contraceptives, the type of days of menstruation each month and as a result experience
synthetic progestin was modied to create third generation less blood loss with each menstrual period.1,13 Some studies
progestins (e.g., desogestrel and norgestimate). These syn- suggest that oral contraceptive use decreases overall monthly
thetic progestins are extremely potent in their ability to inhibit menstrual ow by 60% or more, which may be particularly
ovulation and prevent pregnancy. benecial in women who are anemic.1
Relief of Benign Breast Disease for cardiovascular events, women should have their blood pres-
Women who use oral contraceptives are less likely to develop sure checked prior to initiating oral contraceptives, as well as
benign breast cysts or broadenomas.1,8 periodically throughout oral contraceptive use. If signicant ele-
vations in blood pressure are noted, oral contraceptives should
Prevention of Ovarian Cysts be discontinued. Estrogen-containing contraceptives are not
Because oral contraceptives suppress ovarian stimulation, recommended for smokers who are older than 35 years of age,
women who take them are less likely to develop ovarian cysts.8 for women with hypertension, or for women who experience
migraine headaches (especially those with focal neurologic
Reduction in the Risk of Symptomatic Pelvic symptoms).8,19
Inammatory Disease
The risk of hospitalization owing to symptomatic pelvic Venous Thromboembolism
inammatory disease caused by gonorrheal infection is It is believed that the estrogen component of combined oral
reduced in oral contraceptive users.14 While the exact protec- contraceptives stimulates the liver to produce higher levels of
tive mechanism is unknown, it is believed that thickening of clotting factors. Lower-dose estrogen pills have been associated with
the cervical mucus and/or reduction in the ability of a three- to four-fold increase in the risk of venous thromboem-
pathogens to enter the fallopian tubes may contribute.1 bolism compared with women who do not use oral contracep-
tives.8 Contraceptive users at greatest risk for the development of
Improvement in Acne Control venous thromboembolism include those who are obese, those
All combination oral contraceptives can improve acne by who smoke, those who have hypertension, and those with dia-
increasing sex hormonebinding globulin and decreasing free betes complicated by end-organ damage. It is important to note,
testosterone concentrations.8 The newer progestins, such as however, that the increase in risk of venous thromboembolism
desogestrel and norgestimate, are believed to have less andro- in oral contraceptive users is lower than that of pregnant
genic activity.8 However, it is not clear that combined oral con- women.8 Newer progestins, such as desogestrel, were reported
traceptives containing these progestins confer any advantage initially to be associated with a higher risk of venous throm-
over other combined oral contraceptives with respect to their boembolism.20,21 However, prospective studies validating this
ability to improve acne control. Only Ortho Tri-Cyclen risk are lacking. In general, progestin-only contraceptives are
(ethinyl estradiol and norgestimate) and Estrostep Fe (ethinyl preferred for women who are at increased risk of cardiovascular
estradiol and norethindrone acetate) are approved by the Food or thromboembolic complications, including women with a
and Drug Administration (FDA) for the treatment of acne.1,8 prior history of thromboembolic disease.8
Potential Risks of Combined Oral Contraceptives Glucose Intolerance

While there are many non-contraceptive benets associated Older oral contraceptive formulations containing higher
with the use of combined oral contraceptives, their use is doses of hormones were shown in some cases to induce
not without risk or potential for adverse effects. hyperglycemia.1 Because estrogens may inhibit the release of
insulin from islet cells of the pancreas, low-dose estrogen for-
Sexually Transmitted Diseases mulations may be preferred in patients with diabetes.
Since the use of combined oral contraceptives may decrease Progesterone competes with insulin for binding to its recep-
the use of selected barrier contraceptive methods that do pro- tor. Although it is thought that progestins may increase
tect against STDs (e.g., latex condoms), one of the most com- insulin resistance, the newer progestins are thought to be less
mon risks associated with the use of oral contraceptives is the androgenic and have little effect on carbohydrate and lipid
risk of acquiring an STD.8 metabolism. In general, the use of combined oral contracep-
tives is relatively contraindicated in patients with diabetes.
Cardiovascular Events and Hypertension
A World Health Organization (WHO) collaborative study Gallbladder Disease
found that high-dose (50 mcg or more of ethinyl estradiol) oral In women with preexisting gallstones, low-dose estrogen-
contraceptive users with uncontrolled hypertension have an containing oral contraceptives may enhance the potential for
increased risk of experiencing a myocardial infarction or the development of symptomatic gallbladder disease.1
stroke.8,15 In this study, women who had the lowest risk for expe- Although this risk has not been demonstrated with the use of
riencing a myocardial infarction or stroke were those who did higher-dose oral contraceptives, combined oral contraceptives
not smoke, took low-dose oral contraceptives, and had their containing estrogen should be used with caution in patients
blood pressure checked prior to beginning oral contracep- with a history of gallbladder disease.
tives.1618 Hypertension secondary to oral contraceptive use is
thought to occur in up to 1% to 3% of women, and this is Hepatic Tumors
believed to be attributed to the effect that estrogens and prog- Although the use of oral contraceptives is not associated
estins can have on aldosterone activity.1 Given this and the risk with an increased risk for the development of hepatocellular
carcinoma, long-term use of high-dose oral contraceptives TABLE 453. Contraindications to the use of Combined
has been associated with the development of benign liver Oral Contraceptives1
tumors.1 Because even benign liver tumors may pose signi-
Absolute Contraindications
cant risk to the patient, oral contraceptives should be discon-
History of thromboembolic disease
tinued if liver enlargement is noted on physical examination. History of stroke (or current cerebrovascular disease)
History of (or current) coronary artery disease
Cervical Cancer History of carcinoma of the breast (known or suspected)
There appears to be an increased risk for the development of History of any estrogen-dependent neoplasm
Undiagnosed abnormal uterine bleeding
cervical cancer among long-term users of oral contraceptives.1
Pregnancy (known or suspected)
Whether or not this increase in risk can be attributed directly Heavy smokers (greater than or equal to 15 cigarettes per day)
to the use of oral contraceptives is uncertain, however. Data who are greater than 35 years of age
suggest that oral contraceptive users, on average, tend to have History of hepatic tumors (benign or malignant)
more sexual partners and use condoms less frequently, and as Active liver disease
a result, this may increase their susceptibility to becoming Relative Contraindications
infected with human papilloma virus (HPV), a known risk Smoking (less than or equal to 15 cigarettes per day) at any age
History of migraine headache disorder
factor for cervical cancer. Hypertension
Fibroid tumors of the uterus
Breast Cancer Breast-feeding
While a history of breast cancer traditionally has been consid- Diabetes
ered an absolute contraindication to the use of oral contra-
ceptives, most recent studies evaluating the relationship
between oral contraceptive use and the risk for breast cancer
suggest little, if any, association between the two. A recent diagnosis in oral contraceptive users under age 35 is less clear.1
study illustrated that current or past use of oral contraceptives Absolute and relative contraindications to the use of oral
among women between the ages of 35 and 64 was not associated contraceptives are listed in Table 453.1
with an increased risk for the development of breast cancer.22
In older studies that have suggested a link between oral contra- Adverse Effects of Oral Contraceptives and
ceptive use and the diagnosis of breast cancer, the cancers diag- Their Management
nosed in those studies were found to be more localized.23 As with all medications, there are potential adverse effects
Although the relationship between oral contraceptive use and with combined oral contraceptives (COCs). Many side
the potential for breast cancer in older patients is becoming effects can be minimized or avoided by adjusting the estrogen
better understood, still the question of risk for breast cancer and/or progestin content of the oral contraceptive. It is also
important to have proper patient selection for oral contracep-
tives because some women are at increased risk for potentially
Patient Encounter, Part 1 serious side effects.
Many women stop their oral contraceptives owing to side
effects such as headaches, nausea, vomiting, or weight gain that
RC, a 22-year-old woman, presents to your clinic requesting
occur during oral contraceptive use. Package labeling reports a
information on contraception. You begin to take a history and higher incidence of these side effects, although it cannot be
determine that the patient is currently sexually active and is determined if they occurred because of the pill or just happened
not using any method of birth control. Her past medical history when the women were on the pill.1 One double-blind trial com-
is signicant only for acne, and she takes no medications pared women taking oral contraceptives with women taking
except occasional ibuprofen for menstrual cramps. On further placebo for 6 months. A similar percentage of patients in each
questioning, you discover that she has a positive family history group experienced headaches, nausea, vomiting, mastalgia, and
for hypertension and coronary artery disease. As you begin to weight gain, and there were no signicant differences in the tra-
discuss various contraceptive options with the patient, it is ditional hormone-related side effects.24 Given that oral contra-
clear that she has a preference for an oral contraceptive agent. ceptives often are discontinued owing to side effects, proper
counseling before initiation of COCs is necessary.
recommending a contraceptive for this patient?
Between 30% and 50% of women complain of breakthrough
Based on the information provided by the patient, what bleeding or spotting when initiated on oral contraceptives.
oral contraceptive agent would you recommend for the These side effects tend to resolve by the third or fourth cycle.1
patient and why? Before changing formulations, other more serious causes of
What education would you provide to this patient regarding bleeding or spotting, such as pregnancy, infection, poor absorp-
the risks associated with oral contraceptive use? tion of the oral contraceptive owing to drug interaction, or gas-
trointestinal problems should be ruled out. Once these causes
have been ruled out, the timing of the spotting must be deter- interval for two to three consecutive cycles (for women with
mined in order to adjust the formulation appropriately. headaches during the pill-free interval only).1
Women who have spotting or bleeding before they nish Although rare, some women may complain of a decrease in
their active pills need a higher progestin content to increase libido. This often is found to coincide with feelings of depres-
endometrial support. Either a monophasic formulation with a sion. Alterations to vaginal lubrication and free testosterone lev-
higher progestin or a triphasic formulation with an increasing els may occur with some COCs, and both can relate to decreased
dose of progestin would be appropriate. Women with continued libido.25 Low levels of estrogen can decrease vaginal lubrication
bleeding after menses need more estrogen support. Either increas- as well and make intercourse painful. Use of the vaginal hor-
ing the estrogen component or having a lower early progestin monal ring (NuvaRing) may help with lubrication problems.1
component (in triphasic pills) should be sufcient. If mid-cycle Dyslipidemias can occur from hormone therapy. Estrogen is
bleeding occurs, it is more difcult to ascertain the reasoning. It known to cause an increase in high-density lipoprotein choles-
may be best to increase both the estrogen and progestin compo- terol (HDL-C), triglycerides, and total cholesterol levels and to
nent for these women.1 decrease low-density lipoprotein cholesterol (LDL-C).
Hormonal methods of contraception usually will decrease Androgenic progestins are more likely to decrease HDL-C and
the amount of withdrawal bleeding quite signicantly, and triglycerides and increase LDL-C. Depending on the ratio of
patients need to be made aware of this. Lower-dose estrogen for- estrogen to progestin content, the HDL-C, LDL-C, and triglyc-
mulations may increase the risk of breakthrough bleeding. eride levels may uctuate up or down. In women with no risk
Switching to a higher estrogen formulation or to a triphasic for- factors for dyslipidemias, it is not necessary to obtain a baseline
mulation will help to minimize breakthrough bleeding and will lipid panel. However, if the lipid panel is monitored, and if dys-
increase the amount of withdrawal bleeding if desired by the lipidemia occurs, then it is recommended to go with a more
patient. estrogenic and less androgenic formulation. In women with a
Acne, oily skin, and hirsutism are all side effects from triglyceride level greater than 350 mg/dL (3.96 mmol/L) at base-
progestins with increased androgenicity. Older progestins line, estrogen-containing formulations should be used only with
such as norgestrel and levonorgestrel have more androgenic caution, and low doses of 20 to 25 mcg ethinyl estradiol or a
effects, whereas agents containing norgestimate or desogestrel progestin-only formulation might be preferred.1
are less likely to have such side effects. If patients are com- Mastalgia can occur in up to 30% of women taking oral
plaining of such side effects, switching to a product with a contraceptives and is most likely due to the estrogen component.
lower risk of androgenic effects is appropriate. The average woman has a 20% increase in breast volume in
Gastrointestinal complaints are seen often with oral contra- the luteal phase owing to venous and lymphatic engorgement.
ceptives. Estrogen can induce nausea and vomiting via the cen- Estrogen also causes adipose cell hypertrophy in the breast.1
tral nervous system, whereas progesterone slows peristalsis, Lower-dose pills (20 mcg) produce less mastalgia than those
causing constipation and feelings of bloating and distention.1 with 35 mcg of ethinyl estradiol.26 If tenderness occurs prior
Most women will adjust to the symptoms, and the symptoms to menses, switching to a contraceptive that offers extended
often will resolve within 1 to 3 months. If women are unable to cycle length (see Unique Oral Contraceptives below) can
tolerate the gastrointestinal side effects, then either a decrease in minimize problems as well.
ethinyl estradiol to a low-dose 20 mcg formulation may mini- Women often are concerned about using oral contraceptives
mize nausea or a decrease in progestin may minimize bloating for fear of gaining weight. It has been proven that low-dose oral
and constipation. Progestin-only products may be considered if contraceptives (less than or equal to 50 mcg ethinyl estradiol) do
even low-dose ethinyl estradiol causes nausea. It also can be sug- not increase the risk of weight gain in women compared with
gested to take the medication with food or at night to minimize placebo.24 Estrogen can cause hypertrophy of adipose cells, and
gastrointestinal side effects. therefore, women see an increase in measurement of their
Headaches are a common occurrence for women but must breasts, hips, and thighs.1 Decreasing the estrogen content of the
be evaluated because they are a major warning sign for stroke. COCs will minimize this effect. Weight gain associated with
If headaches begin or become worse after initiation of COCs, premenstrual uid retention may occur with the combination
all differential diagnoses must be considered. A patients blood of estrogen and a higher androgenic progestin. Switching to a
pressure should be evaluated to rule out hypertension. If any lower-dose estrogen and a progestin with less androgenic
neurologic symptoms or blurred vision occur with the activity may be benecial in this situation.1
headache, the oral contraceptive should be stopped immedi- Additional side effects have been noted in some women.
ately. Migraine headaches with aura showed a signicant Women with contact lenses may have visual changes and more
increase in the risk for ischemic stroke in one WHO study.17 If disturbances with lenses. If normal saline eye drops do not
the headaches are not serious but still are troublesome to the help, referral to an ophthalmologist is recommended.
patient, the following changes are suggested: (1) discontinue Melasma and chloasma can occur secondary to estrogen
the oral contraceptive, (2) lower the dose of estrogen, (3) stimulation of melanocyte production. Women with darker
lower the dose of progestin, and (4) eliminate the pill-free pigmentation are more susceptible. The melasma may not be
completely reversible on discontinuation. Progestin-only This can help clinicians to streamline medications by serving
products may be preferable, and sunscreen use is highly rec- dual purposes.
ommended.1 Yasmin (drospirenone/ethinyl estradiol) is the only oral
As described earlier, many of the side effects of COCs may contraceptive that uses the progestin drospirenone. This hor-
be minimized by adjusting the amount of hormones within mone not only has antiandrogenic properties but also showed
the pill. However, while low- and ultra-low-dose COCs may antimineralcorticoid activity in preclinical trials. It has a unique
cause fewer side effects, it is important to note that in the application in young women who experience problems associ-
event that doses are missed, such COCs may be more likely to ated with producing too much androgen. Drospirenone is a
result in contraceptive failure. spironolactone analog, and the 3 mg dose available in Yasmin
has antimineralcorticoid activity equal to 25 mg spironolactone.
Progestin-Only Pills It can affect the sodium and water balance in the body, although
it has not shown superior efcacy for side effects such as bloat-
For women unable to take estrogen-containing oral contra-
ing compared with other oral contraceptives. Caution should be
ceptives, there is an alternativeoral contraceptives containing
used in women with chronic conditions or other medications
only progestin. There are two active ingredients used in this
that may affect serum potassium.28 It is advised to check a base-
form of contraception, norethindrone and norgestrel. These
line potassium level in patients at risk for hyperkalemia, such as
agents are slightly less effective than COCs but have other
those taking angiotensin-converting enzyme inhibitors or
advantages over COCs. Progestin-only products have not
angiotensin II receptor blockers.
shown the risk of thromboembolic events as products con-
Mircette (desogestrel/ethinyl estradiol) has a unique dos-
taining estrogen have. Therefore, women at increased risk for
ing schedule. After the usual 21 active tablets, there are only
or with a history of thromboembolism may be good candidates
2 tablets with inert ingredients. The last 5 tablets in the package
for progestin-only oral contraceptives. Also, these products can
have 10 mcg of ethinyl estradiol. In theory, this may minimize
minimize menses, and some women have amenorrhea. These
bleeding during the menstrual cycle, although the clinical sig-
products should be taken at the same time every day, and there
nicance of this dosing schedule has not been established.29 It
is no pill-free or hormone-free period.
is important to counsel patients to complete the entire pack
and not to discard the last 7 days of medication.
Unique Oral Contraceptives
Finally, another unique formulation is a chewable tablet avail-
Along with varying doses of ethinyl estradiol and different prog- able to women who have difculty swallowing medications.
estins, there are also formulation modications that may benet Ovcon 35 (norethindrone/ethinyl estradiol) has all 28 tablets in
various patient situations. These formulations include products chewable form and has added spearmint avoring.30 Along with
such as Seasonale, Ortho Tri-Cyclen, Estrostep Fe, Yasmin, each of these unique oral contraceptives, there are preparations
Mircette, and Ovcon 35. Each of these products may show currently being studied that contain 24 active pills and 4 placebo
benet in certain women owing to their unique characteristics. pills per pack, shortening the hormone-free period.1
Seasonale (levonorgestrel/ethinyl estradiol) is a mono-
phasic combination that has been marketed previously. This
product is packaged as a 91-day treatment with 84 active tablets
Patient Encounter, Part 2: Adverse
that are taken consecutively and then 7 placebo tablets. The Effects
extended cycle length of this product allows for one menstrual
cycle per season, or four per year. This formulation may be
appealing to women with perimenstrual side effects or those at After 10 weeks of taking Desogen, RC returns to your clinic
higher risk for anemia with menstrual bleeding. Seasonale may complaining of breakthrough bleeding during her third week
improve anxiety, headache, uid retention, dysmenorrhea, of active pills. The patient also reports a 3-lb weight gain
breast tenderness, bloating, and menstrual migraines. Although, since starting Desogen, and because she has heard that birth
in the SEA 301 clinical trial comparing the efcacy of Seasonale control pills cause weight gain, she expresses concern and
with that of an equivalent-dosage 28-day cycle regimen, 7.7% wants to discuss other birth control options.
versus 1.8% of women discontinued prematurely for unaccept-
What are some potential causes of the breakthrough
able bleeding.27 The risk of intermenstrual bleeding and/or
bleeding that the patient has been experiencing?
spotting is higher for patients taking Seasonale than for What information can you provide to the patient regarding
patients taking 28-day-regimen COCs.27 the potential association between weight gain and oral
Ortho Tri-Cyclen (norgestimate/ethinyl estradiol) and contraceptive use?
Estrostep Fe (norethindrone acetate/ethinyl estradiol) What strategy would you recommend to eliminate or mini-
both have an approved indication for treatment of moderate mize the potential adverse effects experienced by the
acne vulgaris in females 15 years of age or older desiring patient?
contraception who have failed topical antiacne medication.
Drug Interactions with Oral Contraceptives of norelgestromin). A new patch is applied to the abdomen,
buttocks, upper torso, or upper (outer) arm once weekly for 3
Ethinyl estradiol is metabolized in the liver via the
weeks, followed by 7 patch-free days.8 Although some women
cytochrome P-450 system. It is metabolized primarily via
have noted irregular bleeding more commonly during the rst
CYP450 3A4. When reviewing drug interactions of oral
two cycles of patch use, the patch has been demonstrated to pro-
contraceptives, it is important to keep in mind that
vide similar menstrual cycle control and contraceptive efcacy to
antibiotic administration during contraceptive use may
that of combined oral contraceptives.32 It is important to note,
decrease the efcacy of many combined contraceptives. Refer
however, that higher contraceptive failure rates are seen when the
to Table 454 for a list of common drug interactions seen
patch is used in women weighing more than 90 kg.8,32 Further,
with oral contraceptives.1, 31
Ortho McNeil (the manufacturer of Ortho-Evra) recently
updated the prescriber information for the product to indicate
Non-oral Hormonal Contraceptives that women who take Ortho-Evra are exposed to approximately
As an alternative to oral contraceptive pills, which must 60% more estrogen than women who take COCs with 35 mcg
be taken daily in order to reliably prevent pregnancy, non-oral estrogen.33 The clinical signicance of this is unknown. With the
contraceptives in the form of transdermal, transvaginal, and exception of a slightly higher reported incidence of breast dis-
injectable preparations are available and offer patients safe and comfort and local skin irritation, the side effects seen with the
effective alternatives to the pills for prevention of pregnancy. patch are very similar to those observed with COCs.8,34
These formulations also do not require daily administration, The NuvaRing is a unique transvaginal delivery system that
making them more convenient than the pill formulations. provides 15 mcg ethinyl estradiol and 120 mcg etonogestrel for
Ortho-Evra is a transdermal patch that contains both an the prevention of ovulation. The NuvaRing is inserted into the
estrogen (20 mcg of ethinyl estradiol) and a progestin (150 mcg vagina on or before day 5 of the menstrual cycle and is removed
TABLE 454. Commonly Seen Drug Interactions with COCs1,31
Medication Mechanism Clinical Effect

Anticonvulsants (carbamazepine, Increase metabolism of COCs via induction of various Decrease efcacy of OCs (EE doses less
oxcarbazepine, phenytoin, cytochrome P-450 enzymes than 35 mcg are not recommended
phenobarbital, primidone, in women on these medications)
topiramate, and felbamate)
Benzodiazepines (alprazolam) COCs may inhibit oxidative metabolism Increase side effects of benzodiazepines
Corticosteroids (hydrocortisone, COCs may inhibit metabolism of corticosteroids Increase side effects of corticosteroids
methylprednisolone, prednisone)
Griseofulvin Increase metabolism of COCs Decrease efcacy of COCs; backup
method of contraception is
recommended
Modanil Increase metabolism of COCs Decrease efcacy of COCs; alternative
recommended
Penicillins (amoxicillin, ampicillin); Broad-spectrum antibiotics may alter intestinal ora, Decrease efcacy of COCs, although the
tetracyclines (doxycycline, reducing enterohepatic circulation of estrogen recommendation of a backup method
minocycline, tetracycline) metabolites; although the drop in estrogen levels of contraception is controversial
has been shown to be only statistically signicant,
rather than clinically signicant
Protease inhibitors (amprenavir, Increase or decrease serum levels of estrogen Decrease efcacy of COCs or increase
nelnavir, lopinavir, saquinavir, and progestins side effects of COCs
ritonavir)
Rifampin, rifabutin Increase metabolism of COCs Decrease efcacy of COCs; backup
recommended
Selegiline COCs decrease metabolism of selegiline Increase side effects of selegiline; may
adjust dose of selegiline if needed
St. Johns wort Increase metabolism of COCs via induction of Decrease efcacy of COCs; avoid use
various cytochrome P-450 enzymes with COCs
Theophylline COCs decrease theophylline clearance by 34% and Increase side effects of theophylline
increase the t1/2 by 33%
from the vagina after 3 weeks.8 Seven days after the ring is Mirena is inserted for up to 5 years, and Paragard T 380A is
removed, a new ring is inserted. In clinical trials, the NuvaRing inserted for up to 10 years. Surveys have shown that IUDs
demonstrated comparable efcacy and cycle control with that have the highest satisfaction rate among patients using
of COCs.8 Side effects seen with NuvaRing are also similar to reversible contraceptives.
those observed in women taking COCs.8,35 NuvaRing should Although the mechanism of action for IUDs is not com-
not be removed during intercourse. If the ring falls out or is pletely understood, various theories have been considered.
removed for more than 3 hours, efcacy could be compro- The original theory is that the presence of a foreign body in
mised, and a backup method of contraception is recommended the uterus causes an inammatory response that interferes
until a new ring has been in place for 7 days. with implantation. It is believed that copper-containing
Depo-Provera is a progestin-only injectable contracep- IUDs may have a direct toxic effect on spermatozoa. Progestin-
tive that contains depot medroxyprogesterone acetate. containing IUDs can have direct effects on the uterus, such
Depo-Provera is administered intramuscularly as a 150-mg as thickening of cervical mucus and alterations to the endo-
injection once every 3 months. An advantage of Depo-Provera metrial lining. Mirena can inhibit ovulation because it con-
is that it provides an estrogen-free method of contraception tains levonorgestrel, but Paragard T 380A does not prevent
either for women in whom estrogens are contraindicated or ovulation.
for women who cannot tolerate estrogen-containing prepara- It is important to evaluate a patient to determine if she is an
tions. Depo-Provera is extremely effective in preventing preg- appropriate candidate for an IUD. IUDs are recommended for
nancy. However, the incidence of menstrual irregularities women with at least one child, in a monogamous relationship,
(including amenorrhea) and weight gain appears to be much who have no history of pelvic inammatory disease (PID) and
greater than that seen with COCs. The use of Depo-Provera no history or risk of ectopic pregnancy. There are also multiple
also has been demonstrated to result in signicant loss of bone contraindications to IUD use. Evaluation of the patient is essen-
mineral density (BMD).36 Although it is not known whether tial because IUDs cannot be used in the following situations:
the use of Depo-Provera will increase the risk for osteoporotic (1) pregnancy or suspected pregnancy, (2) anatomically abnor-
fracture, a black-box warning within the product labeling cau- mal or distorted uterine cavity, (3) acute PID or history of PID,
tions against the risk of potentially irreversible BMD loss asso- unless there has been a subsequent intrauterine pregnancy,
ciated with long-term use (e.g., greater than 2 years) of the (4) postpartum endometritis or infected abortion in the past
injectable product. While the extended duration of activity of 3 months, (5) known or suspected uterine or cervical neoplasia
this product may offer women the advantage of less frequent or unresolved abnormal Pap smear, (6) genital bleeding of
administration, it is important to note that on discontinuation unknown etiology, (7) untreated acute cervicitis or vaginitis,
of Depo-Provera, the return of fertility can be delayed by (8) acute liver disease or liver tumor, (9) woman or her partner
approximately 10 to 12 months (range 431 months).8 has multiple sexual partners, (10) previously inserted IUD still
Depo-SubQ Provera 104 is also an injectable contraceptive in place, (11) conditions associated with increased suscepti-
product that contains only a progestin (depot medroxyproges- bility to infections (e.g., leukemia or acquired immune de-
terone acetate). This product, which was approved by the FDA ciency syndrome), (12) genital actinomycosis, (13) hypersensi-
in 2005, is different from Depo-Provera in that it is given sub- tivity to any component of the IUD, (14) known or suspected
cutaneously rather than intramuscularly, and it provides only carcinoma of the breast, (15) history of ectopic pregnancy or a
104 mg medroxyprogesterone acetate (approximately 30% less condition that would predispose to ectopic pregnancy, and
hormone) every 3 months for the prevention of pregnancy.37 (16) Wilsons disease.40,41
Clinical trials have demonstrated that the subcutaneous formu- There are potential side effects of IUD use. The most com-
lation of depot medroxyprogesterone acetate is as effective as mon adverse effects are cramping, abnormal uterine bleeding,
the intramuscular formulation in the prevention of preg- and expulsion of the device. Other side effects seen are ectopic
nancy.38 Although this product carries the same warning in its pregnancy, sepsis, PID, embedment of the device, uterine or
package labeling regarding possible effects on BMD as Depo- cervical perforation, and ovarian cysts.40,41
Provera,37 it is not yet known if the lower progestin dose will
lessen the potential for long-term side effects.
Nonpharmacologic Contraceptive Methods
Implantable Devices
Barrier Contraceptives
Although IUDs are the most common form of reversible con- As an alternative to hormonal contraceptives, several barrier
traception in the world, only 1% of women in the United contraceptive options are available for the prevention of preg-
States use IUDs.39 There are currently two IUD products nancy. While barrier contraceptives are associated with far fewer
available, one containing a progestin and one non-hormonal adverse effects compared with hormonal contraceptives, their
device. Mirena is a levonorgestrel-releasing intrauterine efcacy is highly user-dependent. Overall, compared with both
system, and Paragard T 380A is a copper intrauterine device. hormonal contraceptives and IUDs, barrier contraceptives are
8 should be stored in a cool, dry place, away from exposure to

associated with much higher accidental pregnancy rates
(Table 451). direct sunlight. When stored improperly or when used with oil-
based lubricants, however, latex condoms can break during
intercourse, increasing the risk of pregnancy.8 For latex-sensitive
Diaphragms and Cervical Caps
individuals, condoms made from lamb intestine (natural
Diaphragms and cervical caps are dome-shaped rubber caps membrane condoms) and synthetic polyurethane condoms are
that are placed over the cervix to provide barrier protection dur- available. Unlike latex condoms, condoms made from lamb
ing intercourse. Both diaphragms and cervical caps require t- intestine contain small pores that may permit the passage of
ting by a health care professional, and they must be retted for viruses and therefore do not provide adequate protection
the patient in the event of weight gain or weight loss. against STDs.44 Both latex and synthetic condoms do provide
Diaphragms or cervical caps typically can be placed over the protection against many STDs. Data from one meta-analysis sug-
cervix as much as 6 hours prior to intercourse. They must be gested that HIV transmission can be reduced by as much as 90%
left in place for at least 6 hours after intercourse before they when condoms are consistently used.45 This is in contrast to hor-
can be removed. Diaphragms should not be left in place monal contraceptives (oral, transdermal, or vaginal), IUDs, and
longer than 24 hours, and smaller cervical caps should not be most other barrier contraceptives, which do not protect against
left in place longer than 48 hours owing to the risk of toxic STDs. Relative to male condoms, female condoms may offer
shock syndrome (TSS). Diaphragms and cervical caps are even better protection against STDs because they provide
used along with spermicides to prevent pregnancy. When more extensive barrier coverage of external genitalia, includ-
sexual intercourse is repeated with the diaphragm, reapplica- ing the labia and the base of the penis.46 It is important to note
tion of the spermicide is necessary. However, when sexual that the male and female condoms are not recommended to be
intercourse is repeated with a cervical cap, reapplication of the used together because they may adhere to one another, causing
spermicide typically is not necessary.8 Whether or not displacement of one or both condoms.46
diaphragms or cervical caps provide adequate protection
against STDs without concurrent use of a spermicide remains
Sponge
unclear.42
The Today sponge is a small, pillow-shaped polyurethane
sponge containing nonoxynol-9.46 It is an over-the-counter
Spermicides barrier contraceptive that has been shown to be generally less
Nonoxynol-9, a surfactant that destroys the cell membranes of effective at preventing pregnancy than diaphragms.47 The
sperm, is the most commonly used spermicide in the United sponge is moistened with water and then is inserted and
States.8,43 Nonoxynol-9 is available in a variety of forms, includ- placed over the cervix for up to 6 hours prior to sexual inter-
ing a cream, foam, lm, gel, suppository, and tablet. Spermicides course. The sponge then is left in place for at least 6 hours fol-
may be used alone, with a barrier method, or adjunctively with lowing intercourse.46 Although the sponge maintains efcacy
other forms of contraceptives to provide additional protection for 24 hours (even if intercourse is repeated), as with
against unwanted pregnancy.43 To be used most effectively, sper- diaphragms, the sponge should be removed after 24 hours
micides must be placed in the vagina not more than 1 hour prior owing to the risk of TSS.8
to sexual intercourse, and they must come in contact with the
cervix.8 While the efcacy of spermicides depends largely on
Fertility Awareness and Periodic Abstinence
how consistently and correctly they are used, their efcacy is
Periodic abstinence and fertility awarenessbased methods repre-
enhanced when they are used in combination with a barrier
sent another nonpharmacologic means of pregnancy prevention.
contraceptive device.43 Clinical trials assessing the ability of
Although failure rates of such methods can be high, some couples
spermicides to protect against STDs have failed to produce pos-
still prefer these types of approaches. Fertility awarenessbased
itive results.43 Further, there exists some evidence to suggest that
methods depend on the ability of the couple to identify the
frequent use of spermicides actually may increase risk for trans-
womans fertile window, or the period of time in which preg-
mission of human immunodeciency virus (HIV) secondary to
nancy is most likely to occur as a result of sexual intercourse.48
vaginal mucosal tissue breakdown, which may allow a portal of
During the fertile window, the couple practices abstinence, or
entry for the virus.8
avoidance of intercourse, in order to prevent pregnancy. In some
cases, rather than practicing abstinence during the fertile period,
Condoms some couples may prefer to employ barrier methods or spermi-
Condoms, which are available for both male and female use, act cides as a means of preventing pregnancy rather than to avoid
as physical barriers to prevent pregnancy.44 Condoms are easy to intercourse altogether.8 In order to identify the fertile window, a
use, available without a prescription, and inexpensive. Most con- number of different fertility awarenessbased methods may be
doms are made of latex. When used correctly, condoms can be tried. The calendar (rhythm) method involves counting the
very effective in prevention of unwanted pregnancy. Condoms days in the menstrual cycle and then using a mathematical
equation to determine the fertile window.48 The temperature TABLE 455. Emergency Contraception Methods Available in
method involves monitoring changes in the womans basal the United States49
body temperature.48 The cervical mucus (or ovulation) method
Dose 2
involves observing changes in the characteristics of cervical Levonorgestrel Only (12 Hours Apart) Color
secretions throughout the cycle.48 The symptothermal method, a
Plan B 1 + 1 pill White pills
which is considered to be the most difcult to learn but potentially Ovrette 20 + 20 pills Yellow pills
the most effective, is a combination of both the temperature
EE + Levonorgestrel Dose 2
method and the cervical mucus method.8 In general, fertility
or Norgestrel (12 Hours Apart) Color
awarenessbased methods are not recommended for women a
PREVEN 2 + 2 pills Blue pills
who have irregular menstrual cycles or who have difculty inter-
Ogestrela White pills
preting their fertility signs correctly.48 Ovrala White pills
Alesse 5 + 5 pills Pink pills
LevliteTM Pink pills
Emergency Contraception AvianeTM Orange pills
LessinaTM Pink pills
Emergency contraception (EC) is used to prevent pregnancy CryselleTMa 4 + 4 pills White pills
after known or suspected unprotected sexual intercourse. Low-Ogestrela White pills
There are two hormonal forms of FDA-approved emergency Lo/Ovrala White pills
Levora White pills
contraception: combination products containing an estro-
Levlen Light orange pills
gen and a progestin and a progestin-only formulation49 Nordette Light orange pills
(Table 455). PREVEN is a combination of ethinyl estra- Triphasil Yellow pills
diol 0.05 mg and levonorgestrel 0.25 mg, and patients should Tri-Levlen Yellow pills
take two tablets within 72 hours of intercourse and then two Trivora Pink pills
tablets 12 hours later. This method of using two hormones is a
FDA approved agent for EC.
also known as the Yuzpe regimen, after Alfred Yuzpe, who
discovered it in 1974. Other marketed products containing
ethinyl estradiol and levonorgestrel or norgestrel can be used
with the same efcacy. The second and more preferred regi-
men uses only levonorgestrel and is marketed as Plan B.
Patient Encounter, Part 3: Missed With this formulation, patients take one 0.75-mg tablet
Doses within 72 hours of intercourse and then a second dose 12
hours later. In August of 2006, the FDA approved Plan B for
non-prescription sale to patients 18 years of age and older. It
RC calls your clinic in a panic today because she forgot to
start a new package of oral contraceptives. Three days have
is important to note that EC is more effective the earlier it is
elapsed since she took her last placebo pill, and she reports used after unprotected intercourse. This progestin-only for-
having had unprotected sexual intercourse last night. The mulation has shown decreased risk of side effects such as
patient is very concerned about her risk of pregnancy, and she nausea and vomiting, which decreases the risk of emergency
would like to discuss her options for prevention of pregnancy. contraception failure. The only other approved form of
When a contraceptive dose is missed, the risk of acciden- emergency contraception is the placement of a copper IUD
tal pregnancy may be increased. Depending on how many within 5 days of intercourse, although this is most com-
doses were missed, the contraceptive formulation being monly used in women who are appropriate candidates for
used, and the phase of the cycle during which doses were long-term use of such a device.
missed, counseling regarding the use of additional methods
of contraception may be warranted.
Given this patients reported imperfect use of her oral OUTCOME EVALUATION/MONITORING
contraceptive, what information can you provide to the
patient regarding her risk of pregnancy?
Compare and contrast the available emergency contra-
Side effects of contraceptives tend to occur in the rst few
ceptive (EC) options for this patient, and provide a recom- months of therapy. Thus, schedule a follow-up visit 3 to 6
mendation for this patient. months after initiating a new contraceptive. Yearly checkups
Provide appropriate patient education regarding the usually are sufcient for patients who are doing well on a par-
adverse effects associated with the option you have ticular product.1 At each follow-up visit, assess blood pressure,
recommended. headache frequency, and menstrual bleeding patterns, as well
as compliance with the prescribed regimen.
ABBREVIATIONS
BMD: bone mineral density
COC: combined oral contraceptive
EC: emergency contraception
1. Obtain a thorough medical and family history and carefully EE: ethinyl estradiol
evaluate each patients risk factors prior to prescribing FDA: Food and Drug Administration
contraceptives. FSH: follicle-stimulating hormone
2. Educate all women taking hormonal contraceptives to pre- GnRH: gonadotropin-releasing hormone
vent pregnancy regarding self-monitoring for early warning HDL: high-density lipoprotein
signs that may precede adverse events. Health care profes- HIV: human immunodeciency virus
sionals can easily recall the major warning signs by using HPV: human papilloma virus
the two simple pneumonics highlighted below: IUD: intrauterine device
ACHESfor women taking hormonal contraceptives LDL: low-density lipoprotein
A = Abdominal pain. This may be an early warning sign LH: luteinizing hormone
of the presence of an abdominal thromboembolism, liver PID: pelvic inammatory disease
adenoma, or gallbladder disease. STD: sexually transmitted disease
C = Chest pain. The presence of chest pain may indicate TSS: toxic shock syndrome
pulmonary embolism, angina, or myocardial infarction. WHO: World Health Organization
H = Headaches. Headaches (particularly those associ-
ated with focal neurologic symptoms, such as blurred Reference lists and self-assessment questions and answers are
vision, speech impairment, and/or weakness) may repre- available at www.ChisholmPharmacotherapy.com.
sent strokelike symptoms. Headaches also may indicate
poorly controlled blood pressure. Log into the website: www.pharmacotherapyprinciples.com
E = Eye problems. Blurred vision and/or ocular pain may for information on obtaining continuing education credit for
be early warning signs for stroke and/or blood clots. In this chapter.
addition, visual changes may occur in patients wearing
contact lenses (secondary to changes in corneal shape).
S = Severe leg pain. Patients taking hormonal contracep-
tives who complain of severe leg pain should be evalu-
ated for the presence of venous thromboembolism.
PAINSfor women with an IUD
Anonymous. Choice of contraceptives: Treatment Guidelines from
P = Period late
The Medical Letter. Med Lett 2004; 2:5562.
A = Abdominal pain, pain with intercourse
Hatcher RA, Namnoum AB. The menstrual cycle. In: Hatcher RA,
I = Infection, abnormal or odorous vaginal discharge
Trussel J, Stewart F, et al, eds. Contraceptive Technology. 18th
N = Not feeling well, fever, chills
revised ed. New York: Ardent Media; 2004: 6372.
S = String (missing, shorter, longer)
Hatcher RA, Nelson A. Combined hormonal contraceptive methods.
3. In addition to the preceding, monitor patients taking hor- In: Hatcher RA, Trussel J, Stewart F, et al, eds. Contraceptive
monal contraceptives for missed periods, signs of preg- Technology. 18th revised ed. New York: Ardent Media; 2004:
nancy, appearance of jaundice, and/or severe mood 391460.
changes. Instruct patients to consult a health care profes- Petitti DB. Clinical practice: Combination estrogen-progestin oral
sional on noticing or experiencing any of these warning contraceptives. N Engl J Med 2003; 349:14431450.
signs.1 Trussel J. Contraceptive efcacy. In: Hatcher RA, Trussel J, Stewart F,
4. Stress the importance of adherence to the patients cho- et al, eds. Contraceptive Technology. 18th revised ed. New York:
sen method of contraception in order to reliably prevent Ardent Media; 2004: 773845.
pregnancy. Educate the patient on what to do in the
event of missed doses with hormonal contraception.
46 MENSTRUATION-RELATED DISORDERS
Elena M. Umland, Lara C. Weinstein, and Abby Morris
LEARNING OBJECTIVES
1. Describe the underlying etiology and pathophysiology of amenorrhea, menorrhagia,

