Pharmacology

A Text Book Of
PHARMACOLOGY - I
As Per PCI Regulations
SECOND YEAR B. PHARM.
Semester - IV
Dr. S. B. Bhise Mrs. M. S. Bhise

Ex. Principal, Ex. Hon. Lecturer,
Govt. College of Pharmacy Government College of Pharmacy,
and Director of KARAD.
LNBC Institute of Pharmacy Raigon, SATARA
KLK Consultants Pune.
Sowmya B.A.
M. Pharm.
Assistant Professor
East West College of Pharmacy
Bengaluru.
N4360
Pharmacology - I ISBN 978-93-88293-84-6
First Edition : January 2019
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Acknowledgement
We are extremely thankful to Mrs. Roshan Shaikh and Mrs. Manasi Pingle for technical
editing of the content of the book. Encouragement from Prof. S. B. Gokhale and support
from Mr. Jignesh Furia is kindly acknowledged. We are thankful to Mr. Sameer Tuli for his
able assistance.
Nirali Prakashan and their employees are acknowledged for their active support in
bringing out the book at an appropriate time.
Dr. S. B. Bhise
Mrs. M. S. Bhise
Mrs. Sowmya B. A.
Preface
Clinical role of pharmacists have been identified during last 9 years after establishment
of regulations for Pharm. D in 2008 followed by establishment of Pharmacy practice
regulations in 2015 by Pharmacy Council of India. The practice of Pharmacy needs some
time to get strong footing in our country. During such time, subject like Pharmacology-I
need strong base by budding pharmacists.
The subject of Pharmacology has a different context for pharmacists in comparison to

doctors. While doctors give more importance to clinical effects, pharmacists are more
concerned with mechanism of action, and effects of drugs on animals can have equal
relevance in case of pharmacists. Trade names have equal relevance to both doctors and
pharmacists. This approach has been reflected in the content. Strong background of
physiology is needed for understanding of Pharmacology-I. Trade names of drugs have
been included in the appendix. The list is not exhaustive but includes common tradenames.
The content is as per new regulations of PCI and contains several additions as compared
to syllabi of conventional universities. It is expected that the book will be welcomed by
teachers and students of pharmacy. Still if there is any constructive criticism, it will be
appreciated and considered while revising next edition of the book. We appeal to all the
readers to forward their suggestions on the contents of the book.
Dr. S. B. Bhise
Mrs. M. S. Bhise
Mrs. Sowmya B. A.
Syllabus
Unit I [08 Hours]
1. General Pharmacology
(a) Introduction to Pharmacology: Definition, historical landmarks and scope of
pharmacology, nature and source of drugs, essential drugs concept and routes of
drug administration, Agonists, antagonists (competitive and non competitive), spare
receptors, addiction, tolerance, dependence, tachyphylaxis, idiosyncrasy, allergy.
(b) Pharmacokinetics: Membrane transport, absorption, distribution, metabolism and
excretion of drugs. Enzyme induction, enzyme inhibition, kinetics of elimination
Unit II [12 Hours]
General Pharmacology
(a) Pharmacodynamics: Principles and mechanisms of drug action. Receptor theories
and classification of receptors, regulation of receptors. drug receptors interactions
signal transduction mechanisms, G-protein–coupled receptors, ion channel receptor,
trans-membrane enzyme linked receptors, trans-membrane JAK-STAT binding
receptor and receptors that regulate transcription factors, dose response
relationship, therapeutic index, combined effects of drugs and factors modifying
drug action.
(b) Adverse drug reactions.
(c) Drug interactions (pharmacokinetic and pharmacodynamic)
(d) Drug discovery and clinical evaluation of new drugs: Drug discovery phase,
preclinical evaluation phase, clinical trial phase, phases of clinical trials and
pharmacovigilance.
Unit III [10 Hours]
2. Pharmacology of drugs acting on peripheral nervous system
(a) Organization and function of ANS.
(b) Neurohumoral transmission, co-transmission and classification of neurotransmitters.
(c) Parasympathomimetics, Parasympatholytics, Sympathomimetics, sympatholytics.
(d) Neuromuscular blocking agents and skeletal muscle relaxants (peripheral).
(e) Local anesthetic agents.
(f) Drugs used in myasthenia gravis and glaucoma
Unit IV [08 Hours]
3. Pharmacology of drugs acting on central nervous system
(a) Neurohumoral transmission in the C.N.S.special emphasis on importance of various
neurotransmitters like with GABA, Glutamate, Glycine, serotonin, dopamine.
(b) General anesthetics and pre-anesthetics.
(c) Sedatives, hypnotics and centrally acting muscle relaxants.
(d) Anti-epileptics
(e) Alcohols and disulfiram
Unit V [07 Hours]
4. Pharmacology of drugs acting on central nervous system
(a) Psychopharmacological agents: Antipsychotics, antidepressants, anti-anxiety agents,
anti-manics and hallucinogens.
(b) Drugs used in Parkinsons disease and Alzheimer’s disease.
(c) CNS stimulants and nootropics.
(d) Opioid analgesics and antagonists
(e) Drug addiction, drug abuse, tolerance and dependence.
Contents
1. General Pharmacology - I 1.1 - 1.40
1.1 Introduction to Pharmacology 1.1
1.1.1 Definitions 1.1
1.1.2 Historical Landmarks and Scope of Pharmacology 1.10
1.1.2.1 Historical Landmarks 1.10
1.1.2.2 Scope of Pharmacology 1.12
1.1.3 Nature and Sources of Drugs 1.13
1.1.4 Essential Drugs Concept 1.14
1.1.5 Routes of Drug Administration 1.14
1.1.6 Agonists 1.20
1.1.7 Antagonists (Competitive - Non-competitive) 1.20
1.1.7.1 Competitive Antagonists 1.21
1.1.7.2 Non-competitive Antagonists 1.21
1.1.7.3 Uncompetitive Antagonists 1.21
1.1.8 Spare Receptors 1.22
1.1.9 Addiction 1.23
1.1.10 Tolerance 1.23
1.1.11 Dependence 1.24
1.1.12 Tachyphylaxis 1.24
1.1.13 Idiosyncrasy 1.24
1.1.14 Allergy 1.24
1.2 Pharmacokinetics 1.25
1.2.1 Membrane Transport 1.25
1.2.2 Absorption 1.28
1.2.3 Distribution 1.30
1.2.4 Metabolism 1.32
1.2.5 Excretion 1.33
1.2.6 Enzyme Induction 1.34
1.2.7 Enzyme Inhibition 1.36
1.2.8 Kinetics of Drug Elimination 1.37
• Questions 1.39
2. General Pharmacology - II 2.1 - 2.36
2.1 Pharmacodynamics 2.1
2.1.1 Principles and Mechanisms of Drug Action 2.1
2.1.2 Receptor Theories 2.3
2.1.3 Classification of Receptors 2.3
2.1.4 Regulation of Receptors 2.4
2.1.5 Drug-Receptor Interaction 2.5
2.1.6 Signal Transduction Mechanisms 2.7
2.1.7 G-protein Coupled Receptors 2.9
2.1.8 Ion-channel Receptors 2.12
2.1.9 Trans-Membrane Linked Receptors 2.15
2.1.10 JAK-STAT Binding Receptor 2.16
2.1.11 Receptors Regulating Transcription Factors 2.18
2.1.12 Dose-Response Relationship (DRR) 2.20
2.1.13 Therapeutic Index (TI) 2.22
2.1.14 Combined Effects of Drugs 2.22
2.1.15 Factors Modifying Drug Action 2.23
2.2 Adverse Drug Reactions (ADRs) 2.23
2.3 Drug Interactions (Pharmacokinetic and Pharmacodynamic) 2.24
2.3.1 Pharmacokinetic Drug Interactions 2.24
2.3.1.1 Absorption Interactions 2.24
2.3.1.2 Transport and Distribution Interactions 2.24
2.3.1.3 Metabolism Interactions 2.25
2.3.1.4 Excretion Interactions 2.26
2.3.2 Pharmacodynamic Drug Interactions 2.27
2.4 Drug Discovery and Clinical Evaluation of New Drugs 2.27
2.4.1 Drug Discovery 2.27
2.4.2 Pre-clinical Evaluation 2.28
2.4.3 Phases of Clinical Trial 2.29
2.4.3.1 Phase 0 2.29
2.4.3.2 Phase I 2.29
2.4.3.3 Phase II 2.30
2.4.3.4 Phase III 2.30
2.4.3.5 Phase IV 2.31
2.4.4 Pharmacovigilance 2.32
• Questions 2.35
3. Pharmacology of Peripheral Nervous System 3.1 - 3.80
3.1 Introduction 3.1
3.2 Organisation and Functions of Autonomic Nervous System (ANS) 3.2
3.2.1 Organisation of ANS 3.2
3.2.1.1 Somatic Nervous System 3.2
3.2.1.2 Autonomic Nervous System (ANS) 3.3
3.2.2 Functions of ANS 3.6
3.3 Neuro-humoral Transmission, Co-transmission and Classification of Neuro-
transmitters 3.9
3.3.1 Neuro-humoral Transmission and Co-transmission 3.9
3.3.2 Classification of Neurotransmitters 3.10
3.4 Parasympathomimetics, Parasympatholytics 3.10
3.4.1 Biosynthesis, Storage and Release of ACh 3.10
3.4.2 Parasympathomimetics 3.15
3.4.3 Parasympatholytics 3.20
3.5 Sympathomimetics and Sympatholytics 3.28
3.5.1 Endogenous Sympathomimetics 3.28
3.5.1.1 Endogenous 3.28
3.5.1.2 Synthetic Sympathomimetics 3.36
3.5.1.2.1 Directly Acting Sympathomimetics 3.36
3.5.1.2.2 Indirectly Acting Sympathomimetics 3.46
3.5.1.2.3 Mixed Action Sympathomimetics 3.49
3.5.2 Sympatholytics 3.50
3.5.2.1 α-Adrenergic Blockers 3.50
3.5.2.2 β-Adrenergic Blockers 3.54
3.6 Neuro-muscular Blocking Agents and Skeletal Muscle Relaxants (Peripheral) 3.62
3.6.1 Neuromuscular Blocking Agents 3.62
3.6.2 Peripheral Skeletal Muscle Relaxants 3.68
3.7 Local Anaesthetic Agents 3.69
3.8 Drugs used in Myasthenia Gravis and Glaucoma 3.75
3.8.1 Drugs for Myasthenia Gravis 3.75
3.8.2 Drugs for Glaucoma 3.76
• Questions 3.78
4. Pharmacology of Central Nervous System - I 4.1 - 4.44
4.1 Organisation of CNS 4.1
4.2 Neuro-humoral Transmission in the CNS, Special Emphasis on
Importance of Various Neurotransmitters like GABA, Glutamate, Glycine,
Serotonin, Dopamine 4.3
4.2.1 Neurohumoral Transmission in the CNS 4.3
4.2.2 GABA 4.4
4.2.2.1 GABAA Receptors 4.4
4.2.2.2 GABAB Receptors 4.5
4.2.3 Glutamate 4.5
4.2.3.1 NMDA Receptors 4.6
4.2.3.2 AMPA and Kainate Receptors 4.7
4.2.4 Glycine 4.7
4.2.5 Serotonin (5-Hydroxytryptamine, 5-HT) 4.7
4.2.6 Dopamine (DA) 4.10
4.3 General Anaesthetics and Pre-anaesthetics 4.11
4.3.1 Stages of Anaesthesia 4.11
4.3.2 General Anaesthetics 4.12
4.3.2.1 Specific Inhalation Anaesthetics 4.13
4.3.2.2 Specific Intravenous Anaesthetics 4.16
4.3.2.3 Dissociative Anaesthetic - Ketamine 4.17
4.3.3 Pre-Anaesthetics 4.18
4.4 Sedatives, Hypnotics and Centrally Acting Muscle Relaxants 4.18
4.4.1 Sedatives and Hypnotics 4.18
4.4.2 Centrally Acting Skeletal Muscle Relaxants (Spasmolytics) 4.25
4.5 Anti-epileptics 4.27
4.5.1 Classification of Seizures 4.27
4.5.2 Mechanism of Action of Anti-Epileptic Drugs 4.29
4.5.3 Individual Drugs 4.30
4.6 Alcohol and Disulfiram 4.38
4.6.1 Alcohol (Ethyl Alcohol/Ethanol) 4.38
4.6.1.1 Pharmacological Effects (Acute) 4.38
4.6.1.2 Pharmacological Effects (Chronic) 4.40
4.6.1.3 Treatment of Acute and Chronic Alcoholism 4.41
4.6.2 Drug Interactions 4.42
4.6.3 Clinical Uses of Ethanol 4.42
4.6.4 Disulfiram 4.42
• Questions 4.43
5. Pharmacology of Central Nervous System - II 5.1 - 5.40
5.1 Psycho-pharmacological Agents: Anti-psychotics, Anti-depressants, Anti-anxiety
agents, Anti-maniacs and Hallucinogens 5.1
5.1.1 Antipsychotics 5.1
5.1.1.1 Classification of Antipsychotics 5.2
5.1.1.2 Mechanism of Action 5.2
5.1.1.3 Therapeutic Uses 5.2
5.1.1.4 Adverse Effects 5.3
5.1.1.5 Drug Interactions 5.4
5.1.2 Anti-Depressants 5.6
5.1.2.1 Classification 5.6
5.1.2.2 Mechanism of Action 5.6
5.1.2.3 Pharmacokinetics 5.7
5.1.2.4 Therapeutic Uses 5.8
5.1.2.5 Adverse Effects 5.8
5.1.2.6 Drug Interactions 5.9
5.1.3 Anti-anxiety Agents 5.11
5.1.4 Anti-maniacs 5.12
5.1.5 Hallucinogens 5.13
5.2 Drugs used in Parkinson’s Disease and Alzheimer’s Disease 5.16
5.2.1 Drugs for Parkinson’s Disease 5.16
5.2.1.1 Drugs which Increase Dopamine Levels 5.17
5.2.1.2 Drugs which Prevent Dopamine Degradation 5.19
5.2.1.3 Drugs which Stimulate Dopamine Receptors 5.19
5.2.1.4 Drugs which Restore DA-ACh Balance 5.20
5.2.2 Drugs for Alzheimer’s Disease (AD) 5.21
5.3 CNS Stimulants and Nootropics 5.22
5.3.1 CNS Stimulants 5.22
5.3.1.1 Methylxanthines 5.24
5.3.2 Nootropics 5.26
5.4 Opioid Analgesics and Antagonists 5.27
5.4.1 Pathophysiology of Pain 5.27
5.4.2 Endogenous Opioid Peptides 5.29
5.4.3 Opioid Receptors 5.29
5.4.4 Opioid Analgesics 5.29
5.4.5 Morphine Related Drugs (Opioids) 5.32
5.4.6 Opioid Antagonists 5.34
5.5 Drug Addiction, Drug Abuse, Tolerance and Dependence 5.36
5.5.1 Drug Addiction 5.37
5.5.2 Drug Abuse 5.37
5.5.3 Drug Tolerance 5.37
5.5.4 Drug Dependence 5.37
5.5.5 Treatment of Drug Dependence 5.38
• Questions 5.38
Appendix A.1 - A.18
Unit...
Unit... 1
GENERAL PHARMACOLOGY - I
♦ LEARNING OBJECTIVES ♦
After completing this chapter, student should be able to understand:
• History, Landmarks and Scope of Pharmacology
• Nature and Sources of Drugs
• Concept of Essential Drugs
• Basic Concepts of Agonists, Antagonists, Spare Receptors
• Special terms like Addiction, Tolerance, Dependence, Allergy etc.
• Concepts of Pharmacokinetics involving ADME
• Enzyme Induction, Inhibition and Kinetics
1.1 INTRODUCTION TO PHARMACOLOGY

1.1.1 Definitions
• Active ingredient (Active Substance, Compound, Active Pharmaceutical Ingredient)
Ingredient that alone or in combination with one or more other ingredients is
considered to fulfil the intended activity of a medicine.
• Acute care
A type of health care in which a patient is treated for an acute (immediate and severe)
episode of illness, for the subsequent treatment of injuries related to an accident or
other trauma, or during recovery from surgery.
• Adherence
The extent to which a person’s behaviour - taking medication, following a diet, and/or
executing life-style changes, corresponds with agreed recommendations from a health
care provider.
• Adverse reaction
A response to a reaction which is noxoious and unintended and which occurs at doses
normally used in man for the prophylaxis, diagnosis or therapy of disease or for the
restoration, correction or modification of physiological function.
• Batch (Lot)
A specific quantity of material produced in a process or series of processes so that it is
expected to be homogenous within specified limits. In the case of continuous
production, a batch may correspond to a defined fraction of the production. The batch
size can be defined either by a fixed quantity or by the amount produced in a fixed time
interval.
(1.1)
Pharmacology - I (B.Pharm. Sem. IV) 1.2 General Pharmacology - I
• Bioavailability
It is defined as, "the rate and extent to which the active substance or active moiety is
absorbed from a pharmaceutical form and becomes available at the site of action".
• Bioequivalence
Two medicines are bioequivalent if they are pharmaceutically equivalent or
pharmaceutical alternatives and if their bioavailabilities after administration in the same
molar dose are similar to such degree that their effects, with respect to both efficacy and
safety, will be essentially the same.
• Biological marker (Biomarker)
A characteristic that is objectively measured and evaluated as an indicator of normal
biological processes, pathogenic processes, or pharmacologic responses to a therapeutic
intervention.
• Biological medicine
It is a product, the active substance of which is a biological substance.
• Bio-similar
It is defined as, "a biological medicine that is developed to be similar to an existing
biological medicine (the “reference medicine”)". Biosimilar medicines can only be
marketed following the patent expiry of reference medicine.
• Brand Name (Innovator’s Name/Proprietary Product Name/Medicine Speciality
Product Name/Medicinal Product Speciality Name)
It is the name given for marketing purposes to any ready-prepared medicine placed on
the market under a special name and in a special pack. A brand name may be a
protected trade mark.
• Bulk product
It is defined, "as any product that has completed all processing stages up to, but not
including, final packaging".
• Burden of disease
It is a measurement of the gap between a population’s current health and the optimal
state where all people attain full life expectancy without suffering major ill-health.
• Chronic care
The ongoing provision of medical, functional, psychological, social, environmental and
spiritual care services that enable people with serious and persistent health and/or
mental conditions to optimize their functional independence and well-being, from the
time of condition onset until problem resolution or death.
• Chronic condition (Chronic Disease)
A disease which has one or more of the following characteristics: is permanent; leaves
residual disability; is caused by no reversible pathological alteration; requires special
training of the patient for rehabilitation; or may be expected to require a long period of
supervision, observation or care.
• Clinical pharmacology
It is defined as, "the study of effects of the pharmaceuticals in humans".
• Clinical trial (Clinical study)
Any investigation in human subjects intended to discover or verify the clinical,
pharmacological and/or the pharmacodynamic effects of an investigational product(s),
and/or to identify any adverse reactions to an investigational product(s), and/or to study
absorption, distribution, metabolism, and excretion of an investigational product(s) with
the object of ascertaining its safety and/or efficacy.
• Combination product
It is defined as, "a medicine that contains more than one active ingredient".
• Community care
Services and support to help people with care needs to live as independently as possible
in their communities. (Considered as synonym for the out-patient health care sector in
contract to the hospital sector).
• Community pharmacy
It is defined as, "health care facility dispensing medicines (prescription-only medicines/
POM and Over-the-Counter/OTC medicines), reimbursable and non-reimbursable
medicines to out-patients".
• Co-morbid condition (co-morbidity)
It is defined as, "conditions that exist at the same time as the primary condition in the
same patient. Two or more conditions may interact in such a way as to prolong a stay in
hospital or hinder successful rehabilitation".
• Complication
A medical condition that arises during a course of treatment and is expected to increase
the length of stay by at least one day for most patients.
• Cost-benefit analysis
It compares the cost of a medicinal intervention to its benefit. Both costs and benefits
must be measured in the same monetary units (e.g. Rupees, Euro or Dollars).
• Cost-effectiveness
It is defined, "as value for money". A specific health care treatment is said to be ‘cost-
effective’ if it gives greater health gain than could be achieved by using the resources in
other ways.
• Counterfeit medicine
It describes a product with a false representation of its identity and/or source. This
applies to the product, its container or other packaging or labelling information.
Counterfeiting can apply to both branded and generic medicines.
• Defined daily dose (DDD)
The DDD is a unit of measurement defined as, "the assumed average maintenance dose
per day for a pharmaceutical used for its main indication in the adult".
• Disability-Adjusted Life Years (DALYs)

It is defined as, "a measure of the burden of the disease on a defined population and the
effectiveness of the intervention". DALYs are advocates as an alternative to Quality
Adjusted Life Years (QALY) and claimed to be a valid indicator of population health.
• Disease
A failure of the adaptive mechanisms of an organism to counteract adequately, normally
or appropriately to stimuli and stresses to which the organism is subjected, resulting in a
disturbance in the function or structure of some part of the organism.
• Dispensing
To supply a clinically appropriate medicine to a patient or care giver, usually against a
written prescription, for self-administration by another professional, and to advise on
safe and effective use.
• Drug utilisation research
It is defined as, "the research on marketing, distribution, prescription, and use of
medicines in a society, with special emphasis on the resulting medical, social and
economic consequences".
• Effectiveness
It is the extent to which an intervention does more good than harm when provided
under the usual circumstances of health care practice.
• Efficacy
It is the extent to which an intervention does more good than harm under ideal
circumstances.
• Emergency
Sudden unexpected onset of illness or injury which requires the immediate care and
attention of a qualified physician, and which, if not treated immediately, would
jeopardise or impair the health of the individual.
• Essential medicines
These are the medicines that satisfy the priority healthcare needs of the population. They
are selected with due regard to public health relevance, evidence on efficacy and safety,
and comparative cost effectiveness.
• Excepient
A substance, other than the active ingredient, which has been appropriately evaluated
for safety and is included in a medicine delivery system to:
o Aid in the processing of the medicine delivery system during its manufacture;
o Protect, support or enhance stability, bioavailability, or patient acceptability;
o Assist in product identification; or
o Enhance any other attribute of the overall safety and effectiveness of the medicine
during storage or use.
• Fixed dose combination (FDC) product

It is defined as, "a combination of two or more active substances in a fixed ratio of
doses". It may be administered as single entity products given concurrently or as a
finished pharmaceutical product.
• Generic (Generic medicine)
A pharmaceutical product (medicine) which has the same qualitative and quantitative
composition in active substances and the same pharmaceutical form as the reference
medicine, and whose bioequivalence with the reference medicine has been
demonstrated by appropriate bioavailability studies.
• Generic substitution
Practice of substituting a medicine, whether marketed under a trade name or a generic
name (branded or unbranded generic), with a less expensive medicine (e.g. branded or
unbranded generic), often containing the same active ingredient(s).
• Good clinical practice (GCP)
A standard for the design, conduct, performance, monitoring, auditing, recording,
analyses, and reporting of clinical trials that provides assurance that the data and the
reported results are credible and accurate, and that the rights, integrity, and
confidentiality of trial subjects are protected.
• Good distribution practices (GDP)
This is that part of quality assurance which ensures that the quality of a pharmaceutical
product is maintained through adequate control throughout the numerous activities
which occur during the distribution process.
• Good manufacturing practices (GMP)
This is that part of quality assurance which ensures that pharmaceutical products are
consistently produced and controlled to the quality standards appropriate to their
intended use and as required by the marketing authorisation.
• Haemovigilance
It is defined as, "a set of organised surveillance procedures relating to serious adverse or
unexpected events or reactions in donors or recipients of blood products, and the
epidemiological follow-up of donors".
• Health
It is defined as, "a state of complete physical, social and mental well-being, and not
merely the absence of disease or infirmity".
• Herbal medicine
It is defined as, "any medicine, exclusively containing as active ingredients, one or more
herbal substances or one or more herbal preparations, or one or more such herbal
substances in combination with one or more such herbal preparations".
• Herbal substances
They are defined as, "whole, fragmented or cut plants, plant parts, algae, fungi, lichen in
an unprocessed, usually dried form, but sometimes fresh". Certain exudates that are not
being subjected to a specific treatment are also considered to be herbal substances.
• Herbal preparations
They are defined as, "preparations obtained by subjecting herbal substances to
treatments such as extraction, distillation, expression, fractionation, purification,
concentration or fermentation". These include comminuted or powdered herbal
substances, tinctures, extracts, essential oils, express juices and processed exudates.
• Home care
It comprises medical and paramedical services delivered to patients at home.
• Homeopathic medicines
Any medicine prepared from substances called homeopathic stocks in accordance with a
homeopathic manufacturing procedure described by the European Pharmacopoeia or, in
the absence thereof, by the Pharmacopoeias currently used officially in the Member
States.
• Hospice (Hospice care)
It is defined as, "a facility or a programme providing care for the terminally ill".
• Hospital pharmacists
Health care professionals who provide services to patients and health care professionals
in hospitals are called as hospital pharmacists.
• Hospital pharmacy
It is the health care service, which comprises the art, practise, and profession of
choosing, preparing, storing, compounding and dispensing pharmaceuticals and medical
devices, advising health care professionals and patients on their safe, effective and
efficient use.
• Illness
A person’s own perceptions, experience and evaluation of a disease or condition, or how
he or she feels is called as illness; e.g. an individual may feel pain, discomfort, weakness,
depression or anxiety, but a disease may or may not be present.
• Infusion
Administration, from a syringe or other rigid or collapsible container e.g. plastic bag, of a
volume of sterile solution of an injectable medicine directly into a tissue, organ, vein or
artery, at a constant rate, under gravity or by means of an electronic or mechanical
pump or other means of rate control, over a defined period usually of at least 10
minutes is called as infusion.
• In-patient care
An in-patient is a patient who is formally admitted (or hospitalised) to an institution for
treatment and/or care and stays for a minimum of one night in the hospital or other
institution providing in-patient care. In-patient care is delivered in hospitals, or in
nursing and residential care facilities or in other establishments.
• International Non-proprietary Name (INN, Generic name)
The shortened scientific name based on the active ingredient is called as INN. WHO is
responsible for assigning INNs to pharmaceutical substances. INN is a unique name that
is globally recognised and is public property.
• Internet pharmacy (Online pharmacy)

It is an umbrella term for retailers of prescription-only medicines (POM) and Over-the-
Counter (OTC) medicines who sell their products via World Wide Web.
• Life expectancy
A statistical abstraction based on existing age-specific death rates is termed as life
expectancy.
• Medical device
A medical device is any instrument, apparatus, appliance, software, material or other
article, whether used alone or in combination, including the software intended by its
manufacturer to be used specifically for diagnostic and/or therapeutic purposes and
necessary for its proper application, intended by its manufacturer to be used for human
beings for the purpose of:
o Diagnosis, prevention, monitoring, treatment or alleviation of disease, diagnosis,
monitoring, treatment, alleviation of or compensation for an injury or handicap;
o Investigation, replacement or modification of the anatomy or of a physiological
process;
o Control of conception, and which does not achieve its principle intended action in or
on the human body by pharmacological, immunological or metabolic means, but
which may be assisted in its function by such means.
• Medication error
Any preventable event that may cause or lead to inappropriate medication use or
patient harm while the medication is in the control of the health care professional,
patient, or consumer, is termed as medication error.
• Medicine (Pharmaceutical, Pharmaceutical product, Medication, Medicinal product)
(a) Any substance or combination of substances presented as having properties for
treating or preventing disease in human beings; or
(b) Any substance or combination of substances which may be used in or administered
to human beings either with a view to restoring, correcting or modifying
physiological functions by exerting a pharmacological, immunological or metabolic
action, or to making a medical diagnosis is termed as medicine.
• Mortality rate
An estimate of the proportion of a population that dies during a specified period is
called as mortality rate.
• Out-patient
An out-patient is a person who goes to a health care facility for a consultation/
treatment, and who leaves the facility within several hours of the start of the
consultation without being admitted to the facility as a patient.
• Out-patient care (Ambulatory care, Community care)
It comprises of medical and para-medical services delivered to out-patients.
• Palliative care
The active total care offered to a person and that person’s family when it is recognised
that the illness is no longer curable, in order to concentrate on the person’s quality of
life and the alleviation of distressing symptoms is called as palliative care.
• Patent
It is a set of exclusive rights granted by a state (National Government) to an inventor or
their assignee for a limited period of time in exchange for public disclosure for its
invention.
• Pharmaceutical alternatives
Medicines are pharmaceutical alternatives if they contain the same active moiety but
differ in chemical form (salt, ester etc.) of that moiety in the dosage form or strength.
• Pharmaceutical care
It is the responsible provision of medicine therapy for the purpose of achieving definite
outcomes that improve a patient’s quality of life. These outcomes are:
o Cure of a disease
o Elimination or reduction of a patients’ symptomatology
o Arresting or slowing of a disease process; or
o Preventing a disease or symptomatology.
• Pharmaceutical equivalence
Medicines are pharmaceutically equivalent if they contain the same amount of the same
active substance(s) in the same dosage forms that meet the same or comparable
standards.
• Pharmacovigilance
It is the process and science of monitoring the safety of medicines and taking action to
reduce risks and increased benefits from medicines. It comprises of:
o Collecting and managing data on safety of medicines,
o Looking at the data to detect signals (any new or changing safety issue), evaluating
the data and making decisions with regard to safety issues,
o Acting to protect public health (including regulatory action); communicating with
stakeholders,
o Audit, both the outcomes of action taken and of the key processes involved.
• Polypharmacy
The administration of many medicines at the same time or the administration of
excessive number of medicines is called as polypharmacy.
• Quality-Adjusted Life Years (QALYs)
It is a measure of health outcome which looks at both length of life and quality of life.
QALYs are calculated by estimating the years of life remaining for a patient following a
particular care pathway and weighing each year with a quality of life score (on a zero to
one scale). One QALY = one year of life in perfect health, or two years at 50% health, and
so on.
• Rational use of medicines

It requires that, patients receive medications appropriate to their clinical needs, in doses
that meet their own individual requirements, for an adequate period of time, and at the
lowest cost to them and their community.
• Reference product (Reference medicine)
A medicine which has been granted a marketing authorisation by a country or by the
regulatory authority on the basis of submitted quality, pre-clinical and clinical data, to
which the application for marketing authorisation for a generic or a bio-similar product
refers.
• Risk
The probability that an event will occur, e.g., that an individual will become ill or die
within a stated period of time or by a certain age.
• Risk-benefit balance
An evaluation of the positive therapeutic effects of the medicine in relation to its risks
(any risk relating to the quality, safety or efficacy of the medicinal product as regards
patients’ health or public health and any risk of undesirable effects on the environment)
is called risk-benefit balance.
• Self-medication
It is the treatment of common health problems with medicines especially designed and
labelled for use without medical supervision and approved as safe and effective for such
use.
• Therapeutic benefit (Therapeutic value)
The effect conveyed on a patient following administration of a pharmaceutical which
restores, corrects or modifies a physiological function(s) for that patient is called as
therapeutic benefit.
• Therapeutic equivalence
Two pharmaceutical products are considered to be therapeutically equivalent if they are
pharmaceutically equivalent or pharmaceutical alternatives and after administration in
the same molar dose, their effects, with respect to both efficacy and safety, are
essentially the same when administered to patients by the same route under the
conditions specified in the labelling.
• Therapeutic group
A group of medicines according to their indications of use are called as a therapeutic
group.
• Tertiary care
Services provided by highly specialised providers (e.g. neurosurgeons, thoracic surgeons,
intensive care units), usually in in-patient facility is called as tertiary care.
• Vulnerable groups
Groups within a society facing higher risks of poverty and social exclusion compared to
the general population are called as vulnerable groups; e.g. people with disabilities,
isolated elderly people, children, migrants, ex-prisoners and drug addicts.
1.1.2 Historical Landmarks and Scope of Pharmacology

The science of pharmacology has evolved over the period of time. Knowledge about
various events during evolution of drugs constitutes historical landmarks of pharmacology.
Along with knowing the history, the scope of pharmacology is also advancing with time.
Both the topics are of interest to students of Pharmacology.
1.1.2.1 Historical Landmarks
The knowledge of primitive pharmacology developed from human experiences with use
of plants. Some plants were safe while others were toxic. Based on this knowledge, a
catalogue of good and bad evolved and was passed down through oral traditions. Over the
period of time, the knowledge was transformed to include natural sources which appeared
to cure some diseases.
The oldest recorded event cites about events in 16th Century bc when beer, turpentine,
myrrh, juniper berries and poppy and other therapies were described to treat disease.
Similar historical records exist for most ancient civilizations including the Sumerian, Indian
and Chinese. In India, Ayurveda has older traditions even before 16th century BCE. Sumerians
around 3400 BCE cultivated the opium poppy in lower Mesopotamia and recorded its action
in clay tablets. It was referred to as the “joy plant” and its reputation lead to its spread across
neighbouring civilizations like Egypt. Around 460 BCE Hippocrates, a famous Greek physician
and teacher of medicine, described opium as having narcotic properties and described use
of opium in treating internal diseases. In 330 BCE, Alexander the great, introduced opium to
Persia and India and by the year 400 it reached China. In the 10th century, the noted Islamic
physician Avicenna of Persia described opium as the “most powerful stupefacients”. About
the year 1200, the Indian medical treatises The Shodal Gadanigraph and Sharangdhar-
Samahita describe the use of opium for diahorrhoea and sexual debility. In the 1300’s opium
disappeared from European historical record till 1527; during which Paracelsus prescribed
opium as a pain killer.
The modern era began in 1680 when the English apothecary, Thomas Sydenham
introduced Sydenham’s Laudanum which mentioned about many opium proprietary brands
useful for various ailments. In 1803, the German Friedrich Serturner dissolved opium in acid
and then neutralised it with ammonia resulting in formation of morphine which exhibited
long-lasting and predictable effects. By 1827, morphine became a commercial product. In
1874, an English researcher, Wright synthesised heroin which went into commercial
production in Germany by 1898.
The molecular basis of opioid action was revealed by Snyder and Pert who located the
molecular site of action for opium in 1972. These opioid receptors were found in neural
tissues and mediate the pain reducing effect. Later Hughes and Kosterlitz discovered that
humans produce endogenous morphine-like compounds, called as enkephalins, which act
on opioid receptors.
Besides opium there are few more milestones in historical development of
pharmacology. In early 19th century, physiologists performed many pharmacological studies.
Magendie studied the action of Nux Vomica (a strychnine-containing plant drug) on dogs
and showed that the spinal cord was the site of convulsant action. His work was presented
to the Parris academy in 1809. Later in 1842, Bernard discovered that the arrow poison
curare acts at the neuro-muscular junction to interrupt the stimulation of muscle by nerve
impulses. Till 1846, the science of effect of drugs developed under physiology only. It was
only in 1847, Buchheim was appointed as professor of pharmacology at University of Dorpat
in Estonia (then a part of Russia). Initially there were no funds and professor Buchheim built
a laboratory on his own expense in the basement of his home. His studies were mostly
descriptive. His student Schmiedeberg (1838-1921) is recognised as founder of modern
pharmacology. He obtained his medical doctorate in 1866 with a thesis on the measurement
of chloroform in blood. He worked at Dorpat till 1869. In 1872, he became professor of
pharmacology at the University of Starssburg, receiving generous Government support for
developing an institute of pharmacology. He studied the pharmacology of chloroform and
chloral hydrate. In 1869, he showed that muscarine evoked the same effect on heart as
electrical stimulation of the vagus nerve. In 1885, he introduced urethane as a hypnotic. He
was largely responsible for the pre-eminence of German pharmaceutical industry up to
Second World War.
In USA, the first chair in pharmacology was established in the University of Michigan in
1890 under Abel who was trained under Schmiedeberg. In 1893, Abel went to Johns Hopkins
University in Baltimore. His contributions include isolation of epinephrine from adrenal gland
extracts (1897-98), isolation of histamine from pituitary extract (1919), and preparation of
pure crystalline insulin (1926). His student Hunt discovered acetyl choline in adrenal extracts
in 1906.
Pharmacology largely depends on experiments conducted in laboratory animals;
however there are isolated cases where human beings have been used to study the effect of
drugs. Serturner, the German pharmacist who isolated the first alkaloid from opium in 1805,
administered a dose of 100 mg to himself and his three friends. All of them experienced the
symptoms of severe opium poisoning for several days. Another interesting story where
human beings were used for testing drugs occurred in 1940s. Biological assays (bioassays) of
digitalis performed in frogs, pigeons and cats were highly unsatisfactory. In 1942, a group of
cardiologists published “a method for bioassay of digitalis in humans”. The assay was based
on changes in ECG of patients. Of 97 patients in whom ECG was tried, only 18 proved to be
satisfactory assay subjects.
Animals are primarily used to detect toxicity of substances,. Most frequently pharmaco-
logical studies are conducted in mammals. Mice are preferred because of their small size,
ease of breeding and short generation time. Rats, guinea pigs, rabbits and dogs are also
used; each has special characteristics that make it optimal for certain type of tests. The
efforts of animal activists have restricted use of animals for experimental study on drugs. In
India, permission from the Committee for the Purpose of Control and Supervision of
Experiments on Animals (CPCSEA) is necessary for conducting any animal experiments. It is
suggested that animals should be used only for research and development and not for
education/demonstration. Every pharmacy college is supposed to take permission from
CPCSEA, with one of their representative in the committee.
Early in the development of pharmacological techniques, it was found that an isolated

organ or tissue remained functional for several hours in a bath containing a physiologic
solution of salts through which oxygen was bubbled. Magnus (1802-1870) first applied this
method to a strip of small intestine. Later Heymans (1904) worked with mammalian heart
and Bernard experimented with isolated nerve-muscle preparation. In 1924, Allen and Doisy
used ovarictomized rats to test the action of estrogenic hormone.
With advancement of knowledge of human biochemistry and molecular biology,
pharmacological actions are often studied on actions of enzymes and receptors. The drug
Captopril was developed by Ondetti and co-workers at Squib in 1970s to inhibit the
enzyme - Angiotensin Converting Enzyme (ACE). Subsequently, it was proved that inhibitors
of ACE work as anti-hypertensive drugs. Knowledge of cell receptors is yet another
milestone. Adrenalin is the neurotransmitter for sympathetic nervous system. Adrenalin acts
on α- and β- receptors. Propranolol was the first β-adrenergic receptor blocking agent. From
1964, β-blockers have been used for treating hypertension and cardiac arrhythmia.
Synthetic organic chemistry was born in 1828, when Wohler synthesised urea from
inorganic substances. Several substances, existing in the body or their derivatives were
synthesised in laboratories as an extension of developments in organic chemistry. With the
knowledge of receptors, a complimentary substance can be synthesised in laboratories. With
the help of Structure – Activity Relationship (SAR) derivatives of main active moiety can be
synthesised. In recent years, developments in medicinal chemistry have greatly contributed
to development of various synthetic drugs.
1.1.2.2 Scope of Pharmacology
The science of Pharmacology has interfaces with Anatomy and Physiology, Organic and
Inorganic Chemistry, Microbiology and Pathophysiology. Pharmacology is related to action
and uses of drugs. In development of new drugs, pharmacology has greatest contribution. It
has two main components: pharmacodynamics and pharmacokinetics. Pharmacodynamics
deals with what drug does to the human/animal body. It involves study of action of drugs on
receptors, its mechanism of action, indications for clinical use, contra-indications and
adverse reactions caused by drugs. Pharmacokinetics deals with what body does towards
drugs. It has four main components: Absorption, Distribution, Metabolism and Excretion
(ADME). Out of these four components, absorption, distribution and excretion are
dependent on transport through membranes without any chemical change in the entity. In
metabolism, there is chemical change in the moiety because of action of enzymes in the
body. Cytochromal enzymes in the liver are the main metabolising enzymes in the liver. A
drug may have n number of metabolites. Every metabolite can have different action in the
body. Thus, what we observe as action(s) of drugs is the net effect of main drug moiety and
its metabolites. Several factors can alter ADME of drugs. It is the main reason why we get
different kinds of actions for the same drug in different individuals.
Clinical pharmacology and therapeutics primarily deals with actions of drug in human
beings. It incorporates indications, therapeutic uses, contra-indications, posology, bio-
availability, prescription writing and drug nomenclature. The science of clinical toxicology is
an extension of clinical pharmacology. Forensic toxicology addresses to medico-legal

aspects of use of drugs. Pharmacovigilance is gaining vital importance in last few decades. It
involves study of adverse reactions of drugs and their safety. Based on observations on
pharmacovigilance, some drugs have been withdrawn from the market due to severe
adverse reactions.
1.1.3 Nature and Sources of Drugs
Several drug candidates have been derived from various naturally occurring medicinal
sources. They can be broadly divided in to four major categories:
• Plant sources
• Animal sources
• Microbial sources
• Marine sources.
In addition to the above mentioned natural sources, two other sources need specific
mention. A drug may be derived either as a semi-synthetic product from any of the naturally
occurring resources or it may be of totally synthetic origin. Having knowledge about the
receptor and Quantitative Structure-Activity Relationship (QSAR), one may predict possible
structure of a drug. Subsequently, a drug with optimum biological action can be
synthesised, tested and evaluated for possible clinical activity.
The use of plants as medicines has a long history. Opium has been the first known drug
from plant sources. Plants continue to be a significant part of traditional medicine and
herbal medicine. Several important drugs like Taxol, Camptothecin, Morphine and Quinine
have been isolated from plant sources.
Animals have been sources for some drugs. Insulin and heparin are two common names
of drugs of animal origin. Till last few decades insulin was obtained from pancreas of
animals. Now insulin is available by genetic engineering from microbial sources. Heparin is
obtained from lungs of animals. Epibatidine, obtained from the skin of an Ecuadorian poison
frog, is ten times more potent than morphine. Teprotide, extracted from a Brazilian snake
viper, has led to the development of Cilazapril and Comptopril, which are effective against
hypertension.
Microorganisms as a source of potential drug candidates were not explored till the
discovery of penicillin in 1929. Subsequently several antibiotics have been obtained either
from microbial sources or from their semi-synthetic derivatives.
Marine organisms have also been sources for new drugs. The first active compounds to
be isolated from marine species were Spongouridine and Spongothymidine from the
Carribean sponge Cryptotheca crypta in 1950s. These compounds are nucleotides and show
a great potential as anticancer and antiviral agents. Discodermolide, isolated from the
marine sponge, Discodermia gissoluta has a strong antitumour activity and has mode of
action similar to that of Paclitaxol. Few antibiotics also originate from ocean.
Several derivatives of antibiotics, β-blockers, anti-protozoal drugs, anti-malarial drugs
are of totally synthetic origin. The examples of the categories of drugs are illustrative only. In
recent years most of the new drugs are of synthetic origin based on the knowledge about
the receptor.
1.1.4 Essential Drugs Concept

Although a large number of medicines are available in the market, all of them may not
be necessary for majority of population. Based on this observation, World Health
Organisation (WHO) proposed a concept of ‘essential medicines’ in 1977. According to this
concept, essential medicines are those that satisfy the priority health care needs of the
population. They are selected with due regard to public health relevance, evidence on safety
and efficacy, and comparative cost-effectiveness. Essential medicines are intended to be
available within the context of functioning health systems at all times in adequate times, in
the appropriate dosage forms, with assured quality and adequate information, and at a price
the individual and the community can afford. The implementation of the concept of
essential medicines is intended to be flexible and adaptable to many different situations;
exactly which medicines are regarded as essential remains responsibility of that country.
In the first, 1977 version of list of essential medicines, 208 medicines were identified to
address the global burden of disease at that time. The list is revised by a committee of
independent experts after every two years to reflect new health challenges, pharmaceutical
developments and changing resistance patterns by microorganisms. In 2007, 30th
anniversary of WHO was celebrated. By then 156 of 193 WHO member states have official
essential medicine lists, of which 127 countries have been updating it in past 5-10 years. The
list of essential medicines published in 2007 contains 340 medicines including drugs for
malaria, HIV/AIDS, tuberculosis, reproductive health, chronic diseases like cancer and
diabetes. The list of essential medicines published in October 2007 contained for the first
time “Essential Medicines for children”. The list of essential medicines for children is also
updated every two years. In the year 2015, 19th model list of essential medicines and 5th
revised list of essential medicines for children has been published by WHO. The 20th revision
of essential medicines and the 6th revision of essential medicines for children is in the
process.
Government of India has published a list of essential medicines. Few states have
implemented it. In the year 2013, eighth edition of essential medicines list for the National
Capital Territory of Delhi has been published. Few other states like Rajasthan, Kerala,
Karnataka and Madhya Pradesh have essential lists prepared by an expert committee and
the concept is implemented in these states.
1.1.5 Routes of Drug Administration
Route of administration refers to the starting point for the drug’s introduction in to the
body up to the place where it acts upon the target organ or system. The route of
administration for the drug depends on a number of factors like nature of the drug, its
pharmacokinetics, and the nature and urgency of the medical condition. The main routes of
administration are: local and systemic. The local route is further sub-classified into topical
like administration to eye, ear, nose etc. The systemic route is further divided as enteral and
parenteral. Enteral route consists of oral, rectal and sub-lingual. Parenteral route consists of
inhalation, and various injections like sub-cutaneous, intra-muscular and vascular types.
Definitions of all routes of administration are presented below:
• Enteral
It means through gastro-intestinal tract. It includes oral, sublingual and rectal routes.
• Parenteral
It means through routes other than enteral. It includes all types of injections, inhalations.
• Local
It includes administration of a drug at the site where the desired action is intended. It
includes topical administration in oral cavity, gastro-intestinal tract, rectum/anal canal,
eye, ear, nose, bronchi, skin, intra-arterial, injection in deep tissues e.g. joints.
• Systemic
It includes drugs administered to enter the blood to produce systemic effects.
• Oral
It means drugs taken by mouth e.g. tablets, capsules, syrups, mixtures etc.
• Intravenous
It includes drugs injected directly in to blood stream through a vein. It may be
administered as: bolus, slow intravenous injection or an intravenous infusion.
• Intrathecal
It includes drugs injected in to the sun-arachnoid space e.g. spinal anaesthetics like
lignocaine.
• Intra-articular
It includes drugs injected directly in to the joint space e.g. hydrocortisone injection for
rheumatoid arthritis.
• Subcutaneous
It includes drugs injected in to the sub-cutaneous tissues of the thigh, abdomen and arm
e.g. adrenalin, insulin etc.
• Intradermal
It includes drugs injected in to the dermis layer of the skin e.g. tuberculin and allergy
tests.
• Intramuscular
It includes drugs injected in to large muscles such as deltoid, gluteus maximus and
vastus lateralis. A volume of 5-10 ml can be given at a time e.g. paracetamol, diclofenac.
• Intraosseous
It includes injecting a drug directly in to the marrow of a bone.
• Transdermal (patch)
It includes administration of a drug in the form of a patch or ointment that delivers the
drug into the circulation for systemic effect.
• Rectal
It includes administration of drugs in the form of suppository or enema in to the rectum.
• Sublingual
In this case, the preparation is kept under the tongue. The drug is absorbed through the
buccal membrane and enters the systemic circulation bypassing the liver e.g.
nitroglycerine for acute angina attack.
• Inhalation
It includes volatile gases and liquids which are given by inhalation for systemic effects
e.g. general anaesthetics.
• Endotracheal
It includes a catheter inserted in to the trachea for primary purpose of establishing and
maintaining an airway to ensure adequate exchange of oxygen and carbon dioxide.
The broad classification is presented in Fig. 1.1.
Otic
Ocular Parenteral:
IV, IM, SC
Inhalation
Oral
Sublingual
Buccal
Transdermal
patch Topical
Epidural
Rectal
Fig. 1.1: Routes of administration

Fig. 1.2 indicates pictorial presentation of various injectable routes.
Subcutaneous
Intramuscular Intravenous
Epidermis
Dermis
Subcutaneous
tissue
Muscle with
vein
Fig. 1.2: Injectable routes of drug administration

Brief characteristics of different routes of administration are presented in table 1.1.