anovulatory bleeding, and dysmenorrhea and how they relate to selection of effective
treatment modalities.
2. Differentiate between premenstrual syndrome and premenstrual dysphoric disorder with
respect to pathophysiology, clinical presentation, and treatment.
3. Describe the clinical presentation of amenorrhea, menorrhagia, anovulatory bleeding,
dysmenorrhea, and premenstrual dysphoric disorder.
4. Recommend appropriate lifestyle and dietary modications and pharmacotherapeutic
interventions for patients with amenorrhea, menorrhagia, anovulatory bleeding,
dysmenorrhea, premenstrual symptoms, and premenstrual dysphoric disorder.
5. Identify the desired therapeutic outcomes for patients with amenorrhea, menorrhagia,
anovulatory bleeding, dysmenorrhea, premenstrual symptoms, and premenstrual dysphoric
disorder.
6. Design a monitoring plan to assess the effectiveness and adverse effects of pharmacotherapy
for amenorrhea, menorrhagia, anovulatory bleeding, premenstrual symptoms, and
premenstrual dysphoric disorder.
KEY CONCEPTS is directly proportional to the amount of pretreatment

blood loss.
Unrecognized pregnancy remains the most common cause of The use of metformin and thiazolidinediones for anovulatory
amenorrhea, and a urine pregnancy test should be one of the bleeding associated with polycystic ovary syndrome is bene-
rst steps in the evaluation of this disorder. cial for anovulatory bleeding and fertility and also improves
Causes of menorrhagia can be divided into systemic disorders glucose tolerance and decreases overall cardiovascular risk.
and specic uterine abnormalities. Intrauterine devices (IUDs) are considered therapeutic options
Intrauterine pregnancy, ectopic pregnancy, and miscarriage in a variety of menstrual-related disorders. Recent guidelines
must be at the top of the differential diagnosis list for any from the American College of Obstetricians and Gynecologists
woman presenting with heavy menses. indicate that nulliparous and multiparous women at low risk of
Anovulatory bleeding, also referred to as dysfunctional uter- sexually transmitted diseases are good candidates for IUD use.
ine bleeding, is secondary to the effects of unopposed estro- First-line pharmacologic treatment options for premenstrual
gen and does not include bleeding owing to an anatomic dysphoric disorder include the selective serotonin reuptake
lesion of the uterus. inhibitors (SSRIs).
For most conditions associated with primary and secondary
amenorrhea, estrogen (along with a progestin to minimize the Problems related to the menstrual cycle are exceedingly com-
risk of endometrial hyperplasia) is provided. mon in women of reproductive age. The issues considered in
The reduction in menorrhagia-related blood loss with the use of this chapter are the most frequently encountered menstrual-
non-steroidal anti-inammatory drugs and oral contraceptives related difculties and include amenorrhea, menorrhagia,
751
dysfunctional uterine bleeding, dysmenorrhea, and premen-

strual syndrome/premenstrual dysphoric disorder. The need
for effective treatments for these disorders stems from their
impact on any or all of the following: a reduced quality of life,
negative effects on reproductive health, and the potential for
long-term detrimental health effects, such as osteoporosis in
the case of amenorrhea and cardiovascular disease in the case
of polycystic ovary disease.
AMENORRHEA
Amenorrhea traditionally is described as either primary or

secondary in nature. Primary amenorrhea is the absence of
menses by age 16 in the presence of normal secondary sexual
development or the absence of menses by age 14 in the
absence of normal secondary sexual development. Secondary FIGURE 461. Summary of the normal menstrual cycle.
amenorrhea is the absence of menses for three cycles or
6 months in a previously menstruating woman. However, in
clinical practice, there is a signicant amount of overlap. The
initial evaluation of amenorrhea is often the same regardless
of age of onset, except in unusual clinical situations.1 that is secreted by the corpus luteum during the luteal phase
of the cycle causes endometrial organization. If conception
does not occur, the drop in estrogen and progesterone stimu-
Epidemiology and Etiology lates the shedding of the endometrium.4
Unrecognized pregnancy remains the most common cause Table 461 illustrates the pathophysiology of amenorrhea
of amenorrhea, and a urine pregnancy test should be one of the relative to the organ system(s) involved, as well as the specic
rst steps in the evaluation of this disorder. To help organize an condition that results in amenorrhea. Amenorrhea is also a
approach to diagnosis and treatment, it is helpful to consider normal side effect that may result from the use of low-dose
the organs involved in the menstrual cycle, which include the oral contraceptives (OCs), extended-cycle OC pill use, or
uterus, ovaries, anterior pituitary, and hypothalamus. depot medroxyprogesterone acetate use.5 Many women may
After pregnancy, the ve most common causes of secondary experience delayed return of menses after discontinuation of
amenorrhea, in descending order of prevalence, include:2 OCs. Postpill amenorrhea usually is a self-limited condition.
Further evaluation for other unrecognized conditions, such as
Hypothalamic suppression (33%) polycystic ovary syndrome (PCOS), should be considered if
Chronic anovulation (28%) spontaneous resolution of the amenorrhea does not occur
Hyperprolactinemia (14%) within 3 to 6 months following discontinuation of the OCs.6,7
Ovarian failure (12%)
Uterine disorders (7%)
MENORRHAGIA
Pathophysiology The traditional denition of menorrhagia is a menstrual
The physiology of the normal menstrual cycle depends on a blood loss of greater than 80 mL per cycle. This denition has
coordinated system of hormonal interactions involving the been questioned for several reasons, including difculty with
hypothalamus, anterior pituitary gland, ovary, and quantifying menstrual blood loss in clinical practice. Many women
endometrium. Figures 461 and 462 summarize these with heavy menses but blood loss of less than 80 mL will merit
points. Pulsatile gonadotropin-releasing hormone (GnRH) consideration for treatment because of problems with con-
secretion from the hypothalamus stimulates the anterior pitu- tainment of ow, unpredictable heavy ow days, and other
itary to secrete follicle-stimulating hormone (FSH) and associated symptoms.8,9
luteinizing hormone (LH). In the specialized cells of the ovar-
ian follicle, FSH and LH stimulate the release of estradiol. Epidemiology and Etiology
Estradiol stimulates endometrial growth during the follicular
phase of the cycle. Following the LH surge and ovulation, the Rates of menorrhagia in healthy women range from 9% to
follicle is transformed into the corpus luteum. Progesterone 14%.10 Causes of menorrhagia can be divided into systemic
CHAPTER 46 / MENSTRUATION-RELATED DISORDERS 753
Follicular phase Luteal phase Clinical Presentation and Diagnosis of

Menorrhagia
Ovulation
General
Patient may or may not be in acute distress.
Symptoms
Complaints of heavy/prolonged menstrual ow and
fatigue and light-headedness in the case of severe blood
loss. These symptoms may or may not occur with
dysmenorrhea.
Estradiol Luteinizing hormone Signs

Orthostasis, tachycardia, and pallor may be noted, espe-
Progesterone Follicle-stimulating hormone
cially in cases of signicant acute blood loss.
FIGURE 462. Hormonal uctuations with the normal menstrual Laboratory Tests
cycle. (Reprinted, with permission, from ref. 3.)
Complete blood count (CBC) and ferritin levels; hemoglo-
bin and hematocrit results may be low.
If the history dictates, testing may be done to identify coag-
ulation disorder(s) as a cause.
Amenorrhea Other Diagnostic Tests
Pelvic ultrasound
Pelvic magnetic resonance imaging (MRI)
General Pap smear
Patients may be concerned about cessation of menses Endometrial biopsy
and fertility implications but generally are not in acute Hysteroscopy
distress. Sonohysterogram
Symptoms
Cessation of menses
Possible complaints of infertility, vaginal dryness,
decreased libido
Signs
Cessation of menses for longer than 6 months in women disorders and specic uterine abnormalities. Pregnancy,
with established menstruation, or absence of menses by including intrauterine pregnancy, ectopic pregnancy, and mis-
age 16 in the presence of normal secondary sexual devel- carriage, must be at the top of the differential diagnosis list for
opment, or absence of menses by age 14 in the absence any woman presenting with heavy menses. In several studies of
of normal secondary sexual development adolescents with acute menorrhagia, underlying bleeding dis-
Recent signicant weight loss or weight gain
orders accounted for 3% to 13% of emergency room visits.
Presence of acne, hirsutism, hair loss, or acanthosis
von Willebrands disease has an incidence of 1% in the general
nigricans may suggest androgen excess.
population and may present initially as heavy menses in an
Laboratory Tests adolescent.5 Hypothyroidism also may be associated with
Pregnancy test heavy menses. Specic uterine causes of menorrhagia are
TSH
more common in older childbearing women, and they include
Prolactin
broids, adenomyosis, endometrial polyps, and gynecologic
If suspect PCOS, consider free or total testosterone,
17-hydroxyprogesterone, fasting glucose, and fasting malignancies.
lipid panel.
If suspect premature ovarian failure, consider FSH and
LH.
Pathophysiology
Progesterone challenge Table 461 illustrates the pathophysiology of menorrhagia
Pelvic ultrasound to evaluate for polycystic ovaries relative to the organ system(s) involved, as well as the specic
conditions that result in menorrhagia.
TABLE 461. Pathophysiology of Selected Menstrual Bleeding Disorders1,10,11,13,15
Organ System Condition Pathophysiology/Laboratory Findings

1
AMENORRHEA
Uterus Ashermans syndrome Postcurettage/postsurgical uterine adhesions
Congenital uterine abnormalities Abnormal uterine development
Ovaries Turners syndrome Lack of ovarian follicles
Gonadal dysgenesis Other genetic anomalies
Premature ovarian failure Early loss of follicles
Chemotherapy/radiation Gonadal toxins
Anterior pituitary Pituitary prolactin-secreting adenoma Prolactin suppresses HPO axis
Hypothyroidism TRH causing prolactin, other abnormalities
Medicationsantipsychotics, verapamil Prolactin suppresses HPO axis
Hypothalamus Functional hypothalamic amenorrhea Pulsatile GnRH secretion in the absence of other abnormalities
Disordered eating Pulsatile GnRH secretion, FSH and LH secondary to weight loss
Exercise Pulsatile GnRH secretion, FSH and LH secondary to low body fat
Anovulation/PCOS Asynchronous gonadotropin and estrogen production, abnormal
endometrial growth
ANOVULATORY BLEEDING
Physiologic causes Adolescence Immaturity of the hypothalamic-pituitary-ovarian axis: no LH surge
Perimenopause Declining ovarian function
Pathologic causes Hyperandrogenic anovulationPCOS Hyperandrogenism: high testosterone, high LH, hyperinsulinemia,
and insulin resistance
Hypothalamic dysfunction (physical Suppression of pulsatile GnRH secretion and estrogen deciency:
or emotional stress, exercise, low LH, low FSH
weight loss)
Hyperprolactinemia (pituitary gland High prolactin
tumor, psychiatric medications)
Hypothyroidism High TSH
Premature ovarian failure High FSH
MENORRHAGIA
Hematologic von Willebrand disease Factor VII defect causing impaired platelet adhesion and increased
bleeding time
Idiopathic thrombocytopenic purpura Decrease in circulating plateletscan be acute or chronic
Hepatic Cirrhosis Decreased estrogen metabolism, underlying coagulopathy
Endocrine Hypothyroidism Alterations in HPO axis
Uterine Fibroids Alteration of endometrium, changes in uterine contractility
Adenomyosis Alteration of endometrium, changes in uterine contractility
Endometrial polyps Alteration of endometrium
Gynecologic cancers Various dysplastic alterations of endometrium, uterus, cervix
, high; , low; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; HPO, hypothalamic-pituitary-ovarian axis; LH, luteinizing
hormone; PCOS, polycystic ovary disease; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.
ANOVULATORY BLEEDING their menstrual cycle or improve fertility. All women of reproduc-
tive age should have a pregnancy test when presenting with irreg-
Anovulatory bleeding is irregular menstrual blood ow from the ular menstrual bleeding. Anovulation may be secondary to phys-
uterine endometrium that ranges from light spotting to heavy iologic or pathologic causes. It is common at menarche and in the
blood ow.11 Anovulatory bleeding, also referred to as dysfunc- perimenopausal period. During adolescence, ovulatory menstrual
tional uterine bleeding, is secondary to the effects of unopposed cycles may not be regular for a year or more after menarche.11 In
estrogen and does not include bleeding owing to an anatomic lesion the year following menarche, there may be an immature feedback
of the uterus. Anovulatory bleeding includes polycystic ovary mechanism in the hypothalamic-pituitary-ovarian (HPO) axis
syndrome (PCOS), which typically presents with irregular men- whereby the LH surge needed for ovulation does not occur.
strual bleeding, hirsutism, obesity, or infertility. During perimenopause, anovulatory cycles may occur owing to a
declining quality and quantity of ovarian follicles. As ovarian
function declines, estrogen secretion continues, and progesterone
Epidemiology
secretion decreases. Chronic anovulatory cycles and unopposed
Anovulatory bleeding is the most common form of non-cyclic estrogen secretion lead to endometrial proliferation and increased
uterine bleeding.11 Patients often seek medical care to regulate risk of polyps, endometrial hyperplasia, and carcinoma.
During the cycle, the endometrium undergoes proliferation,

Patient Encounter, Part 1 secretory change, and desquamation. This cycle is inuenced
rst by the effects of estrogen alone, then by estrogen and
progesterone, and culminates with estrogen and progesterone
withdrawal. Progesterone stops the growth of the
TP, a 22 year-old woman, presents to your ofce for a routine
endometrium and stimulates its differentiation. In patients
gynecologic examination. She entered menarche at the age of
12. Her last menstrual period was 3 months ago. Her periods with anovulation, a corpus luteum is not formed, and the
are often irregular and occur about every 2 to 3 months. She ovary does not secrete progesterone. Without progesterone,
has had all normal Pap smears in the past and no history of there is no desquamation or differentiation of the
sexually transmitted infections. She is currently in a monoga- endometrium. Chronic unopposed estrogen causes continu-
mous relationship with a male partner. She has had a total of ous endometrial proliferation, and the endometrium becomes
four sexual partners. She is not taking oral contraceptives and vascular and fragile, resulting in non-cyclic menstrual bleed-
does not routinely use condoms. She has never been pregnant ing. In addition, the endometrium may become hyperplastic
in the past, but she plans on starting a family in the near and progress to a precancerous state, placing the patient at
future. As you examine the patient, you note facial and chest increased risk of endometrial cancer.13 See Table 461 for the
acne, increased facial and abdominal hair, and obesity.
pathophysiology of anovulatory bleeding relative to the spe-
What anovulatory disorder is most likely present, and
cic conditions that contribute to it.
what signs/symptoms support this conclusion? The most common pathologic cause of anovulation is
What diagnostic test should be done rst in the ofce? PCOS. It is a syndrome of ovarian dysfunction diagnosed by
the presence of two of the following three characteristics:
oligoanovulation or anovulation, clinical or laboratory evi-
dence of hyperandrogenism, and polycystic ovary morphology
on ultrasound.14 No gene or environmental substance has been
Anovulation also may occur at any time during the repro- found to cause PCOS.15 However, the observance of familial
ductive years due to a pathologic cause. The most common clustering of cases suggests that genetics plays a role.16 It is
causes of non-physiologic ovulatory dysfunction and their thought that insulin resistance, hyperandrogenism, and
prevalence rates11 are: changes in gonadotropins also inuence the development of
PCOS (70%) PCOS.12 The underlying cause for increased androgens is
Hypothalamic amenorrhea (10%) unknown.16
Hyperprolactinemia (10%) PCOS is associated with a three to seven times increased risk
Premature ovarian failure (10%) of developing type 2 diabetes.14 Patients diagnosed with PCOS
should be screened for impaired glucose tolerance, diabetes,
PCOS, while responsible for 70% of the cases of ovulatory hypertension, and dyslipidemia.12 If any of these conditions are
dysfunction, occurs in approximately 4% of women.12 present, there is an increased risk of cardiovascular events.
Etiology
Anovulation may result from a problem at any level of the Clinical Presentation and Diagnosis of
HPO axis. In addition to various physiologic life stages such as
Anovulatory Bleeding
adolescence, perimenopause, pregnancy, and lactation, other
causes of anovulation include:11 General
May or may not be in acute distress
Hyperandrogenic anovulation (PCOS, congenital adrenal
Symptoms
hyperplasia, androgen-producing tumors) Irregular, heavy, or prolonged vaginal bleeding, perimenopausal
Hypothalamic dysfunction (anorexia nervosa, physical or symptoms (hot ashes, etc.)
emotional stress)
Hyperprolactinemia Signs
Acne, hirsutism, obesity
Hypothyroidism
Primary pituitary disease Laboratory Tests
Premature ovarian failure If suspect PCOS, consider free or total testosterone, fast-
ing glucose, fasting lipid panel.
Pathophysiology If suspect perimenopause, FSH.
A normal ovulatory cycle consists of follicular development, Pelvic ultrasound to evaluate for polycystic ovaries
ovulation, corpus luteum development, and luteolysis.
Patient Encounter, Part 2: The Medical Clinical Presentation and Diagnosis of

History, Physical Examination, and Dysmenorrhea
Diagnostic Tests
PMH General
Obesity Patient may or may not be in acute distress depending on
Acne the level of menstrual pain experienced.
FH Symptoms
Father is living and has hypertension. Mother is living and Complaints of crampy pelvic pain beginning shortly before
has diabetes mellitus and hypercholesterolemia. Both par- or at the onset of menses. Symptoms typically last from 1 to
ents are obese. 3 days.
SH Laboratory Tests
The patient works as a secretary. She lives with her ance. Sexually active females should have a pelvic examination
She denies any tobacco or recreational drug use. She drinks to screen for sexually transmitted diseases.
about ve alcoholic beverages per week. She is sedentary. Gonorrhea, chlamydia cultures or PCR, wet mount.
Meds Other Diagnostic Tests
None Pelvic ultrasound may be used to identify anatomic abnor-
malities such as masses/lesions or to detect ovarian cysts
ROS
and endometriomas.
(+) acne, (+) hirsutism, () dysmenorrhea, () breast tenderness,
() vaginal discharge
PE Etiology and Epidemiology
VS: blood pressure 128/82, pulse 80 beats per minute,
Rates of dysmenorrhea range from 20% to 90%.1719
respiratory rate 18, weight 270 lb (123 kg), height 5 ft,
3 in (160 cm), BMI 47.9 kg/m2 Dysmenorrhea can be associated with signicant interference
Abd: Obese, soft, non-tender, non-distended, (+) bowel in attendance at work and school. Risk factors for dysmenor-
sounds, no hepatosplenomegaly rhea include young age, heavy menses, and nulliparity.17
Gyn: Normal external appearance of labia minora and
majora, vaginal walls within normal limits, cervix well Pathophysiology
visualized and without lesions, midposition uterus, no
cervical motion tenderness, no adnexal masses palpated The most signicant mechanism for primary dysmenorrhea is
the release of prostaglandins in the menstrual uid and possi-
Labs bly vasopressin-mediated vasoconstriction.5,17 Causes of sec-
Urine HCG negative, free testosterone 100 ng/dL (3.47 nmol/L)
ondary dysmenorrhea may include cervical stenosis,
(elevated), TSH 2.1 mIU/L (2.1 mU/L) (within normal limits),
endometriosis, pelvic infections, pelvic congestion syndrome,
prolactin 9 ng/mL (9 ug/L) (mcg/L) (within normal limits),
fasting glucose 120 mg/dL (6.66 mmol/L). Fasting lipid panel: uterine or cervical polyps, and uterine broids.20
total cholesterol 181 mg/dL (4.69 mmol/L), HDL cholesterol
58 mg/dL (1.50 mmol/L), triglycerides 65 mg/dL
(0.73 mmol/L), LDL cholesterol 110 mg/dL (2.85 mmol/L). PREMENSTRUAL SYNDROME AND
PREMENSTRUAL DYSPHORIC DISORDER
Pelvic ultrasound
15 follicles in right ovary, 14 follicles in left ovary, increased
Epidemiology
ovarian volume of 12 mL
Premenstrual syndrome (PMS) is a constellation of symp-
What treatment options are available for this patient? toms including mild mood disturbance and physical symp-
Will this patient have fertility problems in the future? toms that occur prior to menses and resolve with initiation of
Given this patients fasting glucose results, what medica- menses. It is estimated that up to 70% of menstruating women
tion would you recommend?
experience symptoms of PMS. However, a spectrum of pre-
menstrual mood disturbances exists and the most severe is
premenstrual dysphoric disorder (PMDD). Approximately
DYSMENORRHEA 4% to 7% of women have PMDD. A summary of the American
Psychiatric Associations criteria for PMDD is as follows1,21:
Dysmenorrhea is commonly dened as crampy pelvic pain
occurring with or just prior to menses. Primary dysmenor- Symptoms are temporally associated with the last week of
rhea implies pain in the setting of normal pelvic anatomy and the luteal phase and remit with onset of menses.
physiology, whereas secondary dysmenorrhea is associated At least ve of the following symptoms are present: markedly
with underlying pelvic pathology.17 depressed mood, marked anxiety, marked affective lability,
marked anger or irritability, decreased interest in activities, may respond to weight gain. Such patients also would bene-
fatigue, difculty concentrating, changes in appetite, sleep t from psychotherapy. In young women for whom excessive
disturbance, feeling overwhelmed, and physical symptoms exercise is an underlying cause, a reduction in exercise is
such as breast tenderness or bloating. recommended.
One of the symptoms must be marked depressed mood,
anxiety, irritability, or affective lability.
Symptoms interfere signicantly with work or social rela-
tionships.
Estrogen/Progestin Replacement Therapy
Symptoms are not an exacerbation of another underlying
For most conditions associated with primary or secondary
psychiatric disorder.
amenorrhea, a goal of therapy is to replace estrogen (along with
The criteria are conrmed prospectively by daily ratings over
a progestin to minimize the risk of endometrial hyperplasia) via
two menstrual cycles.
an OC, conjugated equine estrogen (CEE), or an estradiol patch.
The purpose of estrogen therapy in this patient population is
Etiology and Pathophysiology
two-fold: to reduce the risk of osteoporosis and to improve
PMDD is a complex psychiatric disorder with multiple biologic, quality of life.24,25 Table 462 identies a variety of therapeu-
psychological, and sociocultural determinants.21 While cyclic tic options for amenorrhea, including recommended doses.
hormonal changes are in some way related to PMS and PMDD, Figure 463 illustrates a treatment algorithm for the manage-
the association is neither linear nor simple. However, when ovu- ment of amenorrhea.
lation is suppressed medically or surgically, symptoms do If hyperprolactinemia is identied as the cause of amenor-
improve. There is some evidence to suggest that PMS and PMDD rhea, the use of bromocriptine, a dopamine agonist, results in
symptoms are related to low levels of the centrally active proges- a reduction in prolactin concentrations and the resumption of
terone metabolite allopregnanolone in the luteal phase and/or menses.
lower cortical -aminobutyric acid (GABA) levels in the follicu- Amenorrhea related to anovulation resulting from PCOS
lar phase.21 Women with PMS and PMDD may have enhanced may respond to the use of agents that reduce insulin resist-
sensitivity to progesterone.22 Studies of the relationship of PMS ance. The use of metformin for this purpose will be discussed
and PMDD to testosterone levels are conicting.21 A number of in the anovulatory bleeding section that follows.
studies suggest a link between PMS and PMDD and low levels of Progestins have long been used to induce withdrawal bleeding
serotonin.21,22 A recent study suggests that despite similar affec- in women with secondary amenorrhea. Several factors predict
tive symptoms, the function of the hypothalamic-pituitary- the efcacy of progesterone for this purpose.27 These factors
adrenal (HPA) axis in PMS and PMDD is distinct from that seen include estrogen concentrations greater than or equal to
in major depressive disorder (MDD). Specically, women with 35 pg/mL (128 pmol/L) and endometrial thickness (the greater
PMS show a decrease in stimulated HPA axis response, whereas it is, the greater is the amount of withdrawal bleeding).
this response is increased in MDD.23 The efcacy of progestins for secondary amenorrhea also
Several cross-cultural studies suggest that while the physi- varies depending on the formulation used. For example, proges-
cal symptoms of PMS are consistent across cultures, the neg- terone in oil administered intramuscularly results in withdrawal
ative affective symptoms are part of the negative menstrual bleeding in 70% of treated patients, whereas oral medroxyprog-
socialization in Western culture.1,21 esterone acetate induces withdrawal bleeding in 95% of treated
patients.27 Table 462 identies the types and doses of proges-
terones used for inducing withdrawal bleeding in women with
TREATMENT: AMENORRHEA secondary amenorrhea. Figure 463 illustrates when to consider
the use of progesterone for the treatment of amenorrhea.
Desired Outcomes For all patients experiencing amenorrhea, owing to the
negative impact this has on bone health, it is essential that a
Therapeutic modalities for amenorrhea are targeted at restoring
diet rich in calcium and vitamin D be followed.
the normal menstrual cycle. The goals of treatment are to pre-
serve bone density, prevent bone loss, and restore ovulation,
thus improving fertility as desired. Amenorrhea resulting from Amenorrhea in Adolescents
conditions contributing to hypoestrogenism also may affect
Amenorrhea in the adolescent population is of great importance
quality of life via the induction of hot ashes (premature
because this is the time in the female life cycle when peak bone
ovarian failure), dyspareunia, and in prepubertal females, lack
mass is achieved. The cause of amenorrhea and appropriate
of secondary sexual characteristics and absence of menarche.
treatment must be identied promptly in this population
because hypoestrogenism contributes negatively to bone devel-
opment. Estrogen replacement, typically via an OC, is impor-
Nonpharmacologic therapy for amenorrhea varies depending tant. In addition, ensuring that the patient is receiving adequate
on its underlying cause. Amenorrhea secondary to anorexia amounts of calcium and vitamin D is imperative.
TABLE 462. Therapeutic Agents for Select Menstrual Disorders15,17,2426,28,29
Specic
Menstrual Dose Common
Disorders(s) Agent(s) Recommended Adverse Effects
Amenorrhea (primary Conjugated equine estrogen 0.6251.25 mg by mouth daily Thromboembolism, breast
or secondary) (CEE) on days 125 of the cycle25 enlargement, breast
Ethinyl estradiol patch 50 mcg/24 hours27 tenderness, bloating, nausea,
Combination OC 3040 mcg formulations24 gastrointestinal (GI) upset,
headache, peripheral edema
Amenorrhea Oral medroxyprogesterone 510 mg by mouth on days Edema, anorexia, depression,
(secondary) acetate 1425 of the cycle25 insomnia, weight gain or loss,
increase in serum total and
LDL cholesterol, may reduce
HDL cholesterol
Amenorrhea related to Bromocriptine 2.5 mg by mouth 23 Hypotension, nausea,
hyperprolactinemia times daily constipation, anorexia,
Raynauds phenomenom
Anovulatory bleeding Combination OC Optimal dose unknown15 As noted above for CEE, ethinyl
estradiol, and combination
OC (progesterone side
effects with the OC depend
on agent chosen)
Dysmenorrhea Combination OC Less than 35 mcg formulations + As noted above for CEE, ethinyl
norgestrel or levonorgestrel28; estradiol, and combination
use of extended-cycle OC (progesterone side
formulations are benecial for effects with the OC depend
this indication on agent chosen)
Depo-medroxyprogesterone 150 mg intramuscularly every Irregular menses, amenorrhea
acetate 12 weeks
Levonorgestrel IUD29 20 mcg released daily Irregular menses, amenorrhea
NSAIDsany are acceptable; Diclofenac 50 mg by mouth 3 GI upset, stomach ulcer, nausea,
the most commonly times daily vomiting, heartburn,
studied/cited are Ibuprofen 800 mg by mouth 3 indigestion, rash, dizziness
included in this table times daily
Mefenamic acid 500 mg by
mouth as a loading dose,
then 250 mg by mouth up to
4 times daily as needed17
Naproxen 550-mg loading dose
by mouth started 12 days
prior to menses, followed
by 275 mg by mouth every
612 hours as needed28
Treatment should begin 12
days prior to the suspected
onset of menses17
Menorrhagia Combination OC Optimal dose unknown As noted above
Levonorgestrel IUD 20 mcg released daily As noted above
Medroxyprogesterone 510 mg by mouth on As noted above
acetate (oral) days 526 of the cycle or
during the luteal phase29
NSAIDs Doses as recommended for As noted above
above; therapy should
be initiated with the
onset of menses29
PCOS-related Clomiphene15 50 mg by mouth daily Hot ashes, ovarian enlargement,
amenorrhea 5 days starting 35 days thromboembolism, blurred
and/or anovulatory after the start of menses vision, breast discomfort
bleeding Depo-medroxyprogesterone 150 mg intramuscularly As noted above
acetate every 12 weeks
Medroxyprogesterone acetate 10 mg by mouth 10 days15 As noted above
(oral)
Metformin 15002000 mg by mouth daily Anorexia, nausea, vomiting, diarrhea,
in 23 divided doses15 atulence, lactic acidosis
TABLE 462. Therapeutic Agents for Select Menstrual Disorders15,17,2426,28,29 (Continued )
Specic
Menstrual Dose Common
Disorders(s) Agent(s) Recommended Adverse Effects
Thiazolidinediones15 Pioglitazone 1545 mg by Weight gain; increase in total,
mouth daily; rosiglitazone LDL, and HDL cholesterol;
48 mg by mouth daily edema; headache; fatigue;
hepatic injury (rare)
PMDD Clomipramine26 2575 mg by mouth daily Dry mouth, fatigue, vertigo,
taken continuously or only sweating
during the luteal phase
Drospirenone 3 mg (+30 mcg ethinyl estradiol) As noted with other OCs above;
by mouth on days 121 of drospirenone may contribute
the menstrual cycle31 to hyperkalemia in patients
with reduced renal function
Leuprolide 3.75 mg intramuscularly26 Hot ashes, night sweats,
headache, nausea
SSRIs Citalopram 1030 mg; uoxetine Sexual dysfunction
1020 mg; uvoxamine (reduced libido, anorgasmia),
50 mg; paroxetine 1030; insomnia sedation,
sertraline 25150 mg; hypersomnia, nausea, diarrhea
all agents are given by
mouth daily and can be
dosed continuously or
during the luteal phase only26
TREATMENT: MENORRHAGIA includes their dosing and common side effects. Figure 464
illustrates how to decide which treatment(s) to use and when.
Desired Outcomes
Menorrhagia therapy should focus on reducing menstrual
blood ow, improving the patients quality of life, and deferring
the need for surgical intervention. Table 462 identies the var- Nonpharmacologic interventions for menorrhagia include sur-
ious agents used in the management of menorrhagia. It also gical interventions that are reserved for patients not responding
FIGURE 463. Treatment algorithm for amenorrhea. FIGURE 464. Treatment algorithm for menorrhagia.
to pharmacologic treatment. These interventions may vary have completed childbearing or who have failed medical man-
from conservative endometrial ablation to hysterectomy.32 agement, endometrial ablation or resection and hysterectomy
are surgical options. It is unclear as to which procedure is pre-
ferred. Short term, it appears that ablation or resection results in
Pharmacologic Therapy less morbidity and shorter recovery periods. However, a signi-
cant number of these women eventually undergo hysterectomy
Non-steroidal anti-inammatory drugs (NSAIDs) are rst-
in the 5 years that follow.11
line treatments for menorrhagia associated with ovulatory
cycles.33 They have the advantage of being taken only during
menses, and their use is associated with a signicant reduc-
tion in menstrual blood loss. A 20% to 50% reduction in Estrogen is the recommended treatment for managing acute
blood loss has been observed in 75% of treated women.29 In bleeding episodes because it promotes endometrial growth
some patients, as much as an 80% reduction has been and stabilization.11 Following its initial use for controlling
observed. This reduction is directly proportional to the acute bleeding episodes, it is necessary to continue therapy to
amount of pretreatment blood loss.29 prevent future occurrences. The use of OCs fullls this role.
The use of OCs is benecial in women with menorrhagia The role of OCs is to prevent recurrent anovulatory bleeding.
who do not desire pregnancy. A 43% to 53% reduction in They suppress ovarian hormones and adrenal androgen pro-
menstrual blood loss has been observed in 68% of patients duction. They also, indirectly, increase sex hormonebinding
treated with OCs containing greater than or equal to 35 mcg globulin (SHBG). This, in turn, binds and reduces circulating
estradiol for the treatment of menorrhagia.29 As with the use androgen. For women with high androgen levels and related
of NSAIDs, the reduction in blood loss is proportional to pre- signs (e.g., hirsutism), low-dose OCs (less than or equal to
treatment blood loss. 35 mcg ethinyl estradiol) are the treatment of choice.11 In the-
Menorrhagia also may be treated with the levonorgestrel- ory, one may consider the use of an OC with a progesterone
releasing intrauterine device (IUD). This is a very effective that has a larger impact on increasing SHBG. To date, there is
treatment that consistently reduces menstrual ow by 90% or no best OC choice for these women (e.g., those with PCOS).15
greater.29,30 Its use has resulted in the postponement or can- Specically, for women with PCOS, the use of depot and
cellation of scheduled endometrial resection surgery or hys- intermittent oral medroxyprogesterone acetate suppresses
terectomy. Specically, 60% of treated patients have been able pituitary gonadotropins and circulating androgens.15 Further,
to avoid hysterectomy.30,34,35 the use of cyclic progesterone may benet women over age
Progesterone therapy either during the luteal phase of the 40 and in whom anovulatory bleeding occurs.11
menstrual cycle or for 21 days starting on day 5 after the onset The use of metformin and the thiazolidinediones pioglita-
of menses results in a 32% to 50% reduction in menstrual zone and rosiglitazone results in improved insulin sensitivity. In
blood loss.29 Its use has not been shown to be superior to patients with PCOS, this is associated with reducing circulating
other medical treatments, including NSAIDs.29 In addition, it androgen concentrations, increasing ovulation rates, and
is not associated with any contraceptive benet.33 improving glucose tolerance.15 These improvements can be
attributed to the increase in SHBG that occurs via increased
insulin sensitivity. These agents are of benet not only for
anovulatory bleeding and fertility but also because they improve
TREATMENT: ANOVULATORY BLEEDING glucose tolerance and decrease overall cardiovascular risk.15 If
pregnancy is a desired outcome, it is important to note that met-
Desired Outcomes formin is a pregnancy category B agent, whereas pioglitazone
and rosiglitazone are category C.
In the short term, the desired outcome is to stop acute bleed-
Although the use of insulin-sensitizing agents may
ing. The long-term goals of therapy include preventing future
improve fertility, if the goal of treatment is to improve fer-
episodes of non-cyclic bleeding, decreasing the long-term
tility via inducing ovulation, then the treatment of choice is
complications of anovulation (e.g., osteopenia and infertility),
clomiphene citrate. Treatment with 50 mg/day for 5 days can
and improving overall quality of life.11 Table 462 identies
be initiated between days 3 and 5 of the menstrual cycle. This
the agents used in the management of anovulatory bleeding,
often may occur following the induction of withdrawal bleeding
their doses, and common side effects.
with a progesterone such as medroxyprogesterone acetate at
10 mg/day by mouth for 10 days.
Anovulatory Bleeding in Adolescents
Nonpharmacologic treatment options for anovulatory bleeding
depend on the underlying cause. In a woman of reproductive Anovulatory cycles are not unusual in the perimenarchal
age with PCOS, weight loss may be benecial. In women who reproductive years. Ovulation typically is established a year or
more following menarche. When anovulatory bleeding occurs exercise, and following a low-fat vegetarian diet all have been
in this population, it may be excessive. If the bleeding is exces- shown to reduce the intensity of the dysmenorrhea.17,28 Dietary
sive, the patient should be evaluated for blood dyscrasias. The changes also may shorten the duration of dysmenorrhea. These
prevalence of blood dyscrasias, including von Willebrands interventions require little time and minimal cost and are asso-
disease and prothrombin deciency, and the prevalence of ciated with little risk. Other nonpharmacologic options that may
idiopathic thrombocytopenia purpura in this population be considered before or, in most cases, after a trial of pharmaco-
ranges from 5% to 20%.11 logic interventions include the use of transcutaneous electric
In the adolescent population, specic blood dyscrasias nerve stimulation (TENS), acupressure, and acupuncture.17
should be treated. In addition, acute, severe bleeding may be
managed with high-dose estrogen. Low-dose OCs (less than Pharmacologic Therapy
or equal to 35 mcg ethinyl estradiol) are the treatment of
choice in adolescents with chronic anovulation.11 Given the role of prostaglandins in the pathophysiology of
dysmenorrhea, NSAIDs are the treatment of choice. There
does not appear to be a difference between agents in efcacy.
TREATMENT: DYSMENORRHEA Choice of one agent over another may be based on cost, con-
venience, and patient preference.17 The most commonly used
Desired Outcomes agents are naproxen and ibuprofen.
The medical management of dysmenorrhea should relieve the It has been suggested that a loading dose (twice the usual
related pelvic pain. Effective management of dysmenorrhea single dose) of the NSAID be taken, followed by the usually
also results in a reduction in lost school and work days. recommended dose until symptoms resolve.28 An alternate
Table 462 identies the agents used in the management of recommendation is to begin the NSAID at the onset of
dysmenorrhea, their recommended doses, and their common menses or perhaps even the day prior and to continue treat-
side effects. Figure 465 is a treatment algorithm for the man- ment around the clock instead of waiting until the onset of
agement of dysmenorrhea. symptoms. For patients in whom NSAID use is contraindi-
cated, the agents discussed below should be considered. The
use of acetaminophen has been proven inferior to the use of
Nonpharmacologic Therapy NSAIDs for the treatment of this disorder.17
Several nonpharmacologic interventions exist for the manage- OCs help to improve dysmenorrhea by inhibiting the pro-
ment of dysmenorrhea. Among these, topical heat therapy, liferation of endometrial tissue. This reduction in tissue trans-
lates into a reduction in endometrial-derived prostaglandins
that are thought to contribute to the pelvic pain experienced.28
A trial of 2 to 3 months of OC dosing is required to establish
whether the patient is a responder or a non-responder.36
Signicant improvements in mild, moderate, and severe dys-
menorrhea have been noted with the use of OCs. These agents
have other benets, such as the prevention of pregnancy,
improving acne, and reducing ovarian cancer risk. While
monophasic formulations may be more efcacious for this
indication, the supporting evidence for this is limited.17
The benet of depo-medroxyprogesterone acetate in dys-
menorrhea is related to its ability to render most patients amen-
orrheic within 1 year of use.17 This is an expected side effect.
Since the pelvic pain of dysmenorrhea is related to the
prostaglandins released during menses, in the setting of amen-
orrhea, the underlying cause of dysmenorrhea is removed.
Observational data illustrate a reduction in dysmenorrhea
from 60% to 29% with the levonorgestrel-releasing IUD after
3 years.17 As observed with depo-medroxyprogesterone
acetate, this reduction is likely secondary to the increasing
incidence of amenorrhea in users of this contraceptive device.
Dysmenorrhea in Adolescents
FIGURE 465. Treatment algorithm for dysmenorrhea.