Table 1.1: Absorption pattern, advantages and disadvantages of most common routes
of administration
Sr. Name of Absorption Advantages Disadvantages
No. route pattern
1. Oral Variable; Safest and most • Limited
affected by common, convenient, absorption of
many factors. and economical some drugs.
• Food may affect
absorption.
• Patient
compliance is
necessary.
• Drugs may be
metabolised
before systemic
absorption.
2. Intravenous Absorption not • Can have • Unsuitable for oily
required. immediate substances.
effects. • Bolus injection
• Ideal if dosed in may result in
large volumes. adverse effects.
• Suitable for • Most substances
irritating must be slowly
substances and injected.
complex • Strict aseptic
mixtures. techniques
• Valuable in needed.
emergency
situations.
• Dosage titration
permissible.
• Ideal for high
molecular weight
proteins and
peptides.
3. Subcutaneous Depends on • Suitable for slow- • Pain or necrosis if
drug diluents; release drugs. drug is irritating.
Aqueous • Ideal for some • Unsuitable for
solution: prompt; poorly soluble drugs adminis-
Depot suspensions. tered in large
preparations: volumes.
Slow and
sustained
contd. …
4. Intramuscular Depends on • Suitable if drug • Affects certain lab

drug diluents; volume is tests (creatine
Aqueous moderate. kinase).
solution: prompt; • Suitable for oily • Can be painful.
Depot vehicles and • Can cause
preparations: some irritating intramuscular
Slow and substances. haemorrhage.
sustained • Preferable to • Avoided during
intravenous if anticoagulant
patient can self- therapy.
administer.
5. Transdermal Slow and • Bypasses the • Some patients are
sustained. first-pass effect. allergic, causing
• Convenient and irritation.
painless. • Drug must be
• Ideal for lipophilic highly lipophilic
and poorly • May cause.
bioavailable delayed delivery
drugs. to the site.
• Ideal for drugs • Limited to drugs
which are quickly which can be
eliminated. taken in small
daily doses.
6. Rectal Erratic and • Partially bypasses • Drugs may irritate
variable. first-pass effect. the rectal mucosa.
• Bypasses • Not a well-
destruction by accepted route.
stomach acid.
• Ideal if drug
causes vomiting.
• Ideal in patients
who are vomiting
or comatose.
7. Inhalation Systemic • Absorption is • Most addictive
absorption may rapid; can have route (drug can
occur; it is immediate enter the brain
undesirable. effects. quickly).
• Ideal for gases. • Patient may have
• Effective for difficulty in
patients with regulating dose.
respiratory • Some patients
problems. may have
• Dose can be difficulty in using
titrated. inhalers.
• Localised effect
to target lungs:
lower doses can
be used.
• Fewer systemic
side effects.
contd. …
8. Sublingual Depends on the • Bypasses first- • Limited to certain

drug: few drugs pass effect. types of drugs.
have rapid direct • Bypasses • Limited to drugs
systemic destruction by which can be
absorption. Most stomach acid. taken in small
drugs are • Drug stability is doses.
absorbed maintained • May lose part of
incompletely because pH of the drug dose if
and erratically. saliva is relatively swallowed.
neutral.
• May cause
immediate
pharmacological
effects.
Duration in which the effect can initiate also depends on route of administration. Table
1.2 provides information in this context.
Table 1.2: Effect of route of administration on initiation of effect of drugs
Sr. No. Route of administration Time until effect
1. Intravenous 30-60 seconds
2. Intraosseous 30-60 seconds
3. Endotracheal 2-3 minutes
4. Inhalation 2-3 minutes
5. Sublingual 3-5 minutes
6. Intramuscular 10-20 minutes
7. Subcutaneous 15-30 minutes
8. Rectal 5-30 minutes
9. Oral 39-90 minutes
10. Transdermal (topical) Variable (minutes to hours)
Drug and patient related factors determine the selection of routes for drug
administration. The factors are:
• Characteristics of drugs.
• Emergency/routine use.
• Site of action of the drug - local or systemic.
• Condition of the patient (unconscious, vomiting, diarrhoea).
• Age of the patient.
• Effect of gastric pH, digestive enzymes and first-pass metabolism.
• Patient’s/doctor’s choice.
1.1.6 Agonists
An agonist is a chemical which binds to a receptor and activates the receptor to produce
a biological response. Receptors can be activated by either endogenous agonists
(like hormones or neurotransmitters) or exogenous agonists (like drugs). Agonists can be
divided into following sub-categories:
• Full agonists
They bind to and activate a receptor with the maximum response that an agonist
can elicit at the receptor e.g. isoproterenol mimics the action of adrenaline at
β-adrenoceptors.
• Co-agonists
A co-agonist works with other co-agonists to produce the desired effect together;
e.g. NMDA receptor activation requires binding of glutamate, glycine and D-serine
co-agonists.
• Selective agonists
A selective agonist is selective for a specific type of receptor only; e.g. buspirone is a
selective agonist for serotonin 5-HT1A.
• Partial agonists
Partial agonists like buprinorpine also bind and activate a given receptor but have only
partial efficacy at the receptor relative to a full agonist, even at maximal receptor
occupancy.
• Inverse agonists
An inverse agonist is an agent which binds to the same receptor binding-site as an
agonist and inhibits the constitutive activity of the receptor. Inverse agonists exert the
opposite pharmacological effect to that of an agonist. This is unlike an antagonist;
e.g. Cannabinoid inverse agonists rimonabant.
• Super agonists
It is a term used to identify a compound which is capable of producing a greater
response than the endogenous agonists for the target receptor.
• Irreversible agonists
An irreversible agonist is a type of agonist which binds permanently to a receptor
through formation of covalent bonds.
1.1.7 Antagonists (Competitive and Non-competitive)
An antagonist is a type of receptor ligand or drug which blocks or dampens a biological
response by binding to and blocking a receptor rather than activating it like an agonist. They
are sometimes called as blockers e.g. α-blockers, β-blockers, calcium channel blockers etc.
Antagonists have affinity but no efficacy for their cognate receptors. The concept of affinity
and efficacy is presented below.
Affinity
The affinity of an antagonist for its binding site is its ability to bind to a receptor. It
determines the duration of inhibition of agonist activity. It can be measured experimentally.
Efficacy and Potency

By definition, antagonists display no efficacy to activate the receptors to which they
bind. Antagonists do not maintain the ability to activate a receptor. However, once bound
they will inhibit the function of agonists, inverse agonists and partial agonists.
Thus, antagonists can have variable affinity but no efficacy.
Antagonists are of different types: Competitive, Non-competitive and Uncompetitive.
1.1.7.1 Competitive Antagonists
Competitive antagonists bind to receptors at the same binding site (active site) as the
endogenous ligand or agonist, but without activating the receptor. Agonists and antagonists
compete for the same binding site on the receptor. Once bound, an antagonist will block
binding of agonist. Sufficient concentration of an antagonist will displace the agonist from
the binding sites, resulting in a lower frequency of receptor activation. The level of activity of
the receptor will depend on relative affinity of each molecule for the site and their relative
concentrations. Competitive antagonists are used to prevent the activity of drugs and to
reverse the effects of drugs that have already been consumed. Naloxone is an antagonist of
morphine/heroine and is used to reverse effects of opioid overdose.
Competitive antagonists are sub-classified as reversible (surmountable) or irreversible
(insurmountable) competitive antagonists, depending on how they interact with their
receptor protein targets. In case of irreversible antagonism, the bond with receptor is
probably of covalent nature.
1.1.7.2 Non-competitive Antagonists
A non-competitive antagonist is a type of unsurmountable antagonist that may act in
one of two ways: by binding to the active site of receptor or by binding to an allosteric site
of the receptor. If it binds to the allosteric site, it is called as allosteric antagonist. In both the
cases, end-results are functionally similar. Unlike competitive antagonists, which affect the
amount of agonists necessary to achieve a maximal response but do not affect the
magnitude of that maximal response, non-competitive antagonists reduce the magnitude of
the maximum response that can be attained by any amount of agonists. This property
makes the title as “non-competitive” because their effects cannot be negated, no matter
how much agonist is present. Cyclothiazide is known to be a reversible non-competitive
antagonist of mGluR1 receptor.
1.1.7.3 Uncompetitive Antagonists
Uncompetitive antagonists differ from non-competitive antagonists in that, they require
receptor activation by an agonist before they can bind to a separate allosteric binding site.
This type of antagonism produces a kinetic profile in which the same amount of antagonist
blocks higher concentrations of agonists better than lower concentrations of agonists.
Memantine, used for treating Alzheimer’s disease, is an uncompetitive antagonist of the
NMDA receptor.
Dose-response Curve
Dose-response relationships, or exposure-response relationship can be conveniently
used to know the type of antagonism. Dose-response relationship describes the change in
effect of an organism caused by differing levels of exposure (or doses) to a stress or (usually
a drug) after a certain exposure time. Biologic effect is usually placed on Y-axis in terms of
percentage. Drug concentration is depicted on X-axis in terms of units of dose.
Dose-response curve is usually S-shaped as depicted in Fig. 1.3. The dose corres-ponding to
50% of the response is termed as EC50, (effective concentration for 50% effect). In case of a
competitive antagonist, the dose-response curve shows a parallel right shift with increase in
value of EC50. Unlike this, in case of non-competitive or uncompetitive antagonists, shift to
the right is not parallel and there is only a slight change in the value of EC50.
Drug with non- Drug with
competitive competitive
antagonist antagonist
Biologic effect
EC50 EC50
for drug for drug
alone or in the presence
in the presence of a competitive
of a non-competitive antagonist
antagonist
EC50 = Drug dose that shows 50% of maximal response.
Fig. 1.3: Effect of drug antagonists
1.1.8 Spare Receptors
Spare receptors are defined as those receptors without combining with which maximal
response can be obtained. In order to understand this concept, understanding of receptor
occupancy theory is essential.
Receptor Occupancy Theory
Consider dose response curves A, B and C for an agonist along with various antagonists.
(Fig. 1.4) In this graph, X-axis indicates log agonist (M) indicating that log molar
concentration of agonist is plotted. Y-axis indicates percentage of maximal effect. In Fig. 1.4,
maximal responses, as shown in dose-response curves B and C have been obtained with
incremental change in concentrations of agonists in presence of antagonists, as needed for
50% of effects. Further, the maximal response (100%) has not changed as indicated in dose
response curve B and C, even in presence of antagonist which has occupied certain fraction
of receptors. In other words, maximal response in case of dose-response curve A was
obtained without binding to all receptors. These receptors, without binding with which
maximal response was obtained, are termed as spare receptors.
120
100
% of maximal effect
A
80 B
Increasing
C concentration of
60 D irreversible inhibitor
0.5 Effectmax
40
E-
20
0
-11 -10 -9 -8 -7 -6 -5 -4
EC50 (A) EC50 (B) EC50 (C) EC50 (D, E) = KD
Log agonist (M)
Fig. 1.4: Pharmacodynamics
1.1.9 Addiction
Addiction is a brain disorder characterised by compulsive engagement in rewarding
stimuli despite adverse consequences. It is related to addictive behaviour which is both
rewarding and reinforcing. Rewarding stimuli are interpreted by brain as intrinsically positive
and desirable or as something to be approached. Reinforcing stimuli increase the probability
of repeating behaviours paired with them. Addiction is caused by addictive drug,
consumption of which compels addictive behaviour.
1.1.10 Tolerance
Drug tolerance is defined as, "the diminishing effect of drug resulting from repeated
administration at a given dose". Drug tolerance is a pharmacological concept describing
subjects’ reduced reaction to a drug following its repeated use. Increasing its dosage may
re-amplify the drug’s effects, however this may accelerate tolerance, further reducing the
drug’s effects. Drug tolerance is indicative of drug use but is not necessarily associated with
drug dependence or addiction. The process of tolerance development is reversible and can
involve both physiological factors and psychological factors.
It is divided in to three types: pharmacodynamic, pharmacokinetic (metabolic) and
behavioural. Pharmacodynamic tolerance begins when the cellular response to a substance
is reduced with repeated use. A common cause is high concentration of a substance
constantly binding with a receptor, desensitizing it through constant interaction. Usually, it
occurs after sustained exposure to a drug. Pharmacokinetic tolerance occurs because of a
decreased quantity of the substance reaching the site it affects, this may be caused by
increase in induction of enzymes required for degradation of drug e.g. CYP450 enzymes.
Alcohol is a common example. In addition to enzyme induction, several other mechanisms
contribute to tolerance. Behavioural tolerance occurs with the use of some psycho-active
drugs, where tolerance to a behavioural effect of a drug occurs with repeated use of the
drug. Amphetamine causes behavioural tolerance.
1.1.11 Dependence
It is defined as, "an adaptive state associated with a withdrawal syndrome upon
cessation of repeated exposure to a stimulus (e.g. drug intake)". Withdrawal syndrome is
identified as a set of symptoms that occur upon cessation of repeated drug use.
Dependence is of two types: physical and psychological. Physical dependence involves
persistent physical-somatic withdrawal symptoms (e.g. fatigue and delirium tremens).
Psychological dependence involves emotional-motivational withdrawal symptoms
(e.g. dysphoria and anhedonia).
1.1.12 Tachyphylaxis
Tachyphylaxis is a sub-category of drug tolerance referring to cases of sudden, short-
term onset of tolerance following the administration of drug. It is a rapid and short term
onset of drug tolerance. It can occur after an initial dose or after a series of small doses.
Increasing the dose of the drug may be able to restore the original response. Tachyphylaxis
is characterised by the rate sensitivity: the response of the system depends on the rate with
which a stimulus is presented. To be specific, a high-intensity prolonged stimulus or often-
repeated stimulus may bring about a diminished response also known as desensitization.
Opioids, nicotine, nitroglycerine and metoclopramide are examples of some drugs which are
known to cause tachyphylaxis.
1.1.13 Idiosyncrasy
Idiosyncratic drug reactions occur rarely and unpredictably amongst the population.
They frequently occur with exposure to new drugs. They are listed as rare adverse drug
reactions. They do not appear to be concentration dependent. A minimal amount of drug
will cause an immune response but only after second administration; since development of
antibodies need time and first dose is mandatory. The proposed mechanism of most
idiosyncratic drug reactions is immune-mediated toxicity. The classical example is allergy
caused by penicillin. A drug may cause an immune response if it binds to a larger molecule.
In few cases a metabolite rather than the parent drug may bind to proteins. Thus a drug/its
metabolite, injury or infection may sensitize a person and can cause idiosyncratic reactions.
These reactions are studied under toxicology.
1.1.14 Allergy
Allergic reaction to a drug will not occur on the first exposure to a substance. The first
exposure allows the body to create antibodies and memory lymphocyte cells for the antigen.
Subsequently antibodies or lymphocytes interact with the antigen causing what we
understand as allergic reactions.
Following signs and symptoms are observed with allergy:
• Hives
• Itching
• Rash
• Fever
• Facial swelling
• Shortness of breath due to the short term constriction of lung airways or long-term
damage to lung tissues.
• Anaphylaxis, a life threatening drug reaction causing low blood pressure.
• Cardiac symptoms such as chest pain, shortness of breath, fatigue, chest palpitation,
light headedness, syncope and eosinophilic myocarditis.
Following drugs are known to cause allergy:
• Antibiotics: Penicillin, Sulphonamides, Tetracyclines
• Analgesic: Codine, NSAIDs
• Anti-epileptic: Phenytoin, Carbamazepine
The list is given for illustration only. It is not an exhaustive list.
Risk Factors
Risk factors for drug allergies can be attributed to the drug itself or the characteristics of
the patient. Drug-specific risk factors include dose, route of administration, duration of
treatment, repetitive exposure to the drug. The patient related factors include concurrent
illness, age, sex, specific genetic polymorphism and inherent predisposition to react to
multiple unrelated drugs. A drug allergy is more likely with large doses and extended
exposure.
Mechanisms
Drug allergies are related to drug hypersensitivity. Drug hypersensitivity reactions are
the mediators of a drug allergy. There are two mechanisms for drug allergy: IgE mediated or
non-IgE mediated. In IgE-mediated reactions drug allergens bind to IgE antibodies, which
are attached to mast cells and basophils, resulting in IgE cross-linking, cell activation and
release of performed and newly formed mediators. In case of non-IgE mediated reactions,
probably other immunoglobulins are involved.
1.2 PHARMACOKINETICS
1.2.1 Membrane Transport
Membrane transport refers to the collection of mechanisms which regulate passage of
solutes like ions and small molecules through biological membrane, which are lipid bilayers
containing proteins embedded in them. Regulation of passage through the membrane is
due to selective membrane permeability - a characteristic of biological membranes which
allows them to separate substances of distinct chemical nature. Alternatively, it can be stated
that biological membranes are permeable to certain substances but not to others.
The movements of most solutes through the membrane are mediated by membrane
transport proteins which are specialised to varying degrees in the transport of specific
molecules. There are different types of cells; hence specific transport proteins exist for each
cell type during a specific physiological state. The differential expression of proteins is
regulated through the differential transcription of the genes coding for these proteins. In
addition, production of these proteins can be activated by cellular signalling pathways, at
the biochemical level, or even by cytoplasmic vesicles.
Transport Types:
There are two types of transports in biological tissues viz Passive transport and Active
transport.
1. Passive transport
It is a movement of ions and other atomic/molecular substances across cell membrane
without the input of metabolic energy. The concentration gradient of the transported
substances acts as a source of energy. The rate of passive transport depends on the
permeability of cell membrane, which in turn, depends on the organisation and
characteristics of the membrane lipids. There are four mechanisms for passive transport:
diffusion, facilitated diffusion, filtration and osmosis.
(i) Diffusion: Diffusion is net movement of material from an area of high concentration
to an area with lower concentration. The difference of concentration between two sides of
membrane is called as concentration gradient. Diffusion continues only till the gradient is
eliminated. (Fig. 1.5)
Extracellular space
Lipid bilayer
(cell membrane)
Intracellular space
TIME
Water soluble
molecules
Plasma
membrane
Fat soluble
Channel protein
molecules
Fig. 1.5: Passive diffusion
(ii) Facilitated diffusion: Facilitated diffusion is also called as carrier-mediated osmosis.
It is the movement of molecules across the cell membrane via special transport proteins
embedded within the cell membrane (Fig. 1.6). It is a passive process. Carrier proteins allow
diffusion of molecules across the cell membrane by undergoing conformational alterations

to allow molecules to pass across the membrane. It may be achieved as a consequence of
charged gradients in addition to concentration gradients.
Insoluble molecules
Extracellular fluid Carrier protein
Cytoplasm
Receptor site
Fig. 1.6: Facilitated diffusion

(iii) Filtration: Filtration is movement of water and solute molecules across the cell
membrane due to hydrostatic pressure generated by the cardiovascular system. Depending
on the size of the membrane pores, only solutes of a certain size may pass through it
(Fig. 1.7). An example of water along with ions like sodium, potassium passing through the
membrane pores of Bowman’s capsule, while retaining albumin in the blood can be cited.
Feed
Retentate
Permeate
Fig. 1.7: Filtration
(iv) Osmosis: Osmosis is the movement of water molecules across a selectively
permeable membrane. It can be easily explained by behaviour of red blood cells in a
solution of sodium chloride. Depending on the concentration of sodium chloride, the
solution can be labelled as one of the three types: isotonic, hypertonic or hypotonic. Three
words indicate that the pressure exerted by sodium chloride is the same, higher or lower
than that of pressure exerted by the solutes in red blood cells (RBCs). RBCs do not change
their shape in isotonic solution. They shrink in hypertonic solution and swell in hypotonic
solution. It is due to movement of water across cell membrane.
2. Active transport
Active transport is the movement of molecules across a cell membrane from a region of
lower concentration to a region of higher concentration- in the direction against the
concentration gradient. This is due to expenditure of metabolic energy. Unlike passive
transport, which uses the kinetic energy and natural property of molecules moving down a
gradient, active transport uses metabolic energy to move them against a concentration
gradient, polar repulsion or other resistance. Active transport is associated with
accumulating high concentrations of molecules which the cell needs: e.g. sodium/
potassium/calcium ions, glucose, amino acids etc. if the process uses energy in the form of
ATP, it is termed as primary active transport. Secondary active transport involves use of an
electrochemical gradient.
The best example of primary active transport is of sodium-potassium pump. The pump
maintains the membrane potential by moving three sodium ions out of the cell for every
two potassium ions moved into the cell by hydrolysis of one ATP molecule. The pump is
enzyme dependent on activity of sodium and potassium ions with ability to hydrolyse ATP. It
is located on the membrane of the cell. An example of secondary active transport is that of
enzyme ATP synthase. The energy derived from pumping of proton across a cell membrane
is frequently used as the energy source in secondary active transport. In humans, sodium is
commonly co-transported ion across the plasma membrane, whose electrochemical
gradient is then used to power the active transport of a second ion or a molecule against its
gradient.
1.2.2 Absorption
Absorption is the transfer of the drug from its site of administration to the bloodstream.
The rate and extent of absorption depends on the route of administration, the formulation
and chemical properties of the drug, and physiological factors which can impact the site of
absorption. It is illustrated in Fig. 1.8. When a drug is administered intravenously, the entire
dose is available in systemic circulation. Administration of a drug by any other route may
result in less availability of drug due to incomplete absorption. When a tablet or capsule is
swallowed, it must dissolve before its absorption. The process is called as dissolution. Once
dissolution has occurred, the drug molecules pass through the membrane of the cells lining
gastrointestinal tract to reach the blood stream. The drug will be absorbed by one of the
mechanisms mentioned earlier. The rate and extent of absorption of a drug is termed as its
bioavailability.
Fig. 1.8: Plasma concentration of an oral/intravenous drug

Bioavailability
When a graph of plasma concentration of a drug is plotted against time, one gets a
curve as depicted in Fig. 1.8. The area under curve (AUC) of plasma concentration versus
time represents the total amount of drug reaching systemic circulation. AUC will have a
different shape depending on the route of administration. The AUC obtained after
intravenous administration is considered to be 100%. This is termed as absolute
bioavailability of a drug. Any other route (intramuscular, subcutaneous, oral, dermal etc.) will
have lesser bioavailability. The ratio of AUC for any formulation/ route of administration in
comparison to intravenous formulation is termed as relative bioavailability of a drug.
The acid environment or presence of food in the stomach, the solubility and other
chemical properties of the drug, and the effect of initial exposure to metabolic processes in
the liver may reduce the amount of drug which reaches the systemic circulation after oral
administration, thereby reducing the bioavailability of the drug. If the drug is subject to
metabolism by the liver, the amount of drug reaching the systemic circulation is decreased;
e.g. propranolol, enalapril. As a result, substantial drug is lost due to metabolism during a
single passage through the liver. This is called as first pass effect. When the drugs are highly
susceptible to the first pass effect, the oral dose needed to cause a response will be
significantly higher than the intravenous dose used to cause the same response.
Bioavailability becomes an important parameter in drug-product selection. While two
generic products may contain the same active ingredients, they may not have the same
dissolution or absorption characteristics. Hence, they cannot be considered bioequivalent. In
case of extended-release products, the change in dissolution characteristics is intentional. In
some cases, products are poorly manufactured and should be avoided. Generic equivalent
products approved by Food and Drug Administration (FDA) must meet a standard of less
than 20% variation from the comparison product. Bioequivalency data is published by the
USFDA’s Centre for Drug Evaluation and Research, referred to as “Orange Book”, and is
available on the web.
Factors affecting absorption
A number of patient-specific factors can affect absorption. Proper absorption needs
adequate blood flow to the site of administration. Most absorption after oral administration
occurs in small intestine because of larger surface area and greater blood flow. If small
intestine is partially removed, as in case of bariatric surgery, impairment of absorption of
drugs can occur.
Contact time with epithelial lining of gastrointestinal tract is an important factor in drug
absorption. In patients with severe diarrhoea, drug absorption may be adversely affected
because of rapid transit time in gastrointestinal tract. Contrary to this, if gastric emptying
time is delayed, as in case of large fatty meal, it may delay and potentially reduce
absorption. Some medications exhibit drug-food or drug-drug interactions with other
compounds present in gastrointestinal tract. The interaction between tetracycline and dairy
products or antacids is an example. Absence of hydrochloric acid in stomach is called as

achlohydria. It is common in elderly population. Patients with achlorhydria may experience
inadequate tablet dissolution and therefore poor drug absorption.
1.2.3 Distribution
Once a drug is absorbed in systemic circulation, it can be carried throughout the body.
This process is called as distribution. It is a reversible process. Some molecules may be
interacting with receptors on cell membranes or inside of cells, while other molecules may
move back into the blood stream. The delivery of a drug from the blood stream to the site
of drug action depends on blood flow, capillary permeability, degree of binding to blood
and tissue proteins, and relative lipid-solubility of the drug molecule.
Blood flow to the different organs of the body is unequal. The most vital organs like
brain, liver and kidneys receive greatest supply of blood. Skeletal muscles and bone receive
relatively less blood supply and adipose tissue/fat receives minimum blood supply.
Penetration into central nervous system is yet another factor. The anatomical structure of
capillary networking in the brain creates a barrier to passage of many drugs in the CNS. This
is called as blood-brain barrier. Lipid-soluble substances enter the brain very easily. This
explains why fat-soluble anaesthetic gases easily penetrate the brain to cause anaesthesia
while water soluble penicillin antibiotics penetrate the CNS to a lesser degree.
If impermeable capillaries of the brain are compared with highly permeable capillary
walls in liver and spleen (Fig. 1.9), the anatomical difference and the distribution
characteristics can be clearly seen. Capillaries of the liver have gaps between their cells which
allow large proteins to pass through the capillary basement membrane. In order to function,
the liver must have access to amino acids, sugars and other large molecules from the blood
stream. These molecules undergo chemical processing in the liver, and then must be moved
out of hepatic cells and back to the blood stream. Unlike liver, capillaries of the brain have
endothelium with tight junctions. This prevents entry of water soluble substances in the
brain. Only few drugs which can be transported by carrier mediated mechanisms or are fat
soluble can penetrate the brain. Thus, permeability of capillaries decide distribution of drug
to the organ.
Large gaps allow drugs to
exchange freely between blood
and the liver
Drug
Basement
membrane
Neuron
Slit injections
(a) Structure of endothelial cells in the liver

Neuron
Slit injections Lipid

soluble
(a)
Astrocyte
Blood Carrier
mediated
A few drugs that can be transported

Tight injections between endothelial via carier-mediated transport
cells prevent most substances mechanisms or that are fat-soluble
from entering the brain can penetrate the brain.
Endothelium with
tight junctions
(b) Structure of capillaries in the brain
Fig. 1.9: Structure of capillaries
Factors affecting distribution of drugs:
Most drugs reversibly bind to plasma proteins in varying degree. Albumin is the most
abundant plasma protein with an ability to bind drugs. Only free fraction of the drug is
biologically active. There is an equilibrium between free and bound drug to proteins like
albumin. Albumin acts as a reservoir for administered drug. Some drugs may have binding
of 95-98% to albumin. With highly protein bound drugs, low albumin levels (as in case of
protein calorie malnutrition or chronic illness) may lead to toxicity because of lesser binding
sites. Hence, identifying patient’s serum albumin level can help in deciding dose of a highly
protein bound drug.
Competition for binding sites is yet another factor. If two drugs can compete for the
same site on albumin and one drug is capable of displacing another drug from the site of
binding, then an interesting drug interaction is observed. Known example of this is
phenylbutazone displacing warfarin from protein binding sites. In this case, a patient
receiving warfarin earlier will get the effects of anticoagulation by administration of
phenylbutazone. The cause is displacement of warfarin due to phenylbutazone.
Other patient variables that can affect distribution include body composition, cardiac
decompensation (heart failure), and age of the patient. These factors affect volume of
distribution (Vd) of a drug. Vd is the hypothetical volume needed to account for all of the
drug in the body based on serum concentration in a blood sample. Higher Vd indicates
lower serum concentration and greater distribution of drug in the body. Lower Vd indicates
higher serum concentration and limited distribution of drug in the body.
Dosing of medications in infants and children requires special consideration. It is to be
noted that “children are not simply small adults”. Bodies of children/infants contain a high
percentage of water and low percentage of muscle and fat. Especially in neonates, albumin
may be lower. All these variations can alter Vd significantly; hence dosage for
neonates/infants/children should be carefully adjusted.
1.2.4 Metabolism
While the drugs are getting distributed in different parts of body, there are chemical
changes in their structures due to interaction with various enzymes or due to other chemical
reactions. The process of chemical change is called as biotransformation or metabolism.
Liver is major site for drug metabolism, but specific drugs may undergo metabolism in other
tissues. The purpose of metabolism is to convert the drug into more water soluble
compounds. There are two types of metabolic processes which drugs undergo.
In the first type of reaction, drugs are converted into more polar compounds through
oxidation-reduction reactions or hydrolysis. These reactions use microsomal enzymes
located in the liver, called as cytochrome P450 enzyme system. In enzyme-catalysed
reactions, the rate of reaction is accelerated by presence of enzymes. Since the quantum of
enzymes is limited, metabolism is considered as a saturable process. Once enzymes are
saturated, blood levels of drug increase exponentially which may lead to toxicity. Examples
include metabolism of alcohol or phenytoin.
The second type of metabolism involves conjugation reactions. In this type of reactions,
drugs undergoing metabolism are joined with another substance like glucuronic acid,
sulphuric acid, acetic acid or an amino acid. Glucuronidation reaction is the most common.
As a result of conjugation reaction, the drug or its metabolite is converted to more water
soluble compound which is easier for kidneys to excrete.
For some drugs initially administered compound, called as pro-drug is not biologically
active. Metabolism converts the pro-drug into the active compound. Fosphenytoin is a pro-
drug of phenytoin and is used for controlling seizures. Fosphenytoin is more completely and
quickly absorbed when given by intra-muscular injection than phenytoin.
Factors affecting metabolism
Metabolism of drugs can vary widely between population groups. Deficiency of some
enzymes may be of genetic origin and may result in poor tolerance of certain drugs. An
example of ethanol metabolism can be cited. Asians and Native Americans have difficulty in
metabolising alcohol which requires acetylation for its metabolism. These individuals exhibit
low tolerance towards alcohol; and can suffer adverse reactions at much higher rate than
average population. Age is another important variable for metabolism. In elderly population,
rate of metabolism comes down. Organ function gradually declines with increasing age.
Contrary to this, children require special consideration of drug dosing because of immaturity
of their organ systems.
Drug interactions may occur between two drugs which are metabolised by the same
enzyme systems in the liver. If two drugs are metabolised by the same enzyme system and
one has higher affinity for enzyme, then levels of second drug can build up. In some cases,
the drug being metabolised may induce production of more of the enzymes. Enzyme
induction sets the stage for another type of drug interaction because the increased
production of metabolising enzymes may result in higher rates of removal and the need for
an increased dose of the second drug. Sometimes a drug may induce its own enzymes. Then
it is called as self-inducer. Self-induction is one of the reasons for addiction of drugs
explaining why additional doses are required over the period of time.
1.2.5 Excretion
When a drug is distributed throughout the body and is getting metabolised, there has to
be some way by which it is excreted; otherwise its concentration along with its metabolites
will continue to rise with each successive dose. The complete removal of drug from the body
is termed as its elimination. Elimination of the drug includes its metabolism and excretion
through kidneys and to a lesser degree into bile. Excretion in urine is one of the most
important mechanisms of drug removal.
Kidneys act as a filter for drug and create urine as a vehicle for removal of waste. Blood
enters the kidney through renal arteries and is filtered by the glomerulus. The glomerular
filtrate becomes concentrated and substances are removed as it passes through the renal
tubule, finally getting converted to urine. Drug molecules in blood which are not bound to
albumin also get filtered in the glomerular filtrate. When drugs have not been converted to
water soluble compounds in the liver, they are likely to be reabsorbed into blood at the end
of filtration process and will cycle through the body again. If they are water soluble, they will
be excreted in urine.
When a medication is given repeatedly, the total amount of drug in the body will
increase up to a point and then stabilise. At this point, the amount being taken by the
patient is equal to the amount being removed by the liver and kidneys. This state of
equilibrium is called as steady state, and drug levels remain fairly constant unless there is a
dose change, or interruption in treatment, or failure of the organs of elimination. The
therapeutic effects of many drugs are closely correlated to a specific range of steady state
serum drug levels, which modify from drug to drug.
Factors affecting elimination or excretion
Complete elimination of a drug from the body is dependent on normal liver and kidney
function. The kidney is major organ of excretion; the liver contributes to elimination through
metabolism and excretion into feces via bile. When a patient has reduced renal function or
other problem which increases half-life of a drug, dosage adjustment is necessary to avoid
accumulation of drug in the body.
Kidney or liver failure, or conditions where blood flow to these organs is reduced
selection of drug and it's does is complicated. Drugs which are dependent on excretion
through the kidneys are not the best choice for the patients with renal failure. Similarly
patients with liver disease will better tolerate drugs which can be cleared exclusively through
the kidneys. Age is also a factor related to drug excretion. Very young and very old will have
lower rates of excretion. Doses often require reduction in these patients. Drug interactions,
such as when multiple drugs compete for metabolic processes, can also reduce drug
removal.
1.2.6 Enzyme Induction

Enzyme induction is a process in which a molecule like drug induces i.e. initiates or
enhances the expression of an enzyme. Liver is the principal site of drug metabolising
activity. The enzymes concerned with drug metabolism are located in the hepatic
endoplasmic reticulum. The enzymes catalysing these reactions are versatile and non-
specific while the rate of activity may be under strong genetic influences. Numerous external
and physiological factors may affect drug metabolising enzyme systems. The factors are
categorised into four major types:
• Patient related factors
Patient related factors include age, sex, pregnancy and circadian rhythm of the body.
• Diseases and drugs-related factors
Disease and drugs-related factors include infections, malignancy, enzyme inducers and
enzyme inhibitors.
• Organ function and disease
Organ function and disease related factors include functioning of liver, kidney,
gastrointestinal system, cardiovascular system and endocrine system
• Environment/life style
Environmental and life style factors include occupation, exercise, diet, alcohol and
tobacco.
All these factors are interrelated to genetic constitution. Fig. 1.10 depicts all these
factors.
Organ function
and disease
Liver
Gastrointestinal Renal
Cardiovascular Endocrine
Disease
Patient and drugs
Age Infections
Sex Malignancy
Genetic constitution Enzyme inducers
Pregnancy
Circadian rhythm Enzyme inhibitors
Environment / Lifestyle
Occupation Exercise
Diet Cigarettes
Alcohol
Fig. 1.10: Factors influencing rate and extent of drug metabolism in liver
The classes of enzyme inducing drugs include following categories:

• Phenobarbitone and a wide variety of structurally unrelated compounds.
• Polycyclic aromatic hydrocarbons like 3-methylcholanthrene.
• Steroids including pregnenalone derivatives.
• Ethanol
List of some enzyme inducers is presented in table 1.3.
Table 1.3: List of some enzyme inducers
Sr. No. Name(s) of drugs/substances
1. Barbiturates; specially primidone (phenobarbitone)
2. Carbamazepine
3. Cigarette smoke
4. Dichloralphenazone
5. Ethanol (chronic)
6. Glutethimide
7. Griseofulvin
8. Marijuana smoke
9. Meprobamate
10. Phenetoin
11. Rifampicin
12. Sulfinpyrazone
There are various clinical consequences of liver drug-metabolising enzyme induction by
Phenobarbital-like drugs; e.g. a drug can increase its own rate of metabolism. Due to
induction of cytochrome P 450 enzyme, Phenobarbital needs higher dose for the same
effect on repeated administration. This type of tolerance is called as pharmacokinetic
tolerance. Clinical importance of enzyme induction can be summarised as follows:
• Reduction in some normal body constituents; e.g. adrenal steroids, sex hormones,
vitamin D, bilirubin.
• Development of tolerance; e.g. alcohol, barbiturates (auto induction).
• Increased drug toxicity; e.g. paracetamol, polycyclic hydrocarbons (benzopyrine,
DDT).
In addition to self induction, the metabolism of other drugs and endogenous
compounds can also be increased. This is called as cross-induction. Some examples of cross-
induction are mentioned in table 1.4.
Table 1.4: Some examples of cross-induction

Sr. Enzyme inducer Drugs whose metabolism is increased
No. drug/substance
1. Cigarette Benzodiazepines, paracetamol, propoxyphene, theophylline
(benzopyrene)
2. Ethanol Barbiturates, phenytoin, warfarin, tolbutamide
3. Barbiturates Phenytoin, warfarin, corticosteroids, phenothiazines,
(phenobarbitone) doxycycline, digitoxin, quinidine, calcium channel blockers,
β-blockers.
4. Carbamazepine Corticosteroids, doxycycline, haloperidol.
5. Phenytoin Digitoxin, quinidine, hydrocortisone, β-blockers, methadone,
doxycycline, theophylline.
6. Rifampicin Oral contraceptives, corticosteroids, digitoxin, quinidine,
theophylline, phenytoin, warfarin, β-blockers, calcium
channel blockers, tolbutamide.
7. Grieseofulvin Warfarin.
1.2.7 Enzyme Inhibition
Drugs can inhibit metabolising enzyme activity. Enzyme-inhibition can either be non-
specific of hepatic microsomal mixed function oxidase (MFO) enzymes or of enzymes with
specific functions; e.g. xanthine oxidase, aldehyde dehydrogenase, cholinesterase,
monoamino oxidase (MAO). The inhibition of hepatic MFO can either be due to hepatic
dysfunction or administration of drug. Table 1.5 lists enzyme inhibitors and the drugs for
which the metabolism is inhibited.
Table 1.5: Enzymes, enzyme inhibitors and interacting drugs
Sr. Enzymes Enzyme Drugs whose metabolism is inhibited
No. inhibitors
1. Hepatic microsomal Cimetidine Chlordiazepoxide, diazepam, pheny-
toin, anti-depressants, theophylline,
lidocaine, propranolol, quinidine,
testosterone, warfarin
2. Erythromycin Theophylline, warfarin, cyclosporine,
carbamazetine
3. Sodium Phenytoin, phenobarbital, primidone
valproate
4. Quinolones Theophylline
5. Chloramphenicol Phenytoin, tolbutamine, warfarin
6. Verapamil Theophylline
contd. …
7. Diltiazem Carbamazepine
8. Propoxyphene Cyclosporine, carbamazepine
9. Xanthine oxidase Allopurinol 6-Mercaptopurine, azathioprine
10. Monoamino MAO inhibitors Pethidine, Tricyclic anti-depressants
oxidase
11. Aldehyde Disulfiram, Alcohol, phenytoin, warfarin, some
dehydrogenase metronidazole benzodiazepines
12. Cholinesterase Echophiophate Suxamethonium, procaine, propanidid
13. Angiotensin Captopril, Angiotensin I, bradykinin
converting enzyme enalapril
Whenever an enzyme is inhibited, the plasma half-life, drug efficacy as well as toxicity of
the drug whose metabolism is affected (drugs indicated in column (3) of table 1.3) are
significantly enhanced. In case the drug undergoes hepatic first pass effect, the
bioavailability and toxicity of the drug will be markedly enhanced in presence of enzyme
inhibition. Enzyme inhibition may produce undesirable drug-drug interaction because of
enhanced concentration of the drug of which metabolism is inhibited.
1.2.8 Kinetics of Drug Elimination
Usually two kinds of elimination kinetics are involved in drug elimination: zero-order and
first order. In zero-order elimination kinetics, elimination of a constant quantity of the drug
per unit time is eliminated from the organism. Thus, it is not dependent on concentration of
drug in the blood; hence called as zero-order kinetics. In case of first order elimination
kinetics, elimination of a constant fraction of the drug quantity present in the organism is
eliminated per unit time. Thus, the elimination is dependent on concentration of the drug;
hence it is called as first order kinetics.
Zero-order elimination kinetics
If a graph of drug concentration versus time is plotted, the profile during elimination
phase is linear in nature.
First-order elimination kinetics
If the amount of drug A is decreasing at a rate which is proportional to concentration of
A, the amount of drug A remaining in the body, then the rate of elimination of drug A can
be described as:
dA
= – k.A
dt
where, k = The first order rate constant.
In case of first order reaction, the reaction proceeds at a rate that is dependent on the
concentration of A present in the body. It is assumed that the process of ADME follow first-
order reactions and most drugs are eliminated in this manner.
Most drugs used in clinical practice at therapeutic doses show first order process; i.e. the
rate of elimination is dependent on concentration of drug remaining in the body. However,
there are notable exceptions; e.g. phenytoin and high-dose salicylates. For drugs which show
a first order elimination process, it can be shown that, as the amount of drug administered
increases, the body will eliminate the drug at higher rate and the drug may not accumulate
in the body. However, if you continue to increase the amount of administered drug then all
drugs will change from showing a first order process to a zero-order process, e.g. in an
overdose situation.
The difference between zero-order kinetics and first-order kinetics is depicted in
table 1.6.
Table 1.6: Comparison between zero-order and first-order kinetics
Sr.
Parameter Zero-order kinetics First-order kinetics
No.
1. Definition The process that takes place at The process is directly
a constant rate independent of proportional to the drug
drug concentration. concentration.
2. Nature of Constant rate. Linear kinetic.
process
3. Rate of Rate cannot be increased even Rate increases linearly with
process if drug concentration is increase in concentration.
increased.
4. Salient Process is independent of Process is dependent on
feature concentration of drug. concentration of drug.
5. General dc dc
= – K0 Co = – K0 = – KC1 = – KC
expression dt dt
6. Rate constant K0 K
7. Units of rate mg/min min–1 or hour–1 i.e. per min or
constant per hour
8. General C =C0 – K0t; where C0 is initial C = C0 e–Kt or
equation concentration and C = concen- Kt
log C = log C0 –
tration of drug at time t. 2.303
55 0.9
9. Plot 40 0.8
35 0.7
Concentration (lit./ml.)
30 0.6
25
Log C
Slope = -Ko 0.5 Slope =

-K
2.303
20 0.4
15 0.3
10 0.2
5 0.1
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Time (hours) Time (hours)
Fig. 1.11 (a) Zero-order kinetics Fig. 1.11 (b) First-order kinetics
contd. …
10. Half-life 0.5 C0 0.693

t1/2 = t1/2 =
K0 K
11. Feature of Half-life depends on initial drug Half-life is concentration
half-life concentration. independent and a constant
value.
12. End-stage At some time, the process Theoretically, it never comes to
nature comes to an end. an end.
13. Examples Intra venous infusion, Absorption, distribution,
controlled/sustained drug metabolism and excretion
delivery systems. (ADME), not linked with carriers
or unsaturable state if linked
with carriers.
QUESTIONS
Long Answer Questions:
1. Trace history of the subject of pharmacology from 17th century.
2. What is the scope of subject of pharmacology.
3. Enlist and describe various routes of drug administration.
4. Describe advantages and disadvantages of any two routes of administration.
5. Describe the concept of agonists and antagonists.
6. Discuss different types of antagonism.
7. What is pharmacokinetics? Discuss its components.
8. Describe factors controlling metabolism of drugs.
9. With suitable examples comment on consequences of enzyme induction.
10. With suitable examples comment on consequences of enzyme inhibition.
11. Compare and contrast zero order kinetics and first order kinetics.
Small Answer Questions:
1. Define following terms:
• Adverse reactions
• Bioavailability
• Bioequivalence
• Biomarker
• Biosimilar
• Clinical trial
• Counterfit medicines
• Medical device
• Essential medicines
• Exciepients
• Generic medicine
• Good clinical practice
• Haemovigilance
• Infusion
• Palliative care
• Pharmacovigilance
• Rational use of medicines
• Therapeutic equivalence
• Vulnerable groups
• Tolerance
• Tachyphylaxis
• Idiosyncrasy
• Allergy
2. Write short notes on:
• Passive transport
• Active transport
• Bioavailability
• Absorption of drugs
• Distribution of drugs
• Distribution of drugs
• Excretion of drugs
• Enzyme induction
• Enzyme inhibition
Unit ... 2
GENERAL PHARMACOLOGY - II
• Principles of Pharmacodynamics including Mechanism of Drug Action
• Receptor Theories, Classification and Regulation of Receptors, Drug Receptor Interactions
• Various Signal Transduction Mechanisms
• Dose Response Curve, Therapeutic Index, Combination of Drugs
• Adverse Drug Reactions
• Drug Interactions
• Drug Discovery and Clinical Evaluation of New Drugs
• General pharmacology consists of four main components: Pharmacodynamics, Adverse

drug reactions, Drug interactions and Drug discovery. They are discussed below.
2.1 PHARMACODYNAMICS
• It is defined as, "the study of the actions and effects of drugs at all levels of organisation
of living material and of the handling of the drugs by the organism". It includes
following components:
o The biological effects produced by drugs.
o The site(s) at which and mechanism(s) by which the biologic effects are produced.
o The factors which influence safety and effectiveness of drugs.
o Principles and mechanism of drug action.
• In simpler words, pharmacodynamics involves what drug does to the body and how
does it do it.
2.1.1 Principles and Mechanisms of Drug Action
Principles
Drugs do not create any new functions to any physiological system but can only
increase, decrease or replace existing functions by following one of the following principles:
• Stimulation
There is increase in level of physiological activity of specialised cells or physiological
system; e.g. Pilocarpine may stimulate salivary secretion and induce contraction of pupil;
adrenaline may stimulate heart and induce glycogenolysis.
• Depression
There is a decrease in the level of activity of specialised cells or physiological systems;
e.g. general anaesthetics depress CNS; quinidine depresses the heart.
(2.1)
Pharmacology - I (B.Pharm. Sem. IV) 2.2 General Pharmacology - II
• Replacement
There is replacement of deficient substances, either endogenous (insulin in diabetes
mellitus, thyroxine in myxoedema) or exogenous (vitamin B12 in pernicious anaemia, iron
in microcytic anaemias, vitamin C in beriberi.)
• Chemotherapy
It involves selective targeting of invading microorganisms with minimal effect on the
host cells; e.g. use of Rifampicin/Isoniazid in tuberculosis, use of quinine in malaria.
Mechanism of Drug Action
Following mechanisms operate in the manifestations of drug action:
• Physical action
Some drugs act on the basis of a given physical property, e.g. adsorbent action by
charcoal, kaolin; osmotic activity by osmotic purgatives and diuretics; bulk mass given by
bulk laxatives like psyllium husk; radioopacity given by diagnostic contrast media.
• Chemical action
Some drugs act by participating in a specific chemical reaction, e.g. gastric antacids
neutralise gastric activity: aluminium hydroxide/magnesium hydroxide; chelating agents
form complexes with metals: penicillamine with copper; dimercaprol with mercury;
desferrioxamine with iron; acidifying agents like ammonium chloride; alkalinising agents
like sodium bicarbonate and antioxidants like vitamin C, sylimarin, curcumin.
• Action through enzymes
Enzymes can be important targets of drug action since many body functions are
mediated through activity of certain enzymes. Enzyme induction and inhibition has been
discussed under section 1.2.6 and 1.2.7 respectively. Enzyme stimulation also is a
mechanism of drug action; e.g. adrenaline stimulates adrenaline cyclase while pyridoxine
stimulates dopa decarboxylase.
• Action through ion channels
A number of drugs influence transmembrane ion channels like sodium, potassium,
calcium and chloride. They may open up or close such channels. The net effect depends
on how specific channels are affected. Sodium or calcium channel blockers alter
generation of action potentials. Potassium channel blockers or openers alter membrane
repolarisation. Chloride channel openers induce hyperpolarisation. Irreversible blocker of
sodium channel like tetrodotoxin is one of the most dangerous poison.
• Action through receptors
Receptors for various neurotransmitters like acetyl choline, nor-adrenaline, adrenaline,
serotonin (5-HT), dopamine etc. are discussed separately.
• Action by replacement
Drugs can be used to replace deficient endogenous or exogenous factors e.g. treatment
of anaemia. Replacement of deficient genes in the form of gene therapy has been used
successfully in some genetic disorders. Some common disorders requiring gene therapy
are listed below in table 2.1.
Table 2.1: Some common disorders requiring gene therapy