Dysmenorrhea is very common in adolescent females. Any of
the treatment measures discussed earlier for other patients
would be appropriate in the adolescent population. While SSRIs are efficacious in more than half of treated
NSAIDs and OCs are among the top choices, use of the lev- patients compared with only 20% of patients receiving
onorgestrel IUD is also an option.30 It had been thought pre- placebo.26 This improvement was noted to be a 50% or
viously that nulliparous females should avoid the use of IUDs greater reduction in symptoms compared with baseline.
secondary to an increased risk of pelvic inammatory disease Further, the improvement was noted to occur during the rst
(PID) and a subsequent increased risk of infertility. Recent cycle of use.26
guidelines from the American College of Obstetricians and The tricyclic antidepressant clomipramine also has been
Gynecologists (ACOG) state that any woman (regardless of parity) studied for PMDD. In placebo-controlled trials, both con-
at low risk of sexually transmitted diseases and thus pelvic inam- tinuous daily dosing and luteal phase administration
matory disease is a good candidate for IUD use.30 proved effective.17 Compared with the SSRIs, however,
clomipramine has a less desirable side-effect prole with
low tolerability.
TREATMENT: PREMENSTRUAL SYNDROME AND If treatment with an SSRI or another antidepressant such
PREMENSTRUAL DYSPHORIC DISORDER as clomipramine is not successful, hormonal treatment with a
GnRH agonist, such as leuprolide, may be considered. The use
Desired Outcomes of leuprolide improves premenstrual emotional symptoms as
Interventions for managing PMS and PMDD focus on allevi- well as some physical symptoms such as bloating and breast
ation of the presenting symptoms and subsequent improvement tenderness. Cost, the need for intramuscular administration,
in quality of life. See Table 462 for a listing of the various agents and the side effects of hypoestrogenism (e.g., vaginal dryness
used in the management of this disorder, their recommended and hot ashes) limit its use.
dosing, and common side effects. A randomized, double-blind, placebo-controlled trial evalu-
ating the use of a monophasic OC containing 30 mcg ethinyl
estradiol and 3 mg drospirenone, a progesterone with anti-
Nonpharmacologic Therapy androgenic effects, showed improvement in the treatment
It is recommended that lifestyle interventions be started and arm compared with placebo.31 In particular, appetite, food
followed for 2 months while the patient charts her symptoms. cravings, and acne improved. However, active treatment was
While these interventions lack signicant supporting clinical not associated with a statistically signicant improvement in
trial data, anecdotal reports do exist. Some lifestyle changes for the overall outcome measure, the Calendar of Premenstrual
women suffering from mild to moderate premenstrual symp- Experiences (COPE) scale, perhaps because of the small sample
toms include minimizing caffeine, rened sugar, and sodium size (n = 82).
intake and increasing exercise.26 Vitamin and mineral sup-
plements such as vitamin B6 (50100 mg/day) and calcium
carbonate (1200 mg/day) have been observed anecdotally to OUTCOME EVALUATION
help reduce the physical symptoms associated with PMS.26
A review of clinical trials, however, supports that none of Measure the treatment success for the various menstruation-
the following options should be recommended because of a related disorders by the degree to which the care plan (1) relieves
lack of evidence for safety and efcacy: herbal medicines, or reverses symptoms of the disorder, (2) prevents or reverses
homeopathic remedies, dietary supplements, relaxation, the complications of the disorder (e.g., osteoporosis, anemia,
massage therapy, reexology, chiropractic treatments, and and infertility), and (3) minimizes side effects. The return of a
biofeedback.37 regular menstrual cycle with minimal premenstrual symp-
toms or symptoms of dysmenorrhea should occur. Depending
on the desire for conception and subsequent therapy, this
cycle may be ovulatory or anovulatory.
If symptoms continue after 2 months of symptom charting Assess the effectiveness of therapy in resuming normal men-
and attempting lifestyle modications, pharmacologic ther- strual cycles with minimal related pain after an appropriate
apy may be considered for the management of diagnosed treatment interval (12 months). Assess improvement in quality-
PMDD. of-life measures such as physical, psychological, and social func-
The rst-line therapeutic options for PMDD include the tioning and well-being. Evaluate the patient for adverse drug
selective serotonin reuptake inhibitors (SSRIs) such as uoxe- reactions, drug allergies, and drug interactions. Table 462
tine, uvoxamine, sertraline, paroxetine, and citalopram. These illustrates the common side effects that may occur for which
agents can be given either continuously or only during the monitoring is required. Table 463 illustrates the specic
luteal phase of the menstrual cycle, i.e., initiated at the time of expected outcome measures for each of the menstruation-related
ovulation and discontinued on the rst day of menses. disorders discussed in this chapter.
TABLE 463. Expected Outcome Measures for Select Menstrual

Bleeding Disorders8,10,11,15,18,20,22,33,36 Patient Care and Monitoring
Menstrual
Disorder Expected Outcome Measures
Amenorrhea Efcacy: Normal breast development 1. Assess symptoms to determine if patient-directed therapy
(especially primary amenorrhea in is appropriate (e.g., NSAIDs for dysmenorrhea) or
adolescents) preservation/improvement whether the patient should be evaluated by a physician
of BMD; return of menses. (e.g., amenorrhea, menorrhagia, anovulatory bleeding,
Time to relief/effect: Menses should or PMDD). Does the patient have any related complica-
occur within 12 months of therapy. tions, such as symptoms of anemia in patients present-
Menorrhagia Efcacy: Decline in the amount of blood ing with menorrhagia or complaints of difculty con-
lost with menses (monitor a decline in ceiving in women with amenorrhea or anovulatory
the number of times feminine hygiene bleeding.
products such as pads and tampons
require changing during menses); 2. Review any available diagnostic data, as appropriate,
monitor for an increase in to determine hormonal, reproductive, and pregnancy
hemoglobin/hematocrit if anemia status.
was present as a result of 3. Obtain a thorough history of prescription, non-
menorrhagia.
prescription, and natural drug product use. Determine
Time to relief/effect: A decline in
menstrual blood loss should be
which treatments have been helpful to the patient in the
realized within 12 cycles of therapy past.
being initiated. 4. Educate the patient on lifestyle modications that will
Anovulatory Efcacy: Alleviation of acute bleeding improve symptoms and prevent complications.
bleeding when present; ovulation and 5. Is the patient taking the appropriate dose of the pre-
subsequent pregnancy in women scribed medication? If not, why not?
desiring this; reduced risk of developing
the long-term complications of, for 6. Develop a plan to assess effectiveness of the prescribed
example, PCOS (e.g., diabetes and medication after 1 to 2 months of therapy.
cardiovascular disease); improved 7. Determine if long-term maintenance treatment is
quality of life. necessary.
Time to relief/effect: The acute treatment
of heavy bleeding should result in a 8. Assess improvement in quality-of-life measures such as
decline in bleeding within 10 days of physical, psychological, social functioning and well-
therapy onset; the return of ovulation being.
may require several months of therapy; 9. Evaluate for adverse drug reactions, drug allergies, and
when OCs are used, control of abnormal
drug interactions.
bleeding can be expected within 12
cycles of therapy. 10. Stress the importance of adherence with the therapeutic
Dysmenorrhea Efcacy: Reduction in/absence of pelvic regimen, including lifestyle modications. Recommend
pain related to menses; reduction in a therapeutic regimen that is easy for the patient to
time lost from work/school; improved adhere to.
quality of life. 11. Provide patient education regarding disease state,
Time to relief/effect: Improvement in lifestyle modications, and drug therapy by noting the
pain may be observed within hours of
following:
NSAID therapy; improvement with
What causes the menstruation-related disorder?
other options such as OCs may be
observed after a full 13 cycles of What are the possible complications of the
their use. menstruation-related disorder?
What lifestyle modications may help to reduce the
PMDD Efcacy: Reduction in/absence of initial
symptoms; improved quality of life. risk associated with these complications?
Time to relief/effect: Improvements may When and how should patients take their
be observed within 13 cycles of medications?
therapy. What potential adverse effects may occur?
Which drugs may interact with their therapy?
BMD, bone mineral density; NSAID, non-steroidal anti-inammatory
drug; OCs, oral contraceptives; PCOS, polycystic ovary syndrome;
PMDD, premenstrual dysphoric disorder.
CBC: complete blood count American College of Obstetricians and Gynecologists. Management
CEE: Conjugated equine estrogen of anovulatory bleeding. ACOG Practice Bulletin number 14.
CNS: central nervous system Obstet Gynecol 2000; March: 19.
COPE: calendar of premenstrual experiences American College of Obstetricians and Gynecologists. Polycystic
FSH: follicle-stimulating hormone ovary syndrome. ACOG Practice Bulletin number 41. Obstet
GABA: -aminobutyric acid Gynecol 2002; 100:1389402.
GnRH: gonadotropin-releasing hormone French L. Dysmenorrhea. Am Fam Physician 2005; 71(2):285290.
HCG: human chorionic gonadotropin Gordon CM, Nelson LM. Amenorrhea and bone health in adoles-
HPA: hypothalamic-pituitary-adrenal cents and young women. Curr Opin Obstet Gynecol 2003; 15:
HPO: hypothalamic-pituitary-ovarian 377384.
IUD: intrauterine device Guzick DS. Polycystic ovary syndrome. Obstet Gynecol 2004; 103(1):
LH: luteinizing hormone 181193.
MDD: major depressive disorder Ross LE, Steiner M. A biopsychosocial approach to premenstrual
MPA: medroxyprogesterone acetate dysphoric disorder. Psychiatr Clin North Am 2003; 26(3):
NSAID: non-steroidal anti-inammatory 529546.
drug Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop
OC: oral contraceptive Group. Revised 2003 consensus on diagnostic criteria and long-
PCOS: polycystic ovarian syndrome term health risks related to polycystic ovary syndrome. Fertil
PID: pelvic inammatory disease Steril 2004; 81(1):1925.
PMDD: premenstrual dysphoric disorder Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility.
PMS: premenstrual syndrome 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005.
SHBG: sex hormonebinding globulin Stenchever MA, Droegemueller W, Herbst AL, Mishell DR. Abnormal
SSRI: selective serotonin reuptake inhibitor uterine bleeding: Ovulatory and anovulatory dysfunctional uterine
TENS: transcutaneous electrical nerve bleeding, management of acute and chronic excessive bleeding. In:
stimulation Stenchever MA, ed. Comprehensive Gynecology. 4th ed. St. Louis:
Mosby; 2001: 10791097.
Reference lists and self-assessment questions and answers are Stenchever MA, Droegemueller W, Herbst AL, Mishell DR. Primary and
available at www.ChisholmPharmacotherapy.com. secondary dysmenorrhea and premenstrual syndrome: Etiology,
diagnosis, and management. In: Stenchever MA, ed. Comprehensive
Log into the website: www.pharmacotherapyprinciples.com Gynecolgy. 4th ed. St. Louis: Mosby; 2001: 10651078.
this chapter.
47 HORMONE-REPLACEMENT
THERAPY IN MENOPAUSE
Nicole S. Culhane and Melissa A. Somma
LEARNING OBJECTIVES
1. Explain the pathophysiologic changes associated with menopause.

2. Identify the signs and symptoms associated with menopause.
3. Determine the desired therapeutic outcomes for a patient taking hormone-replacement
therapy.
4. Explain how to evaluate a patient for the appropriate use of hormone-replacement therapy.
5. Recommend nonpharmacologic therapy for menopausal symptoms.
6. List the adverse effects of and contraindications to hormone-replacement therapy.
7. Differentiate between topical and systemic forms of hormone-replacement therapy.
8. Explain the risks and benets associated with hormone-replacement therapy.
9. Educate a patient regarding the proper use and potential adverse effects of hormone-
10. Monitor a patient taking hormone-replacement therapy for efcacy and toxicity.
11. Recognize that alternative, non-hormonal therapies for menopausal symptoms exist and
should be considered in some circumstances for women unable to take hormone-
KEY CONCEPTS breast cancer, hormone-replacement therapy would be an

appropriate therapy option.
Common symptoms of menopause include hot ashes, night Oral or transdermal estrogen products should be prescribed
sweats, vulvovaginal atrophy, and vaginal dryness. Women at the lowest effective dose for the relief of vasomotor symp-
less commonly may experience mood swings, depression, toms. Topical products in the form of creams, tablets, or rings
insomnia, arthralgia, myalgia, and urinary frequency. should be prescribed for women exclusively experiencing vul-
Hormone-replacement therapy remains the most effective vovaginal atrophy.
treatment for vasomotor symptoms and vulvovaginal atrophy Women who have an intact uterus should be prescribed a
and should be considered for women experiencing these progestin in addition to estrogen in order to decrease the risk
symptoms. of endometrial hyperplasia and endometrial cancer.
Women should receive a thorough history and physical exam- Hormone-replacement therapy is also indicated for the pre-
ination, including assessing coronary heart disease (CHD) vention of osteoporosis but is not recommended for long-
and breast cancer risk factors, before hormone-replacement term use. Alternatives such as bisphosphonates or raloxifene
therapy is considered. Patients should be informed of the should be considered as rst-line therapy for the prevention
risks and the benets of hormone-replacement therapy and of osteoporosis, in addition to appropriate doses of calcium
should be encouraged to be involved in the decision-making and vitamin D.
process. If a woman does not have any contraindications to Combined estrogen plus progestin should not be used in the
hormone-replacement therapy, including CHD or signicant prevention of chronic diseases because it increases the risk of
CHD risk factors, and also does not have a personal history of CHD, stroke, breast cancer, and venous thromboembolism.
765
However, colorectal cancer and rates of fracture were reduced

with combined hormonal treatment. Patient Encounter, Part 1
Hormone-replacement therapy improves overall well-being
and mood in women with vasomotor symptoms but has not
demonstrated an improvement in quality of life in women BW, a 50-year-old woman with a history of osteoarthritis and
without vasomotor symptoms. hypothyroidism, presents to the clinic complaining of hot
In appropriate women, hormone-replacement therapy should ashes, vaginal dryness, and insomnia. She states that she
be recommended at the lowest dose for the shortest duration experiences approximately two hot ashes per day and is
and should be tapered before discontinuation in order to pre- awakened from sleep at least three to four times a week in a
pool of sweat requiring her to change her clothes and bed
vent the recurrence of hot ashes.
linens. Her symptoms began about 3 months ago, and over
Since the publication of the Womens Health Initiative study,
that time, they have worsened to the point where they have
there has been an increase in the use of non-hormonal become very bothersome. On questioning, she states her last
therapies for the management of menopausal symptoms. menstrual period was 1 year ago.
Particularly for women with CHD and breast cancer risk fac-
tors, non-hormonal therapies may offer an alternative to Which of the patients symptoms and past medical history
assist with symptom management. A wide range of therapies, are consistent with menopause?
both prescription and herbal, have been studied with varying What laboratory value(s) will help to conrm the diagnosis
degrees of success. In choosing a particular therapy, it is of menopause?
important to match patient symptoms with a therapy that is What additional information do you need to know in order
not only effective but also safe. to make an appropriate therapeutic plan for this patient?
Menopause is the permanent cessation of menses owing to

a loss of ovarian follicular function. The diagnosis of rather could increase the risk in women with underlying CHD
menopause is primarily a clinical one and is made after a risk factors. The risk of breast cancer also was increased after a
women experiences amenorrhea for 12 consecutive months. woman was on therapy for approximately 3 years. As a result of
The loss of ovarian follicular activity leads to an increase in this study, the Food and Drug Administration (FDA) issued a
follicle-stimulating hormone (FSH), which, on laboratory statement that combined HRT should not be initiated or con-
examination, may help to conrm the diagnosis. tinued for the primary prevention of CHD.3
Many women seek medical treatment for the relief of This series of trials, and many more, has led to the dramatic
menopausal symptoms, primarily hot ashes; however, the change in how HRT is currently prescribed and greater under-
role of hormone-replacement therapy (HRT) has changed standing of the associated risks. HRT, once thought of as a cure-
dramatically over the years. HRT has long been prescribed for all for menopausal symptoms, is now a therapy that should be
relief of menopausal symptoms and, until recent years, has used only to reduce the frequency and severity of vasomotor
been purported to protect women from CHD. The original symptoms associated with menopause in women without risk
reason behind recommending HRT in postmenopausal factors for CHD or breast cancer. The changes that have occurred
women revolved around a simple theory: If the hormones lost over the years in the use of HRT further support the importance
during menopause were replaced through drug therapy, of evidence-based practice and judicious medication use.
women would be protected from both menopausal symptoms
and chronic diseases that often follow after a woman experi-
ences menopause. Recent studies have disproved this theory. EPIDEMIOLOGY AND ETIOLOGY
As of 1995, almost 38% of all women 50 to 75 years of age were
using HRT.1 It was in 1996 that the United States Preventive Menopause is a period of time in a womans life marked by the
Services Task Force (USPSTF) rst published its recommenda- cessation of menses. It occurs in all women either naturally or
tions that not all postmenopausal women should be prescribed surgically and usually occurs between the ages of 40 and 58 years.
HRT, but rather, therapy should be individualized based on risk The median age for a woman to experience menopause is 52 years.
factors. This recommendation was further supported with pub- However, women who have undergone a total abdominal
lication of the Heart and Estrogen/Progestin Replacement Study hysterectomy (surgical menopause) generally experience
(HERS) in 1998, which demonstrated that women who had menopause earlier compared with women who experience
established CHD were at an increased risk of experiencing a natural menopause. Some other factors that may be associated
myocardial infarction within the rst year of HRT use compared with early menopause include low body weight, increased
with a similar group of women without CHD risk factors. As a menstrual cycle length, nulliparity, and smoking. Smokers
result, the authors concluded that HRT is not recommended for generally experience menopause approximately 2 years earlier
the secondary prevention of CHD.2 Then, in 2002, the Womens than non-smokers.4
Health Initiative (WHI) report was published. This trial The usual transitional period prior to menopause,
demonstrated that HRT was not protective against CHD but known as perimenopause or the climacteric, is a period
CHAPTER 47 / HORMONE-REPLACEMENT THERAPY IN MENOPAUSE 767
when hormonal and biologic changes begin to occur. These

changes may begin 2 to 8 years prior to menopause and even- Patient Encounter, Part 2: Medical
tually lead to irregular menstrual cycles, an increase in cycle History, Physical Examination, and
interval, and a decrease in cycle length. During this time, Diagnostic Tests
women also may experience physical symptoms similar to
BWs work-up reveals the following additional information:
menopausal symptoms, primarily vasomotor symptoms, and
they may require treatment depending on symptom severity.4,5 PMH
Osteoarthritis of the lower back for 5 years controlled on
Because the perimenopausal and postmenopausal periods
acetaminophen 500 mg two tablets PO 3 to 4 times daily
are marked by many biologic and endocrinologic changes, Hypothyroidism since age 25, currently controlled
women should inform their health care provider when they
FH
experience any signs and symptoms in order to discuss the
Father: Alive with HTN and CHD (MI at age 60)
most appropriate therapeutic approach. Mother: Alive with hypothyroidism and GERD
Siblings: Two sisters alive and well
PATHOPHYSIOLOGY SH
Occupation: nurse
Reproductive physiology is regulated primarily by the Non-smoker
hypothalamic-pituitary-ovarian axis. The hypothalamus Drinks one to two glasses of red wine with dinner on the
secretes gonadotropin-releasing hormone (GnRH), which weekends
Denies illicit drug use
stimulates the anterior pituitary to secrete follicle-stimulating
hormone (FSH) and luteinizing hormone (LH). FSH and LH Meds
regulate ovarian function and stimulate the ovary to produce Acetaminophen 500 mg two tablets PO 3 to 4 times daily
Synthroid 0.075 mg PO once daily
sex steroids. These hormones are inuenced by a negative-
Multivitamin PO once daily
feedback system and will increase or decrease based on the
levels of estradiol and progesterone. ROS
(+) hot ashes, night sweats, vaginal dryness and itching; ()
The pathophysiologic changes that occur during the peri-
insomnia, myalgias, bowel changes, weight gain, constipation
menopausal and menopausal periods are caused by the
decrease and eventual loss of ovarian follicular activity. As PE
VS: BP 128/82, P 78, RR 16, T 37.0C (98.6F), weight
women age, the number of ovarian follicles decreases, and the
164 lb (74.5 kg)
remaining follicles require higher levels of FSH for maturation HEENT: WNL
and ovulation. During perimenopause, FSH concentrations Neck: Supple; no bruits, no adenopathy, no thyromegaly
Breasts: Supple; no masses
CV: RRR, normal S1 and S2; no murmurs, rubs, or gallops
Clinical Presentation and Diagnosis Abd: Soft, non-tender, non-distended; (+) BS, no masses
Genitourinary: Pelvic examination normal except (+)
mucosal atrophy
Labs
Menopausal Symptoms FSH 76 mIU/mL
Vasomotor symptoms (hot ashes, night TSH 2.5 mIU/L
sweats) Chem-7: Na 135 mEq/L (135 mmol/L), K 4.5 mEq/L
Irregular menses (4.5 mmol/L), Cl 109 mEq/L (109 mmol/L), CO2 25 mEq/L
Episodic amenorrhea (25 mmol/L), BUN 9 mg/dL (3.21 mmol/L), SCr 0.9 mg/dL
Sleep disturbances (80 mmol/mol per liter), Glucose 98 mg/dL (5.44 mmol/L)
Mood swings CBC: Hgb 13 g/dL (130 g/L or 8.06 mmol/L), Hct 39% (0.39
Vaginal dryness volume fraction), WBC 5.5 103/mm3 (5.5 103/L or 5.5
Depression 109/L), platelets 234 103/mm3 (234 103/L or 234 109/L)
Fasting lipid levels: TC 232 mg/dL (6 mmol/L), LDL 145
Less Common Symptoms mg/dL (3.76 mmol/L), HDL 45 mg/dL (1.17 mmol/L), TG
Fatigue 200 mg/dL (2.26 mmol/L)
Irritability
Migraine Assess the patients condition based on this additional
Arthralgia information.
Myalgia What are the goals of treatment for this patient?
Assess the patients risk factors for heart disease and breast
Diagnosis
cancer.
Amenorrhea for 1 year
Recommend nonpharmacologic and pharmacologic treat-
FSH greater than 40 mIU/mL
ment for this patient. Justify your recommendations.
Five-fold increase in LH
rise during some menstrual cycles but can fall again during HRT, but they are less efcacious than hormonal therapies.
subsequent menstrual cycles, leading to irregular and unpre- Alternative treatments should be chosen based on the ef-
dictable menses. During menopause, FSH concentrations cacy and safety prole of the treatment and the patients
increase 10- to 15-fold, LH concentrations increase 5-fold, and past medical history and current medications.
levels of circulating estradiol decrease by over 90%.6
Vasomotor symptoms, as well as other menopausal symp- Nonpharmacologic Therapy
toms, occur in over 50% of perimenopausal women and over
80% of menopausal women.5 Menopausal symptoms tend to Nonpharmacologic therapies for menopause-related symp-
be more severe in women who undergo surgical menopause toms have not been studied in large randomized trials, and evi-
compared with natural menopause because of the more rapid dence of benet is not well documented. Owing to minimal
decline in estrogen concentrations. Women who seek medical adverse effects with these types of interventions, it may be pru-
treatment should undergo laboratory evaluation to rule out dent for patients to try lifestyle or behavioral modications
other conditions that may present with similar symptoms, before and in addition to pharmacologic therapy. The most
such as abnormal thyroid function or pituitary adenoma. common nonpharmacologic interventions for vasomotor
Once other conditions have been excluded, HRT should be symptoms include4,7,8
considered.
Smoking cessation
Limit alcohol and caffeine
TREATMENT Limit hot beverages (e.g., coffee/tea, soups)
Limit spicy foods
Desired Outcomes Keep cool, and dress in layers
Stress reduction (e.g., meditation, relaxation exercises)
Hormone-replacement therapy remains the most effective Increase exercise
treatment for vasomotor symptoms and vulvovaginal atrophy Paced respiration
and should be considered for women experiencing these symp-
toms. The goals of treatment are to alleviate or reduce Exercise demonstrated an improvement in quality of life
menopausal symptoms and to improve the patients quality of but did not improve vasomotor symptoms. Paced respiration,
life while minimizing adverse effects of therapy. The appropriate a form of deep, slow breathing, improved vasomotor symp-
route of administration should be chosen based on individual toms in a small group of patients.
patient symptoms and should be continued at the lowest dose Dyspareunia may result from vaginal dryness. Water-
for the shortest duration consistent with treatment goals for based lubricants may provide relief for several hours after
each patient. application. Moisturizers may provide relief for a longer
period of time and potentially can prevent infections by main-
General Approach to Treatment taining the acidic environment in the vagina. Both these treat-
ments require frequent application.
Women suffering from vasomotor symptoms should A decline in estrogen concentrations also may be associated
attempt lifestyle or behavioral modications before seeking with urinary stress incontinence. Kegel exercises are recom-
medical treatment. Women who seek medical treatment mended as a rst-line intervention, although pharmacologic
usually suffer from symptoms that start to disrupt their therapy also may be necessary. Kegel exercises strengthen the
quality of life, such as multiple hot ashes per day or week, pelvic oor muscles and help to keep the urethra from opening
sleep disturbances, vaginal dryness, or mood swings. HRT at inappropriate times, such as when lifting heavy objects,
should be considered for these women but is not the most coughing, or sneezing. These exercises have no adverse
appropriate choice for all women. Women should receive effects, take little time, may be done inconspicuously, and
a thorough history and physical examination, including when done correctly, may help to restore normal urine ow.
assessing CHD and breast cancer risk factors, before HRT is
considered. Patients should be informed of the risks and the
benets of HRT and encouraged to be involved in the decision-
making process. If a woman does not have any contraindica- Estrogens
tions to HRT, including CHD or signicant CHD risk factors, Estrogen currently is indicated for the treatment of moderate
and also does not have a personal history of breast cancer, to severe vasomotor symptoms and vulvovaginal atrophy asso-
HRT would be an appropriate therapy option. Women who ciated with menopause. In addition, it is indicated for the pre-
have undergone a hysterectomy need only be prescribed vention of postmenopausal osteoporosis in women with sig-
estrogen. A progestin should be prescribed only for women nicant risk; however, it is recommended that non-estrogen
with an intact uterus. Alternative, non-hormonal treatment medications receive consideration for long-term use. Oral or
options are available for women who are not candidates for transdermal estrogen products should be prescribed at the lowest
effective dose for the relief of vasomotor symptoms. Topical prod- TABLE 471. Estrogen and Progestin Formulations and
ucts in the form of creams, tablets, or rings should be prescribed for Dosages11,4144
women exclusively experiencing vulvovaginal atrophy.
Product Common Dosages
Many systemically administered estrogen products are
available in the United States, but conjugated equine estro- Oral Estrogens
Conjugated equine estrogens (CEE) 0.30.625 mg/day
gens (CEEs), prepared from the urine of pregnant mares, is
(Premarin)
the most widely prescribed. Transdermal estrogen prepara- Synthetic conjugated estrogens 0.30.625 mg/day
tions are also available and usually are prescribed for (Cenestin)
patients who experience adverse effects, elevated triglyc- Esteried estrogens (Estratab) 0.30.625 mg/day
erides, or liver function abnormalities while taking an oral Estradiol (Estrace) 0.51 mg/day
product. Transdermal preparations also have a lower inci- Estropipate (Ogen, Ortho-Est) 0.625 mg/day
dence of venous thromboembolism than oral preparations.9 Transdermal Estrogens
Estradiol patch
Progestins (Alora, Climara, Esclim, 0.0250.05 mg, changed
Estraderm, FemPatch, Vivelle) weekly (Climara) or
Women who have an intact uterus should be prescribed a changed twice
progestin in addition to estrogen in order to decrease the risk of weekly
endometrial hyperplasia and endometrial cancer.10 Progestins Menostara 0.014 once weekly
should be prescribed for at least 12 to 14 days of the month and Estradiol gel (Estragel 0.06%) 1.25g/day
often are prescribed continuously in order to completely prevent Topical Estrogens
endometrial complications. Low doses of estrogen therapy, as Vaginal creams
well as some forms of vaginal preparations, require daily or inter- Conjugated equine estrogens 0.52g/day
(Premarin)
mittent administration of a progestin in order to provide
Estradiol (Estrace) 1 g 13 times/week
endometrial protection. Table 471 lists estrogen and progestin Estropipate (Ortho-Est) 24 g/day
preparations and dosages. Vaginal rings
Estradiol (Estring, Femring) 1 ring every 3 months
Adverse Effects Vaginal tablet
Estradiol (Vagifem) 1 tablet 2 times/week
Therapy with estrogen with or without a progestin should be Emulsions
initiated at the lowest dose in order to minimize adverse Estradiol (Estrasorb) Apply daily
effects. Because the adverse effects of these preparations can b,c
Oral Progestins
be similar, it may be difcult to assess whether the estrogen or Medroxyprogesterone acetate 2.510 mg
the progestin is the cause. Changing preparations, particularly (Provera)
with the progestin, or changing the method of administration Micronized progesterone 100200 mg
may help to alleviate adverse effects. Table 472 lists the Transdermal Progestins b,c
adverse effects that may be associated with estrogen and prog- Levonorgestrel 0.015 mg
estin preparations. Norethindrone acetate 0.251 mg
Norgestimate 0.09 mg
Contraindications Combination Products
HRT should not be prescribed to women with a history of or Oral
CEE + MPA (Prempro, 0.30.625/2.55 mg/day
active thromboembolic disease, breast cancer or estrogen- Premphase)
dependent neoplasm, pregnancy, liver disease, or undiagnosed Estradiol + norethindrone 1/0.5 mg/day
vaginal bleeding. It also should not be used for the prevention or (Activella)
treatment of cardiovascular disease, cerebrovascular disease, or Ethynyl estradiol + norethindrone 5 mcg/1 mg/day
dementia.11 (FemHRT)
Estradiol + norgestimate 1/0.09 mg/day
(Ortho-Prefest)
Methods of Administration Transdermal
Estradiol + norethindrone 0.05/0.14 or 0.05/0.25
Cyclic Estrogen and Progestin (Combipatch) mg twice weekly
Estradiol + levonorgestrel 0.45/0.015 mg once
Estrogen is administered daily, and progestin is administered
(Climara Pro) weekly
for 12 to 14 days of the month. The disadvantage of this
a
method of administration is the return of monthly menses in Indicated for the prevention of postmenopausal osteoporosis only.
b
May be administered cyclically or continuously.
approximately 90% of women 1 to 2 days following the last c
Dose varies based on daily or weekly administration.
progestin dose. However, the withdrawal bleeding does not MPA, medroxyprogesterone acetate.
last as long or is not as heavy as a typical menstrual period.
Women also may view this disadvantage as an advantage
TABLE 472. Adverse Effects of Estrogens and HRT on the incidence of venous thromboembolism, breast
Progestins11,41,44,45 cancer, or CHD. Lower-dose HRT provides women with an
alternative to standard-dose HRT for menopausal symptoms
Estrogens
Common adverse effects
but also should be recommended only for a short duration.
Nausea
Although many women have switched to lower-dose HRT,
Headache only time will tell if lower doses translate into lower risks.
Bloating
Breast tenderness Benets of Hormone-Replacement Therapy
Bleeding
Serious adverse effects
Vasomotor Symptoms
Coronary heart disease
Stroke
HRT is indicated primarily for the relief of moderate to severe
Venous thromboembolism vasomotor symptoms. It remains the most effective treatment for
Breast cancer vasomotor symptoms and should be considered only in women
Gallbladder disease experiencing those symptoms. Women with mild vasomotor
Progestins symptoms may benet from nonpharmacologic therapy alone;
Common adverse effects however, many women will seek medical treatment for these
Nausea symptoms. The benets of HRT outweigh the risks in women
Headache
who do not have CHD or CHD and breast cancer risk factors;
Weight gain
Bleeding however, careful consideration should be given to alternative
Irritability therapies for the relief of menopausal symptoms in women with
Depression these risks. Women should be involved in the decision and
Serious adverse effects may choose to use HRT despite having some risk factors
Venous thromboembolism owing to the severity of their symptoms. Regardless of the sit-
Decreased bone mineral density uation, HRT should be prescribed at the lowest dose that relieves
or reduces menopausal symptoms and should be recommended
because the bleeding is scheduled and can be anticipated, only for short-term use. Women should be reassessed every
thus limiting spotting or soiling of undergarments. 6 to 12 months, and discontinuation of therapy should be
considered.
Continuous Combined Estrogen and Progestin
Estrogen and progestin are administered daily and result in Vulvovaginal Atrophy
endometrial atrophy. Therefore, women do not experience a HRT is indicated for the treatment of vulvovaginal atrophy.
withdrawal bleed but may experience unanticipated break- Approximately 50% of postmenopausal women experience vul-
through bleeding or spotting during the month. Although this vovaginal atrophy and seek medication attention for relief.
may sound more appealing than a withdrawal bleed, women Vulvovaginal atrophy is associated with vaginal dryness and dys-
may view the unpredictable bleeding or spotting as a disad- pareunia and also may be associated with recurrent urinary tract
vantage to this type of administration. Patients should be edu- infections, urethritis, and urinary urgency and frequency. Topical
cated that the bleeding or spotting usually resolves within 6 to preparations generally should be prescribed as rst-line therapy
12 months. If bleeding persists beyond this time period, unless the patient is also experiencing vasomotor symptoms.
patients should seek medical attention to rule out more serious Topical estrogen has demonstrated increased efcacy over sys-
conditions such as endometrial hypertrophy or carcinoma. temic estrogen and does not require supplementation with a
progestin in women with an intact uterus using low doses of
Low-Dose Hormone Therapy micronized 17-estradiol. Women using regular or high doses of
Lower doses of HRT, primarily CEE, have become more other topical estrogen products do require intermittent treat-
popular following publication of the WHI study results. There ment with a progestin. Although few data are available on the
is an increasing body of evidence proving the effectiveness appropriate progestin dose, some data indicate that 10 days every
of these regimens in the management of menopausal symp- 12 weeks may be sufcient to prevent endometrial hyperplasia.16
toms. The Womens Health, Osteoporosis, Progestin/Estrogen Estradiol in the form of a tablet or a ring is not absorbed system-
(HOPE) trial demonstrated that lower doses of CEE ically and may be used safely in a woman with contraindications
medroxyprogesterone acetate (MPA) (CEE 0.45 mg or 0.3 mg to estrogen therapy and symptoms of vulvovaginal atrophy.17,18
MPA 2.5 or 1.5 mg) decreased hot ashes comparable
with standard hormone therapy, improved vulvovaginal Osteoporosis Prevention
atrophy, increased bone mineral density (BMD) at the spine Postmenopausal osteoporosis is a condition that affects mil-
and hip, and provided sufcient endometrial protection.1215 lions of women and is characterized by low bone mass with
Currently, no data are available on the effects of lower-dose microarchitectural deterioration of bone tissue that can
FIGURE 471. Treatment algorithm for postmenopausal women.3,41,50