Sr. No. Type of disorder Names of diseases
1. Immunodeficiency Adenosine deaminase deficiency, X-linked combined
immune deficiency, chronic granulomatous disease.
2. Hepatic Familial hypercholesterolemia, Haemophilia A.
3. Hematologic Sickle cell anaemia, Thalassemia.
4. Lung Cystic fibrosis, α-antitrypsin deficiency.
5. Skeletal muscle Duchenne muscular dystrophy, limb girdle muscular
dystrophy.
• Chemotherapy
Drugs can be used in antimicrobial and cancer chemotherapy by selective targeting of
invading microorganisms or cancer cells, with minimal action on host cells.
2.1.2 Receptor Theories
There are three major theories for drug-receptor interaction. They are as follows:
(i) Occupation theory
Occupation theory advocates that effect of a drug is directly proportional to the number
of receptors which are occupied. Further, it is argued that a drug effect caeses as a drug-
receptor complex dissociates. The theory introduces towards: affinity and efficacy to
indicate following meaning.
Affinity is the ability of a drug to combine with receptor to create a drug-receptor
complex.
Efficacy is the ability of a drug-receptor complex to initiate a response.
(ii) Rate theory
In contrast to occupation theory, rate theory proposes that the activation of receptors is
directly proportional to the number of encounters of a drug with its receptors per unit
time. Pharmacological activity is directly proportional to the rates of dissociation and
association and not on the number of receptors occupied. Thus, it is the rate at which
drug-receptor complex is formed/dissociated which decides the quantum of response.
In light of this theory; agonist, partial-agonist and antagonist can be identified as
indicated below:
Agonist is a drug with fast association and fast dissociation. Partial agonist is a drug with
an intermediate association and an intermediate dissociation. Antagonist is a drug with
fast association and slow dissociation.
(iii) Induced-fit theory
According to induced-fit theory, as a drug approaches to a receptor, the receptor alters
the conformation of its binding site to produce drug-receptor complex.
2.1.3 Classification of Receptors
Receptors are glycoproteins located in cell membranes which specifically recognise and
bind to ligands/drugs. Drugs are smaller molecules which are capable of ligating themselves
to the receptor protein. This binding initiates a conformational change in the receptor
protein leading to a series of biochemical reactions inside the cell; it is termed as signal
transduction, often involving secondary messengers. Activity of secondary messengers is

eventually translated into a biological response like muscle contraction, hormone secretion
etc. Although drugs are of exogenous origin, receptors in human tissues have evolved to
bind endogenous ligands like neurotransmitters, hormones and growth factors. Formation
of drug-receptor complex is usually reversible and the proportion of receptors occupied is
directly related to the concentration of the drug. Reversibility enables biological responses
to be modulated and means that similar ligands may compete for access to the receptor.
The term receptor is usually restricted to describe proteins whose only function is to bind a
ligand, but it is sometimes used more widely to include other kinds of drug targets such as
voltage sensitive ion channels, enzymes and transporter proteins.
There are five major types of receptors:
• G Protein-coupled receptors
• Ion-channel receptors
• Tyrosine kinase-linked receptors
• Nuclear hormone receptors
• Receptors with intrinsic enzymatic activity
2.1.4 Regulation of Receptors
Cells can increase (up regulate) or decrease (down regulate) the number of receptors to
a given hormone or neurotransmitter to alter their sensitivity to different molecules. This is a
locally acting feedback mechanism.
All living cells have the ability to receive the process signals which originate outside their
membranes, which they do by means of receptors, usually found on a cell’s surface
embedded in the cell membrane. When such signals bind to a receptor, they effectively
direct the cell to do an activity, such as dividing, dying or allowing substances to be created,
or to enter or exit the cell. A cell’s ability to respond to a chemical message depends on the
presence of receptors tuned to that message. The more receptors a cell has that are tuned
to the message, the more the cell will respond to it. Receptors are created, or expressed by
the DNA of the cell, and they can be increased or up regulated when the signal is weak, or
decreased/down regulated, when it is strong.
(i) Up Regulation
Up regulation involves increase in the number of receptors due to external stimulation.
An example of up regulation is the response of liver cells exposed to molecules like dioxin.
In this situation, the cells increase their production of cytochrome P 450 enzyme, which in
turn increases their degradation of these molecules. Up regulation results in super-sensitized
cells especially after repeated exposure to an antagonist drug or prolonged absence of the
agonist.
(ii) Down Regulation
Down regulation involves decrease in the quantity of cellular component, such as RNA
or protein, in response to an external stimulus. It happens when receptors have been
chronically exposed to an excessive amount of neurotransmitters, whether endogenous or in
the form of drugs. This results in ligand-induced desensitization or internalisation of that
receptor. It is usually exhibited by various hormonal receptors. An example of insulin
receptor down regulation can be cited here.
Elevated levels of insulin in the blood, trigger down regulation of the associated
receptors. When insulin binds to its receptors on the surface of the cell, the hormone-
receptor complex undergoes endocytosis and is subsequently attacked by intracellular
lysosomal enzymes. Internalisation of the insulin molecule provides a pathway for the
degradation of the hormone as well as for regulation of the number of sites which are
available for binding on the cell surface. At high plasma concentrations, the number of
surface receptors for insulin is gradually reduced by the accelerated rate of receptor
internalisation and degradation brought about by increased hormonal binding. The rate of
synthesis of new receptors within the endoplasmic reticulum and their insertion in the
plasma membrane do not keep pace with their rate of destruction. Over the period of time,
this self-induced loss of target cell receptors for insulin reduces the target cell’s sensitivity to
the elevated hormone concentration.
Due to elevated levels of blood glucose in an overweight individual, the β-cells in the
pancreas must release more insulin to meet the demand, and return the blood to
homeostatic levels. The near-constant increase in blood insulin levels results from an effort
to match the increase in blood glucose, which will cause receptor sites on the liver cells to
down regulate and decrease the number of receptors for insulin, increasing the subject’s
resistance by decreasing sensitivity to the hormone. There is also a hepatic decrease in
sensitivity to insulin. This can be seen in continuing gluconeogenesis in the liver even when
blood glucose levels are elevated. This is responsible for insulin resistance. Thus, insulin
receptor down regulation helps in explaining Pathophysiology of diabetes.
Some receptor agonists may cause down regulation of their respective receptors, while
most receptor antagonists temporarily up regulate their respective receptors. The
disequilibrium caused by these changes often causes withdrawal when the long-term use of
a drug is discontinued. However, use of certain receptor antagonists may damage receptors
faster than they up regulate. Down regulation of receptors happens when receptors have
been chronically exposed to an excessive amount of neurotransmitters. This results in
ligand-induced desensitization. It is usually exhibited by various hormone receptors. Up
regulation of receptors results in super-sensitized cells especially after repeated exposure to
an antagonist or prolonged absence of agonist. Receptors are created, or expressed, by the
DNA of the cell and they can be increased or up regulated, when the signal is weak or
decreased or down regulated when the signal is strong.
2.1.5 Drug-Receptor Interaction
The idea that drug molecules interact at specific sites in the body is a relatively old
concept. However, proof of the receptor concept lag behind theory. In 1965, Propranolol
was the first β-adrenergic antagonist which entered into clinical practice to completely
convince the scientific community that receptors truly exist.
The basic concept of drug-receptor interactions can be described by the “lock and key”
model in which a receptor structure (the lock) has a region with a particular shaped pocket
at which an appropriately shaped molecule (the key) can interact. See Fig. 2.1. The drug
which interacts at the receptor binding site is known as ligand. In other words every drug is
a ligand. It is to be appreciated that, receptors have been evolved the ages to provide
particular functions within the body; it is coincidence that, the ligand/drug interacts with the
receptor. The purpose of existence of receptors is to interact with some normal endogenous
component or common environmental material. Thus, drug molecules which interact at
receptors either mimic or inhibit normal body compounds. Receptors themselves are
normally categorised as protein structures, either a single protein or a complex comprised of
multiple protein sub-units. The binding sites on the receptor complex where the drug
interacts may only be a small portion of the molecule. The interaction of a drug molecule
with its receptor can be represented in the manner as shown in Fig. 2.2, where D is the drug
concentration, and R is the free receptor concentration, and DR is the concentration of
receptor molecules occupied by drug molecules. The interaction of the drug at its binding
site on the receptor complex is governed by two important concepts: affinity and intrinsic
activity.
Drug
Receptor Drug-receptor complex

Fig. 2.1: Lock-key drug receptor interaction
kon
D+R DR
koff
Fig. 2.2: Rate of binding and release
Affinity describes as how well a particular compound is drawn into and held at the
binding site. Intrinsic activity is used to describe the effect which the drug has, when it
interacts with the receptor site. A drug may have good affinity, but if it has no intrinsic
activity, it will elicit no response even after binding to the receptor. On the other hand, a
drug that has good intrinsic activity will elicit a strong response at the receptor zone if it has
good affinity. Alternatively, if the affinity of a compound for the receptor site is low, even a
high level of intrinsic activity will not elicit much of a response.
Let us have a look at equation mentioned in Fig. 2.2. At equilibrium, the dissociation
constant (KD) of a drug-receptor complex is equal to koff/kon. The equilibrium affinity
constant (KA) is the reciprocal of the equilibrium dissociation constant (1/KD). Therefore, the
smaller the equilibrium dissociation constant is, the greater the affinity of the drug for the
receptor. This is useful while examining how well different drugs bind to a specific receptor
complex. To understand how individual molecules, such as drug molecules move around
receptor zone it is important to remember that, drug molecules are mixed with naturally
available molecules around the cell moving in a random manner driven by Brownian motion.
The interaction of a molecule with its receptor is primarily a matter of chance. The possibility
that a particular type of compound will interact with a given receptor is based on the
number of molecules (concentration) located near the receptor site. The greater the
concentration, the more likely is that, the random motion of a particular molecule will bring
it close to a receptor site to interact. If a molecule is able to interact with the receptor site, it
is said to have affinity for that site. The stronger it interacts, the greater is its affinity for that
receptor site.
The concept of interaction at the receptor site is based mainly on drug’s shape and
chemical makeup. The receptor site may have particular chemical functional groups which
interact at specific places. Most drugs may bind very briefly with the receptor site and are
knocked out of the site by collisions with other molecules which are moving around in the
surrounding area. Therefore, a drug may interact with the receptor zone very briefly.
However, if the concentration of the drug molecules in the surrounding area is high, the
likelihood of continued receptor-drug interaction increases. This idea is critical in
understanding drug action. The greater the drug concentration at receptor zone, the more
likely it is that a drug molecule will be occupying the receptor site at any given time. As the
drug concentration goes down, the fraction of time the receptor is occupied also decreases.
The response generated from a receptor interaction can be plotted against the dose of a
drug to produce the classic dose-response curve (DRC) which is so commonly known in
pharmacology. (Fig. 2.3). Details of DRC are discussed under sub-section 2.1.12.
Rmax
Response
Log/dose
Rmax indicates maximal response
Fig. 2.3: Log dose – Response curve
2.1.6 Signal Transduction Mechanisms
Signal transduction is the process in which a chemical or physical signal is transmitted
through a cell as a series of molecular events, most commonly protein phosphorylation
catalysed by protein kinases, which ultimately results in a cellular response. Proteins
responsible for detecting stimuli are called as receptors or sensors. The changes initiated by
drug-binding/signal sensing in a receptor give rise to a signalling cascade, which is a chain
of biochemical events along a signalling pathway. At molecular level responses include
changes in transcription or translation in genes and post translational and conformational
changes in proteins, as well as changes in their location. In multicellular organisms, signal
transduction pathways have evolved to regulate cell communication in a wide variety of
ways.
Each component of a signalling pathway is classified according to the role it plays with
respect to initial stimulus. Ligands/drugs are called as first messengers, while receptors are
signal transducers, which then activate primary effectors. Such effects are often linked to
second messengers which can activate secondary effectors and so on. Depending on the
efficiency of the nodes, a signal can be amplified, so that, one signalling molecule can
generate a response involving hundreds to millions of molecules. The transduction of

biological signals is characterised by delay, noise, signal feedback, freed forward and
interference, which can range from negligible to pathological state. With the advent of
computational biology, the analysis of signalling pathways and networks has become an
essential tool to understand cellular functions and disease, including signalling rewiring
mechanisms underlined responses to acquired drug resistance. (Fig. 2.4).
Fig. 2.4: Signal transduction pathways

Receptors related to signal transduction pathways can be divided into two major classes:
intracellular and extracellular receptors.
Extracellular Receptors
Extracellular receptors are integral transmembrane proteins and make up most of the
receptors. They are further subdivided into following subtypes:
• G Protein-coupled receptors
• Tyrosine, Ser/Thr and Histidine-specific protein kinases
• Integrins
• Toll like receptors
• Ligand-gated ion channels
• Intracellular receptors
Intracellular receptors, such as nuclear receptors and cytoplasmic receptors are soluble
proteins localised within their respective areas.
Secondary messengers include calcium, lipid messengers, nitric oxide and redox
signalling.
Some of the receptors are discussed in detail in subsequent sections.
2.1.7 G-protein Coupled Receptors
Ions
Out Cell membrane
R R R
AC PL-C
In G G G
5 AMP cAMP ATP P3

I DAG
Change in
excitability PDE
Protein
kinases Protein
Ca kinase-C
CaM
EFFECTS EFFECTS EFFECTS

(a) (b) (c)
(i)
Out Ions Cell membrane
R
R
E
In
Protein R
Depolarisation phosphorylation Nulceus
mRNA
Protein
synthesis
EFFECTS EFFECTS EFFECTS

(ii) (iii) (iv)
(i) G-protein (G)-coupled receptors (R) – (a) Regulation of ion channels.
(b) Adenylyl cyclase (AC)-cAMP system. PDE: phosphodiesterases.
2+
(c) Phospholipase-C (PL-C) Ca /Phosphoinositide system. IP3 Inositotriphosphate;
DAG: Diacylgycerol; CaM: Calmodulin, (ii) Ligand-gated channel, (iii) Tyrosine kinase-linked
receptors, (iv) Receptors that regulate gene expression
Fig. 2.5: Types of transmembrane signaling mechanisms
G-protein coupled receptors (GPCRs) represent the largest family of membrane proteins
in the human genome. It is one of the richest sources of targets for new drugs for the
pharmaceutical industry. There are seven transmembrane proteins in GPCRs; hence another
common word for GPCRs is 7TM receptors.
Many extracellular ligands act by increasing the concentration of intracellular second
messengers, e.g. cAMP, Ca++ or phosphoionositides. Receptor occupancy activates G-protein
which changes the activity of effector element (enzyme or ion channel). Finally there is
change in the concentration of second messenger.
Various receptors like muscarinic cholinergic, adrenergic, histamine H2, serotonin (5HT),
opiate and many peptide hormones (excluding insulin) belong to this family. Receptor
occupancy by an appropriate ligand leads to activation of G-protein which in turn acts on
target enzyme like adenyl cyclase/phospholipase C or an ion channel (Fig. 2.5).
G-proteins
Several varieties of G-proteins have been identified. The most common one are Gs and
Gi. Gs and Gi stimulate or inhibit the enzyme adenyl cyclase respectively, thus producing
opposite effects. Activation of adenyl cyclase increases concentration of cAMP while
inhibition of the enzyme causes decrease in cAMP. β1-adrenergic amines, histamine H2
agonists, 5-HT1 agonists and polypeptide hormones stimulate Gs protein. On the contrary,
β2-agonists, muscarinic M2 and δ-opioid receptor agonists act on Gi.
It is known that, a ligand-receptor interaction lasts only for milliseconds. Once a
G-protein is activated, it remains so for about 10 seconds, during which the original signal is
highly amplified. Thus, in G-protein-receptor coupled system, occupancy of only a fraction
of receptor population is enough to produce maximal tissue response.
Physiological Roles
Following physiological roles have been identified for GPCRs:
• The visual sense: The opsins are used in photoisomerisation reaction to translate
electro-magentic radiation into cellular signals; e.g. rhodopsin uses conversion of
11-cis-retinal to all-trans-retinal for this purpose.
• The gustatory sense (taste): GPCRs in taste cells mediate release of gustducin in
response to bitter - and sweet-tasting substances.
• The sense of smell: Receptors of the olfactory epithelium bind odorants (olfactory
receptants) and pheromones (vomeronasal receptors).
• Behavioural and mood regulation: Receptors in the mammalian brain bind several
neurotransmitters like serotonin, dopamine, GABA and glutamate.
• Regulation of immune system activity and inflammation: Chemokine receptors bind
ligands which mediate inter-cellular communication between cells of the immune
system; receptors such as histamine receptors bind inflammatory mediators and
engage target cell types in the inflammatory response. GPCRs are also involved in
immune modulation and directly involved in suppression of TLR-induced immune
response from T-cells.
• Autonomic nervous system transmission: Both sympathetic and parasympathetic

nervous systems are regulated by GPCR pathways, responsible for control of many
automatic functions in the body like blood pressure, heart rate and digestive
processes.
• A cell-density sensing: A novel GPCR role exists in regulating cell-density sensing.
• Homeostasis modulation: Water balance is controlled through GPCR sensing.
• GPCR system is also involved in growth and metastasis of some types of tumours.
Classification of GPCRs
GPCRs can be grouped into six classes based on sequence homology and functional
similarity:
• Class A (or 1) (Rhodposin-like)
• Class B (or 2) (Secretin family)
• Class C (or 3) (Metabotropic glutamate/pheromone)
• Class D (or 4) (Fungal mating pheromone receptors)
• Class E (or 5) (Cyclic AMP receptors)
• Class F (or 6) (Frizzled/Smoothened)
GPCR Structure
GPCRs are integral membrane proteins possessing seven membrane-spanning domains
or transmembrane helices. The extra-cellular parts of the receptor can be glycosylated. Some
seven-transmembrane helix proteins (channel rhodopsin) that resemble GPCRs may contain
ion channels, with their protein. In 2007, the first structure of human GPCR was resolved.
Human β2-adrenergic receptor GPCR structure is similar to bovine rhodopsin in terms of
relative orientation of the seven-transmembrane helices. Structure-function relationship of
GPCRs has been worked out. In addition, mechanism of action at molecular level is
understood.
Second Messengers
There are four G-protein-coupled effector systems:
(i) Adenyl cyclase-cAMP system
The system has a wide variety of receptor population and produce diverse effects. The
effects include ionotropic and chronotropic effects on heart, relaxation of smooth
muscles, glycogenolysis, lipolysis. In addition, effects related to hormones like
vasopressin, parathyroid hormone, ACTH, FSH, LH and TRH are mediated through the
system. cAMP exerts most of these effects by stimulating cAMP – dependent protein
kinases. The intracellular effects of cAMP are terminated by degradation of cAMP to
5-AMP by the enzyme phosphodiesterases (PDE). Methylxanthines like caffeine inhibit
PDE and thus prolong the action of second messenger cAMP.
(ii) Phospholipase C-Ca++/phosphoionositide system
Some of the agonists which trigger this pathway are Acetyl choline (ACh M1),
Catecholamines (α1), 5-HT2, TRH, Vasopressin (V1) and Angiotensin. This system is more
complex than the cAMP pathway due to presence of two second messengers
(inositotriphosphate, IP3 and diacylglycerol, DAG), and multiplicity of protein kinases.
(iii) cGMP system

cGMP, as a second messenger, has a signalling role only in few cell types. Receptor-
linked-G-protein controls the enzyme guanylyl cyclase in a way similar to that of
adenylyl cyclase. Activation of membrane-bound guanylyl cyclase leads to generation of
cytosolic second messenger, cGMP which acts by stimulating a cGMP-dependent protein
kinase. Increased cGMP concentration leads to relaxation of vascular smooth muscles.
Ligands involved in this case are Acetyl choline, histamine, a peptide hormone-atrial
natricuretic factor (ANF) and vascular endothelial nitric oxide. The system has also been
detected in intestines.
(iv) Regulation of ion channels
G-protein coupled receptors can control some ion channels by mechanisms that do not
seem to involve any second messenger. In this case, G-protein interacts directly with the
channel; ACh M1 receptors enhance permeability of potassium ions in cardiac muscle,
and opiate analgesics open potassium channels reducing neuronal excitability.
2.1.8 Ion-channel Receptors
Ion channels are pore-forming membrane proteins which allow ions to pass through the
channel pore. Their functions include establishing a resting membrane potential, shaping
action potentials and other electrical signals by getting the flow of ions across the cell
membrane, controlling the flow of ions across secretory and epithelial cells, and regulating
cell volume. Ion channels are present in the membranes of all excitable cells. Ion channels
are one of the two classes of ionophoric proteins, along with ion transporters including the
sodium-potassium pump, sodium-calcium exchanger, and sodium-glucose transport
proteins.
There are two distinctive features of ion channels which differentiate them from other
types of transporter proteins:
• The rate of ion transported through the channel is very high; often 106 ions per
second or higher.
• Ions pass through the channel down their electrochemical gradient, which is a
function of ion concentration and membrane potential without the input of
metabolic energy.
Ion channels are located within the membrane of all excitable cells and of many
intracellular organelles. They are narrow, water-filled tunnels that only allow certain size
and/or charge to pass through. Thus, they allow selective permeability. Some channels may
be permeable to the passage of more than one type of ion, typically sharing a common
charge: positive or negative. In many ion channels, passage through the pore is governed by
a gate, which may be opened or closed in response to chemical or electrical signals,
temperature, or mechanical force. Ion channels are integral membrane proteins, typically
formed as assemblies of several individual proteins.
Biological Role
They are the important components of nervous system. Many toxins related to nervous
system like venoms of spiders, scorpions, snakes, fish, bees, sea snails and others work by
modulating ion channel conductance and/or kinetics. In addition, they are key components
involving rapid changes in cells like cardiac, skeletal, smooth muscle contraction, epithelial
transport of nutrients and ions, T-cell activation and pancreatic β-cell insulin release. Ion
channels are also targets for new drugs.
Classification
Ion channels are classified on following parameters:
1. Gating
The classification based on what opens and closes the channels. There are three sub-
types in this category:
(i) Voltage-gated: Voltage-gated ion channels open and close in response to membrane
potential. Some of the examples are as follows:
o Voltage-gated sodium channels
o Voltage-gated calcium channels
o Voltage-gated potassium channels
o Transient receptor potential channels
o Hyperpolarisation- activated cyclic nucleotide-gated channels
o Voltage-gated proton channels
(ii) Ligand gated: They are also known as ionotropic receptors. Some of the examples are
as follows:
o Cation-permeable nicotinic Acetyl choline receptor
o Glutamate-gated receptors
o Acid-sensing ion channels (ASICs)
o ATP-gated P2X receptors
o Anion-permeable GABA-gated GABAA receptor
(iii) Other gating: In this case, gating includes activation and inactivation by second
messengers from inside of the cell membrane rather than outside the cell, as in the case
of ligands. Some of the examples are as follows:
o Some potassium channels like inward-rectifier, calcium activated, two-pore-domain
o Channelrhodopsin opened by photons
o Mechanosensitive ion channels opened by stretch/pressure/shear/displacement
o Cyclic nucleotide-gated channels, activated by cAMP/cGMP
o Temperature related channels, opened by hot or cold temperature
• Type of ions:
These channels are opened by specific ions as indicated below:
o Potassium channels
o Sodium channels
o Calcium channels
o Proton channels
o Non-selective cation channels for sodium/potassium/calcium
• Cellular organisation
Ion channels are classified based on their sub-cellular localisation. The plasma
membrane accounts for about 2% of the total membrane of the cell, while intracellular
organelles contain 98% of cell’s membrane. The major intracellular compartments are
endoplasmic reticulum, Golgi apparatus and mitochondria. On the basis of localisation,
ion channels are classified as follows:
o Plasma membrane channels
o Intracellular channels: They are further sub-classified as endoplasmic reticulum
channels and mitochondrial channels
• Other: The classification is based on number of pores and transient potentials. Most of
the ion channels are single pore; however there are few two-pore channels. Transient
receptor potential channels are also termed as TRP channels.
2. Structure
Channels differ with respect to the ion they let pass (sodium/potassium/chloride), the
ways in which they may be regulated, the number of sub-units they are composed of and
other aspects of the structure. An example of voltage-gated channels which underlie nerve
impulse can be cited here. It consists of four sub-units with six transmembrane helices each.
On activation, these helices move about and open the pore. Two of these six helices are
separated by a loop that lines the pore and is the primary determinant of ion selectivity and
conductance in this channel class. Pore can determine the selectivity of the channel. Gate
can be formed either inside or outside the pore region. (Fig. 2.6).
4
1
1 1 6
1. Channel domains
2 2. Outer vestibule
3. Selectivity filter
3
4. Diameter of selectivity filter
5. Phosphorylation site
6. Cell membrane
Fig. 2.6: Ion-channel diagram

Ion Channel Blockers
A variety of inorganic and organic molecules can modulate ion channel activity and
conductance. Some examples are as follows:
o Tetrodotoxin (TTX): It blocks sodium channels
o Saxitoxin: It blocks voltage-dependent sodium channels
o Lidocaine and Novocaine block sodium ion channels
o Dendrotoxin blocks potassium channels
o Iberiotoxin blocks potassium channels
o Heteropodatoxin blocks potassium channels
3. Diseases
Various disorders which disrupt normal functioning of ion channels have disastrous
consequences for the organism. Genetic and autoimmune disorders are known as
channelopathies. Some of the examples are as follows:
o Shaker gene mutations cause defect in voltage-gated ion channels, slowing down
repolarisation of the cell.
o Equine hyperkinetic periodic paralysis, human hyperkalaemic periodic paralysis
(Hyper PP) are caused by a defect in voltage-dependent sodium channels.
o Generalised epilepsy with febrile seizures plus (GEFS +).
o Episodic ataxia (EA), provoked by stress, startle, or heavy exertion by exercise.
o Familial hemiplegic migraine (FHM).
o Long QT syndrome, due to defect in potassium channels.
o Brugada syndrome, a ventricular arrhythmia caused by defect in voltage-gated
sodium channel.
o Cystic fibrosis, caused by defect in chloride channels.
o Some types of cancers like glioblastoma multiforme, caused by defect in
potassium/chloride channels.
2.1.9 Trans-Membrane Linked Receptors
An enzyme linked-receptor, also known as catalytic receptor, is a transmembrane
receptor, where the binding of an extracellular ligand causes enzymatic activity on the
intracellular side. Hence, a catalytic receptor is an integral membrane protein possessing
both enzymatic catalytic and receptor functions. They have two important domains: an
extracellular-ligand binding domain and an intracellular domain, which has a catalytic
function, and a transmembrane helix. The signalling molecule binds to the receptor on
outside of the cell and causes a conformational change on the catalytic function located on
the receptor inside the cell.
Some examples of the enzyme-linked receptor are as follows:
• Receptor tyrosine kinase, as in fibroblast growth factor receptor. Most enzyme-
linked receptors are of this type.
• Serine/threonine-specific protein kinase, as in bone morphogenic protein
• Guanylate cyclise, as in atrial natriuretic factor receptor
Following major families of catalytic receptors are known:
• Erb (Epidermal growth factor receptor)
• GDNF (glial cell-derived) neurotrophic factor
• NPR (natriuretic peptide receptor)
• trk neurotrophin receptor
• Toll-like receptor (TLR)
Out of these five types, only in case of NPR, catalytic activity is involved with the enzyme
gaunylyl cyclase (EC 4.6.1.2). In all other types, the enzyme involved is tyrosine kinase
(EC 2.7.10.1). For every type of receptor, there are different members, genes and ligands.
2.1.10 JAK-STAT Binding Receptor

Janus kinase (JAK) is a family of intracellular nonreceptor tyrosine kinases which
transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named as
“just another kinase” 1 and 2. Later on, they were named as janus kinase. JAKs possess two
near identical phosphate-transferring domains. One domain exhibits the kinase activity,
while the other negatively regulates the kinase activity of the first.
1. Janus Kinase (JAK)
There are four family members of JAK:
• Janus kinase 1 (JAK 1)
• Tyrosine kinase 2 (TYK 2)
JAK 1 and JAK 2 are involved in type II interferon (interferon-gamma (γ)) signalling, while
JAK 1 and TYK 2 are involved in type I interferon signalling.
Functions
Some members of the type I and type II cytokine receptor families possess no catalytic
kinase activity; they rely on the JAK family of tyrosine kinases to phosphorylate and activate
downstream proteins involved in their signal transduction pathways. The receptors exist as
paired polypeptides, thus exhibiting two intracellular signal-transducing domains.
JAKs associate with a proline rich region in each intracellular region that is adjacent to
cell membrane. After receptor associates with its respective cytokine/ligand, it goes through
a conformational change, bringing the two JAKs close enough to phosphorylate each other.
The JAK autophosphorylation induces a conformational change within itself, enabling it to
transduce the intracellular signal by further phosphorylating and activating transcription
factors. The activated factors dissociate from the receptor and form dimmers before
translocating to the cell nucleus, where they regulate transcription of selected genes. Some
examples of molecules using JAK/STAT signalling pathway are colony-stimulating factor,
prolactin, growth factor and many cytokines.
Clinical Significance
JAK inhibitors are under development for treatment of psoriasis, rheumatoid arthritis,
polycythemia vera, alopecia, essential thrombocytopenia, ulcerative colitis, myeloid
metaplasia with myelofibrosis and vitiligo.
2. Stat Protein
Members of the signal transducer and activator of transcription (STAT) protein family are
intracellular transcription factors which mediate many aspects of cellular immunity,
proliferation, apoptosis and differentiation. They are primarily activated by membrane
receptor-associated Janus kinases (JAK).
Dysregulation of JAK-STAT pathway is frequently observed in primary tumours and leads
to increased angiogenesis which enhances the survival of tumours and immunosuppression.
It is known that STAT proteins are involved in the development and function of the immune
system and play a role in maintaining immune tolerance and tumour surveillance.
The first two stat proteins were identified in the interferon system. There are seven
mammalian STAT family members that have been identified: STAT 1, STAT 2, STAT 3, STAT 4,
STAT 5 (STAT 5A and STAT 5B ) and STAT 6.
Activation
Extracellular binding of cytokines or growth factors induce activation of receptor-
associated Janus kinases, which phosphorylate a specific tyrosine residue within the STAT
protein promoting dimerisation. The phosphorylated dimer is then actively transported to
the nucleus via an importin α/β ternary complex. Once STAT reaches the nucleus, it binds to
a consensus DNA-recognition motif called as gamma-activated sites (GAS) in the promoter
region of cytokine-inducible genes and activates transcription. The STAT protein can be
dephosphorylated by nuclear phosphatases, which leads to inactivation of STAT and
subsequent transport out of the nucleus.
JAK-STAT Signalling Pathway
The pathway transmits information from extracellular chemical signals to the nucleus
resulting in DNA transcription and expression of genes involved in immunity, proliferation,
differentiation, apoptosis and oncogenesis. The signalling cascade consists of three main
components: a cell surface receptor, a Janus kinase (JAK) and two Signal Transducer and
Activator of Transcription (STAT) proteins. Disrupted or dysregulated JAK-STAT functionality
can result in immune deficiency syndromes and cancers.
Mechanism
The binding of various ligands, like cytokines, interferon, interleukin and growth factors
to cell surface receptors, activate associated JAKs, increasing their kinase activity (Fig. 2.7).
Activated JAKs then phosphorylate tyrosine residues on the receptor, creating binding sites
for proteins possessing SH2 domains. SH2 domains containing STATs are recruited to the
receptor where they are also tyrosine-phosphorylated by JAKs. These activated STATs form
hetero- or homo- dimers and translocate to the cell nucleus where they induce transcription
of target genes. STATs may also be tyrosine-phosphorylated directly by receptor tyrosine
kinases, such as epidermal growth factor receptor, as well as by non-receptor (cytoplasmic)
tyrosine kinases.
Cutside Cytokine
cell
JAK JAK
Cytokine receptor
Cytokine receptor
P
P P
JAK JAK JAK JAK JAK JAK P
STAT
STAT
P P Nucleus P
P P P P P
Cytoplasm Transcription
Fig. 2.7: Steps of JAK-STAT pathway
The pathway is negatively regulated on multiple levels. Protein tyrosine phosphatases

remove phosphates from cytokine receptors and activated STATs. Suppressors of Cytokine
Signalling (SOCS) inhibit STAT phosphorylation by binding and inhibiting JAKs or competing
with STATs for phosphotyrosine binding sites on cytokine receptors. STATs are also
negatively regulated by Protein Inhibitors of Activated STAT (PIAS), which act in the nucleus
through several mechanisms.
Janus kinase inhibitor, a type of Janus kinases-blocking drugs are used for cancer
therapy.
2.1.11 Receptors Regulating Transcription Factors
A transcription factor (TF) or sequence-specific DNA-binding factor is a protein which
controls the rate of transcription of genetic information from DNA to mRNA, by binding to a
specific DNA sequence. Their function is to regulate – turn on and off – genes in order to
make sure that they are expressed in the right cell at the right time and in the right amount
throughout the life of the cell and the organism. Groups of TFs function in a co-ordinated
fashion to direct cell division, cell growth and cell death throughout life; cell migration and
organisation (body plan) during embryonic development; and intermittently in response to
signals from outside the cell, such as hormone. There are up to 2600 TFs in the human
genome.
TFs work alone or with other proteins in a complex, by promoting (as an activator) or
blocking (as a repressor) the recruitment of RNA polymerase to specific genes. RNA
polymerase is the enzyme which performs transcription of genetic information from DNA to
RNA.
A defining feature of TFs is that, they contain atleast one DNA-binding domain (DBD),
which attaches to a specific sequence of DNA adjacent to the genes which they regulate. TFs
are grouped in to classes based on their DBDs. Other proteins like co-activators, chromatin
remodelers, histone acetyl transferases, histone deacetylases, kinases and methylases are
also essential to gene regulation, but lack DBDs, and hence they are not TFs.
TFs are of interest in medicine because TF mutations can cause specific diseases, and
medications can be targeted towards them.
Functions
TFs are one of the group of proteins which read and interpret the genetic blue print in
the DNA. They bind to the DNA and help initiate a programme of increased or decreased
gene transcription. They are of vital importance for many important cellular processes. Some
of the important functions are listed below:
(i) Basal transcription regulation
An important class of transcription factors is called as general transcription factors
(GTFs). Many of these GTFs do not actually bind DNA, but are a part of large
transcription pre-initiation complex which interacts with RNA polymerase directly. The
pre-initiation complex binds to promoter regions of DNA upstream to the gene that
they regulate.
(ii) Differential enhancement of transcription

Other transcription factors differentially regulate the expression of various genes by
binding to enhancer regions of DNA adjacent to regulatory genes. These transcription
factors are critical to making sure that genes are expressed in the right cell at the right
time and in the right amount.
o Development
Many transcription factors in multicellular organisms are involved in development.
Responding to stimuli, these transcription factors turn on/off the transcription of
appropriate genes, which in turn, allows for changes in cell morphology or activities
needed for cell fate determination and cellular differentiation; e.g. the Hox
transcription factor family is responsible for proper body pattern formation in
different organisms.
o Response to intercellular signals
Cells can communicate with each other by releasing molecules which produce
signalling cascades within another receptive cell. If the signal requires upregulation
or downregulation of genes in the recipient cell, transcription factors will be
downstreamed in the signalling cascade; e.g. estrogen signalling of a fairly short
signalling cascade involves the estrogen receptor transcription factor.
o Response to environment
Transcription factors can also be downstream of signalling cascades involved in
environmental stimuli; e.g. heat shock factor (HSF) upregulates genes necessary for
survival at higher temperatures.
o Cell cycle control
Many transcription factors like proto-onco genes or tumour suppressors help
regulating the cell cycle. They determine how large a cell will get and when it can
divide into daughter cells; e.g. Myc onco gene has important roles in cell growth and
apoptosis.
o Pathogenesis
TFs can also be used to alter gene expression in a host cell to promote pathogenesis;
e.g. transcription-activator like effectors (TAL effectors) are secreted by
Xanthomonas bacteria. When injected into plants, these proteins can alter the
nucleus of the plant cell, bind plant promoter sequences, and activate transcription
of plant genes that aid in bacterial infection.
Clinical Significance
TFs are of clinical significance for following two reasons:
• Mutations can be associated with specific diseases
• They can be targets of medications
Disorders
Following disorders are related to TFs:
• Rett syndrome
• Diabetes
• Developmental verbal dyspraxia
• Autoimmune diseases
• Li-Fraumeni syndrome
• Breast cancer
• Multiple cancers
Drug Targets
Around 10% of currently prescribed drugs directly target the nuclear receptor class of
transcription factors. Tamoxifen for breast cancer and Bicalutamide for prostate cancer are
some of the examples. In addition, various types of anti-inflammatory and anabolic steroids
are also from this category. TFs are often indirectly modulated through signalling cascades.
TFs outside the nuclear receptor family are more difficult to target with small molecule
therapeutics.
2.1.12 Dose-Response Relationship (DRR)
When the relation between drug dose (X-axis) and drug response (Y-axis) is plotted on a
linear scale, the resulting curve is usually hyperbolic. Clinical responses plotted in this
manner include change in heart rate, blood pressure, gastric pH or blood glucose. Non-
clinical (biochemical) responses can also be plotted; e.g. enzyme activity, accumulation of
intracellular second messenger, membrane potential or contraction of a muscle.
If the drug dose is plotted on a base 10 logarithmic scale, the generated curve is a
sigmoidal dose-response curve (DRC). This representation is more useful because it expands
the dose scale in the region where drug response is changing rapidly and compresses the
scale at higher doses where large changes have little effect on response. In reality, it is ligand
concentration (and resulting receptor occupation) which affects the response. The term DRC
assumes that, the drug dose and ligand concentration are closely related.
Basic Principles of DRR
A C
Response
Concentration
Fig. 2.8: Hypothetical dose-response curve
DRCs are a graphical representation of a specific functional reaction in a cell, tissue, or
organism evoked by a range of doses of a given stimulus at a certain point of time. Stimuli
can be internal or external, physical or chemical. In basic pharmacology, DRCs are used to
calculate binding affinities for receptor-ligand interactions. Fig. 2.8 shows a hypothetical
DRC, highlighting some important parameters which can be drawn from it.
DRCs typically have dose on the X-axis and response on the Y-axis. Plotting the
logarithm of concentration generally results in sigmoidal plots as shown in the Fig. 2.8. The
main parameters which can be identified by DRCs are as follows:
• Potency: The position of the curve along X-axis (Curve A).
• Maximal efficacy: The greatest response attainable (Curve B).
• Slope: Change in response per unit dose (and half maximal dose) (Curve C).
DRCs are more likely to be evaluating responses to drugs. Drug dose response involves
the principles of pharmacokinetics and pharmacodynamics and can be used to determine
the required dose and frequency to achieve the desired response. Multiple factors can cause
variation in DRCs: population differences, patient-related factors and measurement
methodology. In view of biological variation, it is suggested to take repeated measurements
under identical conditions to establish pharmacological profile of the drug being evaluated.
The dose response relationship is important because the concentration of a drug at its site
of action controls its effect.
Comparison between different types of DRCs is depicted in Fig. 2.9.
Drug A is more Drug C has lower
potent than drug B. potency and efficacy
Both have same efficacy than A and B
Drug A Drug B
100
Blocking effect
Drug C
50
0
Log drag concentration
EC50 EC50 EC50

Drug A Drug B Drug C
EC50 : Drug dose showing 50% of maximal response
Fig. 2.9: Variation in dose-response curves
The pharmacologic profiles of individual drugs can be differentiated by comparing their
DRCs. In Fig. 2.9, drug A has greater biological activity per dosing unit and is therefore
considered to be more potent than drugs B or C- shown by its left-shifted position on the X-
axis. Drugs A and C have equal efficacy- indicated by their maximal attainable response
(ceiling effect); however drug C is less potent than A because it needs higher concentration.
Drug B is more potent than drug C, however its maximal efficacy is lower.
2.1.13 Therapeutic Index (TI)

TI is also referred to as therapeutic ratio. TI is a comparison of the amount of therapeutic
agent that causes therapeutic effect to the amount that causes toxicity. In an established
clinical setting of an approved drug, TI refers to the dose of drug which causes adverse
effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose
in 50% of subjects, TD50) to the dose which leads to the desired pharmacological effect
(e.g. effective dose in 50% of subjects, ED50).
In early days of toxicology, TI was frequently determined in animals as lethal dose of a
drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the
population (ED50).
Thus in human beings, TI = TD50/ED50; in animals, TI = LD50/ED50
For many drugs, there are several types of toxicities which occur at sub-lethal doses in
human beings. These toxicities often limit the maximum dose of a drug. For any drug, a
higher TI is always preferable. Higher TI indicates more margin of safety. Generally, a drug
with narrow therapeutic range (having little difference between toxic and therapeutic doses)
may have its dosage adjusted according to measurements of the actual blood levels
achieved in a person. An example of digoxin can be cited here. Its dose for CHF is 8-12
mcg/kg by IV route, and 10-15 mcg/kg by oral route. The therapeutic range is 1-2.5 nmol/L
(0.5-2.0 ng/mL). It indicates that, when the serum concentration of digoxin exceeds to 2.0
ngm/ml, it can be toxic and lethal. Thus, digoxin is a drug with low TI.
The therapeutic index varies widely among substances. Amongst the opium pain killers,
Remifentani has a therapeutic index of 33,000 : 1, while morphine has TI of 70 : 1. Diazepam
has a TI of 100 : 1. Digoxin has TI of 2 : 1.
2.1.14 Combined Effects of Drugs
When two or more drugs are given together, there is a possibility that the effect may be
additive or synergistic. When the total effect of two or more drugs given together is same as
that of their individual administration, the effect is called as additive. Sometimes the effect is
more than expected, i.e. more than additive; in such cases it is called as synergistic effect.
The risk associated with benzodiazepines like diazepam increases significantly when taken
with alcohol in comparison to opiates like morphine or stimulants like amphetamine being
taken alone. This is expressed by the comment that benzodiazepines are synergistic with
alcohol. The explanation for synergistic effect is provided by different mechanisms of actions
exhibited by involved drugs. The opposite of synergy is termed as antagonism. Two drugs
are antagonistic when their interaction causes a decrease in the effects of one or both of the
drugs.
Both synergy and antagonism can occur during different phases of the interaction of the
drug with an organism, with each effect having different name. When the synergy occurs at
a cellular receptor level, it is termed as agonism, and the substances involved are termed as
agonists. On the other hand, in case of antagonism, one of the substances may be agonist
and another antagonist. Different responses of receptors to the action of a drug has resulted
in a number of classifications such as partial agonist, competitive/non-competitive agonist,

etc. These concepts have fundamental applications in the phamacodynamics of these
interactions. See section 1.1.7 for related discussion.
2.1.15 Factors Modifying Drug Action
Following factors or conditions pre-dispose or favour the appearance of drug
interactions:
• Old age
It is known that liver metabolism, kidney function, nerve transmission or functioning of
bone marrow decreases with age. In addition, in old age there is a sensory decrease
which increases the chances of errors being made in the administration of drugs.
• Polypharmacy
More the number of drugs a patient takes, more are the chances amongst their
interaction.
• Genetic factors
Genes synthesise enzymes which metabolise drugs. Some races have genotypic
variations which could decrease or increase the activity of these enzymes. The
consequence of this effect predisposes the patients towards more drug-interactions.
Genotypic variations in isozymes of cytochrome P450 is a classical example.
• Hepatic/renal diseases
Drugs which are metabolised in liver and/or eliminated by kidneys can have
pharmacokinetic alterations if liver and/or kidney is not functioning properly. In such
cases serum concentrations of related drugs may increase, because of which the patients
may show adverse reactions/interactions.
• Serious diseases
For any reason, if dose of the drug is reduced, there is a likelihood that serious diseases
could worsen.
• Drug-dependent factors
Factors like narrow therapeutic index (e.g. digoxin), steep dose response curve, saturable
hepatic metabolism as in case of phenytoin, can alter effects of drugs at different
concentrations.
2.2 ADVERSE DRUG REACTIONS (ADRs)
Whenever a drug is given to treat a disease, it is also likely that the drug may cause
additional responses in the body. A response caused by drug which is noxious and
unintended and occurs at dises normally used in humans for the prophylaxis, diagnosis, or
therapy of disease or for the modification of physiological function is called as adverse
reaction. There is also a term called as adverse event. The difference between ADR and
adverse event is related to causality. Whenever an adverse event is characterised by the
suspicion of a causal relationship between the drug and the occurrence i.e. judged as being
atleast possibly related to treatment, then it is called as ADR. Study of ADRs is called as
pharmacovigilance. See Section 2.4.4.
2.3 DRUG INTERACTIONS

(PHARMACOKINETIC AND PHARMACODYNAMIC)
When more than one drug is administered to a patient, then there is a possibility of
interaction between their effects. The cause may be pharmacodynamic or pharmacokinetic.
Each one of them is discussed below.
2.3.1 Pharmacokinetic Drug Interactions
Drugs do differ in their absorption, transport, distribution, metabolism and/or excretion.
These are called as pharmacokinetic factors. When more than one drug is given, it may alter
pharmacokinetic factors of other drug(s). Thus, they are sub-classified as follows:
2.3.1.1 Absorption Interactions
Some drugs increase the speed with which a drug passes through the intestine. These
drugs decrease gastric emptying time. Such drugs, e.g. domperidon are called as pro-kinetic
drugs. Pro-kinetic drugs can reduce timing of a drug in GIT, resulting in lower concentration
of co-administered drug. Some other drugs like atropine can reduce gastro-intestinal
motility; such drugs may increase stay in GIT and therefore their absorption may increase.
Drugs can exist either in an ionised or in a non-ionised form depending on their pKa (pH
at which the drug reaches equilibrium between its ionised and non-ionised form). The non-
ionised forms of drugs are usually easier to absorb, provided they are small molecules.
Ionisable drugs are usually less absorbed. Increasing absorption of a drug will increase its
bioavailability. Thus, changing the drug’s state from ionised to non-ionised form can be
more useful for increasing its absorption. Change in pH, due to effect of drugs can alter
absorption of other drugs. In addition, substances like antacid may decrease absorption of
other drugs because of adsorption of other drugs on their surface.
Solubility of a drug is an important factor. Absorption of some drugs can be drastically
reduced if they are administered together with food of high fat content.
Formation of non-absorbable complexes is yet another cause for reducing their
absorption. Chelation with cations, binding with proteins and formation of large complexes
are some of the mechanisms. The examples are as follows: tetracycline can chelate calcium
ions; sucralfate binds with proteins; cholestyramine forms complexes with thyroxine/digoxin.
Action of enterocytes on P-glycoprotein is one more mechanism. Consumption of grape
fruit juice increases bioavailability of drugs like verapamil.
2.3.1.2 Transport and Distribution Interactions
In this case, the main mechanism is competition for plasma protein transport. If two
drugs compete for the same site on plasma albumin and if one drug has more affinity than
the other drug, then one drug can replace the other leading to enhanced pharmacological
effect of another drug. Phenylbutazone or sulphamethoxazole can displace warfarin leading
to effects of warfarin.
2.3.1.3 Metabolism Interactions

Many drug interactions are due to alterations in drug metabolism. Cytochrome P450 is
the classical example.
Cytochrome P450 (CYP 450)
CYP 450 is a very large family of haemoproteins, characterised by their enzymatic activity
and their role in metabolism of various drugs. The most important enzymes are CYP1A2,
CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Majority of these enzymes are involved in
metabolism of steroids or drug hormones. As an illustration, drugs related to CYP1A2 are
listed in table 2.2.
Certain drugs may act as substrate for a type of CYP450 enzyme. Some other drug may
inhibit enzymatic action of CYP450. Inhibition of CYP450 will lead to reduced metabolism of
the relevant drug. Some other drugs may induce the enzyme and increase its concentration.
As a result of enzyme induction, metabolism of related drug will be enhanced. Both
induction and/or inhibition of a type of CYP450 can lead to drug interaction.
Table 2.2: Drugs related to CYP1A2
Substrates Inhibitors Inducers
Caffeine Omeprazole Phenobarbital
Theophylline Nicotine Fluvoxamine
Phenacetin Cimetidine Venlafaxine
Clomipramine Ciprofloxacin Ticlopidine
Some food components also act as inducers or inhibitors of enzymatic activity. Some
examples are shown in table 2.3.
Table 2.3: Foods which influence drug metabolism
Food Mechanism Drugs affected
Grape fruit Enzymatic inhibition • nifedipine, felodipine,nimodipine, amlodipine
juice • cyclosporine, tacrolimus
• terfenadine, astemizole
• cisapride, pimozide
• carbamazepine, saquinavir, midazolam,
alprazolam, triazolam
Soya Enzymatic inhibition Clozapine, haloperidol, olanzapine, caffeine,
NSAIDs, phenytoin, warfarin, zafirlukast
Garlic Increases Anticoagulants, NSAIDs, acetyl salicylic acid
antiplatelet activity
Ginkgo biloba Inhibitor of platelet Warfarin, aspirin and NSAIDs
aggregation
St John’s wort Enzyme inducer Warfarin, digoxin, theophylline, cyclosporine,
phenytoin and anti-retrovirals
Ephedra Receptor agonist MAO, CNS stimulants, ergotamines, xanthenes
Ginger Inhibits enzyme Anti-coagulants
2.3.1.4 Excretion Interactions

These are divided in to two excretory mechanisms: renal excretion and bile excretion.
1. Renal excretion
Only the free fraction of the drug which is dissolved in blood plasma can be removed
through kidney. Hence, drugs which are tightly bound to proteins are not available for renal
excretion. Creatinine clearance is used as a indicator for kidney functioning but it is only
useful in cases where the drug is excreted in an unaltered form in the urine. During
formation of urine, drugs pass through nephrons by filtration. Filtration depends on a
number of factors including pH of urine. It is shown that, drugs which act as weak bases are
increasingly excreted as the pH of urine becomes more acidic. Conversely, weak acids are
increasingly excreted as urine becomes more alkaline. Usually, pH of urine is acidic in nature;
however for excretion of weak acids, alkalinisers like sodium citrate are given orally to
promote their excretion. Table 2.4 lists some of the weak acids and weak bases which are
used as drugs.
Table 2.4 Drugs that act as weak acids or bases
Sr. No. Weak acids Weak bases
1. Acetyl salicylic acid Reserpine
2. Furosemide Amphetamine
3. Ibuprofen Procaine
4. Levodopa Ephedrine
5. Acetazolamide Atropine
6. Sulfadiazine Diazepam
7. Ampicillin Hydralazine
8. Chlorothiazide Pindolol
9. Paracetamol Propranolol
10. Chloropropamide Salbutamol
11. Chromoglicic acid Alprenolol
12. Ethacrynic acid Terbutaline
13. Alpha methyldopa Amiloride
14. Pehnobarbital Chlorphenalmine
15. Warfarin
16. Theophylline
17. Phenytoin
2. Bile excretion
Bile excretion involves use of metabolic energy in active transport across the epithelium
of bile duct against concentration gradient. The transport system can be saturated if the
plasma concentration of the drug is too high. Bile excretion of drugs occurs when their
molecular weight is greater than 300 and they contain both polar and non-polar groups. The
glucuronidation of the drug in the kidney facilitates bile excretion. Substances with similar
physico-chemical properties can block the receptor. A drug excreted in the bile duct can
occasionally follow entero-hepatic circulation and may be reabsorbed by the intestine. In
such cases it can lead to interaction with other drugs.
2.3.2 Pharmacodynamic Drug Interactions
The change in an organism’s response on administration of a drug is an important factor
in pharmacodynamic interactions. These changes are difficult to classify due to wide variety
of modes of action and various underlying mechanisms. Whenever the interactions are
based on biological response of a drug at the active site, it is considered in this category.
Pharmacodynamic interactions can occur on:
• Pharmacological Receptors:
Whenever interactions between two or more drugs are directly related to the same
receptor, they are considered in this category. Receptor interactions are further sub-
classified as homodynamic and heterodynamic.
1. Homodynamic
If two or more drugs act on the same receptor, they are considered under this category.
They are further sub-classified as: pure agonists; partial agonists or antagonists. Antagonists
can be either of competitive or uncompetitive type
2. Heterodynamic
If two or more drugs act on different receptors, they are considered under this category.
(i) Signal transduction mechanisms: These mechanisms are molecular processes
which commence after interaction of the drug with receptor. cAMP is signal
transducing substance in the action of insulin.
(ii) Antagonistic physiological systems: When two or more drugs alter a physiological
process by different mechanisms or through different mechanisms, the interaction
falls in this category. The action of digoxin on cardiac fibres can lower levels of
potassium. Diuretic like furosemide also causes lower levels of potassium because of
its action on kidney. Lower potassium levels are termed as hypokalemia. Thus,
hypokalemia caused by diuretics increase toxicity of digoxin.
2.4 DRUG DISCOVERY AND CLINICAL EVALUATION OF NEW DRUGS