lead to fractures.19 Fractures, particularly hip fractures, are of CHD death in years 3 to 5 that prompted a continuation of
associated with a high incidence of morbidity and mortality the study.2 The HERS II was an open-label continuation of the
and a decrease in quality of life (QOL). Before the WHI study, HERS for an additional 2.7 years. No difference was found in
only observational data were available regarding the associa- CHD events between the HRT and placebo groups; however,
tion of HRT and the reduction of fractures. The WHI was the there was an increased risk of VTE and biliary tract surgery in
rst randomized controlled trial (RCT) that demonstrated a the HRT group.22
reduction in total fractures, including the hip, spine, and wrist. The WHI was the rst RCT conducted in women without
There were 138 fewer total fractures in women taking HRT established CHD. Women aged 50 to 79 years with an intact
(1.47%) compared with placebo (1.91%) [Hazard ratio (HR) uterus were assigned to receive HRT (CEE 0.625 mg + MPA
0.76, 95% condence interval (CI) 0.690.85]. This translates 2.5 mg) daily for 8.5 years. The trial was stopped after only
into a number needed to treat (NNT) of 227 and 44 fewer 5.2 years owing to an increased incidence of breast cancer in
overall fractures per year for every 10,000 women treated with women taking HRT compared with placebo. The WHI
HRT.3,20 Similar benet was found in the estrogen-alone arm.21 demonstrated an increased risk of CHD within the rst year
BMD will increase and the risk of fractures will decrease in of treatment of 0.37% in the HRT group compared with 0.3%
women taking HRT. However, when therapy is discontinued, in the placebo group (HR 1.29, 95% CI 1.021.63). This trans-
a decline in BMD will resume at the same rate as in women lates into a number needed to treat to harm (NNTH) of 1428.
not on HRT. Therefore, therapy for osteoporosis prevention There also was an increased risk of stroke in the HRT group
should be considered long term. Since HRT should be (0.29%) compared with placebo (0.21) (HR 1.41, 95% CI
maintained only for the short term, alternative therapies such as 1.071.85), with an NNTH of 1250. Therefore, for every
bisphosphonates or raloxifene should be considered as rst-line 10,000 women treated per year with HRT, there would be 7
therapy for the prevention of postmenopausal osteoporosis, in more CHD deaths and 8 more strokes.3
addition to appropriate doses of calcium and vitamin D. The estrogen-alone arm of the WHI, which included
Because of the risks associated with HRT, it should not be women aged 50 to 79 years with a history of hysterectomy,
prescribed solely for the prevention of osteoporosis. continued for another 1.6 years (average follow-up 6.8 years).
This arm of the study did not demonstrate an increased risk
of CHD in the ERT group compared with placebo. However,
Colon Cancer
there was an increased risk of stroke in the ERT group
Retrospective observational studies suggested that HRT was
(0.44%) compared with placebo (0.32%) (HR 1.39, 95% CI
associated with lower rates of colorectal cancer. The WHI was
1.101.77). This translates into an NNTH of 833 and 12 more
the rst and largest RCT to conrm that HRT decreases the
strokes for every 10,000 women treated per year with ERT.21
risk of colorectal cancer. In the WHI, there were 22 fewer cases
The results of these trials demonstrate that ERT or HRT
of colorectal cancer in women taking HRT (0.1%) compared
should not be prescribed for the prevention of CHD or in
with placebo (0.16%) (HR 0.63, 95% CI 0.430.92). This
patients with preexisting CHD. For women suffering from
translates into an NNT of 1666 and 6 fewer colorectal cancers
vasomotor symptoms with a history of CHD, including CHD
per year for every 10,000 women treated with HRT.3 In the
risk factors, alternative therapies should be considered.
WHI estrogen-alone arm, the cases of colorectal cancer were
Additionally, lifestyle modications should be implemented,
not lower in the estrogen group compared with the placebo
and therapies to treat risk factors such as hypertension and
group.21 Unfortunately, these data are inconsistent and are not
hyperlipidemia should be prescribed. It is important to note
compelling enough to justify long-term use of estrogen-
that the average age of women included in the HERS and the
replacement therapy (ERT) or HRT.
WHI trials was 67 and 63 years, respectively. Therefore, these
trials were unable to assess the true risk in younger, potentially
Risks of Hormone-Replacement Therapy
healthier women with fewer cardiovascular risk factors.
Cardiovascular Disease
CHD is the leading cause of death among women in the Breast Cancer
United States. Retrospective data indicated that HRT was Breast cancer is the most common cancer in women in the
associated with a decrease in risk of CHD by 30% to 50%.21 United States. Observational data indicated an association
However, the results of recent RCTs demonstrate that HRT between HRT and breast cancer risk. The WHI was the rst
does not prevent or treat CHD in women and that it actually RCT to demonstrate an increased risk of invasive breast can-
may cause an increase in CHD events. The HERS, published cer among women taking HRT. In fact, the trial was stopped
in 1998, was the rst RCT conducted in women with estab- early owing to an increased incidence of breast cancer in
lished CHD. This trial demonstrated an increased incidence of women taking HRT (0.38%) compared with placebo (0.3%)
CHD events within the rst year of treatment with HRT and (HR 1.26, 95% CI 11.59). This translates into an NNTH of
an increased risk of venous thromboembolism (VTE) and 1250 and 8 more cases of invasive breast cancer for every
gallbladder disease. There was a trend of decreasing incidence 10,000 women treated per year with HRT. The risk of breast
cancer was evident after only 3 years of treatment and contin- with vasomotor symptoms, HRT should not be prescribed for
ued throughout the study duration. In this arm of the study, the sole purpose of improving QOL measures.
breast cancer was diagnosed at a more advanced stage in the The prevalence of age-associated memory impairment is
HRT group compared with placebo. In addition, the per- approximately 17% to 34% in the general population.26
centage of women with abnormal mammograms after 1 year Observational studies have suggested a potential benet of
was signicantly higher in women taking HRT than in those HRT on cognitive functioning and dementia. However, the
taking a placebo.3,23 WHI Memory Study (WHIMS), conducted in postmenopausal
Breast cancer was not increased in the ERT arm of the women aged 65 years or older, failed to demonstrate an
WHI, and in fact, the risk was non-signicantly lower in the improvement in cognitive function and demonstrated a
ERT group than in the placebo group.21 These conicting data dementia rate, including Alzheimers disease, two times greater
point to a possible link of progestin with breast cancer risk; than with placebo (HR 2.05, 95% CI 1.213.48). In addition,
however, this theory needs to be studied further. women receiving HRT experienced a small decline in cognitive
Because the WHI is the best evidence to date linking HRT function compared with placebo.26,27 The estrogen-alone arm
with breast cancer, women with a personal history of breast of the WHIMS also demonstrated similar results.28,29
cancer and possibly even a strong family history of breast can-
In summary, HRT improves overall well-being and mood
cer should avoid the use of HRT and consider non-hormonal
in women with vasomotor symptoms, but it has not demon-
alternatives for the treatment of vasomotor symptoms.
strated an improvement in QOL in women without vasomotor
symptoms, does not improve cognitive function, and has little
Venous Thromboembolism effect, if any, on QOL measures.
The WHI demonstrated an increased risk in venous throm-
boembolic disease in the HRT group (0.34%) compared with
placebo (0.16%) (HR 2.11, 95% CI 1.582.82). This translates Discontinuation of HRT
into an NNTH of approximately 555 and 18 more cases of In appropriate women, HRT should be recommended at the
venous thromboembolic events for every 10,000 women lowest dose for the shortest duration and should be tapered before
treated per year with HRT.3 The risk for deep vein thrombosis discontinuation in order to prevent the recurrence of hot ashes. It
also was increased in the ERT arm of the WHI, but pulmonary is not entirely clear what time interval is considered safe for HRT
embolism was not increased signicantly.21 because some of the risks associated with HRT were found
Observational and prospective data have consistently within the rst year of treatment. It is also not clear how long
demonstrated an increased risk in thromboembolic events vasomotor symptoms will last in each woman. Although vaso-
with the use of HRT.2,3,19,20 Women taking HRT have approx- motor symptoms in most women will subside within 4 years,
imately doubled the risk of those not taking HRT. Therefore, approximately 10% of women continue to experience symp-
these risks need to be weighed carefully when considering toms that interfere with their QOL. Therefore, it is important to
the use of HRT for the treatment of vasomotor symptoms. continually reassess a womans vasomotor symptoms while tak-
ing HRT and to try to taper the therapy after 1 year. If symptoms
In summary, combined estrogen plus progestin should return following a slow taper of HRT, it may be reinitiated and
not be used for the prevention of chronic diseases because it tried again at a later date. However, the literature suggests that
increases the risk of CHD, stroke, breast cancer, and venous one of every four women need to be reinitiated on HRT owing
thromboembolism. However, colorectal cancer and rates of to persistent and bothersome symptoms.3032
fracture were reduced with combined hormonal treatment. Discontinuing HRT can be complicated. Little evidence is
available to guide health care providers regarding the most
Other Effects of Hormone-Replacement Therapy effective, safe, and least disruptive way to taper HRT. Slowly
discontinuing HRT over time may be associated with less risk
Quality of Life and Cognition of symptom return. This rationale makes sense when you com-
Although women generally consider QOL measures when pare vasomotor symptoms in women who undergo surgical
deciding whether to use HRT, the effects of HRT on overall menopause with those in women undergoing natural
QOL have been inconsistent. HRT or ERT did not demonstrate menopause. It is generally thought that the rapid decline in
a clinically meaningful effect on QOL; however, women taking estrogen concentrations leads to more severe vasomotor symp-
HRT did have a small improvement in sleep disturbances, toms. However, the time frame for tapering HRT is unknown
physical functioning, and bodily pain after 1 year of therapy.24 but can take up to 3 to 6 months or longer in some cases.
Results from the HERS demonstrated that HRT did improve Tapering HRT may be done in one of two ways: dose taper or
emotional measures such as depressive symptoms, but only day taper. The dose taper involves decreasing the dose of estro-
if women suffered from ushing at trial entry. QOL scores gen over several weeks to months and monitoring closely for a
declined signicantly in women without ushing symptoms.25 return of symptoms. If symptoms recur, the next reduction in
Although mood and well-being may be improved in women dose should not occur until symptoms resolve or at least
stabilize on the current dose. The day taper involves decreasing phytoestrogens in treating hot ashes.33,35 It is also unknown
the number of days of the week that a woman takes the HRT as to whether phytoestrogens contribute to or protect from
dose, e.g., decreasing a daily dose of 0.3 mg estrogen to 0.3 mg breast cancer. Therefore, careful consideration should be
estrogen 5 days a week. Again, if symptoms recur, continue on given before widely recommending soy protein to patients.
the current dose until symptoms resolve or stabilize before try- Black cohosh has been one of the most studied herbal reme-
ing a subsequent decrease. It is important to note that these dies for vasomotor symptoms, and it has not demonstrated a
tapering regimens have not been studied in clinical trials and substantial benet over placebo. The mechanism of action,
may not prove to be benecial in individual women.32 safety prole, drug-drug interactions, and adverse effects of
For women who cannot tolerate even a very slow taper, the black cohosh remain unknown. In non-placebo-controlled tri-
benets must be weighed against the risks of HRT, and often als conducted for 6 months or less, black cohosh demonstrated
women choose to continue HRT. Alternative, non-hormonal a small reduction in vasomotor symptoms. It has not been
therapies are available and may be benecial in some women; shown to be effective for vasomotor symptoms in women with
however, the literature suggests that these therapies are less breast cancer.33 There have been case reports of hepatotoxicity
effective than HRT. with the use of black cohosh.36 Caution should be exercised
when considering the use of this product, especially in patients
Non-hormonal Treatments with liver dysfunction.
Since publication of the WHI study, there has been an Dong quai and several other herbal products, including
increase in the use of non-hormonal therapies for the management evening primrose oil, passion owers, sage, valerian root,
of menopausal symptoms. Particularly for women with CHD and axseed, and wild yam, have not demonstrated efcacy with
breast cancer risk factors, non-hormonal therapies may offer an regard to the relief of vasomotor symptoms, and the safety of
alterative to assist with symptom management. A wide range of these products is also questionable.4,33,35 Therefore, these prod-
therapies, both prescription and herbal, have been studied with ucts should not be recommended for the relief of vasomotor
varying degrees of success. In choosing a particular therapy, it is symptoms in postmenopausal women.
important to match patient symptoms with a therapy that is not There are a number of other prescription products that have
only effective but also safe. been studied for the management of menopausal symptoms.
A number of non-hormonal therapies have been studied Gabapentin is thought to exert its effect by affecting the ther-
for symptomatic management of vasomotor symptoms, moregulatory process of the pituitary-hypothalamic region
including antidepressants [e.g., selective serotonin reuptake through modulation of calcium currents that, in turn, affect
inhibitors (SSRIs) and venlafaxine], herbal products (e.g., soy, adrenergic and serotonergic pathways. In an RCT, gabapentin
black cohosh, and dong quai), and a group of miscellaneous was titrated to 300 mg three times daily for 12 weeks and
agents (e.g., gabapentin, clonidine, and megestrol). The choice demonstrated a 66% reduction in the frequency of hot ashes.
of therapy depends on the patients concomitant disease states, Further symptom reduction was noted when the gabapentin
such as depression and hypertension, and the risk for potential dose was increased to 2700 mg daily and was safe for short-term
adverse effects. therapy.37 Clonidine is thought to work by reducing small-vessel
SSRIs are theorized to reduce the frequency of hot ashes by response, both centrally and peripherally, to various stimuli. It
increasing serotonin in the central nervous system and by decreas- has been studied in several small RCTs and demonstrated statis-
ing LH. Of the SSRIs, citalopram, paroxetine, and sertraline all tically signicant reductions in hot ashes.38,39 This agent may
have been studied and have demonstrated a reduction in hot be considered in women with a history of hypertension, but the
ashes while treating other symptomatic complaints such as adverse effects of this medication may outweigh the benets.
depression and anxiety.33 Venlafaxine, which blocks the reuptake Since the early 1970s, a combination of belladonna and pheno-
of serotonin and norepinephrine, has demonstrated a reduction barbital (Bellergal S) has been used to treat hot ashes. Bellergal
in hot ashes primarily in the oncology population.34 Overall, S is no longer available in the United States, but a similar
these antidepressant medications offer a reasonable option for product, Bellamine and Bellamine S [belladonna alkaloids
women who are unwilling or cannot take hormonal therapies, (0.2 mg), ergotamine tartrate (0.6 mg), and phenobarbital
particularly those who suffer from depression or anxiety. These (40 mg)] are available in the United States. Although early
agents should be prescribed at the lowest effective dose to treat studies have demonstrated a reduction in hot ashes compared
symptoms and may be titrated based on individual response. with placebo, the adverse events associated with these products
Herbal products used for the relief of menopausal symp- have resulted in a greater than 30% withdrawal rate. Therefore,
toms are purported to act by a number of different mecha- these products should not be recommended for hot ashes owing
nisms. Phytoestrogens are plant sterols that are structurally to the adverse-effect prole.39 Lastly, megestrol has been used to
similar to human and animal estrogen. Soy protein is a com- manage hot ashes in patients with breast cancer and has demon-
mon source of phytoestrogens and can be found in products strated efcacy in this population. Long-term serious adverse
such as tofu, soy milk, soy our, and tempeh. Various studies effects limit its use, and it should not be prescribed routinely as
have demonstrated conicting results as to the efcacy of an alternative to HRT for the relief of vasomotor symptoms.40
TABLE 473. Non-hormonal Therapies for Menopause4,33,34,3740,4649
Adverse
Agent Demonstrated Efcacy Dosing Effects/Precautions
Citalopram Non-randomized trial 2060 mg daily Nausea, dizziness,
demonstrated efcacy somnolence
in hot ash reduction
Fluoxetine RCT in breast cancer 20 mg daily Nausea, insomnia,
patients demonstrating nervousness, fatigue
50% decrease in hot
ash score
Paroxetine RCT demonstrating 1020 mg daily Headache, nausea,
37.862.2% reduction insomnia
in hot ashes
Sertraline Case series demonstrating 2550 mg daily Nausea, dizziness,
efcacy in hot ash somnolence
reduction
Venlafaxine RCT in breast cancer 12.5 mg twice Nausea, dry mouth
patients demonstrating daily
55% reduction in hot
ashes
Soy protein Conicting evidence; 5080 mg GI upset; other adverse
short-term (less than isoavones effects unknown
6 weeks) symptomatic daily
relief demonstrated;
benet questionable
Black cohosh Short-term (less than Varied dosing GI upset (take with food);
6 months) symptomatic based on potential hepatoxicity
relief demonstrated herbal product
combination;
most studied:
Reminfemin
2080 mg
twice daily
Gabapentin RCT demonstrating 45% 3001600 mg daily Dizziness and somnolence
reduction in hot ash
frequency
Clonidine Demonstrated efcacy in Variety of dose Dry mouth, blood pressure
hot ash reduction regimens; most lowering; monitor
in most trials common blood pressure
0.10.4 mg
daily
Bellamine S Decreased hot ashes versus 2 tablets daily Dry mouth, skin rash,
placebo; withdrawal rate dizziness, sleepiness
greater than 30% owing
to adverse effects
Megestrol RCT in breast cancer 2040 mg daily Vaginal bleeding,
patients demonstrating headache, weight gain,
up to 80% reduction thromboembolism,
in hot ashes edema
Dong quai No demonstrated efcacy Not recommended Structurally similar to
coumarinsavoid
with warfarin because
INR can increase
Evening No demonstrated efcacy Not recommended Caution with all plant
primrose products in women
oil, passion with hay fever and
owers, plant allergies
sage,
valerian
root, and
wild yam
Overall, non-hormonal therapies are less effective in treat-

ing vasomotor symptoms than HRT but do offer an impor- Patient Care and Monitoring
tant option for women experiencing menopausal symptoms
who cannot or are unwilling to take HRT. The antidepressants
gabapentin and clonidine have the best evidence for efcacy of
1. Assess the patient for use of HRT by evaluating for the
all the non-hormonal options and should be considered rst
presence of vasomotor symptoms. If the patient is experi-
as an alternative to HRT. The most important considerations encing bothersome vasomotor symptoms, consider the
in choosing an alternative therapy are the patients comor- use of HRT only after assessing for risk factors for heart
bidities and the efcacy and safety of the medication. disease and breast cancer. If vasomotor symptoms are tol-
erable and/or the patient has risk factors for heart disease
and/or breast cancer, consider alternative, non-hormonal
treatments for vasomotor symptoms.
OUTCOME EVALUATION 2. Obtain a thorough medication history, including the use
of over-the-counter and herbal products.
Evaluating the outcomes of any hormonal or non-hormonal
3. Educate the patient on lifestyle or behavioral interven-
therapy for menopausal symptoms focuses primarily on the tions that may help to alleviate vasomotor symptoms.
patients report of symptom resolution. Ask patients to report
4. Discuss methods of HRT administration, and have the
the resolution or reduction of hot ashes, night sweats, and
patient decide in conjunction with the health care
vaginal dryness and any improvement or change in sleep pat- provider which one she feels will work best for her.
terns. Also ask women taking hormonal therapies to report
5. Recommend the appropriate dose of HRT, and use the
any breakthrough bleeding or spotting. If abnormal or heavy
lowest effective dose for the shortest duration possible.
bleeding occurs, refer the patient to her primary care provider.
6. Educate the patient regarding the proper administration,
Monitor subjective parameters such as adverse effects and
potential adverse effects, and expectations of HRT.
adherence to the therapy regimen, as well as monthly breast
self-examinations. In addition, monitor objective parameters, 7. Monitor the patient for a reduction in vasomotor symp-
toms, vaginal dryness, and improvement in sleep. Also
including blood pressure, at every outpatient visit; encourage
monitor for breakthrough bleeding and spotting,
yearly clinical breast examinations, mammograms, and TSH
adverse effects of HRT, and improvement in QOL.
determination, particularly for women with hypothyroidism
8. Monitor the following objective parameters:
on thyroid therapy, and conduct a BMD test every 5 years.
Blood pressure at every outpatient visit
Also perform endometrial studies, as necessary, in women
Yearly lipoprotein panels
with undiagnosed vaginal bleeding. Lastly, evaluate the patients Yearly fasting plasma glucose determinations
overall QOL. Because the management of menopause is largely Yearly breast examinations and mammograms
symptomatic, it is important to document symptoms at the Yearly TSH determinations, particularly for women
beginning of therapy and monitor symptom improvement with hypothyroidism on thyroid therapy
and potential adverse effects at each visit. Frequent follow-up, Endometrial studies in women with undiagnosed
proper monitoring, and education will help to ensure that the vaginal bleeding
patient achieves optimal results from any hormonal or non- 9. Educate the patient regarding the importance of adher-
hormonal therapy chosen to treat menopausal symptoms. ing to the medication regimen.
10. Educate the patient regarding the importance of obtain-
ing a yearly mammogram and Papanicolaou (Pap) smear
(if applicable), as well as performing a monthly breast
self-examination.
11. Assess patient symptoms every 6 to 12 months, and
Patient Encounter, Part 3: Creating a
consider tapering the HRT dose and discontinuing treat-
Care Plan
ment after 1 year. If vasomotor symptoms return, deter-
mine if a longer tapering schedule is warranted or if
long-term treatment is necessary.
BWs hot ashes and vaginal dryness. The plan should
include: (1) a statement identifying the patient problem and
its severity, (2) goals of therapy, (3) a therapeutic plan based ABBREVIATIONS
on individual patient-specic factors, (4) subjective and
objective monitoring parameters, and (5) a follow-up evalu- BMD: bone mineral density
ation to assess for adverse effects and adherence and to CEEs: conjugated equine estrogens
determine if the goals of therapy have been achieved. CHD: coronary heart disease
ERT: estrogen-replacement therapy
FSH: follicle-stimulating hormone Burger HG. The endocrinology of the menopause. J Steroid Biochem
GnRH: gonadotropin-releasing hormone Mol Biol 1999; 69:3135.
HDL: high-density lipoprotein Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine
HERS: Heart and Estrogen/Progestin Replacement Study estrogens and global cognitive function in postmenopausal
HOPE: Womens Health, Osteoporosis, Progestin/Estrogen trial women: Womens Health Initiative memory study. JAMA 2004;
HRT: hormone-replacement therapy 291:29592968.
LDL: low-density lipoprotein Fugate SE, Church CO. Nonestrogen treatment modalities for vaso-
LH: leuteinizing hormone motor symptoms associated with menopause. Ann
MPA: medroxyprogesterone acetate Pharmacother 2004; 38:14821499.
NNT: Number needed to treat Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus
NNTH: Number needed to treat to harm progestin for secondary prevention of coronary heart disease in
RCT: randomized controlled trial postmenopausal women. JAMA 1998; 280:605613.
QOL: quality of life National Institutes of Health. State-of-the-Science Panel: National
SSRI: selective serotonin reuptake inhibitor Institutes of Health state-of-the-science conference statement:
TG: triglycerides Management of menopause-related symptoms. Ann Intern
TSH: thyroid-stimulating hormone Med 2005; 142:10031013.
USPSTF: United States Preventive Services Task Force Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus
VTE: venous thromboembolism progestin on global cognitive function in postmenopausal
WHI: Womens Health Initiative women: The Womens Health Initiative memory study: A ran-
WHIMS: Womens Health Initiative Memory Study domized, controlled trial. JAMA 2003; 289:26632672.
Utian WH, Shoupe D, Backmann G, et al. Relief of vasomotor symp-
Reference lists and self-assessment questions and answers are toms and vaginal atrophy with lower doses of conjugated
available at www.ChisholmPharmacotherapy.com. equine estrogens and medroxyprogesterone acetate. Fertil Steril
2001; 75:10651079.
Log into the website: www.pharmacotherapyprinciples.com Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estro-
gen plus progestin on stroke in postmenopausal women. The
Womens Health Initiative: A randomized trial. JAMA 2003;
this chapter. 289:26732684.
Writing Group for the Womens Health Initiative Investigators. Risks
KEY REFERENCES AND READINGS and benets of estrogen plus progestin in healthy post-
menopausal women: Principal results from the Womens Health
Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated Initiative randomized, controlled trial. JAMA 2002; 288:
equine estrogen in postmenopausal women with hysterectomy: 321333.
The Womens Health Initiative randomized, controlled trial.
JAMA 2004; 291:17011712.
Section 9. Urologic Disorders
48 ERECTILE DYSFUNCTION
Cara Liday and Catherine Heyneman
LEARNING OBJECTIVES
1. Identify the structures of the male reproductive system and describe the physiology of a
penile erection.
2. Differentiate between organic and psychogenic erectile dysfunction (ED) and describe the
etiology and pathophysiology of each.
3. Identify the drug classes most likely to contribute to erectile dysfunction.
4. Dene the essential components of history, physical examination, and laboratory data
needed to evaluate the patient presenting with ED.
5. Describe current nonpharmacologic and pharmacologic options for treating ED and
determine an appropriate rst-line therapy for a specic patient.
6. Compare and contrast the benets and risks for the current phosphodiesterase inhibitors.
7. Identify patients with signicant cardiovascular risk and recommend an appropriate
treatment approach for their ED.
KEY CONCEPTS Vacuum erection devices and intracavernosal injections are

highly effective for many patients, but side effects, lack of
ED can be classied as organic, psychogenic, or mixed. Many spontaneity, and fear of needles limit their widespread use
patients may initially have organic dysfunction, but develop a as rst-line therapy.
psychogenic component as they cope with their inability to Effectiveness of the three available phosphodiesterase
achieve an erection. inhibitors is essentially comparable, but differences exist in
The introduction of oral medications and direct-to- duration of action, and to a small degree, incidence of side
consumer advertising has made patients feel more com- effects and drug interactions.
fortable approaching practitioners for treatment advice. Androgens are important for general sexual function and
A thorough medical history with emphasis on cardiac disease libido, but testosterone supplementation is only effective in
must be taken before starting any treatment for ED to assess patients with documented low serum testosterone levels.
for ability to safely perform sexual activity and to assess for
possible drug interactions. Erectile dysfunction (ED) is dened as the inability to
A wide range of treatment options are now available for achieve or maintain an erection sufcient for sexual inter-
men with ED. These include medical devices, pharmaco- course. The denition is very subjective due to differences in
logic treatments, lifestyle modications, surgery, and desired or needed rigidity in patients of different ages and in
psychotherapy. different types of relationships. Patients may refer to their dys-
When determining the best treatment for an individual, function as impotence, but the National Institutes of Health
the role of the clinician is to inform the patient and his Consensus Development Conference recommends that the
partner of all available options while understanding his term erectile dysfunction replace the term impotence due to
medical history, desires, and goals. The choice of treatment confusion with other forms of sexual dysfunction and the
is primarily left up to the couple, but most often treatment negative connotation associated with the term impotence.1
is initiated with the least invasive option and then pro- Patients may also develop libido or ejaculatory disorders, but
gresses to more invasive options if needed. these are not considered erectile dysfunction.
779
780 SECTION 9 / UROLOGIC DISORDERS
oxide increases the production of cyclic guanosine monophos-

Patient Encounter, Part 1 phate (cGMP). Vasoactive peptide and prostaglandins E1 and E2
stimulate increased production of cAMP. Both cyclic adenosine
monophosphate (cAMP) and cGMP ultimately lead to a
decrease in calcium concentration within smooth muscle cells
A 52-year-old man with type 2 diabetes, hypertension, and
of the penile arteries and the sinusoidal spaces, leading to
dyslipidemia returns to your clinic for follow-up on his
chronic disease states. When reviewing his history, he smooth muscle relaxation and increased blood ow. As the
describes problems achieving a rm erection. After further sinusoidal spaces become engorged, intracavernosal pressure
questioning, you determine that his dysfunction has progres- increases, subtunical venules are compressed, and the penis
sively gotten worse over the last year. He is quite emotional becomes rigid and elongated (Fig. 481).
and states that the problem is distressing and has caused Detumescence occurs with sympathetic discharge after
signicant marital discord. He wonders about those ads ejaculation. Sympathetic activity induces smooth muscle con-
on television suggesting a pill. traction of arterioles and vascular spaces leading to a reduction
in blood inow, decompression of the sinusoidal spaces, and
What other information do you need to assess for ED? enhanced outow.
Does he have risk factors for ED?
Testosterone also plays a signicant albeit complex role in
Would his ED most likely be organic or psychogenic?
erectile function. Testosterone is responsible for much of a
mans libido. With low serum concentrations, libido declines.
Additionally, testosterone helps with stabilization of intracaver-
EPIDEMIOLOGY AND ETIOLOGY nosal levels of nitric oxide synthase, the enzyme responsible for
triggering the nitric oxide cascade. Interestingly, some patients
ED becomes increasingly frequent as men age. According to with low or borderline low serum concentrations of testos-
data from the Massachusetts Male Aging Study the prevalence terone will have normal erectile function, while some with nor-
of ED of any degree is 40% among 40-year-old men and 70% mal levels will have dysfunction.
among 70-year-old men.2 The increase in incidence could be
due to physiologic changes that occur with aging, the onset of Normal penile erections are complex events that require the
chronic disease states associated with ED, increased medication full function of the vascular, neurologic, and hormonal systems.
use, lifestyle factors, or a combination of the above. Anything that affects the function of these systems may lead to
ED. ED can be classied as organic, psychogenic, or a mixture
of these. Organic dysfunction includes abnormalities in the three
PATHOPHYSIOLOGY systems responsible for a normal erection or may be medication-
induced (Tables 481 and 482). Note that many of the risk
The penis consists of three components, two dorsolateral cor- factors for ED are the same as risk factors for cardiovascular
pora cavernosa and a ventral corpus spongiosum that sur- disease. In many patients, ED is the rst indication of the
rounds the penile urethra and distally forms the glans penis. endothelial dysfunction associated with cardiovascular disease.4
The corpora cavernosa consist of blood-lled sinusoidal or The presence of ED risk factors leads to the assumption that the
lacunar spaces, which are lined with endothelial cells, sup- patient has organic dysfunction. Most commonly, medical con-
ported by trabecular smooth muscle, and surrounded by a ditions that impair arterial ow into or out of the erectile tissue
thick brous sheath called the tunica albuginea. The caver- or affect the innervation will be strongly associated with ED.
nosal arteries, which are branches of the penile artery, pene- Patients with diabetes mellitus have exceptionally high rates of
trate the tunica albuginea and supply blood ow to the penis. ED as a result of vascular disease and neuropathy.
Sympathetic and parasympathetic nerves innervate the Psychogenic dysfunction occurs if a patient does not
penis. In the accid state, 2-adrenergic receptors mediate respond to psychic arousal. It occurs in up to 30% of all
tonic contraction of the arterial and corporal smooth muscles. cases of ED. Common causes include performance anxiety,
This maintains high penile arterial resistance and a balance strained relationships, lack of sexual arousability, and overt
exists between blood ow into and out of the corpora. With psychiatric disorders such as depression and schizophrenia.5
sexual stimulation, nerve impulses from the brain travel down It is postulated that the anxious or nervous man will have
the spinal cord to the thoracolumbar ganglia.3 A decrease in excessive stimulation of the sympathetic system, leading to
sympathetic tone and an increase in parasympathetic activity smooth muscle contraction of arterioles and vascular spaces
then occurs, causing a net increase in blood ow into the erec- within erectile tissue.6 Many patients may initially have
tile tissue. Erections may also occur as a result of a sacral nerve organic dysfunction, but develop a psychogenic component as
reex arc while patients are sleeping (nocturnal erections). they try to cope with their inability to achieve an erection. It
Acetylcholine-mediated parasympathetic activity leads to has been estimated that up to 80% of ED cases have an
production of the non-adrenergicnon-cholinergic transmitter organic cause, with many having a psychogenic component
nitric oxide. By enhancing the activity of guanylate cyclase, nitric as well.1
CHAPTER 48 / ERECTILE DYSFUNCTION 781
FIGURE 481. Mechanism of erection and sites of action of various treatment modalities for erectile dysfunction. Penile
erection is achieved through relaxation of smooth muscle cells lining arterial vessels and sinusoidal spaces in the corpora
cavernosa, which leads to increased arterial inow and pressure, decreased venous outow, and increased intracavernosal
pressure. Smooth muscle relaxation is mediated by intracellular generation of cyclic guanosine monophosphate (cyclic GMP)
from guanosine triphosphate (GTP) via activation of guanylate cyclase by nitric oxide. Treatment modalities for erectile dys-
function (shown in blue) include oral phosphodiesterase type 5 (PDE 5) inhibitors, which inhibit the breakdown of cyclic
GMP, and local vasoactive agents. A link between testosterone and nitric oxide synthase has been demonstrated experimen-
tally, but the signicance of this observation in humans has not been established (indicated by the dashed line and question
mark). Psychotherapy (not shown) may also be effective in selected individuals with erectile dysfunction. (From Morgentaler A.
A 66-year-old man with sexual dysfunction. JAMA 2004;291:2996, with permission.)
CLINICAL PRESENTATION AND DIAGNOSIS medications contraindicate the use of some ED therapies or may
lead to drug interactions. It is also necessary to assess the patients
The evaluation of a patient presenting with ED should con- ability to safely perform intercourse and to review lifestyle factors
sist of a thorough medical history including sexual and psychosocial such as smoking, alcohol consumption, and regular exercise.
issues to determine if the dysfunction is psychogenic. In addition, a The International Index of Erectile Dysfunction (IIED) is the
directed physical exam and laboratory tests should be performed most widely used questionnaire to assess the severity of ED.10 It
such as total and free serum testosterone, serum glucose, a consists of 15 questions with 5 domains: erectile function, libido,
fasting lipid panel, and a thyroid panel.9 Identication of orgasmic function, sexual satisfaction, and overall satisfaction.
concomitant disease states is important for determining rst The erectile function domain has a maximum score of 30 with a
line therapy. Some medical conditions and their associated score of less than 26 indicating some degree of ED.
TABLE 481. Factors Associated with Erectile Dysfunction

Clinical Presentation of ED7.8
Chronic Medical Conditions
Hypertension
Diabetes mellitus
Inammatory conditions of the prostate
Coronary and peripheral vascular disease The introduction of oral medications and direct-to-con-
Neurologic disorders (e.g., Parkinsons disease and multiple sumer advertising has made patients feel more comfortable
sclerosis) approaching practitioners for treatment advice. Despite this,
Endocrine disorders (hypogonadism and pituitary, adrenal, and
some patients may only discuss their dysfunction when ques-
thyroid disorders)
Psychiatric disorders (depression, anxiety, and schizophrenia) tioned directly by their provider or if their partner initiates the
Hyperlipidemia interaction. Patients may still feel that a loss in erectile function
Renal failure translates into a loss of masculinity.
Liver disease Patients presenting with ED may show some of the follow-
Penile disease (Peyronies disease or anatomic abnormalities) ing signs and symptoms:
Surgical Procedures
Perineal surgery Embarrassment
Radical prostatectomy Anxiousness
Vascular surgery
Anger
Lifestyle
Marital problems
Age
Smoking Low self-condence or morale
Excessive alcohol consumption Full inability to achieve erections
Obesity Ability to achieve partial erections, but not suitable for
Poor overall health and reduced physical activity intercourse
Trauma Erections sufcient for intercourse, but early detumescence
Pelvic fractures The problem may have a slow or acute onset, or may wax
Spinal cord injuries and wane
ED may be the presenting symptom of other chronic disease

states.
TABLE 482. Medication Classes Associated with Erectile

Dysfunction3,24,25 TREATMENT
Antihypertensives Desired Outcomes

-Blockers (particularly non-selective)
Thiazide diuretics ED is not a life-threatening condition, but left untreated it can be
Centrally acting agents (clonidine, methyldopa, and reserpine) associated with depression, loss of self-esteem, poor self-image,
Spironolactone and marital discord.11 The primary goal of therapy is achieve-
-Blockers ment of erections suitable for intercourse and improvement in
Lipid medications
Gembrozil patient quality of life. Additionally, the ideal therapy should have
Antidepressants minimal side effects, be convenient to administer, have a quick
Tricyclic antidepressants onset of action, and have few or no drug interactions.7
Monoamine oxidase inhibitors
Selective serotonin reuptake inhibitors General Approach to Treatment
Antipsychotics
Phenothiazines After determining if the ED is organic or psychogenic, the
Risperidone initial step in management is to identify associated disease
Lithium
Anticonvulsants states and lifestyle activities that adversely affect erectile func-
Carbamazepine tion and treat them optimally. Medications suspected to
Phenytoin cause or worsen ED should also be discontinued if possible.
Histamine antagonists A wide range of treatment options are now available for
Cimetidine men with ED. These include medical devices, pharmacologic
Anti-androgens and hormones
5-Reductase inhibitors treatments, lifestyle modications, surgery, and psychotherapy.
Progesterone and estrogen When determining the best treatment for an individual, the
Recreational drugs role of the clinician is to inform the patient and his partner of
Ethanol all available options while understanding his medical history,
Cocaine desires, and goals. Most often treatment is initiated with the
Marijuana
least invasive option and then treatment progresses to more
Patient Encounter, Part 2: Medical
History, Physical Exam, and Diagnostic Lifestyle Modications
Tests Lifestyle modications should always be addressed in the
management of ED. A healthy diet, increase in regular phy-
PMH sical activity, and weight loss are associated with higher IIED
Type 2 diabetes for 15 years; not controlled due to his scores and an improvement in erectile function.12 The clini-
stressful profession; he often works late, eats on the run,
and has no time for exercise
cian should recommend smoking cessation, reduction in
Hypertension for 8 years, currently uncontrolled excessive alcohol intake, and discontinuation of the use of
Dyslipidemia for 8 years, currently controlled illicit drugs.
FH Psychotherapy
Father had type 2 diabetes and died of myocardial infarc- Psychotherapy is an appropriate treatment approach for
tion at the age of 50 years; mother is alive at 75 with no
major illnesses
patients with psychogenic or mixed dysfunction. It should
address immediate causes of dysfunction, and if possible the
SH partner should attend sessions as well. Effectiveness is not well
Works long hours as a business executive; drinks alcohol
documented for organic dysfunction unless combined with
only occasionally, but smokes 1/2 pack per day; has a
20 pack per year history other therapies. Advantages include non-invasiveness and part-
ner participation, while disadvantages include increased cost
Meds
and time commitment.
Metformin 1000 mg PO twice daily
Metoprolol XL 50 mg PO once daily Vacuum Erection Devices
Zocor 20 mg PO once daily
Vacuum erection devices (VEDs) induce erections by creating
ROS a vacuum around the penis; the negative pressure draws blood
() Morning, nocturnal, or spontaneous erections suitable for into the penis by passively dilating arteries and engorging the
intercourse; () nocturia, urgency, symptoms of prostatitis; (+)
corpora cavernosa. The erection is maintained with a con-
signicant life stressors; (+) mild pain in feet
striction band placed at the base of the penis to reduce venous
PE outow (Fig. 482). They may be used as often as desired, but
VS: Blood pressure 148/90 mm Hg, pulse 85 beats per minute, it is recommended that the constriction band not be in place
respiratory rate 18/minute, temperature 37.0C (98.6F)
CV: Normal exam
longer than 30 minutes at a time.
Genit/Rect: Normal scrotum and testicles w/o masses; VEDs are one of the most effective treatment modalities for
penis without discharge or curvature ED. They have a success rate of greater than 90% in obtaining an
Labs erection sufcient for coitus and are considered a rst-line non-
Complete metabolic panel, complete blood cell count, and invasive therapy.13 Rigidity may be improved by using a double
thyroid panel within normal limits pump technique in which the vacuum is applied for a couple
Lipid panel: total cholesterol , low-density lipoproteins, high-
of minutes, removed, then reapplied for another few minutes.
density lipoproteins, triglycerides within normal limits
Hemoglobin A1c: 8.0% (0.08), testosterone: 700 ng/dL Higher efcacy rates can also be achieved by combining VEDs
(24 nmol/L) with other therapies.
Onset of action is slow at around 30 minutes, which limits
Given this additional information, what is your assess- spontaneity. In addition, patients and partners may complain
ment of the patients condition? What is/are the most of a cold, lifeless, discolored penis that has a hinge-like feel.
likely causes of his ED? Painful ejaculation or inability to ejaculate are additional
Identify treatment goals for this patient.
adverse effects. VEDs are contraindicated in persons with
What pharmacologic and nonpharmacologic alternatives
are available for this patient? sickle cell disease and should be used with caution in patients
Which of the above will be your treatments of choice on oral anticoagulants or who have bleeding disorders due to
based on degree of invasiveness, side effects, ease of use, the increased possibility of priapism.
and side-effect prole?
What other information do you need before starting cer- Prostheses
tain pharmacotherapeutic options? Penile prostheses are semi-rigid malleable or inatable rods,
which are inserted surgically into the corpus cavernosa to allow
erections (Fig. 482). The malleable rods are rigid at all times,
invasive options if needed. Ultimately, the choice of therapy but may be bent into position by the patient when desired.
should be individualized, taking into account patient and The inatable prostheses remain accid until the pump within
partner preferences, concomitant disease states, response, the scrotum moves uid from a reservoir to the cylinders within
administration, cost, tolerability, and safety. Common drug the penis. Detumescence is achieved when the uid is then
treatment regimens for ED are listed in Table 483. transferred back to the reservoir by activating a release button.
TABLE 483. Common Drug Treatment Regimens for Erectile Dysfunction
Typical Dosing Maximum Dosing

Route of Administration Generic Name Brand Name Rangea Frequency
Oral Sildenal Viagra 25100 mg 1 hour prior Once daily
to intercourse
Tadalal Cialis 520 mg prior to intercourse Once daily
Vardenal Levitra 520 mg 1 hour prior Once daily
to intercourse
Yohimbineb Aphrodyne, Yocon 5.4 mg three times daily N/A
Intracavernosal Alprostadil Caverject, Caverject 1.2560 mcg 520 minutes Three times weekly, 24 hours
Impulse, Edex prior to intercoursec between injections
Papaverine N/A Usually used in combination Three times weekly, 24 hours
at variable doses between injections
Phentolamine N/A Usually used in combination at Three times weekly, 24 hours
variable doses between injections
Intraurethral Alprostadil MUSE 1251000 mcg 510 minutes Two times daily
prior to intercoursec
Intramuscular Testosterone Depo-Testosterone 50400 mg every 24 weeks Once weekly
cypionate
Testosterone Delatestryl 50400 mg every 24 weeks Once weekly
enanthate
Topical Testosterone Testoderm 46 mg/day applied to scrotum Once daily
patches Testoderm TTS 46 mg/day applied to arm, back, Once daily
or upper buttocks
Androderm 2.55 mg/day applied to back, Once daily
abdomen, upper arms, or thighs
Testosterone gel AndroGel 1%, Testim 510 g daily to shoulders, upper Once daily
arms, or abdomen (AndroGel only)
Buccal Testosterone Striant 30 mg every 12 hours to gum region Twice daily
above incisor; rotate to alternate
sides with each dose
a
Use the lowest effective dose to limit adverse effects.
b
Not FDA approved for this indication.
c
Initial dose must be titrated in physicians ofce.
MUSE, medicated urethral system for erection.
Because prostheses are the most invasive treatment avail- induced, leading to an erection (Fig. 481). However, the PDE
able, they are only considered in patients who do not respond inhibitors are only effective in the presence of sexual stimula-
to medications or external devices, or those who have signi- tion to drive the nitric oxide/cGMP system, making them facil-
cant adverse effects from other therapies. Patient satisfaction itators of an erection, not initiators. Patients must be informed
rates can be as high as 80% to 90% with partner satisfaction of the need for sexual stimulation to induce an erection, as it
rates just slightly lower.9 The primary risks of insertion of will not occur spontaneously.
prostheses are infection and device failure, although these
Effectiveness of the three available phosphodiesterase
only happen in 2% to 3% and 2% to 14% of patients, respec-
inhibitors is essentially comparable, but differences exist in duration
tively. Higher infection rates have been reported in uncon-
of action, and to a small degree, incidence of side effects and drug
trolled diabetic patients, paraplegics, and patients undergoing
interactions (Table 484). Studies directly comparing the side
reimplantation or penile reconstruction.14,15 Most prostheses
effects and efcacy of the drugs in this class have not been pub-
can be expected to last from 7 to 10 years.16
lished. In addition, trials for vardenal and tadalal excluded
subjects who did not respond to sildenal. Review of available
Pharmacologic Therapy data for each individual agent shows a 50% to 80% response rate
depending on the dose of agent used and the etiology of dys-
Phosphodiesterase Type 5 Inhibitors function. Patients with radical prostatectomy tend to have lower
Sildenal (Viagra), tadalal (Cialis), and vardenal response rates.6 Response rates are also lower in patients with dia-
(Levitra) act by selectively inhibiting phosphodiesterase betes, severe nerve damage, or severe vascular disease.17 The PDE
(PDE) type 5, an enzyme that breaks down cGMP. By inhibit- inhibitors are considered rst-line therapies due to high efcacy
ing the breakdown of cGMP, smooth muscle relaxation is rates, convenience of dosing, and minimal severe adverse effects.
The most dramatic difference between the three agents is

tadalals extended duration of action, earning it the nick-
name the weekender drug. While sildenal and vardenal
have average half-lives of 3 to 4 hours, tadalals half life is
approximately 18 hours.18 The extended half-life allows for
more spontaneous sexual activity over a couple of days, but
may increase the duration of adverse effects and liklihood of
drug interactions or sildenal.
The most common side effects experienced with PDE
inhibitors include headache, facial ushing, nasal congestion,
dyspepsia, and rarely priapism. Vardenal and sildenal may
also cause difculty in discriminating blue from green, bluish
tones in vision, or difculty seeing in dim light due to cross-
reactivity with PDE 6 in the retina. There has also been a
recent change in the labeling for all PDE inhibitors warning
about non-arteritic ischemic optic neuropathy (NAION) in a
small number of patients. This is a condition in which blood
ow is blocked to the optic nerve. If patients experience sud-
den or decreased vision loss they should call a health care
provider immediately.
Concern exists about the safety of using PDE inhibitors in
patients with cardiovascular disease. Because of the numerous
adverse cardiovascular events reported after the release of
sildenal, a management approach was developed to give rec-
FIGURE 482. Available devices and prostheses used to treat ommendations for the use of PDE inhibitors in patients with
erectile dysfunction. (From Wagner G, Saenz de Tejada I. cardiovascular disease19 (Table 485). In addition to the inher-
Update on male erectile dysfunction. BMJ 1998;316:681, with
ent risk of renewing sexual activity, PDE inhibitors can lead to
permission.)
signicant hypotension. Patients taking organic nitrates are
TABLE 484. Comparison of Phosphodiesterase Inhibitors
Sildenal (Viagra) Tadalal (Cialis) Vardenal (Levitra)

Available strengths 25-, 50-, 100-mg tabs 5-, 10-, 20-mg tabs 2.5-, 5-, 10-, 20-mg tabs
Initial dosage in healthy adults 50 mg every day taken 1 hour 10 mg every day taken 1 hour 10 mg every day taken 1 hour
(dosing range in mg) prior to sexual activity prior to sexual activity prior to sexual activity
Dosing range for healthy adults (mg) 25100 520 520
Dosage in the elderly 25 mg every day 10 mg every day 5 mg every day
Dosage in renal impairment 50 mg every day (moderatea) 5 mg every day (moderatea 520 mg every day
25 mg every day (severeb) and severeb)
Dosage in hepatic impairment 25 mg every day 10 mgc 510 mgd
Time to onset 30 minutes 15 minutes Less than 1 hour
Onset delayed by high-fat meal? Yes No Yes
Duration of effect Up to 4 hours Up to 36 hours Up to 4 hours
Half-life 34 hours 18 hours 34 hours
Metabolism CYP3A4 (major) CYP3A4 CYP3A4 (major)
CYP2C9 (minor) CYP3A5 (minor)
CYP2C (minor)
Drug present in semen? 18% Less than 0.0005% 0.00018%
Clinically relevant drug interactions Nitrates, protease inhibitors, Nitrates, 1-blockerse, Nitrates, anti-arrhythmic
azole antifungals azole antifungals agents,f 1-blockers
a
Moderate renal impairment = creatinine clearance (CrCl) 3150 mL/minute.
b
Severe renal impairment = CrCl less than 30 mL/minute.
c
Mild to moderate onlycontraindicated in severe liver disease.
d
Mild to moderate onlynot yet evaluated in severe liver disease.
e
Selective 1a-blockers (such as 0.4 mg tamsulosin every day) are appropriate in combination with tadalal.
f
Vardenal can cause QT-interval prolongation; this effect in combination with certain anti-arrhythmic agents can lead to life-threatening arrhythmias.
CYP, cytochrome P-450 isoenzyme.
TABLE 485. Cardiovascular Risk Assessment for Phosphodiesterase Inhibitors
Risk Category Description of Patients Conditions Management Approach

Low risk Has asymptomatic cardiovascular Patient can be started on
disease phosphodiesterase
inhibitor
Has well-controlled hypertension
Has mild, stable angina
Has mild congestive heart failure
(NYHA Class 1)
Moderate risk Has three or more risk factors for Patient should undergo a
coronary artery disease complete cardiovascular
Has moderate, stable angina work-up and treadmill stress
Had a recent myocardial infarction testing to determine tolerance
or stroke within the past 6 weeks to increased myocardial energy
Has moderate congestive heart failure consumption associated with
(NYHA Class 2) increased sexual activity
High risk Has unstable or symptomatic angina, Phosphodiesterase inhibitor is
despite treatment contraindicated
Has poorly controlled hypertension
Has severe congestive heart failure
(NYHA Class III or IV)
Had a recent myocardial infarction or
stroke within the past 2 weeks
Has moderate or severe valvular heart
disease
NYHA, New York Heart Association.