2.4.1 Drug Discovery
Discovery of a new drug involves an elaborate process. It starts with synthesis of a large
number of chemical compounds. Historically, drugs were discovered through identifying the
active ingredient from traditional remedy or by chance discovery. Later, chemical libraries of
synthetic small molecules, natural products or extracts were screened in intact cells or whole
organisms to identify substances which have desirable therapeutic effect in the process of
classical pharmacology. After sequencing of human genome which allow rapid cloning and
synthesis of large quantities of synthetic proteins, high throughput screening of large
compounds libraries against isolated biological targets has become another effort for new
drug discovery.
Modern drug discovery involves identification of screening hits, medicinal chemistry and
optimisation of those hits to increase the affinity, selectivity, efficacy of the potency,
metabolic stability and oral bioavailability (Fig. 2.10). Once a compound which fulfils all these
requirements has been identified, the process of drug development begins with clinical
trials. Before starting a clinical trial safety of the drug is evaluated in experimental animals.
This process is called as pre-clinical evaluation.
Compound
collections
Primary assays Secondary assays

high through-put, counter screens, bioavailability
in-vitro toxicity, metabolism etc.
Chemical Indirect Lead compounds

synthesis and SAR
Structural
Clinical
Design characterization of
Direct candidate
protein-ligand complex
Fig. 2.10: Drug-discovery cycle

2.4.2 Pre-clinical Evaluation
The main goals of pre-clinical studies are to determine the safe dose for first-in-man
study and assess a product’s safety profile. On an average, only one in 5,000 compounds
which enter drug discovery to the stage of clinical development becomes an approved drug.
Each class of product may undergo different types of pre-clinical research. Drugs may
undergo pharmacodynamic (PD), pharmacokinetic (PK) and toxicological testing. This data
allows researchers to estimate a safe starting dose of the drug for clinical trials in humans.
While performing pre-clinical studies, Good Laboratory Practices (GLPs) are followed.
Typically, both in-vitro and in-vivo tests are performed. Studies of a drug’s toxicities include
which organs are targeted by the drug. Three special types of toxicities are performed: they
are carcinogenicity (tests for evaluating potential to cause cancer), mutagenecity (tests for
evaluating mutagenic potential) and tetatogenecity (tests for evaluating potential damage
to fetus during pregnancy of mother).
Animal Testing
Information collected from pre-clinical studies is vital for safe human testing. Typically,
animal testing involves at least two species. The choice of species is based on animals which
will give best correlation to human trials. Usually murine animals like mice/rats and canine
animals like dogs are used for testing. In addition, primates like monkeys or porcine animals
like pigs may be used for pre-clinical testing. Differences in the gut, enzyme activity,
circulatory system, or other considerations based on dosage form, site of activity or noxious
metabolites help in selection of animal species. Canines like dog are good models for oral
dosage form. Regulatory guidelines like those from USFDA, EMA, and other international
and regional regulatory authorities require safety testing in at least two mammalian species
like rabbit, including a non-rodent species, prior to human trials authorisation.
Animal testing also needs ethical considerations. Constitution of animal ethics
committee and approval of test protocol by the animal ethics committee is necessary. In
India, clearance from Committee for the Purpose of Control and Supervision on Experiments
on Animals (CPCSEA) has provided elaborate guidelines on handling of animals, animal care,
physical facilities in animal house, food, water for animals, sanitation and cleanliness and
waste disposal. It is suggested that standard operating procedures (SOPs) for methods
adopted to animal husbandry, maintenance, breeding, animal house microbial analysis and
experimental records need to be maintained.
2.4.3 Phases of Clinical Trial
All new drugs are labelled as Investigational New Drugs (INDs) by UDFDA. All INDs
undergo various stages of development. Clinical trials have been classically divided in to four
phases as described below. In addition, phase 0 has been added in recent years.
2.4.3.1 Phase 0
Phase 0 has been added by USFDA from 2006 guidance on exploratory IND studies.
Phase 0 trials are known as human micro-dosing studies and are designed to speed up the
development of promising drugs or imaging agents by establishing very early on whether
the drug behaves in human subjects as was expected from pre-clinical studies. Distinctive
features of phase 0 trials include administration of sub-therapeutic doses to a small number
of subjects (10-15) to gather preliminary data on pharmacokinetics of the drug.
Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to
cause any therapeutic effect. Based on information from phase 0 studies, a decision
regarding progress of the drug in next phases is taken.
2.4.3.2 Phase I
Phase I trials were formerly called as first-in-humans studies. Normally, a small group of
2-100 healthy volunteers are recruited in phase I trial. These trials are conducted in a clinical
trial clinic, where the subject can be observed by a full time staff. The subject who receives
the drug is usually observed until several half-lives of the drug have passed. This phase is
designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a
drug. Normally, phase I trials include dose-ranging, also called as dose escalation studies, so
that the best and safest dose can be identified. Normally, phase I trials include dose-
ranging, also called as dose escalation studies, so that the best and safest dose can be
identified. The tested range of doses is usually a fraction of a dose which causes harm in
animal testing. Although phase I trials are conducted on healthy volunteers, there are some
circumstances when clinical patients are used for phase I. In such cases where treatment is
likely to make healthy individuals ill, patients of terminal cancer or HIV are used for the trial.
In addition to terminal patients, patients who have been already tried and failed to improve
on existing standard therapies may also participate in phase I trials. Volunteers are paid a
variable inconvenience fee for their participation in phase I trial. In addition, their health
insurance premium is paid by the sponsor of the trial. Before beginning phase I trial, the
sponsor must submit an IND application to FDA detailing the preliminary data on the drug
gathered from cellular models and animal studies.
Three types of studies are included in phase I trials: single ascending dose, multiple
ascending dose and the effect of food.
2.4.3.3 Phase II
Once a dose range of doses is determined, the next goal is to evaluate whether the drug
has any biological activity or effect in human beings. Phase II trials are performed on a
relatively larger group as compared to phase I trials. Normally, 100-300 patients are included
in phase II studies. Genetic testing is common, especially when there is evidence of variation
in metabolic rate of the drug. When the development process for an IND fails, it is usually
during phase II trials. Conveniently, phase II trials can be divided in to two sub-categories:
phase II A and phase II B. Phase II A studies are pilot studies designed to demonstrate
clinical efficacy or biological activity. It can be termed as “proof of the concept” studies.
Phase II B studies find the optimum dose at which the drug shows the biological activity with
minimal side effects. They are also termed as “definite dose-finding” studies. Occasionally,
phase I and phase II may be combined to test both efficacy and toxicity.
Phase II studies historically have recorded lowest success rate. In 2010, the percentage of
phase II trials that have proceeded to phase III was 18 %. During 2006-2015, only 37% of
developmental drugs advanced from phase II to phase III.
2.4.3.4 Phase III
This phase is designed to assess the effectiveness of the IND. Phase III studies are
randomised controlled multicentre trials on a large patient groups ranging from 300-3000.
These studies are aimed at being the definitive assessment of effectiveness of the drug.
Phase III trials are the most expensive, time-consuming and difficult trials to design and run,
especially in chronic diseases. Phase III trials of chronic diseases often have a short follow-up
period of evaluation, relative to the period of time during which intervention might be used
in clinical practice. Phase III studies are also called as “pre-marketing phase”. During this
stage, sub-groups of patients like those having hepatic, renal or cardiac failure may also be
exposed with appropriate modification in dosages. If proof about adequate safety is
available, then paediatric and geriatric patients may also be included. In case of paediatric
patients, a separate clinical study is suggested by regulatory authority.
It is expected that at least two successful phase III trials, demonstrating a drug’s safety
and efficacy are necessary in order to obtain approval from appropriate regulatory agencies
like USFDA, EMA etc. Once a drug has proved satisfactory in phase III trials, the trial results
are usually combined in to a large document containing a comprehensive description of the
methods and results of human and animal studies, manufacturing procedures, formulation
details and shelf life. This collection of information makes up the regulatory submission
which is provided for review to appropriate regulatory authorities in different countries. The
regulatory authorities review the submission, and if found appropriate, give approval for
marketing the drug to the sponsor.
By 2010, about 50% of the INDs fail during phase III trials or are rejected by national
regulatory agencies. An estimate of phase II/III trials depends on various factors, therapeutic
area being studied and types of clinical procedures as key drivers. It is indicated that, phase
II studies may cost about $ 20 million (` 130 crores), and phase III studies $ 53 million
(` 345 crores ).
2.4.3.5 Phase IV
By the end of phase III studies, after review, regulatory authorities provide marketing
permission to the sponsor. Thus, a phase IV trial is also known as post-marketing
surveillance trial/confirmatory trial. Phase IV trials involve surveillance of safety and ongoing
technical support of a drug. Phase IV studies may be required by regulatory authorities or
may be undertaken by the supporting company for competitive or other reasons. The safety
surveillance is designed to detect any rare or long-term adverse effects over a much larger
patient population and longer time period than was possible during the phase I-III clinical
trials. If an adverse drug effect is rare, then it may be detected only in phase IV studies. The
minimum time period mandatory for phase IV clinical trial is of two years. During this period,
if a serious adverse reaction is observed, then the use of drug may be appropriately
restricted. If the adverse reaction is too serious, probably causing death, then the drug may
be withdrawn from the market during phase IV studies.
The entire process of developing a new drug from pre-clinical research to marketing can
take 12-18 years and may cost over $ 1 billion (` 6500 crores). The life of patent of a drug
expires 20 years after its registration. The figures indicate big financial risks in developing a
new drug.
A summary of different phases of trials is presented in table 2.5.
Table 2.5: Summary of trial phases
Sr. Phase Primary goal Dose Typical number of
No. participants
1. Pre-clinical Testing of drug in Unrestricted Not applicable
animals to gather (in-vitro and in-vivo
efficacy, toxicity and only)
pharmacokinetics
2. Phase 0 Pharmacokinetics, Very small, sub- 10 healthy
oral bioavailability therapeutic volunteers
and half-life
contd. …
3. Phase I Testing on healthy Sub-therapeutic with 20-100 healthy

volunteers for dose- ascending doses volunteers (cancer
ranging patients for anti-
cancer drugs)
4. Phase II Testing of drug on Therapeutic dose 100-300 patients
patients to assess with specific diseases
efficacy and side
effects
5. Phase III Testing on patients Therapeutic dose 300-3000 patients of
to assess efficacy, diverse sub-groups
effectiveness and
safety
6. Phase IV Post-marketing Therapeutic dose Anyone seeking
surveillance- treatment from
watching drug use in physician
public
2.4.4 Pharmacovigilance
Pharmacovigilance is defined as, "the science and activities relating to the detection,
assessment, understanding and prevention of adverse effects or any other medicine-related
problem".
In some countries, adverse drug reactions (ADRs) rank among the top ten leading causes
of mortality. In order to prevent or reduce harm to patients and thus improve public health,
mechanisms for evaluating and monitoring the safety of medicines in clinical use are vital.
In practice, this means having in place a well-organised pharmacovigilance system, up to
phase III of clinical development of INDs, maximum 5000 patients are exposed to the new
drug. After marketing approval, the number of patients is unlimited. Hence, rare adverse
reactions may be newly observed during post-marketing surveillance of the drug.
The principal aims of pharmacovigilance programme are as follows:
• To improve patient care and safety in relation to the use of medicines, and all
medical and para-medical interventions.
• To improve public health and safety in relation to the use of medicines.
• To contribute to the assessment of benefit, harm, effectiveness and risk of medicines,
encouraging their safe, rational and more effective (including cost effective) use.
• To promote understanding, education and clinical training in pharmacovigilance and
its effective communication to health professionals and the public.
Several stake holders are involved in monitoring safety of medicines. Some of them are
listed below:
• Government
• Pharmaceutical industries
• Hospitals and academia
• Medical and pharmaceutical associations

• Poisons and medicines information centres
• Health professionals like doctors, pharmacists, nurses
• Patients
• Consumers
• The media
• World Health Organisation (WHO)
WHO’s International Drug Monitoring started in 1968. By 2016, 123 countries have
joined the programme. WHO headquarters in Geneva is responsible for monitoring the
programme. The centre is now known as Uppsala Monitoring Centre (UMC) with the support
of Swedish Government.
Pharmacovigilance in India
The Central Drug Standard Control Organisation (CDSCO), New Delhi, under the control
of Ministry of Health and Family Welfare, Government of India has initiated a nation-wide
pharmacovigilance programme from July 2010. All Institute of Medical Sciences (AIIMS),
New Delhi was the National Co-ordinating Centre (NCC) for monitoring ADRs. From April
2011, the Indian Pharmacopoeia Commission (IPC), Ghaziabad looks after administrative
matters related to NCC. 22 ADR monitoring centres (AMCs) have been established
throughout India.
The scope and objectives of the programme are indicated below:
• To create a nation-wide system for patient safety reporting.
• To identify and analyse new signals from the reported cases.
• To analyse the benefit-risk ratio of marketed medications.
• To generate evidence-based information on safety of medicines.
• To support regulatory agencies in the decision-making process on use of
medications.
• To communicate the safety information on use of medicines to various stake holders
to minimise the risk.
• To emerge as a national centre of excellence for pharmacovigilance activities.
• To collaborate with other national centres for the exchange of information and data
management.
• To provide training and consultancy support to other national pharmacovigilance
centres across globe.
• To identify and analyse new ADR signal from the reported cases.
• To promote rational use of medicines.
There are various regulatory controls over the pharmacovigilance system. The European
Medical Agency (EMA) has published elaborate details of Good Pharmacovigilance Practices
(GPvP). In addition, USFDA has also published several guidance statements related to
pharmacovigilance. International Council for Harmonisation (ICH) and Council for
International Organisations of Medical Sciences (CIOMS) have published several guidelines
related to pharmacovigilance.
There are several pharmacovigilance methods followed in recording adverse events

related to drugs. The methods are as follows:
(i) Passive surveillance
Passive surveillance involves collecting reports generated out of existing system.
o Spontaneous reports: A spontaneous report is an unsolicited communication by
health-care professionals or consumers to a company, regulatory authority or other
organisation which describes one or more adverse drug reactions in a patient who
was given one or more medicinal products and that does not derive from a study or
any organised collection scheme.
o Case series: Series of case reports related to one or more adverse events can
provide evidence of an association between a drug and an adverse event. They may
be spontaneously reported.
(ii) Stimulated reporting
Several methods like online reporting of adverse events encourage and facilitate
reporting by health professionals in specific situations like hospital settings. They are
termed as stimulated reporting.
(iii) Active surveillance
Active surveillance seeks to ascertain completely the number of adverse events via a
continuous pre-organised process.
o Sentinel sites: By reviewing medical records or interviewing patients and/or
physicians in a sample of selected site, termed as sentinel sites, complete and
accurate data on reported adverse events can be ensured.
o Drug event monitoring: In drug event monitoring, patients may be identified from
electronic prescription data or automated health insurance claims.
o Registries: A registry is a list of patients presenting with the same characteristics;
e.g. there can be a registry of diabetic patients.
(iv) Comparative observational studies
There are a number of observation study designs which are useful in validating signals
from spontaneous reports or case series.
o Cross-sectional study (Survey): Data collected on a population of patients at a
single point in time (or interval of time) regardless of exposure or disease status
constitute a cross-sectional study.
o Case- control study: In case-control study, cases of disease (or events) are
identified. Controls, or patients without the disease or event of interest, are then
selected from the source population.
o Cohort study: In a cohort study, a population-at-risk for the disease (or event) is
followed over time for the occurrence of the disease (or event). Information on
exposure status is known throughout the follow-up period for each patient.
(v) Targeted clinical investigations

When significant risks are identified from pre-approval clinical trials, further clinical
studies might be called for to evaluate the mechanism of action for the adverse reaction.
Sometimes, potential risks or un-forcing benefits in special populations (paediatric,
geriatric) might be identified from pre-approval clinical trials. To elucidate the benefit-
risk profile of a drug outside of a traditional clinical trial setting, a special clinical trial
may be conducted. All these trials are termed as targeted clinical investigations.
(vi) Descriptive studies
Descriptive studies are primarily used to obtain the background rate of outcome events
and/or establish the prevalence of the use of drugs in specified populations.
o Natural history of disease: The science of epidemiology initially focussed on the
natural history of disease, including characteristics of disease, patients and
distribution of disease in selected populations, as well as estimating the incidence
and prevalence of potential outcome of interest. Studies which examine specific
aspects of adverse events, like the background incidence rate of or risk factors for
the adverse event of interest, can be used to assist in putting spontaneous reports in
to perspective.
o Drug utilisation study (DUS): DUS describe how a drug is marketed, prescribed,
and used in a population, and how these factors influence outcomes, including
clinical, social, and economic outcomes. These studies provide data on specific
populations, like the elderly, children, or patients with hepatic or renal dysfunction,
often stratified by age, gender, concomitant medication, and other characteristics.
All information about safety of medications has to be communicated to all stake holders
in different ways. Available methods for communication messages are listed in table 2.6.
Table 2.6: Communicating messages about medicine safety
Sr. No Vehicle Issued by
1. “Dear doctor” letters Pharmaceutical manufacturers.
2. Medicine alerts National health authorities.
3. Media statements National health authorities/ pharmacovigi-
lance centres.
4. Patient information leaflets Pharmaceutical manufacturers/National
health authorities/Pharmacovigilance centres.
5. News letters National pharmacovigilance centres and
WHO.
6. Personal feed-back to reporters National pharmacovigilance centres.
QUESTIONS
1. Comment on principles and mechanism of drug action.
2. Discuss theories of drug receptor interaction.
3. With suitable examples classify types of receptors.
4. How can you identify type of antagonism based on dose-response curve.

5. Discuss important features of G-protein coupled receptors.
6. Discuss important features of ion channel receptors.
7. Comment on clinical significance of ion channel receptors.
8. What is the importance of JAK-STAT binding receptor?
9. Comment on clinical significance and disorders related to transcription factors.
10. Discuss basic principles of dose-response relationship.
11. Discuss factors modifying drug action.
12. Present an overview of pharmacokinetic drug interactions with suitable examples.
13. With suitable examples comment on pharmacodynamic drug interactions.
14. Describe sequence of events in drug discovery.
15. What is the importance of pre-clinical drug evaluation.
16. Describe different phases of clinical trial.
17. Who are the stake holders in the process of pharmacovigilance.
18. What are different communication mechanisms for monitoring safety of drugs.
• Signal transduction mechanisms
• G-proteins
• Classification of G-protein coupled receptors
• Structure of G-protein coupled receptors
• Ion channel receptors
• Voltage-gated channels
• Ligand-gated channels
• Ion channel blockers
• Trans-membrane receptors
• JAK-STAT binding receptors
• Janus kinase
• STAT-protein
• Transcription factors.
• Therapeutic index
• Pharmacokinetic drug interactions
• Pharmacodynamic drug interactions
• Spontaneous reports
• Stimulated reporting
• Cross-sectional study
• Case-control study
• Cohert study
• Drug utilisation study
Unit ... 3
PHARMACOLOGY OF PERIPHERAL
NERVOUS SYSTEM
After completing this chapter, students should be able to understand:
• Organisation and functions of ANS
• Neuro-humoral Transmission, Co-transmission, Various Neurotransmitters
• Pharmacology of Parasympathomimetics, Parasympatholytics
• Pharmacology of Sympathomimetics, Sympatholytics
• Pharmacology of Neuromuscular Blocking Agents, Skeletal Muscle Relaxants
• Pharmacology of Local Anaesthetic Agents
• Pharmacology of Drugs used in Myasthenia Gravis and Glaucoma
3.1 INTRODUCTION
• The nervous system has an important role to communicate information from outside the
body; process it and to take corrective action based on the received response. The input
information is processed by sensory nervous system. The processing within is due to
internal communication between cells and the output information is processed by motor
nervous system. The unit of nervous system is a neuron which consists of a cell and its
projections in the form of several small dendrons and a major extension called as axon
or axis cylinder. Fig. 3.1 describes structure of a neuron.
• The nervous system can also be identified in two forms: central and peripheral. Central
nervous system consists of the brain and the spinal cord; and peripheral nervous system
consists of associated nerves and ganglia. Ganglia are structures containing a number of
nerve cell bodies, typically linked by synapses and often forming a swelling on nerve
fibre. Many drugs are known to act on peripheral nervous system (PNS). Before
discussing drugs acting on PNS, knowledge about their structure and functions is
necessary.
(3.1)
Pharmacology - I (B.Pharm. Sem. IV) 3.2 Pharmacology of Peripheral Nervous System
Dendrite
Nucleus
Cell body
Axon
Node of Myelin sheath

ranvier
Axon terminals
Fig. 3.1: Structure of neuron
3.2 ORGANISATION AND FUNCTIONS OF AUTONOMIC NERVOUS

SYSTEM (ANS)
• In biological systems, structure and functions are correlated. In fact, structures get
organised to perform specific functions. Thus, knowledge about structural features and
associated functions is to be understood comprehensively.
3.2.1 Organisation of ANS
• Based on the part of the body which responds, the PNS is sub-divided in to Somatic
Nervous System and Autonomic nervous system (ANS). Traditionally, the ANS and
somatic nervous system are usually described as an output of efferent portion of PNS.
3.2.1.1 Somatic Nervous System
The somatic nervous system consists of two types of neurons: sensory and motor.
Sensory neurons carry information from the skin and special sensory receptors to the CNS.
Motor neurons conduct impulses from the CNS to skeletal muscles. Since the effect of
motor neurons can be consciously controlled, the efferent part of somatic nervous system is
primarily concerned with voluntary functions like locomotion, respiration, posture and deep
tendon reflexes.
The axons of somatic motor neurons extend from the CNS and are myelinated. The
neurotransmitter release by somatic nerves at the Neuromuscular Junction (NMJ) is acetyl
choline (ACh).
3.2.1.2 Autonomic Nervous System (ANS)

The ANS consists of three main anatomical divisions:
• Parasympathetic Nervous System (PSNS) or (Cholinergic Division)
• Sympathetic Nervous System (SNS) or (Adrenergic Division)
• Enteric Nervous System (ENS)
In ANS, a nerve originating from brain/spinal cord first enters ganglia and then reaches
the effector organ. The nerve-fibre coming up to ganglia is termed as pre-ganglionic fibre;
while the nerve from ganglia to the effector organ is called as post-ganglionic fibre. In case
of SNS, post-ganglionic fibres are usually long except in the case of adrenal medulla. Unlike
this, in case of PSNS, pre-ganglionic fibres are relatively long and post-ganglionic fibres are
relatively short. The somatic nervous system differs from both SNS and PSNS in not having
ganglia before reaching the effector organ. Difference between sub-sections of nervous
system is depicted in Fig. 3.2. Distribution of cholinergic and adrenergic neurons in PNS.
Peripheral (efferent part) nervous system
Autonomic nervous system (Involuntry) Somatic

nervous
Sympathetic Parasympathetic system (voluntary)
NN NN NN
ACh ACh ACh
M1 M1 M1
ACh NN NN
ACh
Adrenal
M1
medulla
ACh
DA ACh
NE
AC
NEJ NM
h
NE + E M3
D1 and D2
a1, a2 M1, M2, M3 Skeletal
Renal Sweat muscle
glands b1, b2, or b3 M4 or M5
vasculature (NMJ)
(apocrine)
Key: Preganglionic fibres; Postganglionic fibres
ACh – Acetylcholine; NE – Norepinephrine, E-Epinephrine, DA-Dopamine;
NM – Nicotinic cholinergic receptor (muscular type) at neuromuscular junction (NMJ);
NN – Nicotinic cholinergic receptor at ganglia (neuronal type); α1, α2, β1, β2, β3 – Alpha and beta
adrenergic receptor subtypes; M1 to M5 – Muscarnic cholinergic receptor subtypes; D1 and
D2 – Dopamine receptor subtypes at renal vasculature; NEJ – Neuroeffector junction at the smooth
muscle of the effector organ.
Fig. 3.2: Distribution of cholinergic and adrenergic neurons in PNS
The entire length of CNS including brain and spinal cord can be divided in to four
following sub-sections:
• Cranial: related to brain,

• Thorax: related to upper part of spinal cord (up to diaphragm),
• Lumbar: related to lower part of spinal cord (next to diaphragm),
• Sacral: related to lowest tapering part of spinal cord.
Out of these four parts, output of cranial and sacral region, called as cranio-sacral
belongs to PSNS. The output of thoracic and lumbar region, called as thoracico-lumbar
belongs to SNS. The origin of nerves related to PSNS and SNS and their connection to
effector organs is depicted in Figs. 3.3 and 3.4.
Cranium Ciliary ganglion
III
Ciliary muscle, circular muscle of iris
VII
M
Sphenopalatine ganglion
IX
Lacrimal gland
C
Submaxillary ganglion
X
Submaxillary and sublingual salivary gland
Otic ganglion
Parotid gland
L
Heart, Lung, Intestine