From Lee M. Erectile dysfunction. In: DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy:
A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 1524, with permission.
the most at risk, as they potentiate the drop in blood pressure. in smooth muscle relaxation, rapid arterial inow, and
All three PDE inhibitors are absolutely contraindicated in increased penile rigidity. Alprostadil is available as an intra-
patients taking any form of nitrate, whether scheduled or sub- cavernosal injection (Caverject or Edex) or a transurethral
lingual for acute situations. Caution should be used when suppository (MUSE, medicated urethral system for erec-
using a PDE inhibitor in patients taking -blockers due to an tion), but the injectable form is more effective (Fig. 483).
increased risk of hypotension. In addition, the labeling for Both forms of alprostadil are considered more invasive than
vardenal contains a precautionary statement about the pos- oral medications or VEDs, and are therefore second-line
sibility of QT prolongation with the use of the drug. Other therapies.8
drug interactions and cautions vary slightly between agents MUSE consists of a urethral pellet of alprostadil with an
and are described in Table 484. applicator. Onset of action is within 5 to 10 minutes and it is
The introduction of the oral PDE inhibitors has dramati- effective for 30 to 60 minutes. Initial dose titration should
cally changed the treatment of ED. Direct-to-consumer adver- occur in a physicians ofce to ensure correct dose and prevent
tising has informed patients of the availability of oral drugs adverse events. Although effectiveness rates in clinical trials
for treatment. However, patients must be fully informed of have been as high as 65%,21 its success in practice has been
side effects, drug interactions, mechanism of action, and dos- lower. Aching in the penis, testicles, legs, and perineum,
ing before being prescribed the medication. In addition, they warmth or burning sensation in the urethra, minor urethral
need to understand the need for sexual stimulation to achieve bleeding or spotting, priapism, and lightheadedness are all
the desired result and that a single trial is not adequate. It is possible adverse effects. In addition, partners may experience
estimated that six to eight attempts with a medication and vaginal burning or itching. Disadvantages include lower effec-
specic dose may be needed before successful intercourse tiveness, high cost, adverse effects, complicated insertion tech-
results.20 nique, and a contraindication against use with a pregnant
partner unless using a condom.
Alprostadil Alprostadil injected into the corpus cavernosum is the more
Alprostadil is a prostaglandin E1 analog that induces an erec- effective form and is the only Food and Drug Administration
tion by stimulating adenyl cyclase, which leads to an increase (FDA)-approved agent for injection. The onset of action is
cell disease, those on anticoagulants, or those who have

bleeding disorders, due to an increased risk of priapism and
bleeding.
Papaverine and Phentolamine

Papaverine and phentolamine are nonFDA-approved agents
used for intracavernosal injection. Papaverine is a non-selective
PDE inhibitor that induces an erection by relaxing smooth
muscle and increasing blood ow. Phentolamine is a compet-
itive -adrenergic receptor antagonist that increases arterial
inow by opposing arterial constriction. Both drugs are rarely
used alone, and are most often mixed in various concentra-
tions with alprostadil for increased effectiveness and in an
effort to reduce adverse effects with smaller doses of each
medication. Patients typically must see a specialist for use of
these medications in mixtures, as they are the most likely to
compound them and adjust dosages.
Yohimbine
Yohimbine is an indole alkaloid produced in the bark of
yohimbe trees. It selectively inhibits 2-adrenergic receptors
in the brain that are associated with libido and penile erection.
Since there is only limited data supporting its efcacy, yohim-
bine is not a recommended treatment for any form of ED.22
Adverse effects of the drug include nausea, irritability,
headaches, anxiety, tachycardia, and hypertension.
Testosterone Supplementation
Androgens are important for general sexual function and
libido, but testosterone supplementation is only effective in
patients with documented low serum testosterone levels. In
patients with hypogonadism, testosterone replacement is the
FIGURE 483. Intraurethral and intracavernosal administration of initial treatment of choice, as it corrects decreased libido,
alprostadil. (From Wagner G, Saenz de Tejada I. Update on male fatigue, muscle loss, sleep disturbances, and depressed mood.
erectile dysfunction. BMJ 1998;316:680, with permission.) Improvements in ED may occur, but they should not be
expected to occur in all patients.23 The initial trial should be
for 3 months. At that time, re-evaluation and the addition of
similar to transurethral alprostadil, but duration varies with another ED therapy is warranted. Routes of administration
dose and must be titrated in a physicians ofce to achieve an include oral, intramuscular, topical patches or gel, and a
erection lasting no more than 1 hour. Injections should be buccal tablet.
done into one side of the penis directly into the corpus caver- Injectable esters of testosterone offer the most inexpensive
nosum, and then the penis should be massaged to distribute and effective replacement option. Testosterone cypionate and
the drug. Because of cross-circulation, both corpora will enanthate have the longest duration of action and are therefore
become erect when massaging. Education is extremely impor- the preferred agents. There are several drawbacks associated
tant with intracavernosal injections. Patients must be ade- with parenteral testosterone including the need to administer
quately informed of technique, expectations, side effects, and deep intramuscular injections every 2 to 4 weeks. In addition,
when to seek help. Intracavernosal injections are effective in levels of hormone are well above physiologic values within the
up to 90% of patients, but side effects, lack of spontaneity, and rst few days. Concentrations then decline and eventually dip
fear of needles limit their widespread use as rst-line therapy, below physiologic levels just before the next dose. These
and therefore this therapy is most appropriate for patients in extreme changes in concentration lead to mood swings and a
long-term stable relationships. Adverse effects include pain reduced sense of well-being.23
with injection, bleeding or bruising at the injection site, Treatment with topical products is attractive to patients
brosis, or priapism. Use with caution in patients with sickle due to convenience, but they tend to be more expensive than
the injections. Testosterone patches and gels are administered hypertension, edema, and exacerbations of congestive heart
daily and result in serum levels within the physiological range failure also occur due to sodium retention. Before initiating
during the 24-hour dosing period.23 Most patients prefer the testosterone, the patient should undergo evaluation for benign
non-scrotal patch or the gel since the scrotal patch requires prostatic hypertrophy and prostate cancer. Routine follow-
shaving of the area, and the patch has a tendency to fall off. up includes yearly prostate-specic antigen, digital rectal exam,
Care must be taken with the use of the gel to wash hands thor- hemoglobin, and liver function in addition to assessment of
oughly after use and avoid baths or showers within 5 to 6 hours response.
of application. The most common side effects of topical testos-
terone are dermatologic reactions caused by the absorption
enhancers. OUTCOME EVALUATION
Oral testosterone products are also available for supplemen-
tation. Unfortunately, testosterone has poor oral bioavailability Successful therapy for ED results in an increase in erections
and undergoes extensive rst-pass metabolism. Alkylated deriv- suitable for intercourse, and most importantly in an improve-
atives such as methyltestosterone and uoxymesterone have ment in the patients quality of life. Ideally, the therapy chosen
been formulated to compensate for these problems, but this is free of signicant adverse effects, discomfort, and inconven-
modication makes them considerably more hepatotoxic. This ience. Laboratory evaluation and a physical exam are not nec-
adverse effect makes oral replacement undesirable and this route essary for evaluation of effectiveness, but may be necessary to
of administration should not be used. determine if adverse events are occurring.
An alternative to the oral route is the buccal mucoadhesive Satisfaction and effectiveness are evaluated after a 4-week
system. The Striant buccal system adheres to the inside of the trial unless the patient initiates follow-up sooner. Some ther-
mouth and the testosterone is absorbed through the oral apies such as intracavernosal injections will require multiple
mucosa and delivered to the systemic circulation. There is no visits over the long term to detect adverse effects. If the initial
rst-pass effect, as the liver is bypassed by this route of admin- therapy is not effective, the patient must be further evaluated
istration. Patients apply a 30-mg tablet to the upper gum twice to determine if the initial assessment of comorbid disease
daily. The cost is similar to that of the patch or gel. Side effects states, type of dysfunction, and patient goals were correct.
unique to this dosage form include oral irritation, bitter taste, After ensuring that patient goals are realistic and providing
and gum edema. further counseling, providers will then increase the dose of
General side effects of testosterone include gynecomas- drug if not at maximum, switch to another therapy, or add a
tia, dyslipidemia, polycythemia, and acne. Weight gain, therapy if indicated.
Patient Care and Monitoring 6. Discontinue medications that may cause ED if possible
and optimally treat associated disease states.
7. If the patient is not satised, provide further counseling to
ensure that they are using the therapy appropriately and
1. Assess the patients specic symptoms to determine the type that they have realistic goals.
of dysfunction. Does the patient have ED or an ejaculatory 8. Provide patient education with regard to disease state,
or libido disorder? lifestyle modications, drug therapy, and device technique:
2. If problems are with erectile ability, ask specic questions The causes of ED
related to onset, frequency, and sexual relationships. Does The fact that therapy will not cure ED, but may be help-
the patient history imply psychogenic, organic, or mixed ful in improving erections; it is important to have realis-
dysfunction? tic expectations
3. A thorough medical history and physical exam should be The appropriate use of medications and devices
performed to diagnose ED and to determine potential Typical adverse effects
causes that may be treatable. Drug interactions
Warning signs and their management (e.g., vision
4. Perform a thorough history of prescription and non-
changes, brosis, pain, priapism, or hypotension)
prescription medications. Are any of the patients medica-
The importance of frequent follow-up with the
tions associated with ED or are they contraindicated with
provider
possible ED therapies?
5. Generally treatment is started with the least invasive option
and then progresses to more invasive options, but ultimately
patient preference determines the initial therapy.
cAMP: cyclic adenosine monophosphate AACE Male Sexual Dysfunction Task Force. American Association of
cGMP: cyclic guanosine monophosphate Clinical Endocrinologists medical guidelines for clinical prac-
ED: erectile dysfunction tice for the evaluation and treatment of male sexual dysfunc-
FDA: Food and Drug Administration tion: a couples problem2003 update. Endocr Pract 2003;9:
GTP: guanosine triphosphate 7795.
IIED: International Index of Erectile Dysfunction American Urological Association. The management of erectile dysfunc-
MUSE: medicated urethral system for erection tion: an update, 2005 (www.auanet.org/guidelines /edmgmt.cfm).
NAION: non-arteritic ischemic optic neuropathy Gresser U, Gleiter CH. Erectile dysfunction: comparison of efcacy
PDE: phosphodiesterase and side effects of the PDE-5 inhibitors sildenal, vardenal and
VED: vacuum erection device tadalal: review of the literature. Eur J Med Res 2002;7:435446.
Lue TF. Erectile dysfunction. N Engl J Med 2000;342:18021813.
Reference lists and self-assessment questions and answers are Ralph D, McNicholas T. UK management guidelines for erectile dys-
available at www.ChisholmPharmacotherapy.com. function. BMJ 2000;321:499503.
Wagner G, Saenz de Tejada I. Update on male erectile dysfunction.
Log into the website: www.pharmacotherapyprinciples.com BMJ 1998;316:678682.
this chapter.
49 BENIGN PROSTATIC HYPERPLASIA
Mary Lee and Roohollah Shari
LEARNING OBJECTIVES
1. Explain the pathophysiologic mechanisms underlying the symptoms and signs of benign
prostatic hyperplasia.
2. Recognize the symptoms and signs of benign prostatic hyperplasia in individual patients.
3. List the desired treatment outcomes for a patient with benign prostatic hyperplasia.
4. Identify factors that guide selection of a particular -adrenergic antagonist for an individual
patient.
5. Compare and contrast -adrenergic antagonists versus 5-reductase inhibitors in terms of
mechanism of action, treatment outcomes, adverse effects, and interactions when used for
management of benign prostatic hyperplasia.
6. Describe the indications for combination drug treatment of benign prostatic hyperplasia.
7. Describe the indications for surgical intervention of benign prostatic hyperplasia.
8. Formulate a monitoring plan for a patient on a given drug treatment regimen based on
patient-specic information.
9. Formulate appropriate counseling information for patients receiving drug treatment for
benign prostatic hyperplasia.
KEY CONCEPTS Surgical intervention should be reserved for patients with

severe lower urinary tract symptoms of benign prostatic
The lower urinary tract symptoms and signs of benign prosta- hyperplasia or those with complications of disease (such as
tic hyperplasia are due to static, dynamic, or detrusor factors. recurrent urinary tract infections, renal failure, and blad-
The static factor refers to anatomic obstruction of the bladder der calculi).
neck caused by an enlarged prostate gland. The dynamic factor -Adrenergic antagonists reduce the dynamic factor. They
refers to excessive stimulation of -adrenergic receptors in the competitively antagonize -adrenergic receptors, thereby caus-
smooth muscle of the prostate, urethra, and bladder neck. The ing relaxation of the bladder neck, prostatic urethra, and
detrusor factor refers to irritability of hypertrophied detrusor prostate smooth muscle. They do not shrink an enlarged
muscle as a result of long-standing bladder outlet obstruction. prostate. The onset of action is days to weeks, depending on the
Drug treatment goals for benign prostatic hyperplasia include need for up-titration of the daily dose to achieve a therapeutic
relieving obstructive and irritative voiding symptoms, pre- response. Dose limiting adverse effects include hypotension and
venting complications of disease, and reducing the need for syncope. In addition, delayed or retrograde ejaculation has been
surgical intervention. reported. Combined use with antihypertensives, diuretics, or
Single-drug treatment with an -adrenergic antagonist is pre- phosphodiesterase inhibitors can increase the risk of hypoten-
ferred for patients with moderate symptoms of benign prosta- sive episodes.
tic hyperplasia. Single-drug treatment with a 5-reductase Among the -adrenergic antagonists, alfuzosin is considered
inhibitor should be reserved for patients with signicantly functionally uroselective because in usual therapeutic doses, it
enlarged prostates of at least 40 g (1.4 oz). produces relaxation of the bladder neck and prostatic smooth
791
muscle with minimal peripheral vascular relaxation. Although EPIDEMIOLOGY AND ETIOLOGY
alfuzosin appears to produce less hypotension than terazosin
and doxazosin, it is not clear if it has the same cardiovascular BPH is present as microscopic disease in many elderly males.1
prole as tamsulosin. Tamsulosin is unique in that it is phar- The prevalence increases with advancing patient age. However,
macologically uroselective and exerts greater antagonism of only about 50% and 25% of patients with microscopic BPH
1A- and 1D-receptors, which predominate in prostatic and disease develop an enlarged prostate on palpation and clinical
bladder detrusor muscle, respectively. Tamsulosin exerts voiding symptoms, respectively.2 It is estimated that 25% of
comparatively low antagonism of vascular 1B-receptors. males 40 years of age or more have voiding symptoms consis-
Therefore, tamsulosin can be started with a therapeutic dose, tent with BPH,3 and 20% to 30% of all male patients who live
which achieves peak effects sooner than with immediate- to the age of 80 years will require a prostatectomy for severe
release formulations of terazosin and doxazosin, which must voiding symptoms of BPH.
be up-titrated. Tamsulosin appears to have the lowest poten- Two etiologic factors for BPH include advanced patient age
tial to cause hypotension. In various clinical trials, tamsulosin and the stimulatory effect of androgens.
is well tolerated in the elderly, and in patients taking diuretics
and antihypertensives. It is also commercially available in a Prior to 40 years of age, the prostate in the adult male stays
controlled-release dosage formulation. Therefore, with the same size, approximately 15 to 20 g. However, in males
chronic use, tamsulosin can be taken once daily at the who have reached 40 years of age, the prostate undergoes a
patients convenience. growth spurt, which continues as the male advances in age.
5-Reductase inhibitors shrink enlarged prostates, reducing Enlargement of the prostate can result in BPH.
symptoms caused by the static factor. They do so by inhibiting The testes and adrenal glands produce 90% and 10%,
5-reductase which is responsible for intraprostatic conversion respectively, of circulating testosterone. Testosterone
of testosterone to dihydrotestosterone, the active androgen enters prostate cells, where predominantly type II 5-
which stimulates prostate tissue growth. The onset of action is reductase activates testosterone to dihydrotestosterone,
slow with peak shrinkage of the prostate taking up to 6 months. which combines with a cytoplasmic receptor. The complex
Unlike treatment with -adrenergic antagonists, 5-reductase enters the nucleus and induces changes in protein synthe-
inhibitors have been shown to reduce the incidence of acute sis which promote glandular tissue growth of the prostate.
urinary retention and need for prostate surgery in patients Thus, 5-reductase inhibitors (e.g., nasteride and dutas-
with signicantly enlarged prostate glands (more than 40 g), teride) directly interfere with one of the major etiologic
and those with elevated serum levels of prostate-specic antigen. factors of BPH.
Because 5-reductase inhibitors do not produce cardiovascu- The prostate is composed of two types of tissue: (1) glandu-
lar adverse effects, they are preferred for treatment of moder- lar or epithelial tissue, which produces prostatic secretions,
ate to severe symptoms of benign prostatic hyperplasia when and (2) muscle or stromal tissue, which can contract around
the patient is at risk of hypotension, but wants to be treated the urethra when stimulated. Whereas androgens stimulate
medically. Adverse effects include gynecomastia, decreased glandular tissue growth, androgens have no direct effect on
libido, erectile dysfunction, and ejaculation disorders. Drug stromal tissue growth. It has been postulated that stromal
interactions are uncommon. tissue growth may be stimulated by estrogen. Since testos-
When monitoring efcacy of drug treatment for benign pro- terone is converted to estrogen in peripheral tissues in males,
static hyperplasia, subjective endpoints include relief of testosterone may be associated indirectly with stromal
obstructive and irritative voiding symptoms. Objective end- hyperplasia. Stromal tissue is innervated by 1A-receptors.
points include improvements of urinary ow rates, decreased When stimulated, prostatic stroma contracts around the
post-void residual urinary volume, and decreased complica- urethra, narrowing the urethra and causing obstructive
tions of disease. voiding symptoms.
The prostate is a heart-shaped, chestnut-sized organ that

encircles the portion of the proximal urethra that is located at PATHOPHYSIOLOGY
the base of the urinary bladder. The prostate produces secre-
tions which are part of the ejaculate. The symptoms and signs of benign prostatic hyperplasia
Benign prostatic hyperplasia (BPH) is the most common are due to static, dynamic, and/or detrusor factors. The static
benign neoplasm in males who are at least 40 years of age. BPH factor refers to anatomic obstruction of the bladder neck caused
can produce lower urinary tract voiding symptoms that are by an enlarged prostate gland. As the gland grows around the
consistent with impaired bladder emptying and bladder stor- urethra, the prostate occludes the urethral lumen. The dynamic
age. A common mode of treatment to reduce symptoms and/or factor refers to excessive stimulation of a1A-adrenergic receptors in
delay complications of the disease is drugs. For this reason, cli- the smooth muscle of the prostate and urethra, which results in
nicians should be knowledgeable of the medical management smooth muscle contraction. This reduces the caliber of the ure-
of this disease. thral lumen. The detrusor factor refers to bladder detrusor muscle
CHAPTER 49 / BENIGN PROSTATIC HYPERPLASIA 793
instability, in which bladder muscle bers have decompensated as CLINICAL PRESENTATION AND DIAGNOSIS11
a result of excessive, prolonged hypertrophy in response to pro-
longed bladder outlet obstruction. Patients with detrusor muscle
instability will develop irritative voiding symptoms such as Clinical Presentation of BPH
urinary urgency and frequency.3,4 Detrusor muscle bers are
embedded with a1D-receptors. Therefore, it has been pro-
posed that some a-adrenergic1D antagonists may be particu-
General
larly useful for controlling these symptoms.3
Patients may or may not be in acute distress. In early stages
In an enlarged gland, the epithelial/stromal tissue ratio is 1:5.3 of disease, the patient may complain of obstructive voiding
Androgens stimulate epithelial, but not stromal tissue hyperpla- symptoms. If untreated, in late stages of disease the patient
sia. Hence, androgen antagonism does not induce a complete may complain of irritative voiding symptoms, or acute uri-
reduction in prostate size to normal. This explains one of the nary retention, which is painful due to maximal distention of
limitations of the clinical effect of 5-reductase inhibitors. the urinary bladder. Also, the patient may be symptomatic of
Stromal tissue is the primary locus of 1-adrenergic recep- disease complications, including urosepsis, pyelonephritis,
cystitis, or overow urinary incontinence.
tors in the prostate. It is estimated that 98% of the -adrenergic
receptors in the prostate are found in prostatic stromal tissue. Of Symptoms
Patients may complain of obstructive voiding symptoms (e.g.,
the 1-receptors found in the prostate, 70% of them are of the urinary hesitancy, decreased force of urinary stream, straining
1A-sub-type.5 This explains why -adrenergic antagonists are to void, incomplete bladder emptying, dribbling, and intermit-
effective for managing symptoms of BPH.6 tency) and/or irritative voiding symptoms (e.g., urinary fre-
Symptoms of BPH are classied as obstructive or irritative. quency, nocturia, dysuria, urgency, and urinary incontinence).
Obstructive symptoms result from failure of the urinary blad- Severity of symptoms should be assessed by the patient using a
der to empty urine when the bladder is full. The patient will standardized instrument [e.g., the American Urological
Association (AUA) Symptom Scoring Index; Table 491].
complain of a reduced force of the urinary stream, urinary
However, it is important to recognize that a patients percep-
hesitation, dribbling, and straining to empty the bladder. tion of the bothersomeness of their voiding symptoms may not
Irritative symptoms result from the failure of the urinary match with the AUA Symptom Score. In this case, after thor-
bladder to store urine until the bladder is full. With long- ough evaluation of the signs and complications of BPH dis-
standing bladder outlet obstruction, detrusor muscle bers ease, if present, the physician and patient should discuss the
undergo hypertrophy so that the bladder can generate higher bothersomeness of the patients symptoms and decide together
pressure to overcome the bladder outlet obstruction and on the most appropriate course of treatment for the patient.9
Lower urinary tract symptoms (LUTS) is a term that refers to
empty urine from the bladder. Once maximal bladder muscle the collection of obstructive and irritative voiding symptoms
hypertrophy occurs, the muscle decompensates. The detrusor characteristic of, but not specic for, BPH. That is, other uro-
becomes irritable, contracting abnormally in response to logic diseases (e.g., urinary tract infection, prostate cancer, pro-
small amounts of urine in the bladder. As a result, the patient statitis, or neurogenic bladder) can also cause LUTS.
complains of urinary frequency and urgency. Signs
The natural history of untreated BPH is unclear in Enlarged prostate on digital rectal exam; check for
patients with mild symptoms. It is estimated that up to 38% prostate nodules or induration, which would suggest
of untreated men with mild symptoms will have symptom prostate cancer instead of benign prostatic hyperplasia as
the cause of the patients voiding symptoms
improvement over a 2.5- to 5.0-year period.7 It may be that Distended urinary bladder
such patients attribute their symptoms to aging, grow tolerant Rule out meatal stenosis or urethral masses which could
of their symptoms, or adopt behavioral changes in their cause voiding symptoms similar to LUTS
lifestyle that minimize their voiding symptoms. On the other Check anal sphincter tone as an indirect assessment of
hand, a signicant portion of patients with mild symptoms peripheral innervation to the detrusor muscle of the bladder.
will likely experience disease progression. In one Veterans Complications of Untreated BPH
Affairs study, approximately one-third of men with mild BPH Upper and lower urinary tract infection, urosepsis, urinary
symptoms, who were initially randomized to watchful waiting, incontinence refractory urinary retentions chronic, renal
failure, bladder diverticuli, bladder stones, or recurrent
developed progressive symptoms and required surgical inter- gross hematuria.
vention within 5 years of initial diagnosis.8 In patients with
Medical History
moderate to severe symptoms, the likelihood of developing Check the patients general health including previous sur-
complications of BPH is higher.9 Complications of BPH gery, presence of diabetes mellitus, or medications that
include acute refractory urinary retention, renal failure, uri- may cause or worsen voiding symptoms.
nary tract infection, urinary incontinence, bladder stones, Have the patient provide a diary of his voiding pattern for
large bladder diverticuli, and recurrent gross hematuria. the past week: date and time of each voiding, volume
Predictors of disease progression include an enlarged prostate voided, and whether or not the patient had urinary leak-
age during the day.
of at least 40 g (1.4 oz) and a prostate-specic antigen (PSA)
level of at least 4 ng/mL (4 mcg/L).10 (Continued )
TABLE 491. Questions to Determine the American

Clinical Presentation of BPH (Continued ) Urological Association Symptom Score5
Laboratory Tests Directions for the patient: The patient should be asked to respond
Serum prostate specic antigen (PSA) will be increased. to each question based on the absence or presence of symptoms
Urinalysis to rule out infection as a cause of the patients over the past month. For each question, the patient can respond
using a 1 to 5 scale, where 0 = not at all or none, 1 = less than
voiding symptoms; also check urinalysis for microscopic
1 time in 5, 2 = less than half of the time, 3 = about half of the
hematuria, which typically accompanies benign prostatic time, 4 = more than half of the time, and 5 = almost always.
hyperplasia. Directions for the clinician: After the patient completes the
Plasma blood urea nitrogen (BUN) and serum creatinine questionnaire, the scores for individual items should be tallied
may be increased as a result of long-standing bladder for a nal score. Scores of 07 = mild symptoms; scores of 819 =
outlet obstruction. moderate symptoms; scores more than 20 = severe symptoms.
Urinalysis to rule out urinary tract infection as the cause Questions to Assess Obstructive Voiding Symptoms
of irritative voiding symptoms. 1. How often have you had a sensation of not emptying your
bladder completely after you nished urinating?
Other Diagnostic Tests (Table 492) 2. How often have you found you stopped and started again sev-
Decreased peak and mean urinary ow rate (less than 10 eral times when you urinated?
to 15 mL/s) on uroowmetry; decreased urinary ow rate 3. How often have you had a weak urinary stream?
is not specic for BPH; it can also be due to other urolog- 4. How often have you had to push or strain to begin urinating?
ical disorders (e.g., urethral stricture, meatal stenosis, or Questions to Assess Irritative Voiding Symptoms
bladder hypotonicity) 5. How often have you found it difcult to postpone urination?
Increased post-void residual urine volume (more than 50 mL) 6. How often had you had to urinate again less than 2 hours after
you nished urinating?
Digital rectal exam to check for an enlarged prostate (more
7. How many times did you most typically get up to urinate from
than 15 to 20 g)
the time you went to bed at night until the time you got up in
Transurethral cytoscopy reveals an enlarged prostate, the morning?
which decreases urethral lumen caliber; information from
this procedure helps the surgeon decide on the best surgi-
cal approach Slowing disease progression. When compared to baseline,
Transrectal ultrasound of the prostate; a transrectal probe is serum BUN and creatinine should stabilize or decrease to
inserted to evaluate prostate size and best surgical approach
the normal range with treatment.
Transrectal prostate needle biopsy to be done if the patient
Preventing disease complications and reducing the need for
has areas of nodularity or induration on digital rectal exami-
nation; tissue biopsy can document the presence of prostate surgical intervention.
cancer, which can also cause enlargement of the prostate Avoiding or minimizing adverse treatment effects.
Intravenous pyelogram (IVP) will show retention of radio- Providing economical therapy.
contrast in the bladder if the patient has bladder outlet Maintaining or improving quality of life.
obstruction due to an enlarged prostate; only indicated in
patients with recurrent hematuria, recurrent urinary tract General Approach to Treatment
infection, renal insufciency, and urolithiasis
Filling cystometry provides information on bladder capac- Until recently, the principal approach to treatment focused on
ity, detrusor contractility, and the presence of uninhibited reducing BPH symptoms.
bladder contractions, which could also cause LUTS For patients with mild symptoms, which the patient does not
consider to be bothersome, watchful waiting is a reasonable
approach to treatment (Fig. 491). The patient is instructed to
schedule return visits to the physician every 3 to 6 months. At
each visit, the patients symptoms are reassessed using the AUA
TREATMENT Symptom Scoring Index and results are compared to baseline
(Table 493). In addition, the patient is educated about avoiding
Desired Outcomes factors that worsen obstructive and irritative voiding symptoms.
The digital rectal exam is repeated annually. If the patients symp-
11 Reducing or eliminating obstructive and irritative voiding
toms are unchanged, then watchful waiting is continued. If the
symptoms. An improvement in the AUA Symptom Score should
patients symptoms worsen, then specic treatment is initiated.11
be observed. Drug treatment with an a-adrenergic antagonist or
5a-reductase inhibitor is expected to reduce the AUA Symptom For patients with moderate to severe symptoms, the patient
Score by 30% to 50%, improve peak and mean urinary ow rate is usually offered drug treatment rst. a-Adrenergic antag-
by 1 to 3 mL/second, and decrease post-void residual urine onists are preferred over 5a-reductase inhibitors because the
volume to normal (less than 50 mL total) when compared to former have a faster onset of action (days to a few weeks) and
pretreatment baselines. The AUA Symptom Score may not improve symptoms independent of prostate size. 5a-reductase
correlate with response to therapy. inhibitors have a delayed onset of action (i.e., peak effect may
TABLE 492. Objective Tests Used to Assess the Size of the Prostate and Complications of Benign Prostatic Hyperplasia (BPH)
How the Test Is Normal Test Test Result in

Test Performed Result Patients with BPH
Digital rectal exam of Prostate is palpated Prostate is soft, symmetric, Prostate is enlarged, greater than 20 g;
the prostate (DRE) through the rectal mobile; size is 1520 g no areas of induration or nodularity
mucosa; the physician
inserts an index nger
into the patients rectum
Peak and mean urinary Patient drinks water until Peak and mean urinary ow Peak and mean urinary ow rates are
ow rate bladder is full; patient rate are at least 10 mL/second less than 10 mL/second
empties bladder; volume
of urine output and time
to empty the bladder are
measured; the ow rate
(mL/second) is calculated
Post-void residual urine Measurement of urine left in Post-void residual urine volume Post-void residual urine volume greater
volume (PVR) the bladder after the patient should be 0 mL than 50 mL is a signicant amount of
has tried to empty out his retained urine; this is associated
bladder; assessed by urethral with recurrent urinary tract
catheterization or infection
ultrasonography
Urinalysis Midstream urine is analyzed Urine should have no white Urine with white cells and bacteria
microscopically for white cells or bacteria in it is suggestive of inammation and
blood cells and bacteria infection; if positive, urine is sent for
bacteriologic culture
Prostate needle biopsy Transrectally, a biopsy needle is A normal prostate should have The biopsy is consistent with BPH
inserted into the prostate. no evidence of BPH or
Tissue core is sent to a prostate cancer
pathologist for analysis
Prostate-specic Blood test for this chemical Less than 4 ng/mL (4 mcg/L) Greater than or equal to 4 ng/mL
antigen (PSA) secreted by the prostate (4 mcg/L)
be delayed for up to 6 months), and are seldom effective in erectile dysfunction, retrograde ejaculation, urinary inconti-
patients with 2 smaller size gland (less than 40 g or 1.4 oz). nence, bleeding, or urinary tract infection. The gold standard
Any drug treatment must be continued as long as the patient is a prostatectomy, which can be performed transurethrally or
responds (Table 494).11 as an open surgical procedure. To avoid complications of
prostatectomy, minimally invasive surgical procedures, such as
For patients with complications of BPH disease (e.g., recur- transurethral incision of the prostate and laser prostatectomy
rent urinary tract infection, urosepsis, urinary incontinence, refrac-
are becoming popular options. Drug treatment is used in
tory urinary retention, chronic renal failure, large bladder diverticuli,
patients with severe disease when the patient refuses surgery or
recurrent gross hematuria, or bladder calculi secondary to prolonged
when the patient is not a surgical candidate because of con-
urinary retention), surgery is indicated. Although it is potentially
comitant diseases.11
curative, surgery can result in signicant morbidity, including
In the Multiple Treatment of Prostate Symptoms Study, it
was found that selected patients with moderate to severe
symptoms will benet from a combination of -adrenergic
antagonist plus 5-reductase inhibitor drug therapy.12
Patient Encounter 1, Part 1 Specically, the use of doxazosin plus nasteride is more effec-
tive than doxazosin alone or nasteride alone in relieving
symptoms, reducing the need for prostatectomy, and
AA is a 65-year-old male patient with an AUA symptom decreasing the incidence of BPH complications in patients at
score of 19, urinary hesitancy, a slow urinary stream, urinary highest risk of developing disease complications [i.e., those
frequency, and nocturia. He wakes up three times every night with prostate size of at least 40 g (1.4 oz) and a PSA of at least
to void. A digital rectal exam reveals an enlarged prostate of 4 ng/mL (4 mcg/L)]. Combination therapy is more expensive
approximately 40 g (1.4 oz). His PSA is 4 ng/mL (4 mcg/L). than monotherapy and also produces more adverse effects.
Therefore, the clinician should discuss the advantages and
What stage of BPH does this patient have? disadvantages of combination therapy with a patient before
deciding on a nal treatment regimen.
FIGURE 491. Algorithm for selec-

BPH tion of treatment of BPH based on
symptom severity. (From Lee M.
Benign prostatic hyperplasia. In:
DiPiro JT, Talbert RL, Yee GC, et al,
Severe symptoms and (eds.) Pharmacotherapy: A
Mild symptoms Moderate symptoms complications of BPH Pathophysiologic Approach.
6th ed. New York: McGraw-Hill;
Watchful waiting -Adrenergic antagonists -Adrenergic antagonists Surgery
or 5-reductase inhibitor plus 5-reductase inhibitor
If response, If no response, If response, If no response,

continue surgery continue surgery
Nonpharmacologic Therapy 4. Avoid taking over-the-counter medications that can worsen

obstructive voiding symptoms (e.g., antihistamines or
To reduce nocturia, patients should be instructed to stop
decongestants) (Table 495)
drinking uids several hours before going to bed, and then
voiding before going to sleep. During the day, patients should
avoid excessive caffeine intake, as this may cause urinary fre- Pharmacologic Therapy
quency. In addition, toilet mapping (knowing the location of
toilets on the way to and from various destinations) may help Alpha-Adrenergic Antagonist Monotherapy12
reassure the patient that he can still continue with many of his a-Adrenergic antagonists reduce the dynamic factor causing
routine daily activities. BPH symptoms. These drugs competitively antagonize a-adrenergic
Below is a list of several items clinicians should tell patients receptors, thereby causing relaxation of the bladder neck, prostatic
to do to minimize obstructive and irritative voiding symptoms: urethra, and prostate smooth muscle. A secondary mechanism of
action may be that -adrenergic antagonists induce prostatic
1. Discontinue or minimize oral uid intake after 6 P.M. apoptosis,14 which suggests that these agents may cause some
2. Void before going to bed shrinkage of an enlarged prostate. However, the clinical impor-
3. If taking a diuretic, take the diuretic in the morning, not the tance of this remains to be elucidated.3
evening All -adrenergic antagonists are considered equally effec-
tive in relieving symptoms.11 In various clinical trials, 30% to
80% of patients experience improvement in AUA Symptom
TABLE 493. Staging the Severity of BPH Based on AUA Score by 30% to 45% and 20% to 40% of patients experience
Symptom Score and Example Signs of Disease urinary ow rate increases of 2 to 3 mL/second.15 The onset
of action is days to weeks, depending on the need for up-
AUA Symptom
Score Signs of Disease titration of the dose from a subtherapeutic starting dose to a
therapeutic dose. An adequate clinical trial is considered to be
Mild Less than or equal Enlarged prostate on DRE,
to 7 peak urinary ow rate less
at least 1 to 2 weeks of continuous treatment at a full mainte-
than or equal to nance dose with any of these agents.11 Durable responses have
10 mL/second been demonstrated for up to 5 years of continuous use of
Moderate 819 All of the above, PVR greater terazosin,16 10 years with doxazosin,17 and 6 years with
than 50 mL, irritative tamsulosin.18 However, some patients will develop disease
symptoms
Severe Greater than 20 All of the above plus one or
progression despite treatment.19 -Adrenergic antagonists are
more complications hepatically catabolized. Therefore, in patients with signicant
of BPH hepatic dysfunction, these drugs should be used in the lowest
Note: The AUA Symptom Score focuses on seven items (incomplete emp- possible dose. None of these drugs require dosage modica-
tying, frequency, intermittency, urgency, weak stream, straining, and noc- tion in patients with renal dysfunction. These agents can be
turia) and asks that the patient quantify the severity of his complaints on differentiated by their adverse effect prole. Dose limiting
a scale of 0 to 5. Thus, the score can range from 0 to 35.
AUA, American Urological Association; BPH, benign prostatic hyper- adverse effects include hypotension and syncope, which are
plasia; DRE, digital rectal exam; PVR, post-void residual urine volume. more common with immediate-release terazosin and doxazosin,
TABLE 494. Comparison of -Adrenergic Antagonists and 5-Reductase Inhibitors for Treatment of Benign
Prostatic Hyperplasia47
Characteristic -Adrenergic Antagonists 5-Reductase Inhibitors

Relaxes prostatic smooth muscle Yes No
Reduces size of enlarged prostate No Yes
Useful in only enlarged prostates of No (works independent of the Yes
at least 40 g size of the prostate)
Efcacy in relieving voiding symptoms ++ +
and improving ow rate
Frequency of daily dosing Once or twice daily, depending Once daily
on the agent
Requirement for up-titration of dose Yes (for terazosin and doxazosin No
immediate-release); no (for
alfuzosin; possibly for
doxazosin extended-release
and tamsulosin)
Peak onset of action Days to 6 weeks, depending on 6 months
need for dose titration
Decreases PSA No Yes
Cardiovascular adverse effects Yes No
Drug-induced sexual dysfunction Ejaculation disorders Decreased libido, erectile
dysfunction, ejaculation
disorders
PSA, prostate-specic antigen.
less frequent with extended-release doxazosin and alfuzosin, Generation of -adrenergic antagonist. First-generation
and least frequent with tamsulosin.2022 Delayed or retrograde agents (e.g., phenoxybenzamine) block presynaptic and
ejaculation has been reported most often with tamsulosin postsynaptic -adrenergic receptors. Whereas blockade of
0.8 mg orally once a day. Combined use with antihyperten- postsynaptic -adrenergic receptors is desirable for BPH
sives, diuretics, or phosphodiesterase inhibitors can lead to management, blockade of presynaptic -adrenergic receptors
additive blood pressurelowering effects; however, this appears is undesirable, as it results in release of catecholamines and
to be less of a problem with tamsulosin.2022 tachycardia. Thus, rst-generation -adrenergic antagonists
-Adrenergic antagonists are recommended as rst-line are not used for treatment of BPH.3 Second-generation -
treatment for moderate to severe BPH. The agents in this adrenergic antagonists selectively block post-synaptic -adren-
pharmacologic class can be classied by several characteristics ergic receptors. Examples include terazosin, doxazosin, and
(Table 496): alfuzosin. Third-generation -adrenergic antagonists (e.g.,
tamsulosin) selectively block postsynaptic 1A-receptors.
Uroselectivity. Pharmacologic uroselectivity refers to prefer-
TABLE 495. Drugs That Can Cause Irritative or Obstructive ential inhibition of 1A- and 1D-receptors, which predom-
Voiding Symptoms inate in the prostatic stroma and bladder detrusor muscle,
respectively. Pharmacologically uroselective 1A-adrenergic
Pharmacologic antagonists have the potential to produce less hypotension,
Class Example Drugs Mechanism of Effect
as they have a lower propensity to antagonize -adrenergic1B
Androgens Testosterone Stimulate prostate receptors in the peripheral vasculature. Tamsulosin is the
enlargement
only commercially available -adrenergic antagonist with
-Adrenergic Phenylephrine, Stimulate contraction pharmacologic uroselectivity. Despite the potential of
agonists pseudoephedrine of prostatic
smooth muscle
inhibiting -adrenergic receptors in both the prostate and
peripheral vasculature, functionally uroselective -adrenergic
Anticholinergic Antihistamines, Block bladder
agents phenothiazines, detrusor muscle antagonists in usually-prescribed doses, produce effective
tricyclic contraction, thereby relaxation of prostatic smooth muscle with minimal vascular
antidepressants, impairing bladder vasodilation. Thus, blood pressurelowering effects are mild
antiparkinsonian emptying or absent. The only functionally uroselective -adrenergic
agents
antagonist is alfuzosin extended-release tablets. The mecha-
Diuretics Thiazides diuretics, Produce polyuria nism of functional uroselectivity is unclear. It may be related
loop diuretics
to a drug formulation which produces a higher concentration
TABLE 496. Comparison of Pharmacologic Properties of -Adrenergic Antagonists
Terazosin Doxazosin Alfuzosin Tamsulosin

Brand Name Hytrin Cardura Uroxatral Flomax
Generation Second Second Second Third
Uroselective No No Functionally and clinically Pharmacologically and clinically
uroselective uroselective
Need for uptitration Yes Yes (with immediate- No No
release); no (with
extended-release)
Daily oral dose (mg) 520 28, immediate-release; 10 0.40.8; 0.8-mg/day dose has not
48, extended-release consistently produced clinical
improvement over 0.4 mg/day20
Best time to take doses At bedtime Immediate-release: After meals for best On an empty stomach
anytime during the oral absorption for best oral absorption;
day; however, it is if taken 30 minutes after a
typically given meal, as recommended by the
at bedtime manufacturer, peak absorption
Extended-release: time is delayed, thereby further
anytime during reducing the potential for
the day hypotensive adverse effects20,24
Half-life (hours) 12 22 5 10
Formulation Immediate- Immediate-release and Extended-release Modied-release
release extended-release
Cardiovascular adverse ++ ++ + 0 to +
effects
Ejaculation disorders + + + ++
Rhinitis + + + +
Malaise + + + +
in target tissues than in non-target tissues.23,24 Both pharma- Adverse effects. Hypotensive adverse effects of -adrenergic
cologic and functional uroselective agents appear to be clin- antagonists can range from asymptomatic blood pressure
ically uroselective, in that they improve BPH symptoms reductions to dizziness and syncope. This adverse effect is
without causing cardiovascular adverse effects in humans.13 most commonly associated with immediate-release terazosin
Pharmacologic and functional uroselectivity are dose- and doxazosin, and is less commonly associated with
related phenomena. Large daily doses of tamsulosin or alfu- extended-release alfuzosin, and least commonly associated
zosin may cause loss of uroselectivity with resultant with tamsulosin.2022 To minimize rst-dose syncope from ter-
hypotension and dizziness in some patients. azosin and doxazosin immediate-release, a slow up-titration
Need for up-titration of daily dose. Up-titration is required from a subtherapeutic dose of 1 mg/day to a therapeutic dose
for terazosin and immediate-release doxazosin. It is mini- is essential. The rst dose should be given at bedtime so that
mally required for extended-release doxazosin and tamsu- the patient can sleep through the peak serum concentration
losin. It is not required for extended-release alfuzosin. of the drug when the adverse effect is most likely to occur. A 3-
Plasma half-life. -Adrenergic receptors with short plasma to 7-day interval between each dosage increase should be
half-lives (e.g., prazosin) require multiple doses during the allowed and the patient should be maintained on the lowest
day. This is challenging for most patients, and, thus, prazosin effective dose of -adrenergic antagonist. If the patient is
is not recommended for BPH.11 non-compliant with his regimen of terazosin or doxazosin,
Dosage formulation. Immediate-release formulations of and he skips or interrupts treatment, the -adrenergic antag-
terazosin and doxazosin are quickly absorbed and produce onist should be restarted using the usual starting dose and
high peak plasma levels. Modied- or extended-release for- then retitrated up.3 He should not be instructed to simply
mulations of doxazosin, alfuzosin, and tamsulosin produce double up on missed doses or resume treatment with his cur-
lower peak levels, but more sustained therapeutic plasma rently prescribed daily dose, as this can lead to signicant
levels, than immediate-release formulations and have less hypotension.
potential for producing hypotensive episodes, thereby
allowing initiation of treatment with a therapeutic dose and Ejaculation disorders, including delayed and retrograde
once daily dosing.2527 ejaculation, occur with all adrenergic antagonists and are an
extension of the pharmacologic blockade of -adrenergic

receptors at the bladder neck (i.e., the bladder neck is unable Patient Encounter 2
to close during ejaculation in the presence of -adrenergic
blockade). However, the incidence appears to be dose-related
and highest with tamsulosin 0.8 mg daily, occurring in up to
BB has moderate BPH symptoms and is started on tamsulosin
26% of treated patients.28 Ejaculation disorders generally do
0.4 mg orally once a day. After 2 to 3 weeks, BB states that
not necessitate discontinuation of treatment. Although they his symptoms have not improved. He is not experiencing any
may decrease the patients satisfaction with the quality of drug-related adverse effects.
sexual intercourse, ejaculation disorders are not harmful to
the patient. What should be the next step in management of this
Rhinitis and malaise occur with -adrenergic antagonists patient?
and are an extension of the pharmacologic blockade of -
adrenergic receptors in the vasculature of the nasal mucosa
use, tamsulosin can be taken at any time of the day and at the
and in the central nervous system, respectively. Tolerance
patients convenience. Although the package insert states that
often develops to these adverse effects and they rarely require
the dose can be increased to 0.8 mg daily, no consistent
discontinuation of treatment. Avoid use of topical or oral
improvement in clinical efcacy has been observed in patients
decongestants, as these may exacerbate obstructive voiding
taking the higher dose.21,33
symptoms. Cautious use of antihistamines with anticholiner-
In patients with BPH and hypertension, it is not recom-
gic adverse effects is also recommended in patients with BPH,
mended to use an -adrenergic antagonist alone to treat both
as these drugs may cause acute urinary retention in patients
disorders. In the ALLHAT study, where doxazosin was com-
with an obstructed bladder neck.
pared to other agents for treatment of essential hypertension,
Alfuzosin has been linked to two cases of hepatitis.29.30 The
doxazosin was associated with a higher incidence of conges-
cause-effect relationship remains to be elucidated.
tive heart failure. Therefore, in patients with hypertension and
BPH, it is recommended that an appropriate antihypertensive
Potential for drug interactions. Hypotensive adverse effects
be added to an -adrenergic antagonist.11
of terazosin and doxazosin can be additive with those of
diuretics, antihypertensives, and phosphodiesterase inhibitors
5-Alpha-Reductase Inhibitor Monotherapy
(e.g., sildenal). In patients at greatest risk for hypotension,
5-Reductase inhibitors reduce the static factor, which
or in those patients who tolerate hypotension poorly,
results in shrinkage of an enlarged prostate. They do so by
including those with poorly controlled coronary artery dis-
inhibiting 5a-reductase which is responsible for intraprostatic
ease or severe orthostatic hypotension, tamsulosin appears
conversion of testosterone to dihydrotestosterone, the active
to be the safest choice.22,31,32 In patients who cannot toler-
androgen which stimulates prostate tissue growth. In the
ate tamsulosin, a 5-reductase inhibitor or prostatectomy
prostate, there are two subtypes of 5-reductase; the majority
should be considered. When using -adrenergic antago-
is the type II isoenzyme type and the minority is the type I
nists in patients taking sildenal, tadalal, or vardenal,
isoenzyme type. In addition, 5-reductase inhibitors induce
patients should be instructed to allow a 4-hour interval
apoptosis of prostatic epithelial cells.34 The onset of action is
between each drug to minimize the likelihood of hypoten-
slow with peak shrinkage of the prostate taking up to 6 months.11
sive effects.
Unlike treatment with -adrenergic antagonists, 5-reductase
Among the a-adrenergic antagonists, tamsulosin is inhibitors have been shown to reduce the incidence of acute
unique in that it is the only commercially available third- urinary retention and need for prostate surgery in patients
generation a-adrenergic antagonist. It is pharmacologically with signicantly enlarged prostate glands [greater than 40 g
uroselective and exerts greater antagonism of a1A- and a1D- (1.4 oz)],11 and those with serum levels of prostate-specic
receptors, which predominate in prostatic and bladder detrusor antigen of at least 4 ng/mL (4 mcg/L).10 Because 5-reductase
muscle. Tamsulosin exerts comparatively low antagonism of inhibitors do not produce cardiovascular adverse effects, they
vascular a1B-receptors. Therefore tamsulosin can be started are preferred for treatment of moderate to severe BPH when
with a therapeutic dose, which achieves peak effects sooner the patient has an enlarged prostate of at least 40 g (1.4 oz), is
than with terazosin and doxazosin immediate-release, which at risk of hypotension, and wants to be treated medically. When
must be up-titrated. Tamsulosin appears to have the lowest compared to -adrenergic antagonists, 5-reductase inhibitors
potential to cause hypotension.2022 In various clinical trials, relieve BPH symptoms in 30% to 70% of patients and increase
tamsulosin has minimal hypotensive adverse effects and is well urinary ow rate by 1 to 2 mL/second, which is less improve-
tolerated in the elderly, as well as in patients taking diuretics, ment than that seen with -adrenergic antagonists.11 A mini-
antihypertensives, or phosphodiesterase inhibitors. It is also mum of 6 months is required to evaluate the effectiveness of
commercially available in a modied-release dosage formula- treatment. This is a disadvantage in patients with moderate to
tion, which is dosed at 0.4 mg orally once a day. With chronic severe symptoms, as it will take that long to determine if the
drug is or is not effective. Durable responses have been

demonstrated in responding patients treated up to 6 years with Patient Encounter 1, Part 2
nasteride and 4 years with dutasteride.3538 These agents are
hepatically metabolized. No specic recommendations for
dosage modication are currently available in patients with sig-
AA is started on nasteride 5 mg orally once a day. Four
nicant hepatic dysfunction; however, due to drug specicity for
weeks later the patient returns for a follow-up visit and
its enzyme target, it is unlikely that any dosage adjustment will be complains that he is not experiencing any symptom
required. No dosage adjustment is needed in patients with renal improvement.
impairment. Adverse effects include decreased libido, erectile
dysfunction, and ejaculation disorders, which generally decrease What should be the next step in management of this
in frequency with continued use, and gynecomastia and breast patient?
tenderness.34 Serum testosterone levels increase by 10% to 20%
in treated patients; however, the clinical signicance of this is not
clear at this time.11 Drug interactions are uncommon. These hypothesized that 5-reductase inhibitors may prevent the
drugs do produce a mean 50% decrease in serum levels of PSA. development of prostate cancer. The Predict Trial reported that
Therefore, to preserve the usefulness of this laboratory test as a finasteride reduced the detection of prostate cancer with pro-
diagnostic and monitoring tool, it is recommended that pre- static needle biopsy by 25%; however, higher-grade tumors
scribers obtain a baseline PSA prior to the start of treatment and were more common in treated patients.40 The ongoing
repeat it at least annually during treatment. A signicantly ele- Reduce Trial, which will follow dutasteride-treated patients
vated PSA in treated patients is an indicator for further diagnos- for 4 years, may provide more clarication on this issue.41
tic work-up.36 Exposure to 5-reductase inhibitors is contraindi-
cated in pregnant females, as the drugs may cause feminization of Combination Therapy
a male fetus. Pregnant females should not handle these drugs A combination of an -adrenergic antagonist and 5-reductase
unless they are wearing gloves. inhibitor may be considered in patients at high risk of BPH
5-Reductase inhibitors include nasteride and dutasteride. complications, which are dened as those with an enlarged
Finasteride is a selective type II 5-reductase inhibitor, whereas prostate of at least 40 g (1.4 oz) and a PSA of at least 4 ng/mL
dutasteride is a non-selective type I and II 5-reductase (4 mcg/L). In such patients, combination therapy may relieve
inhibitor. When compared to nasteride, dutasteride pro- voiding symptoms, and also reduce the risk of developing BPH-
duces a faster and more complete inhibition of 5-reductase related complications and reduce the need for prostatectomy by
in prostate cells. However, no difference in clinical efcacy or 67%.12 Since combination therapy is more expensive and asso-
adverse effects has been demonstrated between these two ciated with the array of adverse effects associated with each
agents. Thus, nasteride and dutasteride are considered ther- drug in the combination, clinicians should discuss the advan-
apeutically interchangeable (Table 497).39 tages and disadvantages of each treatment regimen with the
By reducing serum levels of dihydrotestosterone, which is patient before a nal decision is made.11
linked to the development of prostate cancer, it has been To streamline and reduce the cost of treatment regimens, it
has been suggested that the -adrenergic antagonist may be dis-
TABLE 497. Comparison of Pharmacologic Properties of continued after the rst 6 to 12 months of combination therapy.
5-Reductase Inhibitors36,48 However, long-term treatment is required to determine if such a
regimen is as effective as continuous combination therapy.42,43
Finasteride Dutasteride Another enhancement to BPH symptom management is
Brand name Proscar Avodart the addition of an anticholinergic agent to an -adrenergic
Sub-type inhibition of the Type II Types I and II antagonist. The rationale for the anticholinergic agent is that
5-reductase enzyme irritative symptoms are thought to be due to hyper-reactive
Percent of inhibition of serum 7076 9095
dihydrotestosterone level bladder detrusor muscle contraction, which can be amelio-
Percent of patients with 49 Greater rated by blockade of acetylcholine receptors.4 A recent study
reduction in serum than 85 documenting the addition of tolterodine to tamsulosin
dihyrotestosterone showed signicant irritative symptom improvement, more
Time to peak onset of 6 months 1 month than what was observed with tamsulosin alone. No cases of
reduction in serum
dihydrotestosterone level urinary retention were reported.45 In another study, the addi-
Percent inhibition of 8590 Greater tion of tolterodine to doxazosin improved overactive bladder
intraprostatic than 95 symptoms in patients with BPH; however, acute urinary
dihydrotestosterone retention developed in 3.3% of patients treated with the com-
Half-life 6.2 hours 35 hours bination. This adverse effect responded to discontinuation of
Daily dosage (mg) 5 0.5
tolterodine and insertion of an indwelling urethral catheter.46
OUTCOME EVALUATION It is likely that the dynamic factor may predominate as the
cause of symptoms in these patients. In contrast, drug treat-
Once the peak effects of drug treatment are expected to occur, ment failures after an initial good response to drug therapy
monitor the drug for effectiveness. Assess symptom improvement will likely be an indication of progressive BPH disease. In such
using the AUA Symptom Scoring Index. A reduction in symptom patients, surgical intervention may be indicated.
score is anticipated with symptom improvement. However, it Table 498 summarizes the adverse effects of the agents
should be noted that the AUA Symptom Score may not match the used to treat BPH and has management suggestions for these
patients perception of the bothersomeness of his voiding symptoms. situations.
If the patient perceives his symptoms as bothersome, independent
of the AUA Symptom Score, consideration should be given to mod-
TABLE 498. Summary of Adverse Effects of -Adrenergic
ifying the patients treatment regimen. Similarly, a patient may Antagonists and 5-Reductase Inhibitors and
regard his symptoms as not bothersome even though the AUA Management Suggestions
symptom score is high. In this case, the physician should objectively
assess symptoms at baseline and during treatment by performing a Drug Class Adverse Reaction Management Suggestion
repeat uroowmetry, which can detect an improvement in peak -Adrenergic Hypotension Start with lowest effective
and mean urinary ow rate. If the patient shows a response to antagonist dose, give doses at bed-
treatment, instruct the patient to continue the drug regimen and time, and slowly
have the patient return at 6-month intervals for monitoring. If up-titrate
at 0.5- to 1-week
the patient shows an inadequate response to treatment, the dose of intervals to a full
a-adrenergic antagonist can be increased (except for extended- therapeutic dose,
release alfuzosin) until the patients symptoms improve or until the if using terazosin or
patient experiences adverse drug effects. doxazosin immediate-
For the -adrenergic antagonists, the severity of release
Use tamsulosin, extended-
hypotensive-related adverse effects, which may manifest as release doxazosin, or
dizziness or syncope, may require a dosage reduction or a alfuzosin, as alternatives
slower up-titration of immediate-release terazosin or doxa- to immediate-release
zosin, or halting the up-titration of extended-release doxazosin products, particularly in
or tamsulosin. Extended-release alfuzosin is only available as a patients taking other
antihypertensives
single 10 mg tablet. If the patient develops adverse effects at Malaise Educate the patient that this is
this dose, the drug should be discontinued. Other adverse a common adverse effect;
effects of -adrenergic antagonists are nasal congestion, tolerance may develop to
malaise, headache, and ejaculation disorders. None of these malaise; usually it is not
generally require discontinuation of treatment and these often so severe that it requires
discontinuation of
improve as treatment continues. For the 5-reductase treatment
inhibitors, the most bothersome adverse effects are decreased Rhinitis Educate the patent that this is
libido, erectile dysfunction, and ejaculation disorders. In sex- a common adverse effect;
ually active males, erectile dysfunction may be improved with tolerance may develop to
erectogenic drugs; however, this adverse effect may necessitate rhinitis; usually it is not so
severe that it requires
discontinuation of treatment. discontinuation of
During continuing treatment of BPH, the patient should treatment
undergo an annual repeat PSA and DRE. A rising PSA level Retrograde Educate the patient that
suggests that the patient has worsening BPH, new-onset ejaculation this is a common
prostate cancer, or that the patient is non-compliant with his adverse effect and it is
not harmful
regimen of 5-reductase inhibitor. An abnormal DRE sug- 5-Reductase Gynecomastia Educate the patient that
gestive of prostate cancer would reveal a nodule or area of inhibitor this may be bothersome,
induration on the prostate, or a gland which is xed in place. but not harmful
In such a case, a prostate biopsy is required to rule out Decreased libido If the patient is sexually
prostate cancer. active, sexual counseling
may be helpful
Drug treatment failures may result from a variety of fac- Erectile dysfunction The addition of sildenal or
tors. Initial failure to respond to -adrenergic antagonists an other erectogenic drug
occurs in 20% to 70% of treated patients. It is likely in these may be helpful
patients that the static factor may predominate as the cause of Ejaculation Educate the patient that this
symptoms in these patients. Initial failure to respond to 5- disorders may occur but it is not
harmful
reductase inhibitors occurs in 30% to 70% of treated patients.

Chapple CR. Pharmacological therapy of benign prostatic hyperplasia/
lower urinary tract symptoms: an overview for the practicing
clinician. BJU Int 2004;94:738744.
Monitor the patient for the drugs effectiveness in reliev- Djavan B, Chapple C, Milani S, Marberger M. State of the art on the
ing symptoms by using the AUA Symptom Scoring Index. efcacy and tolerability of alpha1 adrenoceptor antagonists in
Monitor ensure that the score improves and that the patients with lower urinary tract symptoms suggestive of
patient subjectively feels that symptoms have improved. benign prostatic hyperplasia. Urology 2004;64:10811088.
If the patient has no improvement after several weeks of Flanigan RC, Reda DJ, Wasson JHM, et al. 5 year outcome of sur-
a therapeutic dose of -adrenergic antagonist or after gical resection and watchful waiting for men with moder-
6 months of a 5-reductase inhibitor, consider surgical ately symptomatic benign prostatic hyperplasia: a Department
intervention. of Veterans Affairs cooperative study. J Urol 1998;160:1217.
If the patient is started on an -adrenergic antagonist, Larson TR. Current treatment options for benign prostatic hyper-
monitor the patient for hypotension, dizziness, or syn- plasia and their impact on sexual function. Urology 2003;61:
cope. If present, assess the severity of each symptom. 692698.
Reduce the drug dose or discontinue the drug, as neces- Marberger M, Harkaway R, de la Rosette J. Optimising the medical
sary. If the patient has malaise or rhinitis, reassure the management of benign prostatic hyperplasia. Eur Urol 2004;45:
patient that these are usual, but bothersome, adverse 411419.
effect, that often improve with continued therapy. Marks LS. Use of 5-alpha reductare inhibitors to prevent benign pro-
If the patient is started on a 5-reductase inhibitor, moni- static disease. Curr Urol Rep 2006;7(4):293303.
tor the patient for drug-induced decreased libido, erectile McConnell JD, Roehrborn CG, Bautista OM et al. The long term
dysfunction, or ejaculation disorders. If severe, discon- effect of doxazosin, nasteride, and combination therapy on the
tinue the drug. clinical progression of benign prostatic hyperplasia. N Engl J
Med 2003;349:23872398.
Milani S, Djavan B. Lower urinary tract symptoms suggestive of
benign prostatic hyperplasia: latest update on 1 adrenoceptor
ABBREVIATIONS antagonists. BJU Int 2005; 95(Suppl 4):2936.
AUA: American Urological Association

BPH: benign prostatic hyperplasia
DRE: digital rectal exam
IVP: intravenous pyelogram
LUTS: lower urinary tract (voiding) symptoms
PSA: prostate-specic antigen
PVR: post-void residual urine volume


this chapter.
50 URINARY INCONTINENCE
AND PEDIATRIC ENURESIS
David R.P. Guay
LEARNING OBJECTIVES
1. Explain the pathophysiology of the major types of urinary incontinence (urge, stress,
overow, and functional) and pediatric enuresis.
2. Recognize the signs and symptoms of the major types of urinary incontinence and pediatric
enuresis in individual patients.
3. List the treatment goals for a patient with urinary incontinence or pediatric enuresis.
4. Compare and contrast anticholinergics/antispasmodics, -adrenoceptor agonists, dual
serotonin-norepinephrine reuptake inhibitors, vaginal estrogens, cholinomimetics, tricyclic
antidepressants, and vasopressin analogues in terms of mechanism of action, treatment
outcomes, adverse effects, and drug-drug interaction potential when used to manage
urinary incontinence or pediatric enuresis.
5. Identify factors that guide drug selection for an individual patient.
6. Formulate a monitoring plan for a patient on a given treatment regimen based on patient-
specic information.
7. Describe indicators for combination drug therapy of urinary incontinence or pediatric
enuresis.
8. Describe nonpharmacologic treatment approaches (including surgery) for urinary
incontinence or pediatric enuresis.
9. Formulate appropriate patient counseling information for patients undergoing drug therapy
for urinary incontinence or pediatric enuresis.
KEY CONCEPTS Many medications can inuence the lower urinary tract,
including those not used for managing genitourinary disor-
Accurate diagnosis and classication of urinary inconti- ders, and can precipitate new onset or aggravate existing void-
nence type is critical to the selection of appropriate drug ing dysfunction and urinary incontinence.
therapy. Nonpharmacologic treatment can allow the use of lower drug
Patient-specic treatment goals should be identied. This fre- doses. The combination of both therapies may have at least an
quently requires reaching a compromise between efcacy and additive effect on urinary incontinence signs and symptoms.
tolerability of drug therapy. These goals are not static and may The anticholinergic/antispasmodic drugs are the pharmaco-
change with time. logic rst-line treatments for urge urinary incontinence. They
Patient characteristics (e.g., age, comorbidities, concurrent are the most effective agents in suppressing premature detru-
drug therapies, and ability to adhere to the prescribed regi- sor contractions, enhancing bladder storage, and relieving
men) can also inuence drug therapy selection. symptoms.
Careful dose titration is necessary to maximize efcacy and Vaginally-administered estrogen plays only a modest role in
tolerability. managing stress urinary incontinence (urethral underactivity),
If therapeutic goals are not achieved, a switch to an alternative unless it is accompanied by local signs of estrogen deciency
agent should be made. (e.g., atrophic urethritis or vaginitis).
803
The major impediment to using the -adrenoceptor ago- perceived loss of self-control, loss of independence, and lack
nist class is the extensive list of contraindications. of self-esteem, and often curtail or substantially modify their
The use of duloxetine in stress urinary incontinence is com- activities for fear of an accident. Serious medical and eco-
plicated by (1) the potential for multiple clinically relevant nomic consequences may also occur in untreated or under-
drug-drug interactions with cytochrome P-450 2D6 and 1A2 treated patients, including perineal dermatitis and infections,
inhibitors, (2) withdrawal reactions if abruptly discontinued, worsening or lack of healing of pressure ulcers, urinary tract
(3) high rates of nausea and other side effects, (4) the hepa- infections (UTIs), falls, and the need for long-term institu-
totoxicity that contraindicates its use in patients with any tionalization in extended care facilities [including skilled
degree of hepatic impairment, and (5) its mild hypertensive nursing facilities (SNFs), or nursing homes].
effect.
In overow urinary incontinence due to atonic bladder, a
trial of bethanecol may be reasonable if contraindications do EPIDEMIOLOGY AND ETIOLOGY
not exist.
In overow urinary incontinence due to obstruction, the goal The true prevalence of UI has been difcult to determine
of treatment is to relieve the obstruction. because of methodologic issues such as varying denitions of UI
Considering that pharmacotherapy is inferior to select non- and reporting bias.2 Although the condition occurs across the
pharmacologic treatment modalities in pediatric enuresis, lifespan, the peak prevalence, at least in women, is around the
pharmacotherapy will be most valuable in patients who are age of menopause (~50 years) which is followed by a slight
not candidates for nonpharmacologic therapy due to non- decrease in the 55- to 60-year-old age group, and then a steadily
adherence or who do not achieve the desired outcomes on increasing prevalence after age 65. In general, the median preva-
nonpharmacologic therapy alone. lences of UI are as follows3:
Desmopressin is the rst-line drug choice in pediatric enuresis.
20% to 30% in young females
30% to 40% in middle-aged females
30% to 50% in elderly females (50% to 75% in female SNF
URINARY INCONTINENCE residents)
10% in adult males (in excess of 50% in elderly male SNF
Urinary incontinence (UI) is dened as the complaint of
residents)
involuntary leakage of urine.1 It is often associated with other
bothersome lower urinary tract symptoms such as urgency,
Urinary incontinence can result from abnormalities within
increased daytime frequency, and nocturia. Despite its preva-
(intrinsic to) and outside of (extrinsic to) the urinary tract.
lence across the lifespan and in both sexes, it remains an
Within the urinary tract, abnormalities may occur in the urethra
underdetected and underreported health problem that can
(including the bladder outlet and urinary sphincters), the blad-
have signicant negative consequences for the individuals
der, or a combination of both structures. Focusing on abnor-
quality of life. Patients with UI may be depressed due to a
malities in these two structures, a simple classication scheme
emerges for all but the rarest intrinsic causes of UI. Accurate
diagnosis and classication of UI type is critical to the selection of
appropriate drug therapy.
Stress Urinary Incontinence (SUI) (Urethral

Underactivity)4
A 50-year old woman with hypertension and diabetes comes
into your clinic seeking advice about which incontinence In SUI, the urethra and/or urethral sphincters cannot gener-
pads work best. After questioning her, you determine that ate enough resistance to impede urine ow from the bladder
she has multiple issues of low volume urine loss daily, when intra-abdominal pressures (that are transmitted to the
which is a signicant change (increase) from 1 year ago. All bladder, which is an intra-abdominal organ) are elevated.
episodes occur at times of physical activity. Shes a single Intra-abdominal pressures are elevated by exertional activi-
mother of three grown children, all delivered vaginally. Her
ties like exercise, running, lifting, coughing, and sneezing.
last menstrual period was 11 months ago.
The amount of urine lost is generally small with each episode.
What information suggests that she has UI? Nocturia and enuresis are rarely seen. The factors responsible
Does she have risk factors for UI? for urethral underactivity are incompletely understood,
What additional information do you need to know before although the loss of the trophic effects of estrogen on the
creating a treatment plan for this patient? uroepithelium at menopause is thought to be important. The
peak of SUI prevalence in the perimenopausal years supports
CHAPTER 50 / URINARY INCONTINENCE AND PEDIATRIC ENURESIS 805
this hypothesis. Clearly established risk factors for SUI be overcome by detrusor contractility. This functional or
include5: anatomic obstruction results in incomplete bladder emptying.
Clinically, in males this most frequently occurs in the context
Pregnancy of long-term chronic bladder outlet obstruction as outlined
Childbirth (vaginal delivery) previously. In females, urethral overactivity is rare but may
Menopause result from cystocele formation or surgical overcorrection
Cognitive impairment during anti-SUI surgery. In both sexes, systemic neurologic
Obesity diseases such as multiple sclerosis or spinal cord injury may be
Increasing age the etiology.
Unless the sphincter mechanism is compromised by surgery

Functional Urinary Incontinence4
or trauma, SUI is exceedingly rare in males. The most common
surgeries predisposing to SUI in males are radical prostatectomy Functional urinary incontinence is not generally caused by
for prostate cancer and transurethral resection of the prostate intrinsic urinary tract pathology. It is usually caused by factors
for benign prostatic hyperplasia. extrinsic to the urinary tract. Examples of factors predispos-
ing to functional incontinence include:
Urge Urinary Incontinence (UUI) (Bladder Immobility (due to pain, traction, or use of non-portable
Overactivity)4 medical devices)
Lack of or slowed access to toileting facilities
In UUI, the detrusor (bladder) muscle is overactive and con- Cognitive impairment (difculty with recognition of the
tracts inappropriately during the lling phase. The amount of urinary urge and proper response to it)
urine lost per episode can be as large as the entire contents of UTIs
the bladder may empty. Sleep may be disrupted by nocturia Postmenopausal atrophic urethritis and/or vaginitis
and enuresis. Diabetes mellitus (glucosuria leading to polyuria)
In most patients, the cause of bladder overactivity is unknown Diabetes insipidus (polyuria due to decreased antidiuretic
(idiopathic). Clearly-established risk factors for UUI include: hormone)
Pelvic malignancy (extrinsic pressure on urinary tract struc-
Increasing age tures causing obstruction)
Neurologic disorders (e.g., stroke, Parkinsons disease, multi- Constipation or fecal impaction (see section on pelvic
ple sclerosis, and spinal cord injury) malignancy)
Bladder outlet obstruction (e.g., benign or malignant pro- Congenital malformations
static enlargement or hyperplasia) Central nervous system disorder resulting in a decreased
level of consciousness (see section on cognitive impairment)
Overactivity may be myogenic or neurogenic in origin or a Depression (apathy leading to recognition and response
combination of both. These etiologies appear to be intercon- difculties)
nected and complementary.
Mixed and Drug-Induced Urinary Incontinence4

Overow Urinary Incontinence (OUI) (Urethral Frequently, two or more types of UI may co-exist in a given
Overactivity and/or Bladder Underactivity)4 patient, combinations termed mixed UI. This can lead to
diagnostic and therapeutic difculties due to the confusing
In OUI, an important but uncommon form of UI in both
array of presenting symptoms and the opposing effects that a
sexes, the bladder is lled to capacity at all times but cannot
given treatment can have in different types of UI (i.e., a given
empty, causing urine to leak out episodically. If caused by
drug may reduce symptoms of one type of UI but worsen
bladder underactivity, the detrusor muscle has weakened, in
those of other types). Another interesting type of mixed UI is
some cases enough to lose the ability to voluntarily contract.
co-existing bladder overactivity (UUI) and impaired bladder
In this case, the bladder cannot be emptied completely and
contractility (OUI). Most common in the elderly, this combi-
large volumes of residual urine remain after micturition.
nation is called detrusor hyperactivity with impaired contrac-
Clinically, this is most commonly seen in the setting of long-
tility (DHIC).
term chronic bladder outlet obstruction due to benign or
malignant prostatic enlargement. However, this may also be a Many medications can inuence the lower urinary tract,
manifestation of neurogenic bladder, frequently a consequence including those not used for managing genitourinary disorders,
of neuropathy in patients with diabetes. If due to urethral over- and can precipitate new onset or aggravate existing voiding dys-
activity, the resistance of the urethra and/or sphincters cannot function and UI (Table 501).
CLINICAL PRESENTATION AND DIAGNOSIS TABLE 501. Medications Inuencing Lower Urinary Tract
Function
Clinical Presentation of Urinary Medication Effect

Incontinence Related to Urethral Diuretics Polyuria, frequency, urgency
Underactivity4 -Adrenoceptor antagonists Urethral relaxation; may relieve
obstruction in males,
General induces/worsens SUI in
The patient usually notes UI during activities like exercise, run- females
ning, lifting, coughing, or sneezing. This type of UI is much -Adrenoceptor agonists Urethral constriction; aggravates
more common in females (seen only in males with lower uri- obstruction in males (may
nary tract surgery or injury compromising the sphincter). cause urinary retention),
Symptoms potential SUI treatment in
females
Urine leakage with physical activity (volume is proportional
to activity level). No UI with physical inactivity, especially Calcium channel blockers Urethral constriction (may
when supine (no nocturia). May develop urgency and fre- (dihydropyridines) cause urinary retention),
quency as a compensatory mechanism (or as a separate especially in males
component of bladder overactivity). Opioid analgesics Impaired bladder contractility
(may cause urinary
Diagnostic Tests retention)
Observation of urethral meatus (opening) while patient
Sedative-hypnotics Functional UI due to
coughs or strains.
immobility, delirium,
sedation
Psychotherapeutics with Urinary retention due to
Clinical Presentation of Urinary anticholinergic properties impaired bladder
Incontinence Related to Bladder Anticholinergics contractility or potential UUI
Overactivity4 treatment
TCAs Combination of anticholinergic
General and -adrenoceptor
Can have bladder overactivity and UI without urgency, if blocking activities can lead
sensory input from the lower urinary tract is absent. to unpredictable effects on
UI
Symptoms
Ethanol Polyuria and frequency (via
Urinary frequency (greater than 8 micturitions/day), urgency with
effects on ADH), functional
or without urge incontinence; nocturia (greater than or equal to UI (delirium, sedation),
2 micturitions/night) and enuresis may be present as well. urgency
Diagnostic Tests ACEIs Cough leading to SUI (ARBs do
Urodynamic studies are the gold standard for diagnosis. not induce cough)
Also urinalysis and urine culture should be negative (rule Cyclophosphamide Hemorrhagic cystitis due to
out urinary tract infection as cause of frequency). acrolein metabolite (prevent
with MESNA)
ACE-I, angiotensin-converting enzyme inhibitor; ADH, antidiuretic hor-
Clinical Presentation of Urinary mone (or vasopressin); ARB, angiotensin II receptor blocker, MESNA,
Incontinence Related to Urethral sodium 2-mercaptoethanesulfonate; TCA, tricyclic antidepressant; UI,
Overactivity and/or Bladder urinary incontinence; SUI, stress urinary incontinence; UUI, urge uri-
Underactivity4 nary incontinence.
General
Important but rare type of UI in both sexes. Urethral over- The clinical presentation of UI depends on the underlying
activity usually due to prostatic enlargement (males) or cys- pathophysiology. The literature evaluating the prevalences of
tocele formation or surgical overcorrection following different UI types by age and sex has produced widely varying
antiurethral underactivity (SUI) surgery (females). results due to a number of factors. The clinician should thus
Symptoms consider a given patient as having virtually any type of UI
Lower abdominal fullness, hesitancy, straining to void, until ruled out during diagnostic evaluation.
decreased force of stream, interrupted stream, sense of incom- A complete medical history and targeted physical examina-
plete bladder emptying. May have urinary frequency and tion are essential to correctly classify the type(s) of UI present.
urgency, too. Abdominal pain if acute urinary retention is also
It is important to assess the degree of annoyance due to symp-
present.
toms of the patient during the assessment. The degree of
Signs annoyance to the patient may not correlate well with the results
Increased postvoid residual urine volume. of quantitative tests such as symptom frequency/severity, use of
absorbent products, frequency/severity of neurologic signs, and ability to perform a voluntary pelvic muscle contraction in
postvoid residual urine volume. This is especially the case in females and size and surface quality of prostate in males)
hypersensitive and stoic individuals. Items to address during Pelvic exam (females) (look for evidence of prolapse of blad-
the evaluation are illustrated in Table 502. Components of the der, small bowel, rectum, or uterus, or estrogen deciency)
physical examination include4: Genital/prostate exam (men)
Direct observation of urethral meatus (opening) when
Abdominal examination (look for distended bladder) patient coughs/strains (urine spurt consistent with SUI)
Neurologic evaluation of perineum and lower extremities Perineum exam (looking for skin maceration, redness, break-
(includes digital rectal exam to check rectal tone, reexes, down, ulceration and evidence of fungal skin infection)
TABLE 502. Items Which Should Be Addressed During Diagnostic Evaluation of Urinary
Incontinence (UI)
Item Comments
Urine leakage
Use of absorbent products Yes/no, type(s), quantity, times of day worn
Quantity may relate more to personal
preference and hygiene than to UI type
and severity (e.g., use of large number
of pads by a fastidiously hygienic
patient with low volume loss)
Quantity lost per episode Dribbling versus small volumes
intermittently versus large volumes
Consistent or varied quantities
Precipitants Yes/no, physical activity, excessive uid
intake, drug(s)
Times of day Daytime/nighttime/both
Symptoms
Urgency Yes/no, how often, how severe, duration
from urge onset to micturition
Frequency Yes/no, daytime/nighttime/both, how often
Nocturia Yes/no, how often, proportion with UI
Obstructive symptoms Yes/no, type(s) (hesitancy, strain to void,
decreased force of stream, start and
stop stream, sense of incomplete
emptying), severity
Lower abdominal fullness Yes/no, how often, how severe
Comorbidities
Current medication use See Table 501 Remember CAMs, OTCs
Evidence of preexisting or new-onset
Diabetes mellitus
Metastatic or genitourinary malignancy
Multiple sclerosis or other neurologic disease
CNS disease above the pons Usually UUI
Spinal cord injury UUI or OUI, depending on level and
degree of completeness of injury
Recent non-genitourinary surgery Functional UI
Previous local surgery/radiation Prostate surgery, lower abdominal cavity
surgery (direct injury vs. denervation),
radiation (direct injury)
Gynecologic history Childbirth (vaginal vs. cesarean section),
prior gynecologic surgery, hormonal
status (pre- vs. postmenopausal)
Pelvic oor disease Constipation, diarrhea, fecal incontinence,
dyspareunia, sexual dysfunction, pelvic
pain
UTI Dysuria, CVA tenderness, frequency
Gross hematuria Possible bladder or other genitourinary cancer
CAM, complementary and alternative medications; CNS, central nervous system; CVA, costovertebral
angle; OTC, over-the-counter; OUI, overow urinary incontinence; SUI, stress urinary incontinence; UTI,
urinary tract infection; UUI, urge urinary incontinence.
Prevention of disease complications (e.g., dermatologic

Patient Encounter, Part 2: The Medical infections and skin breakdown, delay institutionalization)
History, Physical Examination, and Avoidance or minimization of adverse consequences of
Diagnostic Tests treatment
Minimization of treatment costs
PMH
Improvement in patients quality of life
Insulin-dependent diabetes mellitus since age 7; it is rea-
sonably well-controlled per patient
Hypertension for 2 years, currently controlled per patient
FH
Mother had diabetes and died of a myocardial infarction at At the primary care level, nonpharmacologic treatment of UI
62 years of age; father smoked 1 to 3 packs of cigarettes constitutes the chief approach to UI management. In patients in
per day and developed fatal lung cancer at age 57 whom pharmacologic or surgical management is inappropriate
SH or undesirable or refused, non-surgical nonpharmacologic
Works two jobs as a waitress; denies alcohol use or smoking treatment is the only option. Examples of patients tting this
scenario include:
Meds
NPH insulin 20 units before breakfast and 5 units before
supper Those not medically t for surgery
Enalapril 10 mg twice daily Those who plan future pregnancies (as pregnancy/childbirth
Aspirin 325 mg once daily can compromise the long-term results of certain types of
continence surgery)
ROS
Those with OUI whose condition is not amenable to surgi-
(+) Recurrent coughing, urinary incontinence, dyspareunia,
vaginal itching, multiple UTIs; () nocturia, enuresis, cal or drug treatment
urgency, dysuria, frequency, lower abdominal fullness, Those with comorbidities which place them at high risk for
decreased force of stream signicant side effects to drug therapy
Those who wish to delay or avoid surgery
PE
Those with mild to moderate symptoms who do not wish to
VS: Blood pressure 124/70 mm Hg, pulse 80 beats per minute,
respiratory rate 16/minute, temperature 37.0C (98.6F) undergo surgery or take medication
CV: RRR; normal S1, S2; no murmurs, rubs, gallops
Abd: Soft, non-tender, non-distended; (+) bowel sounds; Nonpharmacologic approaches include lifestyle modica-
bladder not palpable tions, scheduled voiding regimens, pelvic oor muscle rehabilita-
Neuro: Within normal limits (gross sensory, motor, reexes) tion, anti-incontinence devices, and supportive interventions.4,6
GU: Valsalva caused urine spurt; friable, bleeding vaginal Many of these are best utilized through attendance at multidis-
lining on pelvic exam ciplinary UI clinics staffed by specialist nurses and/or physical
Labs therapists in addition to physicians. Behavioral interventions
Hemoglobin A1c 8.2% (0.082); rest within normal limits are among the rst-line treatment approaches for SUI, UUI,
and mixed UI. However, these lifestyle modications, schedul-
Given this additional information, what is your assessing regimens, and pelvic oor muscle rehabilitation methods
ment of the patients condition? require a motivated patient and/or caregiver who can play an
Identify your treatment goals for the patient. active role in developing the treatment plan. Anything that inter-
What nonpharmacologic and pharmacologic alternatives feres with active participation (including cognitive dysfunction)
are available to the patient?
will render these approaches suboptimal. Patients/caregivers
also must attend regular follow-up visits to monitor outcomes.
Even if the results of nonpharmacologic treatment have not
TREATMENT
fully achieved the desired outcomes, if it has provided at least
some improvement in UI signs and symptoms, it should be con-
Patient-specic treatment goals should be identied. This tinued during pharmacologic treatment. Nonpharmacologic
frequently requires reaching a compromise between efcacy and
treatment can allow the use of lower drug doses. The combination
tolerability of drug therapy. These goals are not static and may
of both therapies may have at least an additive effect on UI signs
change with time.
and symptoms.
Surgery is rarely a rst-line treatment for UI. Surgery is gen-
Desired Outcomes
erally considered only when the degree of bother or lifestyle com-
Restoration of continence promise is sufcient and other non-operative therapies are either
Reduction of the number of UI episodes (daytime and undesired or have been ineffective. Surgery can be used to man-
nighttime) and frequency of nocturia age urethral overactivity due to benign prostatic enlargement and
bladder outlet obstruction (via endoscopic incision using a cys- tolterodine, which formulations should be recommended.
toscope). Bladder underactivity cannot be managed surgically There are few head-to-head clinical trials to assist in decision
and rarely is surgery considered for UUI. Surgery is most effec- making and those few that exist have demonstrated either
tive in the management of SUI. Surgery for SUI is directed broad equivalence or clinically-unimportant differences in
toward stabilizing the urethra and bladder neck and/or aug- efcacy. Patient characteristics (e.g., age, comorbidities, con-
menting urethral resistance using periurethral collagen and other current drug therapies, and ability to adhere to the prescribed
injectables. In males, SUI is best treated by implanting an arti- regimen) can also inuence drug therapy selection. Drug selec-
cial urinary sphincter.4 tion frequently will be based on differences in tolerability
(wherein the extended-release oral or transdermal formula-
Pharmacologic Treatment tions are better tolerated than the immediate-release formula-
tions) and cost. Careful dose titration is necessary to maxi-
The anticholinergic/antispasmodic drugs are the rst-line
mize efcacy and tolerability. The selected agent should be
pharmacologic treatment for urge urinary incontinence. They
titrated to the maximum tolerated dose and maintained there
are the most effective agents in suppressing premature detrusor
for at least 4 weeks in order to assure an adequate therapeutic
contractions, enhancing bladder storage, and relieving symp-
trial. If therapeutic goals are not achieved, a switch to an
toms. It must be emphasized that the improvements in clinical
alternative agent should be made. There is no rationale for use
and urodynamic parameters are modest at best, although still
of two or more anticholinergics concurrently at low doses.
considered by experts in the eld to be positive.13 In a recent
Other drugs, such as propantheline, avoxate, tricyclic
systematic review/meta-analysis of 56 clinical trials in UUI,
antidepressants (especially imipramine), dicyclomine, and
only four statistically-signicant differences in efcacy
scopolamine, are less effective, no safer, and/or have not been
between drugs were found. Solifenacin produced greater
adequately studied; therefore, their use is not recommended.6
reductions in the frequency of urgency episodes and fre-
Women with mixed UI (UUI plus SUI) or UUI plus
quency of micturition than did tolterodine immediate-release
atrophic vaginitis and/or urethritis may also benet from the
(IR). Oxybutynin extended-release (ER) produced a greater
addition of a locally-administered (per vagina) estrogen to
reduction in the frequency of incontinence episodes and a
anticholinergic therapy.
greater proportion of patients returned to continence com-
pared to tolterodine long-acting (LA).13
The major problem with existing agents is their lack of Stress Urinary Incontinence
selectivity to bladder muscarinic receptors, thus leading to The goal of pharmacologic therapy of urethral underactivity
dose-limiting side effects outside of the urinary tract. These is to improve the urethral closure mechanism by one or more
include dry mouth, constipation, blurred vision, confusion, cog- of the following:
nitive dysfunction, and tachycardia. With oxybutynin, orthosta-
sis due to -receptor blockade and sedation and weight gain due Stimulating adrenoceptors in the smooth muscle of the
to histamine-receptor blockade may also occur. Dry mouth is proximal urethra and bladder neck
the most problematic of the anticholinergic side effects and is fre- Enhancing the supportive structures underlying the urethral
quently dose-limiting. In the systematic review and meta-analysis mucosa
cited previously, there were multiple signicant differences Enhancing the positive effects of serotonin and norepinephrine
between agents. From the perspective of all-cause premature in the afferent and efferent pathways of the micturition reex
discontinuation from therapy, tolterodine LA followed by dar-
ifenacin and solifenacin were the best tolerated, while oxybu- There is no role for pharmacologic therapy in SUI in males
tynin IR was the least tolerated. From the perspective of adverse- resulting from surgery or trauma.17 It should be kept in mind
event proles, oxybutynin IR 5 to 7.5 mg/day and tolterodine (IR that SUI (in contrast to UUI) is frequently curable by surgery,
and LA) were the best tolerated, while darifenacin, oxybutynin IR at thus obviating years of drug therapy that may be incompletely
greater than 7.5 mg/day, oxybutynin transdermal (TD), solifenacin effective in symptom relief.
(5 and 10 mg/day), and trospium chloride (40 mg/day) were the
least tolerated. Oxybutynin IR at greater than 7.5 mg/day was the Estrogens4
least tolerated compared to all other anticholinergics in 13/20 Vaginally-administered estrogen plays only a modest role
(65%) rate comparisons, and was the only drug to be signi- in managing stress urinary incontinence (urethral underactiv-
cantly associated with urinary retention.13 ity), unless it is accompanied by local signs of estrogen deciency
Details regarding the pharmacokinetics, contraindica- (e.g., atrophic urethritis or vaginitis).
tions/precautions, and dosing of the ve recommended agents Although not supported by rigorous clinical trial evidence,
(oxybutynin, tolterodine, trospium chloride, solifenacin, and local (per vagina) and systemic estrogens have been considered
darifenacin) are illustrated in Table 503.712,1416 A current mainstays of pharmacologic management since the 1940s.
clinical controversy is which of these agents should be consid- They are believed to work by a trophic effect on uroepithelial
ered rst-line in UUI, and in the case of oxybutynin and cells and underlying collagenous subcutaneous tissue,
810
TABLE 503. Anticholinergic/Antispasmodic Drugs Recommended For Urge Urinary Incontinence
Parameter Oxybutynin Tolterodine Trospium chloride Solifenacin Darifenacin

Dosage forms IR tablets, solution IR tablets IR tablets IR tablets ER tablets
SR-XL tablets, SR-LA capsules
SR-TD patch
Dosing IR: 2.55 mg two to IR: 1 or 2 mg twice daily 20 mg twice daily 510 mg 7.515 mg once daily
four times daily once daily
SR (oral): 530 mg SR: 2 or 4 mg once daily
once daily
SR (TD): 3.9 mg/day patch
applied twice weekly
Kinetics Active metabolite Active metabolite Food decreased BA 7080% Metabolized Complex metabolism
(N-desethyl) (5-hydroxymethyl) Sign. altered in renal via CYP4503A4 (polymorphic
Not altered in renal or Polymorphic metabolism disease (decreased CL) but only one CYP4502D6,
hepatic disease or (CYP4502D6) but not hepatic disease active metabolite CYP4503A4)
advanced age Not altered in advanced or advanced age (4-hydroxy) Not altered in
age. Sign. altered in Sign. altered in severe advanced age,
hepatic disease (decreased renal impairment, renal impairment,
CL in cirrhosis) and renal moderate hepatic mild hepatic
disease (decreased CL) impairment (Child- impairment (Child
Pugh B), and Pugh A)
advanced age Sign. altered in
(decreased CL in all) moderate hepatic
impairment
(Child-Pugh B)
(decreased CL)
Contraindications Use caution if CYP4503A4 Reduce dose 50% in those Give on empty stomach Do not exceed 5 mg/day Do not exceed
and precautions inhibitors are also being taking CYP4503A4 inhibitor(s) Decrease dose 50% if CrCl less than 30 7.5 mg/day if patient
taken (decreased or with hepatic cirrhosis or when CrCl less than mL/minute, patient has is taking potent
oxybutynin CL) with CrCl less than 30 mL/minute moderate hepatic CYP4503A4
30 mL/minute impairment, or patient is inhibitor(s)
Antacid-SR (oral) prep. interaction taking CYP4503A4 Use caution if patient
(dose-dumping) (not seen inhibitor(s) is taking moderate
with PPI) If severe hepatic CYP4503A4
impairment, do not use inhibitor(s) or
CYP4503A4 or
2D6 substrate(s)
Do not chew, divide,
or crush the
extended-release
tablets
BA, bioavailability; CL, total body clearance; CrCl, creatinine clearance; CYP450, cytochrome P-450; ER, extended-release; IR, immediate-release; LA, long-acting; PPI, proton pump
inhibitor; Sign., signicantly; SR, sustained-release; TD, transdermal.
enhancement of local microcirculation, and enhancement of the SUI. Systemic estrogen therapy also carries numerous short- and
number and/or sensitivity of adrenoceptors. Open trials have long-term side effect risks (mastodynia, uterine bleeding, nau-
supported the use of estrogens administered by the parenteral, sea, thromboembolism, cardiac and cerebrovascular ischemic
oral, transdermal, and local routes of administration. However, events, and enhanced breast and endometrial cancer risks). If
randomized controlled trials have found no signicant clinical estrogens are to be used in SUI management, only locally-
or urodynamic effects of oral estrogen compared to placebo in administered products should be used (Table 504).
TABLE 504. Drugs Used for Stress Urinary Incontinence
Parameter Estrogens Pseudoephedrine Duloxetine

Dosage forms Avoid systemic (parenteral, oral, TD); vaginal: Tablets, solution DR capsules
tablet, cream, intravaginal ring
Dosing Estradiol 25 mcg vaginal tablets (insert one PV daily 1560 mg three 4080 mg/day
14 days, then one PV twice weekly) times daily (1 or 2 doses)
CEE vaginal cream (1/22 g daily PV; consider 3 weeks
on, 1week off; may be able to decrease frequency
of use over time)
Estradiol 2 mg vaginal ring (1 ring PV every 3 months)
Kinetics Use local route to minimize systemic BA and side effects Less than 1% of dose is Extensive metabolism
metabolized (inactive via CYP4502D6 and
metabolite) 1A2 (inactive
Primarily renal elimination metabolites)
of unchanged drug Not altered in advanced
Would not expect hepatic age, mild to moderate
impairment to have renal impairment, mild
an effect (no data) hepatic impairment
Expect sign. effect of renal (Child-Pugh A). Sign.
impairment and no altered in severe renal
effect of advanced age disease and moderate
(beyond decreased CrCl hepatic impairment
with age) (no data) (Child-Pugh B)
Systemic exposure to
duloxetine decreased
by 1/3 in smokers
(dose change
not recommended)
Contraindications/ Contraindications include known or suspected breast or Contraindications include Multiple drug-drug
Precautions endometrial cancer hypertension, interactions possible
Abnormal genitourinary bleeding of unknown etiology tachyarrhythmias, with CYP4502D6 and
Active thromboembolism (or history of TE assoc. with coronary artery disease, 1A2 substrates/
previous estrogen use) MI, cor pulmonale, inhibitors
hyperthyroidism, renal Avoid if CrCl less than
failure, narrow-angle 30 mL/minute and in
glaucoma all patients with
hepatic disease
Can raise BP
Do not discontinue
abruptly (withdrawal
syndrome)
Suicide risk even in
patients without
psychiatric disease
Avoid in uncontrolled
narrow-angle glaucoma
(causes mydriasis)
Hepatotoxic; avoid in
alcoholics even if
signs/symptoms of
hepatic disease are
absent.
BA, bioavailability; BP, blood pressure; CEE, conjugated equine estrogens; CrCl, creatinine clearance; CYP450, cytochrome P-450; DR, delayed-release;
MI, myocardial infarction; PV, per vagina; Sign., signicantly; TD, transdermal; TE, thromboembolism.
Alpha-Adrenoceptor Agonists4
Open and randomized controlled trials utilizing clinical and Patient Encounter, Part 3: Creating a
urodynamic endpoints have supported the use of a variety of Care Plan
-adrenoceptor agonists, including phenylpropanolamine,
ephedrine, and pseudoephedrine, in the therapy of mild and
moderate SUI. In addition, several studies have demonstrated this patients UI. Your plan should include: (1) a statement
clinical and urodynamic benets for combination estrogen of the drug-related needs and/or problems, (2) the goals of
-adrenoceptor agonist use over those of the individual therapy, (3) a patient-specic detailed therapeutic plan, and
agents. Phenylpropanolamine was removed from the United (4) a plan for follow-up to determine whether or not the
States market in late 2000 due to the risk of ischemic stroke in goals have been achieved and adverse events avoided.
women taking this drug.18 However, this drug is still available
via the Internet, so clinicians need to monitor and discourage
its use. Although still available by prescription, ephedrine is
considerably more toxic than other -adrenoceptor agonists Overow Incontinence Due to Bladder Underactivity4
and its use is not recommended. Although phenylephrine is In overow UI due to atonic bladder, a trial of bethanecol
now available in oral formulations, the lack of data regarding may be reasonable if contraindications do not exist. There is no
its use in SUI and the reported lack of efcacy in maximum established effective pharmacologic therapy for OUI due to poor
recommended doses for rhinitis suggest that this agent should bladder contractility (atonic bladder). The efcacy of the choli-
be avoided at present. nomimetic bethanecol (25 to 50 mg three or four times daily) is
This leaves the clinician with only one practical agent to use: uncertain and in well done clinical trials it has had mixed results.
pseudoephedrine (Table 504). Side effects include hyperten- In addition, its cholinomimetic effect is not urospecic and its
sion, headache, dry mouth, nausea, insomnia, and restlessness.19 side effects are bothersome, including muscle and abdominal
The major impediment to using the a-adrenoceptor agonist cramping, hypersalivation, diarrhea, and potentially life-threat-
class is the extensive list of contraindications (Table 504). In the ening bradycardia and bronchospasm. -Adrenoceptor blockers
past, -adrenoceptor agonist therapy was generally added to such as prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin
estrogen therapy in those insufciently improved with estro- may benet this condition by relaxing the bladder outow tract
gen alone and in whom its use was not contraindicated. With and hence reducing outow resistance. If pharmacologic therapy
the recent availability of duloxetine, treatment is now available fails, intermittent urethral catheterization by the patient or care-
for estrogen non- or hypo-responders who cannot take - giver three or four times per day is recommended. Less satisfac-
adrenoceptor agonists. tory alternatives include indwelling urethral or suprapubic
catheters or urinary diversion.
Duloxetine20
Overow Incontienence Due to Obstruction
Duloxetine is a selective serotonin-norepinephrine reuptake
In overow UI due to obstruction, the goal of treatment is
inhibitor similar pharmacologically to venlafaxine. Approved
to relieve the obstruction.
for the treatment of major depression and painful diabetic
peripheral neuropathy, its use in SUI is off-label. Duloxetine
enhances central serotonergic and adrenergic tone which is OUTCOME EVALUATION
involved in ascending and descending control of urethral
smooth muscle and the internal urinary sphincter. Urethral Monitor the patient for symptom relief. Have the desired
and urinary sphincter smooth muscle tone during the lling outcomes jointly developed by the health care team and the
phase are thus enhanced.21,22 The pharmacokinetics, con- patient/caregiver been achieved and to what degree? Inspect
traindications/precautions, and dosing of duloxetine are illus- the daily diary completed by the patient/caregiver since the
trated in Table 504.20,23 Clearly, duloxetine has demonstrated last clinic visit and quantitate the clinical response (e.g.,
modest efcacy in SUI and a major question is its role in SUI number of micturitions, number of incontinence episodes,
compared to estrogen and -adrenoceptor agonists. In the and pad use). If a diary has not been used, ask the patient
absence of head-to-head clinical trial data, this is a difcult how many incontinence pads have been used and how they
question to answer, at least for the comparison of duloxetine have been doing in terms of accidents since the last visit. If
to -adrenoceptor agonists. The use of duloxetine in stress appropriate, administer a short-form instrument used to
UI is complicated by (1) the potential for multiple clinically- measure symptom impact and condition-specic quality of
relevant drug-drug interactions with cytochrome P450 life and compare previous result(s).
(CYP450)2D6 and CYP4501A2 inhibitors, (2) withdrawal reac- Elicit adverse effects of drug therapy using a non-leading
tions if abruptly discontinued, (3) high rates of nausea and other approach and ask the patient/caregiver to judge their severity
side effects, (4) hepatotoxicity contraindicating its use in patients and what measures, if any, the patient used to ameliorate them.
with any degree of hepatic impairment, and (5) its mild hyper- Assess adherence (ask patient about missed doses or do a pill
tensive effect. count if the prescription container was brought to the visit).
The balance of clinical response and tolerability will dictate PEDIATRIC ENURESIS
the approach to adjusting drug dosage. Potential approaches
include dosage increase, maintenance, or decrease. If adverse Pediatric enuresis is not a disease but a symptom, which can
effects are quite bothersome to the patient and patient safety present alone or at the same time as other disorders, in chil-
and/or adherence are compromised, stop, or taper, the dren and adolescents. It is dened as the repeated voiding of
offender and initiate another drug option. urine into bed or clothes at least twice a week for at least three
consecutive months in a child at least 5 years old (per the
Diagnostic and Statistical Manual of Mental Disorders,
Patient Care and Monitoring Fourth Edition, Text Revision).24,25 Enuresis can still be present
even if the above frequency and duration parameters are not
met, provided that associated distress or functional impair-
ment exists. The terms nocturnal and diurnal refer to
1. Assess the patients symptoms to determine if patient- periods during sleep and while awake, respectively. Primary
enuresis refers to a process wherein the patient has never been
should be evaluated by a physician. Assessment
consistently dry throughout the night. Secondary enuresis
includes the types and severities of symptoms and the
presence or absence of exacerbating factors. Does the refers to a process wherein the patient has resumed wetting
patient have any UI-related complications? after a period of dryness of at least 6 months in duration.
Lastly, monosymptomatic and polysymptomatic enuresis
2. Review any available diagnostic data to determine dis-
ease status. should be differentiated. Monosymptomatic enuresis refers to
wetting at nightttract symptoms and no daytime symptoms.
3. Obtain a thorough medication history, including use of
Polysymptomatic enuresis refers to wetting at nighttime
prescription, non-prescription, and complementary and
alternative drug products. Determine which, if any, associated with other urinary tract symptoms (e.g., urge or
treatments in the past had been helpful as judged by the freqime without any other urinary uency) and daytime
patient. Could any of the patients current medications symptoms as well.
be contributing to UI? Enuresis is not a benign disorder that children will just
4. Educate the patient on lifestyle modications that may grow out of. Emotional and/or physical abuse of the child by
improve symptoms, including but not limited to, smoking adult caregivers lead to secondary problems such as chronic
cessation (for patients with cough-induced stress UI), anxiety, low self-esteem, and delayed developmental mile-
weight reduction for those patients with stress and urge stones such as attending camp or going on sleepovers at the
UI, prevention of constipation in patients at risk, caffeine homes of friends. The emotional and developmental damage
reduction, and modication of diet and uid intake produced by enuresis may be more signicant to the child
(e.g., timing and quantity of uid intake and avoidance than the enuresis itself.
of foods or beverages that worsen UI). The American Academy of Child and Adolescent
5. Is the patient taking the appropriate drug(s) for his or Psychiatrists and the International Childrens Continence
her type(s) of UI? Are the dose(s) appropriate? If not Society (ICCS) have published practice guidelines for the
(to either question), why? assessment and treatment of pediatric enuresis.24,25
6. Develop a plan to assess efcacy after a minimum of
4 weeks.
7. Assess changes in quality of life (physical, psychologi-
cal, social functioning, and well-being).
8. Evaluate the patient for drug-related adverse events, Five to seven million children and adolescents in the United
allergies, and interactions (drug-drug and drug-disease).
States suffer from nocturnal enuresis. Primary enuresis is
9. Stress the importance of adherence with the pre- twice as common as secondary enuresis. Enuresis is twice as
scribed regimen, including lifestyle modications. common in boys as compared to girls. The incidence of enure-
Recommend the most patient-friendly treatment
sis varies as a function of age24,25:
regimen possible.
10. Provide patient education regarding the disease state, 40% in 3-years-old
lifestyle modications, and drug therapy:
12% to 25% in 4-years-old
Causes of UI and what things to avoid (see #3 and #4,
15% to 20% in 5-years-old
above)
Possible UI complications 10% in 6-years-old
Timing of medication intake 6% to 10% in 7- and 8-years-old
Potential adverse events (limit to most frequent and/or 5% in 10-years-old
clinically-relevant) 2% to 3% in 12-years-old
Potential drug-drug interactions 1% to 3% in adolescents
0.5% in adults
Five to ten percent of children with enuresis will suffer the TABLE 505. Major Potentially Treatable Organic Causes of
condition as adults. It may also predispose to UUI in adults. In Enuresis
the enuretic population, 80% to 85% are monosymptomatic,
Potentially Treatable by Surgery
5% to 10% are polysymptomatic, and under 5% have an Ectopic ureter
organic cause. The spontaneous annual cure rate (i.e., restora- Lower UTI (correct congenital anomalies)
tion of continence) ranges from 14% to 16% (exception: at Neurogenic bladder
about 4 or 5 years of age, it may be as high as 30%). Bladder calculus (stone) or foreign body
The etiology of enuresis is poorly understood, but there is a Obstructive sleep apnea
Potentially Treatable by Drugs
clear genetic link. The incidence in children from families in UTI
whom there are no members with enuresis, where one parent Diabetes mellitus
had enuresis as a child, and where both parents had enuresis as Diabetes insipidus
children are 14%, 44%, and 77%, respectively. Loci for enuresis Fecal impaction
have been located on chromosomes 12, 13, and 22. Sleep disor- Constipation
ders are not considered major contributors with the exception of UTI, urinary tract infection.
sleep apnea. Enuresis occurs in all sleep stages in proportion to
the time spent in each stage. However, a small proportion of valproic acid, and theophylline can rarely cause and aggravate
individuals are not aroused from sleep by bladder distention and enuresis. Psychological factors are clearly contributory in only
have uninhibited bladder contractions preceding enuresis. a minority of individuals. The most frequent example of this
is secondary enuresis precipitated by a stressor such as
divorce, school trauma, sexual abuse, or hospitalization. In
PATHOPHYSIOLOGY rare cases, the family may be so dysfunctional that the child
has never been properly toilet-trained.
The vast majority of children with enuresis have normal uro-
dynamics, including nocturnal bladder capacity. Functional
bladder capacity can be estimated using this formula: age in TREATMENT
years + 2 = ounces of capacity. In some children, there appears
to be a relationship between developmental immaturity Desired Outcomes
(motor and language milestones) and enuresis, but the mech- Restoration of continence, which may not be an initially
anism is unknown. Drugs like lithium, clozapine, risperidone, realistic outcome
Reduction in the number of enuresis episodes
Prevention or amelioration of disease complications includ-
Clinical Presentation and Diagnosis ing adverse psychological effects on the patient and care-
givers or delay in developmental milestones
Avoidance or prevention of adverse treatment effects
Minimization of treatment costs
Proper assessment of the child or adolescent with enuresis
Improvement in the patients and caregivers quality of life
should explore every aspect of urinary incontinence, espe-
cially the genitourinary and nervous systems. The minimum
assessment should include24,25: General Approach to Treatment
Treatment is guided by the ndings of the patient assessment.
Interview of child and parent(s), being sensitive to the Daytime wetting, abnormal voiding such as unusual postur-
emotional consequences of the enuresis
Direct physical examination, looking for enlarged ade-
ing, discomfort, straining, or poor stream, history of recurrent
noids/tonsils, bladder distention, fecal impaction, abnor- UTIs, and abnormalities of the genitalia suggest the need for
mal genitalia, spinal cord anomalies, and abnormal neu- referral to a urologist. In the rare circumstance of a true psy-
rologic signs (look for an organic cause amenable to sur- chological cause, individual and/or family psychotherapy and
gery or drugs; Table 505) crisis intervention are recommended.
Obtain a urinalysis (consider a urine culture at the same In the absence of an identied cause and comorbidities,
time) monosymptomatic nocturnal enuresis is present which can be
amenable to nonpharmacologic and pharmacologic therapies.
A 2-week diary of wet and dry nights prior to intervention
is useful in that it can be used to monitor the response to Nonpharmacologic therapy should be utilized initially, pro-
treatment. A rst-morning urine specic gravity may help to vided that the patient and family are sufciently motivated.
predict response to desmopressin therapy. Polysymptomatic Use of one nonpharmacologic method at a time is reasonable,
presentation may require a more elaborate work-up, includ- provided that each is given an adequate trial period. If
ing voiding cystourethrogram, renal and/or bladder ultra- response is suboptimal after 6 months, a different method
sound, urodynamics, and sleep studies. should be substituted or added. There is some evidence to
justify combination therapy. There is no consensus as to when Dietary changes

pharmacologic therapy should be added to or substituted for Desensitization to allergens
nonpharmacologic therapy. Considering that pharmaco- Acupuncture27
therapy is inferior to select nonpharmacologic treatment modalities Chiropractic
in pediatric enuresis, pharmacotherapy will be most valuable in
patients who are not candidates for nonpharmacologic therapy due Pharmacologic Treatment
to non-adherence or who do not achieve the desired outcomes on The two primary agents used to treat enuresis are desmo-
nonpharmacologic therapy alone. pressin and imipramine (Table 507). Desmopressin is the
drug of choice in pediatric enuresis. Anticholinergics have a
Nonpharmacologic Treatment26 limited role (Table 507). Other agents have been studied with
The standard rst-line therapy is supportive in nature. This inconclusive results.28
involves education about the condition, demystication, and
29,30
assurance that the parents do not punish the child for enure- Desmopressin (DDAVP)
sis. Journal keeping, uid restriction, and nighttime awaken- A synthetic analogue of antidiuretic hormone (ADH), desmo-
ings of the child to preempt accidents make for a high level pressin (DDAVP) was rst studied in enuresis in the 1970s. It
of caregiver involvement. The behavioral treatments of enuresis was approved by the Food and Drug Administration (FDA) in
are explained in Table 506. Alarms, overlearning, and dry-bed 1990 for the treatment of nocturnal enuresis in children at least
training are the most complex and effective nonpharmacologic 6 years of age. It decreases the number of wet nights per week by
treatments available and compare favorably to pharmacologic a mean of 1.34. The between-study variability in response to
therapy. A 3- to 6-month trial is recommended. Once dryness DDAVP is quite large, with a frequency of wetting ranging from
is achieved, relapse rates are low. 10% to 91% of patients, but only 25% become completely dry
on the drug. Response is dose-independent for the nasal formu-
Measures that do not help include: lation (20 = 40 = 60 mcg); however, 20 mcg is the minimum dose
resulting in therapeutic benet. Response is dose-dependent for
Bladder stretching exercises (done by delaying voiding the oral formulation (for example, the number of wet nights fell
despite the urge to do so) 27%, 30%, and 40% with 0.2-, 0.4-, and 0.6-mg doses, compared
Hypnotherapy to 10% with placebo in one study). Benet exists only as long as
TABLE 506. Behavioral Treatments For Enuresis
Lifting Procedure wherein the caregiver takes the child to the toilet at regular
intervals during the night to urinate without fully awakening him or her
Night awakening Procedure wherein the caregiver fully awakens the child to void shortly
before he or she would usually have wet the bed; once the child is consis-
tently dry, the frequency of awakening drops or (for single awakenings) the
time of awakening is gradually moved to earlier in the night (i.e., closer to
bedtime) until the child is dry when awakened 1 hour after going to bed
Alarm An alarm device and a moisture-sensitive sensor are used in combination,
with the sensor being placed under the sheets, or more commonly,
attached to the childs pajamas or underwear near the urethra
Overlearning This is commenced at a minimum of 2 weeks after the alarm has rendered
the child dry; the child drinks 500 mL during the hour before going to
bed; alarm use is continued until he or she is dry for 14 consecutive
nights with the extra uid intake; is used to reduce relapse rates seen with
alarm use alone
Dry-bed training This begins with an intensive rst night of training which involves increased
uid consumption, hourly awakenings, praise when the bed is dry at
hourly awakenings, and, when the alarm goes off, a mild reprimand and
cleanliness training (child changes wet clothes and bed linens, remakes
the bed, resets the alarm); before going to bed and after each wetting, the
child engages in 20 practice trials of appropriate toileting (i.e., positive
practice): for each practice trial, the child lies in bed, counts to 50, arises
and attempts to urinate in the toilet, then returns to bed; on subsequent
nights, child is woken only once, usually about 3 hours after the child has
gone to bed; after a dry night, the night awakening moves up 30 minutes
earlier; it is discontinued when it is scheduled to occur 1 hour after bed-
time; after 7 consecutive dry nights, the alarm is discontinued, but is rein-
stitated if two episodes of wetting occur in a 1-week period
TABLE 507. Dosing of Pharmacologic Treatments of Enuresis signicant correlation of drug concentration with response. If
sufciently effective short-term, a 4- to 6-month trial is rea-
Desmopressin Nasal: Start with 10 mcg 1 hour before
sonable, followed by a weaning-off period of 3 to 4 weeks.
bedtime and titrate upward in 10 mcg
increments every week to a maximum of There is a high frequency of neurologic side effects in children,
40 mcg per day including lethargy, dizziness, and headache in 5%; irritability
Oral: Start with 0.2 mg 1 hour before bedtime in 11%; anxiety in 10%; and sleep disturbances in 16%.31
and titrate upward in 0.1 mg increments Gastrointestinal symptoms occur in about 25% of pediatric
every week to a maximum of 0.6 mg
patients.31
per day
Imipramine Start with 1 mg/kg per day (approx. 25 mg in
5- to 8-years-old and 50 mg in older children
Anticholinergics
and adolescents) and titrate in 0.5 mg/kg-
per-day increments every 2 weeks to a Oxybutynin has no signicant effect in monosymptomatic
maximum of 2.5 mg/kg per day nocturnal enuresis. Oxybutynin and related agents (see adult
Oxybutynin Start with 0.1 mg/kg per day and titrate UI section of this chapter) should be used only if the patient
upward; available in oral solution to has concurrent daytime urgency or frequency.
facilitate pediatric dosing.
Comparison of Therapies
Most of the comparisons between treatments have been made
the patient takes DDAVP, with relapse rates of up to 94% after by means of meta-analyses conducted by the Cochrane Enuresis
discontinuation. Insufcient data are available to judge the rela- Collaborative.28,30,3234 Unfortunately, most enuresis treatment
tive efcacies of the two formulations. DDAVP appears to work studies have been so poorly designed they compromise the
better with monosymptomatic versus polysymptomatic enuresis.
The oral route is generally preferred since nasal congestion and
sinusitis can reduce the bioavailability of the nasal formulation.
Careful screening to rule out Obstructed Manage
DDAVP is an ideal agent for rapid-onset, short-term use such as
functional or mechanical obstruction obstruction
attendance at camp or going on a sleepover. If the desire is for appropriately
long-term therapy and if it is sufciently effective short-term, a
3- to 6-month trial is reasonable. At the end of this period, the
drug should be tapered off by 0.1 mg (oral) or 10 mcg (nasal) Monotherapy with alarm or DDAVP
for 12 weeks minimum
per month. Relapse is less likely with a tapered withdrawal com-
pared to an abrupt discontinuation. Side effects to DDAVP are
minor and infrequent.31 The most serious complication, water Combine alarm with half-dose
intoxication, is extremely uncommon when DDAVP is used to DDAVP (allows 4 wet nights/week)
treat enuresis, with only 50 reported cases.31 However, electrolyte for 810 weeks
monitoring is recommended if intercurrent illness complicates
the situation. Children should also not drink more than 8
ounces of uid at dinnertime, 8 ounces in the evening, and none Increase DDAVP dose to allow only
1 wet night/week. Continue alarm
in the 2 hours prior to bed in order to reduce the risk of water
intoxication.
Imipramine32 Withdraw alarm when dry for

1 month. Continue DDAVP
The tricyclic antidepressant (TCA) imipramine was rst used in
the treatment of enuresis in the 1960s. Although trials involving
other TCAs have been performed over the years, there is insuf-
cient evidence to assess the relative performance of these agents DDAVP dose by 50% after dry for
2 more months
versus imipramine and the latter is considered the gold standard
TCA in enuresis management. Its mechanism of action is
unclear, although it is an anticholinergic and antispasmodic and
may increase plasma ADH concentrations. Up to 80% of treated Wean off DDAVP after dry for
2 more months
patients may respond, although the long-term continence rate is
only about 25%. A patient can expect approximately one fewer
wet night per week with imipramine use. As with DDAVP, ben- FIGURE 501. Preliminary (unvalidated) enuresis protocol pro-
posed by the International Childrens Continence Society
et only occurs as long as the drug is being taken, with relapse (2004). DDAVP, desmopressin.
rates after discontinuation of therapy of up to 50%. There is no
ability to pool studies for meta-analysis. With this in mind, the

comparative efcacies of monotherapy and combination Patient Care and Monitoring
therapies using the best data available follow.
The most effective nonpharmacologic method is the use
of bed alarms. Dening success as less than 1 wet night per
1. Assess the patients symptoms to determine if patient-
month, the initial success rate for alarms is 66%, with long-
term success after discontinuation occurring in 45% (versus should be evaluated by a physician. Assessment
1% with no treatment). However, this method requires highly includes the types and severities of symptoms and the
motivated families and the development of improvement is presence or absence of exacerbating factors. Does the
slow (over 4 to 12 or more weeks). Data are inadequate to patient have any enuresis-related complications?
compare the various commercial brands of alarms available 2. Review any available diagnostic data to determine dis-
to consumers or to compare alarms to other behavioral ease status.
interventions. Supplementing this method with either over- 3. Obtain a thorough medication history, including use of
learning or dry-bed training significantly reduces the prescription, non-prescription, and complementary and
already low relapse rates seen with alarms. Alarm therapy is alternative drug products. Determine which, if any,
also signicantly more effective than DDAVP, evaluated at treatments in the past had been helpful as judged by the
both the end of therapy and long-term. Similar ndings are patient and/or caregiver(s). Could any of the patients
noted for the alarm-versus-imipramine comparison. There current medications be contributing to enuresis?
are conicting data regarding the value of supplementing 4. Educate the patient and/or caregiver(s) on lifestyle mod-
the alarm method with DDAVP. A preliminary algorithm ications that may improve symptoms or assist the clini-
utilizing a combination of alarm therapy and DDAVP for cian in monitoring the responses to therapy, including
the treatment of pediatric enuresis has been formulated by but not limited to, uid restriction and journal keeping.
the ICCS (Fig. 501).25 The patient and/or caregiver(s) should be referred to
local enuresis clinics (if available) for training in non-
pharmacologic treatments such as use of bed alarms,
overlearning, and dry-bed training.
OUTCOME EVALUATION 5. Assess if the patient is taking the appropriate drug(s) for
his or her enuresis? Are the doses appropriate?
Monitor the patient for symptom relief. Have the desired 6. Develop a plan to assess efcacy after a minimum of
outcomes jointly developed by the health care team, the 3 months.
patient, and his or her parents/guardians been achieved and
7. Assess changes in quality of life (physical, psychological,
to what degree? Evaluate the daily diary completed by the and social functioning and well-being).
patient or parents/guardians since the last clinic visit and
8. Evaluate the patient for drug-related adverse events,
quantitate the clinical response (the number of dry nights
allergies, and interactions (drug-drug and drug-disease).
versus the total number of nights, and the frequency of
9. Stress the importance of adherence with the prescribed
nights with greater than or equal to 2 enuresis episodes). If a
regimen, including lifestyle modications and non-
diary has not been used, elicit the clinical response, in gen-
pharmacologic treatment. Recommend the most
eral terms, since the last visit. patient-friendly treatment regimen possible.
Elicit adverse events of therapy in a non-leading manner and
10. Provide the patient and/or caregiver(s) with education
ask the patient to judge their severity. Ask the patient or par-
regarding the disease state, lifestyle modications, and
ents/guardians what measures if any were used to ameliorate drug therapy:
them. Assess adherence (ask patient or parents/guardians The causes of enuresis and what things the patient
about missed doses; do pill counts if the prescription vial is and/or caregiver(s) can do to reduce its frequency
available). Possible enuresis complications
The balance of clinical response, tolerability, and burden Timing of medication intake
on the family will dictate the approach to management. As Potential adverse events (limit to most frequent and/or
most nonpharmacologic approaches are all or none and clinically relevant)
drug dosages after an initial titration period are fixed, the Potential drug-drug interactions.
major decision process involves either changing therapy
if clinical results are inadequate, or beginning or continuing
tapering-off and discontinuation of therapy after success. ABBREVIATIONS
There is no consensus on which approach to withdraw
rst, although the ICCS recommends the nonpharmaco- ADH: antidiuretic hormone
logic (alarm) therapy rst, then pharmacologic (DDAVP) BA: bioavailability
therapy. CAM: complementary and alternative medicine
CL: total body clearance KEY REFERENCES AND READINGS

CrCl: creatinine clearance Fritz G, Rockney R, Bernet W, et al. Practice parameter for the
CVA: costovertebral angle assessment and treatment of children and adolescents with
CYP450: cytochrome P-450 enuresis. J Am Acad Child Adolesc Psychiatry 2004;43:
DDAVP: desmopressin 15401550.
DHIC: detrusor hyperactivity with impaired contractility Guay DRP. Clinical pharmacokinetics of drugs used to treat urge
ER: extended-release incontinence. Clin Pharmacokinet 2003;42:12431285.
FDA: Food and Drug Administration Guay DRP. Duloxetine for management of stress urinary inconti-
ICCS: International Childrens Continence Society nence. Am J Geriatr Pharmacother 2005;3:2538.
IR: immediate-release Guay DRP. Drug forecast: Darifenacin: another investigational anti-
LA: long-acting cholinergic for overactive bladder. Consult Pharm 2005;20:
MESNA: sodium 2-mercaptoethanesulfonate 424431.
OTC: over-the-counter Guay DRP. Drug forecast: Solifenacin: an investigational anticholin-
OUI: overow urinary incontinence ergic for overactive bladder. Consult Pharm 2004;19:437444.
PV: per vagina Guay DRP. Trospium chloride: an update on a quaternary anti-
SNF: skilled nursing facility cholinergic for the treatment of urge urinary incontinence.
SR: sustained-release Ther Clin Risk Manag 2005;1:157166.
SUI: stress urinary incontinence Hjalmas K, Arnold T, Bower W, et al. Nocturnal enuresis: an inter-
TCA: tricyclic antidepressant national evidence based management strategy. J Urol 2004;
TD: transdermal 171(6 Pt 2):25452561.
UI: urinary incontinence Rovner ES, Wyman J, Lackner T, Guay D. Urinary incontinence. In:
UTI: urinary tract infection DiPiro JT, Talbert RL, Yee GC et al, eds. Pharmacotherapy: a
UUI: urge urinary incontinence Pathophysiologic Approach. 6th ed. New York: McGraw-Hill,
2005: 15471563.

this chapter.
Section 10. Immunologic Disorders
51 ALLERGIC AND
PSEUDOALLERGIC DRUG REACTIONS
J. Russell May and Philip H. Smith
LEARNING OBJECTIVES
1. Describe the potential incidence of allergic and pseudoallergic drug reactions and why it is
difcult to obtain accurate numbers.
2. Describe the Gell and Coombs categories of reactions.
3. Identify the classes of drugs associated most commonly with allergic and pseudoallergic
reactions.
4. Recommend specic treatment for a patient experiencing anaphylaxis.
5. Recommend an approach to drug selection in patients with multiple drug allergies.
6. Describe drug desensitization procedures for selected drugs.
KEY CONCEPTS penicillins and cephalosporins occurs. However, because of

their structural differences, the extent of cross-allergenicity
Allergic and pseudoallergic reactions represent 23.8% of between penicillins and cephalosporins appears to be relatively
reported adverse drug reactions, cause considerable morbid- low. Cross-allergenicity is less likely with newer-generation
ity and mortality, and are costly. cephalosporins than with the rst-generation agents.
Drug allergy is an adverse immune response to a stimulus; Reactions to sulfonamide antibiotics, ranging from mild
such responses traditionally are placed in the Gell and (most common) to life-threatening (rare), occur in 2% to 4%
Coombs categories: type I (immediate hypersensitivity), of healthy patients, with rates as high as 60% in patients with
type II (complement-mediated antibody reactions), type III acquired immune deciency syndrome (AIDS).
(immune complex reactions), and type IV (cellular or IgE-mediated urticarial/angioedema reactions and anaphy-
delayed-type hypersensitivity). However, drug exposures may laxis are associated with aspirin and non-steroidal anti-
stimulate several or all of these types of reactions. To compli- inammatory drugs. Urticaria is the most common form of
cate the picture further, drug reactions do not always t the IgE-mediated reaction. This class is second only to -lactams
categories. in causing anaphylaxis.
Reactions that resemble allergic reactions clinically but lack an Radiocontrast media may cause serious immediate pseudo-
immune basis have been referred to as pseudoallergic. They allergic reactions such as urticaria/angioedema, bronchospasm,
include almost the entire range of immediate hypersensitivity shock, and death. These reactions have been reduced with the
clinical patterns and range in signicance from the alarming introduction of non-ionic, lower-osmolality products.
but trivial anxiety or vasovagal reactions caused by local den- Opiates (e.g., morphine, meperidine, codeine, hydrocodone,
tal anesthetics to the potentially fatal reactions to ionic radio- and others) stimulate mast cell release directly, resulting in pru-
contrast media. ritus and urticaria with occasional mild wheezing. Although
Penicillins and cephalosporins both have a -lactam ring these reactions are not allergic, many patients state that they are
joined to an S-containing ring structure (penicillins: a thia- allergic to one or more of the opiates. Pretreatment with an
zolidine ring; cephalosporins: a dihydrothiazine ring). antihistamine may reduce these reactions. These pseudoallergic
Because of their structural likeness, allerginicity between reactions are rarely life-threatening.
819
820 SECTION 10 / IMMUNOLOGIC DISORDERS
Drug desensitization is a potentially life-threatening procedure immediate and inborn (the innate immune response) or
that requires continuous monitoring in a hospital setting with learned from previous infections and injuries (the adaptive
suitable access to emergency treatment and intubation. It immune response). Most drug reactions involve the adaptive
should be undertaken only under the direction of a physician response and certainly, in the sense that they cause more harm
with suitable training and experience. In such hands, desensiti- than good, are mistakes.
zation presents less risk than treatment failure with a less effec- T cells control these learned responses and decide which
tive alternative medication. tools to use in the reaction. Sometimes they choose several
different tools at once, and multiple reactions ensue, such as
Allergic and pseudoallergic drug reactions are reported when a person becomes sensitized to penicillin and has not only
together. They are rarely conrmed by testing, making statisti- anaphylaxis but hemolytic anemia and serum sickness. There
cal reporting imprecise, with both overreporting and underre- are different types of T cells, and they communicate either
porting. But there is no doubt that they are costly and cause directly with other cells or by chemical messages called
considerable morbidity and mortality. Allergic and pseudoal- cytokines. The pattern of cytokines released is one way T cells
lergic reactions may represent as many as 23.8% of reported have of determining which kind of response will occur. They are
adverse drug reactions.1 Between 10% and 15% of hospitalized broadly called Th1 and Th2 responses, with Th1 mostly respond-
patients incur drug reactions, with about a third possibly due to ing to infections and Th2 often producing allergy or asthma.
hypersensitivity; however, most allergic drug reactions are not Drug reactions generally represent T cell activation. The type
reported.1,3,4 Patients experiencing an allergic drug reaction of T cell activated determines the type of reaction to the drug.
require longer hospitalizations (close to 2 days) at a cost of Th1 cytokines (largely interferon-) produce many more chronic
more than $2,000 per day.2 A potential nancial burden can (and at times serious) skin reactions and destruction of cells (as
occur owing to the increased indirect cost of: (1) lost time in hemolytic anemia or thrombocytopenia); sometimes these
and labor, (2) the use of costlier alternative medications, and responses can damage tissues, such as the kidney (e.g., interstitial
(3) treatment failures. Outpatient rates are not well studied nephritis). Th2 cytokines tend to cause any antibodies produced
and are much more formidable to collect. Relying on a patients to be switched to the immune globulin E (IgE) or allergic anti-
history without an attempt to clarify the relationships between body class, which can result in hives or anaphylaxis. Other classes
drugs taken and symptoms experienced results in a confusing of antibodies are made frequently, and these can produce serum
scenario. Often, health care professionals and patients use the sickness or indirect destruction of cells (e.g., thrombocytopenia).
term drug allergy in such a general way that it is not useful T-cell receptors respond to one peptide only, which makes each
medically and, further, perpetuates a level of fear and concern activation response exclusive to the original stimulus (drug) or to
in the public and in medical practice that is inappropriate and chemical structures with very close resemblance.
costly. This same confusion often seems to lead medical per-
sonnel to ignore or forget drug allergy with sometimes cata- Antigens
strophic results. Clearly, an understanding of how allergic and
pseudoallergic reactions occur and how they might be man- Antigen-presenting cells recognize complex three-dimensional
aged or prevented is important to health care professionals and protein molecules of at least 1000 daltons (Da) in size. Most
their patients. drugs are much smaller than this and cannot be recognized on
their own. Only proteins such as insulin or exogenous sera are
identied and their peptides presented directly to T cells.
PATHOPHYSIOLOGY Drugs that are reactive chemicals may bond covalently to
body proteins, altering them and forming large enough mole-
Drug allergies are immune responses resulting from different cules for antigen-presenting cells to recognize. This process is
methods of recognition and activation, and reactions are called haptenation, and the smaller reactive molecule is called
affected by multiple physiologic mechanisms. This produces a a hapten. Other drugs are inert until they are partially metab-
confusing spectrum of clinical pictures and complex patho- olized (prohaptens), and their breakdown products bind
physiologic mechanisms. Drug allergy is an adverse immune native proteins to serve as antigens. Metabolic variations in
response to a stimulus; such responses traditionally are placed in some patients may produce more active haptens or prevent
the Gell and Coombs categories: type I (immediate hypersensi- these fragments from being detoxied, causing them to accu-
tivity), type II (complement-mediated antibody reactions), type III mulate and make binding proteins more likely.
(immune complex reactions), and type IV (cellular or delayed-type
hypersensitivity). Drug exposures may stimulate several or all of
Gell and Coombs
these types of reactions, and drug reactions do not always t
neatly into the categories. Type I reactions occur when the drug or its bound hapten
The immune system uses many tools such as blood vessel incites an IgE antibody response. IgE binds to high-afnity
dilation or constriction, causing uid to ood an infected area, receptors on mast cells and basophils. When the original anti-
or designing special cells to kill bacteria or the infected cells in gen cross-links the cell-bound IgE, the effector cell releases
which they harbor. The pattern of these responses is either enormous amounts of preformed mediators, producing the
CHAPTER 51 / ALLERGIC AND PSEUDOALLERGIC DRUG REACTIONS 821
well-known symptoms of immediate hypersensitivity:

urticaria, rhinitis, bronchoconstriction, and anaphylaxis. Clinical Presentation and Diagnosis
Type II reactions are produced by IgG (or IgM) antibody.
The drug or hapten that elicited the antibody response binds
to target cells. When antibody binds the drug, complement
The clinical presentation of a patient experiencing an allergic
activation destroys the cell. Blood dyscrasias such as throm-
reaction varies greatly. The primary reactions are as follows:
bocytopenia and hemolytic anemia are the most common
examples of type II reactions. Anaphylaxis
Type III or immune complex reactions also involve IgG anti- Anaphylaxis is an acute life-threatening allergic reaction.
Signs and symptoms involve the skin (e.g., pruritus and
body production. In this case, when the concentration of the sen-
urticaria), respiratory tract (e.g., dyspnea and wheezing),
sitizing drug or hapten is in slight excess to the antibody, the two
gastrointestinal tract (e.g., nausea and cramping), and car-
combine in the serum, producing lattices of antigen-antibody diovascular system (e.g., hypotension and tachycardia).
complexes. These are deposited, particularly in vessel walls. They Onset is usually within 30 minutes but can be as long as
activate complement, causing vasculitis. The classic forms of type 2 hours. Treatment for anaphylaxis must begin immedi-
III reactions are serum sickness (usually including arthralgias, ately. Anaphylaxis may recur 6 to 8 hours after exposure,
fever, malaise, and urticaria that develop 7 to 14 days after expo- so patients experiencing anaphylaxis should be observed
sure to the causative antigen) and the localized Arthus reaction, for at least 12 hours.
a local inammatory response owing to the deposition of Cytotoxic Reactions
immune complexes in tissues. These reactions usually take the form of hemolytic anemia,
Type IV reactions are mediated by T cells themselves. thrombocytopenia, granulocytopenia, or agranulocytosis.
Delayed-type hypersensitivity reactions from positive tuber-
Immune Complex Reactions
culin tests to contact dermatitis are typical type IV reactions, These reactions involve a serum sickness like syndrome
but understanding T-cell function allows us to further dene (e.g., arthralgias, fever, malaise, and urticaria) that usually
this category, as shown in Table 511. develops 7 to 14 days after exposure to the causative
antigen.
Pseudoallergic Drug Reactions Dermatologic Reactions
Reactions that resemble allergic reactions clinically but Rashes may range from mild to life-threatening.
lack an immune basis have been referred to as pseudoallergic.
They include almost the entire range of immediate hypersensitiv- Urticariaitchy, raised, swollen areas on the skin, also
known as hives.
ity clinical patterns. Pseudoallergic reactions range in signicance
Maculopapular rasha rash that contains both macules
from the alarming but trivial anxiety or vasovagal reactions
and papules. A macule is a at discolored area of the skin,
caused by local dental anesthetics to sometimes fatal reactions to and a papule is a small raised bump. A maculopapular
ionic radiocontrast media. Cytotoxic reactions, serum sickness, rash is usually a large area that is red and has small, con-
and severe dermatologic reactions (e.g., Stevens-Johnson syn- uent bumps.
drome and toxic epidermal necrolysis) are immunologic Erythema multiformea rash characterized by papular
processes that are not likely to be mimicked by non-immune (small raised bump) or vesicular lesions (blisters) and red-
processes seen with pseudoallergic reactions. dening or discoloration of the skin often in concentric
Pseudoallergic reactions are important in patient counsel- zones about the lesion.
ing and management considerations. The reactions represent Stevens-Johnson syndromea severe expression of ery-
common biologic functions [e.g., direct histamine (H) release thema multiforme (also known as erythema multiforme
major). It typically involves the skin and the mucous mem-
by vancomycin and opiates], whereas immunologic (allergic)
branes with the potential for severe morbidity and even
reactions are based on the structure of the drug. Even a mild
death.
drug allergy carries signicant potential for anaphylaxis on Toxic epidermal necrolysisa life-threatening skin disorder
readministration. In contrast, pseudoallergic reactions tend to characterized by blistering and peeling of the top layer of
remain constant whether mild or severe. skin.
Pseudoallergic reactions, then, are reactions where the tools
of the immune system are used in exactly the same way as true
allergic reactions but without the learning response by T cells
and generally without the much greater danger that true PROBLEMATIC DRUG CLASSES
immunologic sensitization implies. Pseudoallergic reactions may AND TREATMENT OPTIONS
be thought of as a sub-type of idiopathic reactions rather than an
activation of the patients immune system with all its potential The rst priority when caring for patients with an allergic
for change and variety of adverse responses. The pathophysio- reaction is to avoid doing serious harm by administering a
logy of pseudoallergic reactions generally is unknown, but indi- drug that the patient cannot tolerate. We can establish the
cators of immune activation are not seen when they occur. likelihood of a relationship between the suspected drug and
TABLE 511. Reaction Classication, Clinical Symptoms, and Potential Causative Drugs5,6
Gell and Coombs

Classication Immune Response Clinical Symptoms Potential Causative Drugsa
Type I IgE Anaphylaxis, urticaria -Lactam antibiotics: penicillins (primarily),
cephalosporins, carbapenems
Non--lactam antibiotics: sulfonamides, vancomycin
Others: insulin, heparin
Type II IgG Hemolytic anemia, thrombocytopenia Quinidine, methyldopa, penicillins, heparin
Type III IgG and IgM Vasculitis, serum sickness, lupus Penicillins, sulfonamides, radiocontrast agents,
phenytoin
Type IV -Lactam antibiotics, sulfonamides, and phenytoin
IVa Th1 cytokines Tuberculin reaction, eczema
IVbb Th2 cytokines Maculopapular and bullous exanthema
IVcb Cytotoxic T cells Same as IVb, also eczema, pustular
(CD4 and CD8) exanthema
IVd T cells (IL-8) Pustular exanthema
a
These drugs represent a list of likely causative agents. Many drugs can cause these reactions.
b
IVb and IVc reactions may combine to produce erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
the observed reaction and also whether it is likely to be an reactions. These drugs and drugs classes include -lactam anti-
immune or idiopathic reaction by examining the time course biotics, sulfonamide antibiotics, aspirin and non-steroidal anti-
and specic signs and symptoms as precisely and objectively as inammatory drugs (NSAIDS), radiocontrast media, opiates,
possible. Re-evaluating the patients physical examination and cancer chemotherapeutics agents, insulin, and anticonvulsants.
laboratory values (taking into account preexisting diseases)
allows further clarication of the need to change treatments -Lactam Antibiotics
and to add therapy for the reaction itself.
Hypersensitivity reactions with -lactam antibiotics, espe-
Reviewing the original indications for the treatment that
cially penicillin, may encompass any of the type I through IV
caused the reaction is important. For example, in many respira-
Gell-Coombs classications. The most common reactions are
tory illnesses, a prescribed antibiotic may be unnecessary. If the
maculopapular and urticarial eruptions.7 While rare (less than
disease persists and indications for some treatment are estab-
0.05%), anaphylaxis to penicillins causes the greatest concern
lished, alternatives must be sought either by adjusting dose or
because they are responsible for the majority of drug-induced
administration rate, nding effective and unrelated alternative
anaphylaxis deaths in patients, accounting for 75% of all ana-
medication, or desensitizating the patient to the original drug.
phylaxis cases in the United States.5,8 The treatment of ana-
When drug reactions occur, the health care provider should
phylaxis is given in Table 512.9
carefully describe the nature of the reaction and the potential
The health care professional is faced with a difcult task
for it to reoccur. Many patients have frightening associations of
when approaching a patient who claims a history of penicillin
the term allergy with severe and unpredictable anaphylaxis. It
allergy. While as many as 12% of hospitalized patients state that
is difcult to undo the fears and behaviors created by injudi-
cious labeling of someone as allergic in the medical record.
Labeling a person as allergic may hamper future medical care Patient Encounter 1
because patients who are labeled allergic to a certain medica-
tion simply may refuse treatment or fail to adhere to regimens
containing the offending medication. If documentation clearly
describes the original reaction, health care providers can JB, a 44-year-old man, is admitted to the hospital for treat-
appropriately counsel patients about any true dangers. ment of a cellulitis. He states that he has no known allergies.
Managing patients experiencing an allergic reaction begins JB is prescribed intravenous nafcillin for his infection. During
the rst infusion, he notices that his ears are itching, and he
with stopping the offending agent. Anaphylaxis is a true medical
calls for a health care practitioner. On the practitioners
emergency and must be treated promptly. Understanding the
arrival, JB appears nervous and is having difculty breathing.
allergic reaction and potential for cross-allergenicity between
similar drugs will assist in selecting an alternative medication. What type of allergic reaction is JB most likely having?
Desensitization is a management option if the patient truly needs What is the rst action that this practitioner should take?
the medication and alternative drugs are not acceptable. While Outline the medical treatment for JBs reaction and when
any drug can cause an allergic or pseudoallergic reaction, sev- the medical treatment should start.
eral drugs and drug classes are strongly associated with such
TABLE 512. Pharmacologic Management of Anaphylactic TABLE 513. Procedure for Performing Penicillin Skin Testing
Reactions9
A. Percutaneous (prick) skin testing
Immediate Intervention MATERIALS VOLUME
Epinephrine 1:1000 (1 mg/mL) Pre-Pena 6 106 M 1 drop
Adults: Give 0.20.5 mg intramuscularly (IM) or subcutaneously Penicillin G 10,000 units/mL 1 drop
(SC); repeat every 5 minutes as needed -Lactam drug 3 mg/mL 1 drop
Children: 0.01 mg/kg (maximum 0.3 mg) IM or SC; repeat every 0.03% albumin-saline control 1 drop
5 minutes as needed Histamine control (1 mg/mL) 1 drop
Subsequent Interventions
Normal saline infusion 1. Place a drop of each test material on the volar surface of the
Adults: 1 to 2 L at a rate of 510 mL/kg in the rst 5 minutes, forearm.
followed by slow infusion 2. Prick the skin with a sharp needle inserted through the drop
Children: Up to 30 mL/kg in the rst hour at a 45 angle, gently tenting the skin in an upward motion.
Epinephrine infusion 3. Interpret skin responses after 15 minutes.
If patient is NOT responding to epinephrine injections and volume 4. A wheal at least 2 2 mm with erythema is considered positive.
resuscitation: 5. If the prick test is non-reactive, proceed to the intradermal test.
Adults: Epinephrine infusion [1 mg in 250 mL dextrose 5% in 6. If the histamine control is non-reactive, the test is considered
water (D5W)]: 14 mcg/minute, titrating based on clinical uninterruptible.
response or side effects B. Intradermal skin testing
Children: Epinephrine 1:10,000 (0.1 mg/mL): 0.01mg/kg (up to MATERIALS VOLUME
0.3 mg) over several minutes Pre-Pena 6 106 M 0.02 mL
Other Considerations after Epinephrine and Fluids Penicillin G 10,000 units/mL 0.02 mL
Diphenhydramine -Lactam drug 3 mg/mL 0.02 mL
Adults: 2550 mg intravenously (IV) or IM 0.03% albumin-saline control 0.02 mL
Children: 11.25 mg/kg (maximum of 300 mg/24 hours) Histamine control (0.1 mg/mL) 0.02 mL
Ranitidine 1. Inject 0.020.03 mL of each test material intradermally
Adults: 50 mg in D5W 20 mL IV over 5 minutes (amount sufcient to produce a small bleb).
Children: 1 mg/kg (up to 50 mg) in D5W 20 mL IV over 5 minutes 2. Interpret skin responses after 15 minutes.
Inhaled albuterol (bronchospasm resistant to epinephrine) 3. A wheal at least 6 6 mm with erythema and at least 3 mm
25 mg in 3 mL of normal saline, nebulized, repeat as needed greater than the negative control is considered positive.
Dopamine (hypotension refractory to uids and epinephrine) 4. If the histamine control is non-reactive, the test is considered
220 mcg/kg per minute titrated to maintain systolic blood pressure uninterruptible.
greater than 90 mm Hg Antihistamines may blunt the response and cause false-negative
Hydrocortisone (severe or prolonged anaphylaxis) reactions.
Adults: 250 mg IV (prednisone 20 mg can be given orally in
a
mild cases) Pre-Pen is not currently commercially available. The product is antici-
Children: 2.510 mg/kg per 24 hours pated to return to the market in the near future. Until it is available, skin
testing is not recommended.
D5W, dextrose 5% in water; IM, intramuscular; IV, intravenous; SC,
subcutaneous.
they have an allergy to penicillin, about 90% will have negative are rare, with a predicted range of 0.0001% to 0.1%. Minor skin
skins tests.10 Table 513 shows the traditional regimen for reactions, including urticaria, exanthem, and pruritus, are the
penicillin skin testing.11 However, Pre-Pen is not commercially most common allergic reactions to cephalosporins, with severe
available at this time. The product is anticipated to return to the reactions seen less often than with penicillins.13 If a patient has a
market in the near future. Until it is available, skin testing is not history of penicillin allergy but a penicillin skin test is negative,
recommended. This test only determines IgE-mediated reac- a cephalosporin may be given. If the test is positive, an alterna-
tions. A patient with a history of other serious reactions such as tive drug should be selected.
erythema multiforme, Stevens-Johnson syndrome, or toxic epi- For other -lactam agents, the recommendations are fairly
dermal necrolysis should not receive penicillins. straightforward.9 Carbapenems should be considered cross-
reactive with penicillins. Monobactams (e.g., aztreonam) do
Penicillins and cephalosporins both have a b-lactam ring not cross-react with any -lactam drugs except ceftazidime
joined to an S-containing ring structure (penicillins: a thiazolidine
because they share an identical R-group side chain.
ring; cephalosporins: a dihydrothiazine ring). Because of their
structural likeness, allerginicity between penicillins and
Sulfonamide Antibiotics
cephalosporins occurs. However, because of their structural differ-
ence, the extent of cross-allergenicity between penicillins and Sulfonamides are compounds that contain a sulfonamide moiety
cephalosporins appears to be relatively low. Cross-allergenicity is (i.e., SO2NH2). This group includes sulfonamide antibiotics,
less likely with newer-generation cephalosporins than with the furosemide, thiazide diuretics, sulfonylureas, and celecoxib.
rst-generation agents. Anaphylactic reactions to cephalosporins The sulfonamide antibiotics contain an aromatic amine at the
N-4 position and a substituted ring at the N-1 position. TABLE 514. Multiple Antibiotic Allergies: Obtaining
Because of this different chemical structure, cross-allergenicity Background Information15
with the other sulfonamides may not occur. However, because
For each antibiotic the patient claims to be allergic to, gather the
this has not been well studied, if a patient has a reaction to a
following information:
sulfonamide antibiotic, whether or not he or she will have a
reaction to these other sulfonamides remains controversial. What type of infection was being treated?
Have you ever received the drug without experiencing a
Predisposition to allergic reactions is a more likely reason than reaction?
cross-reactivity between these differing molecules.14 The sul- How many times have you received the drug and experienced
fonamide antibiotics are signicant because they account for a reaction?
the largest percentage of antibiotic-induced toxic epidermal What was the drug dose and route of administration with the
necrolysis and Stevens-Johnson syndrome cases.15 last reaction?
How many doses did you take before the onset of the last reaction?
Reactions to sulfonamide antibiotics, ranging from mild How many doses did you take after the last reaction?
(most common) to life-threatening (rare), occur in 2% to 4% of Can you describe the adverse reaction?
What was the duration of the reaction?
healthy patients, with rates as high as 60% in patients with acquired What treatment was given for the reaction?
immune deciency syndrome (AIDS).7 Anaphylaxis or anaphylac- Was there any permanent damage?
toid reactions occur within 30 minutes, most commonly after
For each antibiotic that the patient has received and does not
parenteral administration. Isolated angioedema or urticaria can claim to be allergic to, gather the following information:
occur within minutes to days. Serum sickness occurs within 1 to
What was the last type of infection being treated?
2 weeks. Fixed drug eruptions (lesions) occur within a half-hour What was the drug dose and route of administration?
to 8 hours. These lesions resolve within 2 to 3 weeks after drug Have you received this drug more than once without reactions?
removal. The more severe conditions of Stevens-Johnson syndrome
Other information to be gathered:
and toxic epidermal necrolysis occur 1 to 2 weeks after initiation
of therapy. Because trimethoprim-sulfamethoxazole is the drug Have you had adverse reactions to any other drugs? If so, give
dates and describe the reaction.
of choice for patients infected with Pneumocystis carinii, desensi- Document any risk factors for allergic reactions such as
tization may be necessary. A history of Stevens-Johnson syn- chronic urticaria, liver or kidney disease, human immunode-
drome or toxic epidermal necrolysis is an absolute contraindica- ciency virus, or any other immune deciencies.
tion to the desensitization procedure.
Patients with Multiple Antibiotic Allergies or bruising from these agents may describe themselves as
being allergic; however, these are not allergic or pseudoallergic
Dealing with patients who claim to have multiple antibiotic reactions.
allergies can be challenging. Combining knowledge of cross- Two specic conditions, aspirin-exacerbated respiratory disease
allergenicity with a careful assessment of patient history may (AERD) and chronic idiopathic urticaria, are important because
be helpful in designing an antimicrobial regimen. Table 514 they are seen commonly. AERD consists of asthma, rhinitis
outlines a series of questions that can be useful in developing with nasal polyps, and aspirin sensitivity.17 On exposure to
an effective treatment plan.16 If available, skin testing may be aspirin or an NSAID, patients experience rhinorrhea, nasal con-
useful to complete the puzzle. Often, an antibiotic of choice gestion, conjunctivitis, laryngospasm, and asthma. Chronic
may be used when the patients initial history would have sug- idiopathic urticaria is a major risk factor for aspirin- or NSAID-
gested otherwise (i.e., patients initial history suggests the induced pseudoallergic reactions.18 Patients with a history of
patient has an allergy to the medication). Based on data gath- chronic idiopathic urticaria are likely to see a are of urticaria if
ered, the patients record should reect: antibiotics that are aspirin or a cyclooxygenase (COX)-1-inhibiting NSAID is given.
safe to use if needed, antibiotics to be avoided, and antibiotics Cross-reactions between aspirin and older COX-1-inhibiting
that can be used only after desensitization. While this table NSAIDs exist in patients with AERD and chronic idiopathic
was designed with antibiotics in mind, it can be modied for urticaria. Even though product warning labels for COX-2
any allergy situation or multiple allergy situations. inhibitors state that these agents should not be used in these two
conditions, there are no reports of cross-reactivity in AERD and
Aspirin and Non-steroidal Anti-Inammatory Drugs only rare reports in patients with chronic idiopathic urticaria.19
Aspirin and NSAIDs can induce allergic and pseudoallergic IgE-mediated urticarial/angioedema reactions and ana-
reactions. Because these drugs are used so widely, with much phylaxis are associated with aspirin and NSAIDs. Urticaria is the
over-the-counter use, the health care professional must have a most common form of IgE-mediated reaction. This class is second
basic understanding of the types of reactions that can occur and only to b-lactams in causing anaphylaxis. The potential for
how to prevent them. Three types of reactions occur: bron- cross-reactivity between agents in IgE-mediated reactions
chospasm with rhinoconjunctivitis, urticaria/angioedema, and appears small, but caution is advised. Because aspirin therapy
anaphylaxis. Remember that patients with gastric discomfort is highly benecial in primary and secondary prevention in
coronary artery disease (CAD), aspirin desensitization should with corticosteroids and H1 and H2 receptor antagonists. The
be considered in patients who have had reactions to aspirin. platinum compounds have produced anemia, probably via a
Desensitization is contraindicated in patients who have experi- cytotoxic immunologic mechanism.
enced aspirin-induced anaphylactoid reaction, hypotension,
tachypnea, or altered consciousness. Alternate agents must be Insulin
used. A comprehensive approach to aspirin-sensitive patients
Allergic reactions to insulin include erythema, pruritus, and
with CAD has been described.20
indurations,22 which usually are transient. For the more trou-
blesome reactions, treatment options include dexamethasone,
Radiocontrast Media
desensitization, or change in delivery system (i.e., insulin
Radiocontrast media may cause serious immediate pump or inhaled insulin).
pseudoallergic reactions such as urticaria/angioedema, bron-
chospasm, shock, and death. These reactions have been reduced Anticonvulsants
with the introduction of non-ionic, lower-osmolality products.
A life-threatening syndrome can occur following a few weeks of
Because a small percentage of patients who have reacted previ-
therapy with anticonvulsants, such as phenytoin, phenobar-
ously to radiocontrast media will react if re-exposed, several
bital, and carbamazepine. Symptoms include fever, a macu-
steps should be taken to prevent reactions, including:
lopapular rash, generalized lymphadenopathy, and varying
degrees of internal organ dysfunction. The rash may be mild at
Determine if the study is necessary.
rst but can progress to exfoliative dermatitis. The causative
Be sure that the patient understands the risks.
agent should be withdrawn immediately. Valproic acid,
Ensure adequate hydration.
gabapentin, and lamotrigine may be acceptable alternatives.5
Use non-ionic, lower osmolarity agents.
Pretreat with prednisone 50 mg orally 13, 7, and 1 hour before

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PHARMACOTHERAPY

PRINCIPLES & PRACTICE

PATRICK M. MALONE, PHARMD, FASHP

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Contributors ix Section 2. Respiratory Disorders 209

PART TWO. DISORDERS OF ORGAN 14. Gastroesophageal Reux Disease 257

Section 1. Cardiovascular Disorders 9 15. Peptic Ulcer Disease 269

24. Fluids and Electrolytes 403 Section 7. Endocrinologic Disorders

Section 5. Neurologic Disorders 41. Thyroid Disorders 667

29. Parkinsons Disease 473 Section 8. Gynecologic and Obstetric Disorders

31. Headache 501 45. Contraception 737

Section 6. Psychiatric Disorders 46. Menstruation-Related Disorders 751

34. Schizophrenia 549 48. Erectile Dysfunction 779

38. Sleep Disorders 621 52. Solid-Organ Transplantation 829

61. Psoriasis 949 78. Osteomyelitis 1177

67. Central Nervous System Infections 1033

87. Lung Cancer 1323 97. Parenteral Nutrition 1493

88. Colorectal Cancer 1341 98. Enteral Nutrition 1511

89. Prostate Cancer 1357 99. Overweight and Obesity 1529

90. Malignant Lymphomas 1371 Appendices 1541

94. Skin Cancer 1425 Index 1581

Val R. Adams, PharmD Marianne Billeter, PharmD, BCPS

J. V. Anandan, PharmD Bradley A. Boucher, PharmD, FCCP, FCCM

Justin M. Balko, PharmD Toya M. Bowles, PharmD, BCPP

Kirk J. Brower, MD Diane M. Cappelletty, PharmD

Christopher L. Cook, PharmD, PhD Simon de Denus, BPharm, MSc

Clarence E. Curry, Jr., PharmD John M. Dopp, PharmD

Benjamin J. Epstein, PharmD, BCPS Steven Gabardi, PharmD, BCPS

Christopher A. Fausel, PharmD, BCOP Maqual R. Graham, PharmD

Jeffrey J. Fong, PharmD

David R. P. Guay, PharmD, FCCP Charles Hartis, PharmD

Thomas R. Howdieshell, MD, FACS, FCCP Deanna L. Kelly, PharmD, BCPP

W. Greg Leader, PharmD Mark A. Malesker, PharmD, FCCP

Mary Lee, PharmD, BCPS, FCCP J. Russell May, PharmD, FASHP

Cameron C. Lindsey, PharmD, BC-ADM Laura Boehnke Michaud, PharmD

Beverly Mims, PharmD Edith A. Nutescu, PharmD

Abby Morris, MD Catherine M. Oliphant, PharmD

Kimberly J. Novak, PharmD Charles A. Peloquin, PharmD

Jeremy A. Schafer, PharmD Sarah A. Spinler, PharmD, FCCP

Roohollah Shari, MD, FACS Robert J. Straka, PharmD, FCCP

Michael D. Thompson, PharmD, BCNSP William E. Wade, PharmD

Randy Wesnitzer, BS Pharm, PharmD Susan R. Winkler, PharmD, BCPS

Beth Alexander, PharmD, BCPS Kathleen L. Becker, MS, CRNP

John A. Bosso, PharmD, FCCP, BCPS Cynthia Carnes, PharmD, PhD

David M. Brissette, MMSc, PA-C Lorraine Cicero, MS, PharmD

Joseph E. Crea, DO, MHA Jennifer Fair, PharmD

Bonnie A. Dadig, EdD, PA-C Maisha Kelly Freeman, PharmD, BCPS

Michelle Devereaux, MA, RN, CNP Sveinbjrn Gizurarson, PhD

Erich J. Grant, MMS, PA-C Michael K. Jensen, BSPharm, MS

Mark A. Heisler, PharmD, BCPS Michael Kelsch, PharmD, BCPS

Thomas L. Lenz, PharmD, MA Candis M. Morello, PharmD, CDE, FCSHP

Robert Nelson, PharmD, BCPS Edward W. Randell, PhD, DCC, FCACB

Victor A. Padron, RPh, PhD Kathleen Reeve, DrPH, AOCN, ANP

Elaine Rosenblatt, MSN, APRN, BC Susan M. Stein, MS, RPh

Dana Sayre-Stanhope, EdD, PA-C Christopher J. Sullivan, MD, FACP

Karin Schurrer-Erickson, MA, RN, CNP Marianne Vail, MS, PA-C

Thomas White, JD, PA-C

Chap. 1 Introduction Chap. 7 Venous Thromboembolism

Chap. 5 Acute Coronary Syndromes Chap. 10 Hypovolemic Shock