S
Kidney, Bladder, Colon and Genitals

Nervi erigentes
Pelvic ganglion
Key: M–Medullary; C – Cervical; T-Thoracic; L-Lumbar; S-Sacral

myelinated preganglionic parasympathetic fibres. myelinated postganglionic
parasympathetic fibres (to ciliary muscle). non-myelinated postganglionic parasympathetic
fibres. Note that, preganglionic parasympathetic fibres are long while postganglionic
parasympathetic fibres are short. Also, the parasympathetic ganglia related to III, VII, IX and pelvic
nerves are lying close to effector organ while that related to X (vagus) nerves are embedded within
the wall of the effector organ.
Fig. 3.3: Parasympathetic nervous system and its effector organs
Radial muscle of iris, blood vessels of head

and neck, salivary glands
M SCG
MCG
C
ICG
T1
T2 Heart, respiratory tract, thorax etc.
T3
Paravertebral sym. ganglia (22)
T4
T5
T6
T7 CG*
GIT, hepatic and renal blood
T8
vessels and sweat glands
T9
T10
T11
T12 SMG* Adrenal medulla
L1
L1 Colon, rectum, kidney
L3
Genitals etc.
S IMG*
Blood vessels of lower extremities
SG
Sex organs, bladder
Key: preganglionic neuron; postganglionic neuron; * – prevertebral ganglia (not
bilaterally paired); SCG – Superior cervical ganglia; MCG – Middle cervical ganglia; ICG – Inferior
cervical ganglia; CG – Goeliac ganglia; SMG – Superior mesenteric ganglia; IMG – Inferior
mesenteric ganglia; SG – Sacral ganglia; M – Medulla; C – Cervical; T – Thoracic; L – Lumbar;
S – Sacral. Although paravertebral sympathetic ganglia (22) chain is bilaterally paired, yet for
convenience, the innervation has been shown only on the right side of the figure.
Fig. 3.4: Sympathetic nervous system and its effect or organs
There is one more difference between PSNS and SNS. After stimulation of a nerve, a
specialised chemical is secreted at the nerve ending. The chemical is responsible for
transmission of information from nerve to effector organ. The specialised chemical is termed
as neurotransmitter (NT). NT for PSNS and SNS are different. Acetyl choline (ACh) is the NT
for PSNS. Nor-adrenaline/nor-epinephrine (NA) and adrenaline/epinephrine (A) are
neurotransmitters of SNS. Structures of various NTs in ANS are depicted in Fig. 3.5.
HO HO
b a
HO CH CH2 NH CH3 HO CH CH2 NH2
OH OH
(a) Structure of Adrenaline (Epinenphrine) (b) Structure of Nor-adrenaline (Norepinephrine)
Fig. 3.5: Structure of ACh
3.2.2 Functions of ANS

In general, stimulation of SNS promotes catabolism; while stimulation of PSNS promotes
anabolism. However at different organs, the effects are apparently contradictory. This is not
true for every organ as observed in table 3.1. In reality, effects of stimulation of SNS and
PSNS are complimentary to each other so that either of them may be activated depending
on metabolic need of the body. Usually, SNS is called as the system of fight and flight
indicating that, it is stimulated when the need of metabolic energy is very high. On the
contrary, PSNS is stimulated after consumption of food so that anabolic activity leading to
build up of energy is stimulated.
Table 3.1 lists gross effects of stimulation of ANS at the level of different organs.
Table 3.1: Summary and comparison of effects of ANS stimulation
Organ Sympathetic stimulation Parasympathetic stimulation
HEART (Vagal fibres do not reach
ventricles)
Rate Increased; (Positive chronotropy) Decreased; (Negative
chronotropy)
Conductivity Increased Decreased (in SA node, atrium
and AV node only)
Contractility Increased (Both atrium and Decreased in atrium; no effect on
ventricle; positive ionotropy) ventricle
Cardiac output Increased Decreased
BLOOD VESSELS
Arterioles of
Coronary Constriction; ultimate dilation No effect except erectile tissue-
due to other effects vasodilation; erection; salivary
vaso-dilation
Skin Constriction -
Splanchnic Constriction -
Skeletal muscles Dilation -
Veins Constriction/Dilation in some No effect
vessels
BRONCHIAL TREE
Smooth muscles Relaxation (broncho-dilatation) Constriction (broncho-
constriction)
Bronchial glands Increased/decreased secretion Increased secretion
contd. …
GASTRO-
INTESTINAL
TRACT
General smooth Relaxation; decreased peristalisis Contraction; increased peristalisis
muscles
Sphincters Contraction Relaxation
Exocrine glands Variable (increase/decrease) Increased secretion
IEYE Dilation of pupils (mydriasis), Constriction of pupil (miosis),
ciliary relaxation ciliary constriction
SKIN
Hair Piloerection (raising of hair) Variable
Sweat gland Sweating No effect
KIDNEY Rennin production; renal Variable
vasoconstriction
UTERUS Contraction in pregnant; Unpredictable
relaxation in non-pregnant
URINARY Contraction of sphincter; Evacuation of bladder
BLADDER relaxation of detrusor; urinary
retention
MALE SEX Contraction of vas and other Erection of penis
ORGAN ducts; ejaculation
LIVER Glycogenolysis Variable
Receptors
The variation in actions of different neurotransmitters is primarily because of presence of
different sub-types of receptors which execute the biological action. Receptors are located
on the cell membrane of effector cells like smooth muscles/cardiac muscles/exocrine glands
etc. Sub-types of PSNS and SNS are mentioned below:
PSNS
Acetyl choline is the neurotransmitter of PSNS. Hence, the receptors are called as
cholinergic/cholinomimetic/cholinoceptive. There are two major varieties of the receptor:
muscarinic (M) and Nicotinic (N).
Musarinic receptors are found on the cell membranes of effector cells of smooth or
cardiac muscle, bronchial or gastrointestinal tract glands.
They are further sub-classified in to two sub-types: M1 and M2. M1 receptors are present
in the synapses of the brain. They are also present in enteric nervous system (ENS), especially
in relation to parietal cells of stomach. M2 receptors are present in other effector cell
membranes of smooth or cardiac muscles, glands etc.
Nicotinic receptors are of two types: NN and NM. Nicotinic neuronal (NN) are present in
ANS ganglia while nicotinc muscular (NM) are present in the neuromuscular junction and the
skeletal muscle.
SNS
The neurotransmitters for SNS are adrenalin/nor-adrenalin/dopamine. There are two
types of receptors for SNS: α and β. Further sub-types of α−receptors are α1 and α2 whereas
sub-types of β are β1 and β2. α1 receptors are found on smooth muscles of many arterioles,
radial muscles of iris in eye, sphincters of gastrointestinal tract and urinary bladder,
Arrectorus pilorum muscles of skin, vas deferns and seminal vesicle of male reproductive
organs. α2-receptors are scarcely located on skin and coronary arterioles. β1 receptors are
located in the myocardium and its conducting tissues (SA node, AV node, bundle of HIS). In
kidney, they are responsible for increased production of renin. β2-receptors are located on
muscles of arterioles, vessels of lungs, veins, ciliary muscles of eye, bronchial muscles and
glands, smooth muscles of gastrointestinal tract, uterus, detrusor muscle of urinary bladder
and liver. Distribution of adrenergic receptors and their effects are summarised in table 3.2.
Table 3.2: Adrenergic receptors; their distribution and functions
Receptors Distribution Effects of stimulation
α1 Most vascular smooth muscles Vasoconstriction, raised peripheral
resistance
α1 Arrectorus pilorum Piloerection
α1 Dilator pupillae Pupillary dilation
α1 Liver (rat) Glycogenolysis (rat)
α2 Some CNS synapses Stimulation causes inhibition of
vasomotor centre and bradycardia
α2 Platelets Aggregation
α2 Some vascular smooth muscles, not Vasoconstriction
attached with nerve
α2 Adipose tissue Inhibition of lipolysis
α2 Pre-junctional membrane of post- Inhibition of release of
ganglionic SNS and PSNS neurotransmitter
β1 Heart Cardiac stimulation
β1 Kidney Stimulation of renin stimulation
β1 Posterior pituitary Stimulation of ADH secretion
β1 Adipose tissue Lipolysis
β2 Bronchial smooth muscles Dilatation
β2 Smooth muscles of arterioles of Vasodilatation
skeletal muscles
β2 Smooth muscles of uterus Relaxation
β2 Liver cells (human) Glycogenolysis
3.3 NEURO-HUMORAL TRANSMISSION, CO-TRANSMISSION AND

CLASSIFICATION OF NEUROTRANSMITTERS
The transmission of an impulse along a nerve fibre is an electrical phenomenon.
Normally, a cell in resting condition is electronegative; indicating that extracellular charge is
negative and intracellular charge is positive in nature. The difference in charge is along
membrane of the cell. Whenever a cell is stimulated, the charge reverses at the point where
transmission of an impulse is being forwarded. After some time, the cell restores electro-
negativity. In contrast to this, at the nerve ending i.e. at synapses, the transmission is
chemical in nature. A specialised chemical is secreted at the nerve ending. It is called as
neurohumoral transmission. Certain chemicals support and augment action of
neurotransmitters. They are called as co-transmitters.
3.3.1 Neuro-humoral Transmission and Co-transmission
Four processes occur in relation to nerve transmission in CNS. They are as follows:
(i) Neurotransmission
Neurotransmission occurs due to specialised chemicals called as neurotransmitters. They
are synthesised in pre-synaptic neurons and are released in to synaptic cleft to rapidly
stimulate or inhibit post-synaptic neurons or effector organs. The examples are: Acetyl
choline, dopamine, nor-epinephrine/epinephrine, 5-hydroxytryptamine (serotonin),
γ-amino butyric acid, glycine, glutamate, aspartate, endorphins, encephalins.
(ii) Neuromodulation
The chemicals causing neuromodulation are called as neuromodulators. They are
released by neurons and astrocytes to produce slower pre-or post synaptic responses.
Neuromodulation is related to long term changes in synaptic transmission, connectivity
and efficacy following pathological damage as in epilepsy; or following physiological
alterations in neuronal activity as in learning and memory. The examples of
neuromodulators are: Carbon dioxide, adenosine, some purines, peptides,
prostaglandins and nitric oxide.
(iii) Neuromediation
Neuromediation is caused by neuromediators, which are second messengers playing a
crucial role in eliciting post-synaptic responses caused by neurotransmitters. The
examples are: cAMP, cGMP and inositol phosphate.
Neuromodulators and neuromediators are termed as co-transmitting factors.
(iv) Mediation through neurotropic factors
Neurotropic factors are mainly released by CNS neurons, astrocytes and microglia. They
act longer than neuromodulators to regulate the growth and morphology of neurons
and control long term changes in brain like synaptic plasticity, remodelling, phenotype
characteristics. They act by affecting gene transcription through tyrosine kinase-linked
receptors. The examples are: Cytokines, chemokines, growth factors etc.
3.3.2 Classification of Neurotransmitters

Neurotransmitters can be classified in to four major classes as follows:
(i) Acetyl Choline (ACh)
Neurons producing acetyl choline are called as cholinergic neurons. They are present in
cerebral cortex, ascending reticular axcting system, basal ganglia, limbic system,
cerebellum and spinal cord. ACh modulates arousal, respiration, motor activity, vertigo
and memory.
(ii) Amino acids
The central nervous system contains high concentrations of certain amino acids like
glutamate, Gamma amino butyric acid (GABA). The dicarboxylic acids (glutamate and
aspartate) produce excitation and monocarboxylic ω-amino acids (GABA, glycine,
β-alanine and taurine) produce inhibition. It is interesting to note that inhibitor GABA is
generated from excitant glutamic acid through the action of enzyme Glutamic-acid-
decarboxylase (GAD).
(iii) Biogenic amines
Biogenic amine include dopamine, nor-epinephrine/epinephrine, 5-hydroxy tryptamine
and histamine.
(iv) Peptides
Various peptides like vasopressin, oxytocin, tachykinins, neurotensin, vasoactive
intestinal polypeptide (VIP), endogenous opioids like endorphins and encephalins,
cholecystokinin, angiotensin II and neuropeptide Y perform various functions in different
parts of the body. Some of them act as hormones.
Imbalance amongst various neurotransmitters and/or damage to the neurons or parts of
CNS can lead to various disorders.
3.4 PARASYMPATHOMIMETICS, PARASYMPATHOLYTICS
Drugs related to autonomic nervous system (ANS) belong to two major divisions of ANS:
PSNS and SNS. Each division is further sub-classified in to two types: those which mimic the
actions of neurotransmitters or those which antagonise the actions of neurotransmitters.
The drugs mimicking the actions of ACh are called as parasympathomimetics. The drugs
blocking actions of ACh are termed as parasympatholytics. The drugs mimicking actions of
nor-adrenalin/adrenalin are called as sympathomimietics. The drugs antagonising actions of
nor-adrenalin/adrenalin are termed as sympatholytics.
3.4.1 Biosynthesis, Storage and Release of ACh
Acetyl choline, as such, is of no therapeutic use because of its ultra-short action. Its half
life is of few seconds only due to rapid hydrolysis by the enzyme acetylcholinesterase.
Chemically, ACh is the acetic ester of choline. See Fig. 3.6.
O
||
CH3 – C– O – CH2 ⋅ N(CH3)3 Cl
Fig. 3.6: Structure of acetylcholine chloride
Biosynthesis
The events related to biosynthesis of ACh along with sites of action of some
drugs/toxins are summarised in Fig. 3.7. ACh is synthesised in the axon terminal by
acetylation of choline with acetyl CoA (AcCoA). The reaction is catalysed by cytosolic enzyme
named choline acetyl transferase (ChAT). Choline from extracellular fluid is actively
transported inside the cytoplasm of cholinergic nerve terminal by a sodium-dependent
transporter (CDT). The rate-limiting process in synthesis of ACh synthesis is transport of
choline, the activity of which is regulated depending on the need of ACh being released. This
process can be blocked by a group of drugs called hemicholiniums. (see Fig. 3.7)
Hemicholinium
-
AcCoA +
+ Choline Choline
ChAT
ACh
Vesamicol
+ -
ACh rs
to
ep
ATP, P
r ec
2
a
ic
Ca++
pt
M
na
sy
ACh N
e
Pr
-
Botulinum toxin ATP, P
ACh Acetate
E
ACh
N M
Fig. 3.7: Neurochemical events during synthesis, storage, release and degradation of ACh
AcCoA needed for biosynthesis of ACh is synthesised in the mitochondria from pyruvate
by the action of enzyme pyruvate dehydrogenase (PDH). AcCoA is then transported out of
the mitochondria in to the cytoplasm.
Storage
ACh, formed by the process discussed above, is actively transported in to vesicles
by a transporter. This active vesicular uptake of ACh is selectively blocked by vesamicol
(see Fig. 3.7). This results in slow development of neuromuscular block. ATP and peptides are
also stored in the vesicles as co-transmitters.
Release
Arrival of an action potential at the nerve terminal causes an influx of calcium ions, which
in turn triggers release of ACh by the process of exocytosis. This mechanism involves an
interaction between the proteins associated with vesicles, called as synaptobrevin and the
nerve ending membrane, called as syntaxin. The interaction results in fusion of vesicle and
nerve ending membrane, opening of a pore towards extracellular space and release of ACh.
Botulinum toxin alters synaptobrevin to prevent release of ACh. Release of ACh, which
requires nerve action potential through entry of calcium ions is prevented by local
anaesthetics in a reversible manner. Tetrodotoxin binds to sodium channel irreversibly.
Metabolism
ACh is hydrolysed by the enzyme called as acetyl cholinesterase to choline and acetic
acid. The hydrolysis terminates actions of ACh. It is the reason why duration of action of ACh
is very less. (few seconds). Cholinesterase enzyme (ChE) is of two types:
(i) True Acetylcholine Esterase
It is a membrane bound enzyme located in the cholinergic synaptic cleft. It is specific
only to ACh and methacholine. It does not hydrolyse other esters of choline. It is mainly
located in neuronal membrane, cholinergic synaptic cleft and to a small extent in RBCs and
placenta.
(ii) Plasma Choline Esterase (Pseudocholine esterase/Butyryl choline esterase)
It is synthesised in liver and found predominantly in plasma and intestine. It is not
located in membrane. It hydrolyses other esters of choline also; e.g. succinyl choline, benzoyl
choline and butyrl choline esters. There are genetic variants to this enzyme. Some persons,
who have atypical pseudocholinesterase, show slow hydrolysis of succinyl choline, resulting
in longer duration of action with prolonged apnoea after its use.
Actions of ACh are exhibited (see table 3.1; Effects of parasympathetic stimulation)
through two types of receptors: Muscarinic and Nicotinic. The actions are outlined below.
Muscarinic Actions
There are three sub-types of muscarinic receptors: M1, M2 and M3. M1 receptors are
located on sympathetic ganglia, gastric parietal cells and cerebral cortex. They mediate
excitatory effects. M2 receptors are located on myocardium, smooth muscles, pre-synaptic
terminals of peripheral and central neurons. They exert inhibitory effects. M3 receptors are
located on glandular and visceral smooth muscles. Their activation results in excitatory
effects, except for vasodilation due to release of nitric oxide from neighbouring endothelial
cells.
Effects on Different Organs
The codes MiSLUBD and DHR help us to remember the effects of stimulation of PSNS.
The explanation for codes is as follows; Myosis (Mi), Salivation (S), Lacrimation (L),
Urination (U), Bronchoconstriction (B), Defaecation (D), and Decrease in Heart Rate (DHR).
(i) Eye
Circular muscle of iris, ciliary muscle and lacrimal glands possess M3 receptors. Radial
muscle of iris and eyelid smooth muscle have no parasympathetic supply.
ACh causes contraction of circular muscle of iris and of the ciliary muscle. See Fig. 3.8.
Contraction of circular muscle of iris causes myosis. Contraction of ciliary muscles makes the
suspensory ligaments loose. As a result of this, the lens is made more convex resulting in
reduction of focal length. The net result is accommodation of eye for near vision. In addition,
contraction of ciliary muscle, aided by stretching of pupil due to myosis, opens pores of the
canal of Schlemm facilitating drainage of aqueous humour leading to reduction of
intraocular pressure. (See Fig. 3.8). This action is particularly useful in patients of glaucoma,
where intraocular pressure is increased due to accumulation of lacrimal fluid. Stimulation of
M3 receptors at lacrimal glands produces lacrimation, due to vasodilatation.
Canal of
schlemm (winder)
Contraction
Pathway for Better

Cornea aqueous humor drainage of
drainage aqueous
humor
LENS
More convex lens
LENS
Pupillary
constriction
Suspensory Loose
Iris (miosis)
ligaments suspensory
ligaments
Ciliary muscle
Canal of Ocular
schlemm angle Ciliary
Contraction muscle
(a) Normal eye (b) Eye after effect of ACh
Fig. 3.8: Effect of released Acetylcholine on eye
(ii) Salivary glands
Salivary glands have M3 receptors. Their stimulation produces watery saliva due to
vasodilatation resulting from release of bradykinin.
(iii) Lungs
Smooth muscles of bronchii and mucus glands possess M3 receptors. Stimulation of
smooth muscles causes broncho-constriction. Stimulation of mucus glands causes increasd
bronchial secretions. These effects together cause difficulty in breathing.
(iv) GIT
Smooth muscles of GIT, sphincters and gastric glands have M3 receptors. However
gastric parietal cells possess M1 receptors. ACh causes activation of M3 receptors causing
increase in motility and tone of GIT smooth muscle, relaxation of sphincters and increased
secretions from gastric glands, together leading to defaecation. Stimulation of M1 receptors
promotes secretion of gastric acid. All actions of ACh together help in the process of
digestion and promote peristalisis.
(v) Heart
PSNS supply only up to SA node, atria and AV node. In contrast, the ventricular
myocardium has no innervation of PSNS; however they have muscarinic receptors. At SA
node, atria and AV node there are M2 receptors, stimulation of which causes decrease in the
heart rate. This is termed as negative chronotropy. In addition, there is decrease in force of
contraction which is termed as negative ionotropy. M2 receptor activation at AVA node

causes decrease in conduction velocity and increase in the refractory period. Thus, ACh
causes decrease in activity of heart.
(vi) Blood vessels
Arteries have no PSNS innervations, but they have M2 receptors. As a result,
administration of external ACh causes a transient but a marked fall in blood pressure due to
vasodilatation. However, this does not occur by stimulation of PSNS. The fall in blood
pressure evokes baro-receptor reflex, resulting in compensatory sympathetic discharge at
the heart. As a result, ACh administration by intra-venous route initially causes bradycardia,
but after some timer it is followed by tachycardia. Systemic veins have neither PSNS
innervations nor M3 receptors.
(vii) Urinary bladder
Both the detrusor muscle and the sphincter have M3 receptors. Their stimulation causes
contraction of detrusor muscle and relaxation of sphincter, leading to urination due to
effects on urinary bladder.
(viii) Pancreas
Acini cells in the pancreas have M3 receptors and its activation causes increased
secretion of pancreatic juice. There is no effect on β-cells of islets of Langerhans. Thus, there
is no effect on secretion of insulin due to PSNS stimulation.
(ix) Male sex organs
Vascular bed of erectile tissue is dilated due to PSNS stimulation while venous sphincters
are closed leading to erection of penis. The effect is mediated through M3 receptors.
(x) Sweat glands
These glands have M3 receptors. Activation of these receptors leads to increased
sweating. The innervation is sympathetic in origin but cholinergic in character.
(xi) CNS
On CNS, there are complex stimulatory effects due to PSNS. Ataxia, behavioural
disturbances and restlessness are mediated through nicotinic receptors; while tremors and
convulsions are mediated through muscarinic receptors.
On liver and kidney there is no parasympathetic innervations; hence PSNS stimulation
does not cause any effect on liver and kidney.
(xii) Nicotinic actions
Nicotinic receptors are present at neuromuscular junction (NMJ/NM receptors), at all
autonomic ganglia (NN) receptors and in brain. Activation of NM receptors results in
contraction of skeletal muscles. Activation of NN receptors provides the transmission of
impulse through autonomic ganglia and firing of post-ganglionic neuron. In brain, the
nicotinic receptors are located on pre-synaptic membrane and facilitate release of dopamine
and glutamate.
Actions of ACh through nicotinic receptors need a special mention. The actions include:
• Stimulation of SNS as well as PSNS ganglia occurs through nicotinic (NN) receptors,
which ultimately results in discharge of ACh in case of PSNS and NE/E in case of SNS
from the post-ganglionic neurons. Most organs have innervation of both PSNS and
SNS. The net result is dependent on the fact that domination of either PSNS or SNS
for that organ. Thus in case of blood vessels, which are dominated by SNS, activation
of nicotinic receptor causes vasoconstriction. Unlike this, GIT is dominated by PSNS.
Hence ACh increases the motility and secretions because of PSNS discharge. It is to
be noted that all ganglionic transmissions (either PSNS or SNS) is mediated through
nicotinic receptors of ACh.
• Stimulation of adrenal medulla leads to discharge epinephrine/adrenalin (E/A),
because adrenal medulla is a modified ganglion where ACh serves as a
neurotransmitter stimulating nicotinic (NN) receptors present on it.
• Stimulation of nicotinic receptors at the neuromuscular junction (NMJ) results in
spasm of the skeletal muscle. The action is mediated through NM receptor. However,
prolonged activation results in fasciculations followed by paralysis.
3.4.2 Parasympathomimetics
Parasympathomimetics are classified in two categories: (i) directly acting and
(ii) indirectly acting. Those drugs which act by their interaction directly on receptors of ACh
fall in this category. Unlike this, drugs which inhibit the enzyme cholinesterase and thereby
increase the concentration of ACh fall in this category.
[I] Directly Acting Parasympathomimetics
As mentioned earlier, these drugs directly activate ACh receptor and therefore can cause
ACh- like action even after denervation (loss of PSNS nerves). The prototype agent in this
category is ACh. They are sub-classified under three categories as follows:
1. Acetyl choline (ACh): Prototype
ACh is not used clinically because of its ultra-short action (few seconds only)
2. Synthetic choline esters
Methacholine and carbechol are no longer used clinically.
• Methacholine
• Carbachol
• Bethanechol
Bethanechol is resistant to hydrolysis by true cholinesterase and pseudocholinesterase.
Hence, it has relatively longer half-life. It mainly acts on muscarinic receptors, particularly at
urinary bladder and GIT; but it has no action on nicotinic receptors.
Uses:
• It is useful to treat urinary retention. For acute retention, 2.5 mg is given
sub-cutaneously. In chronic cases, 10-15 mg is given orally and is slowly withdrawn.
• It is useful to treat atony (loss of tone) of GIT, if there is no obstruction e.g. to expel
gases from intestine before radiological examination. For this purpose, it is given
orally in a dose of 10-20 mg three times a day.
• It is useful to treat dysfunction of salivary glands, xerostomia (reduced secretion of
salivary glands).
Precautions:
It should not be given by intravenous route. Sudden rise in plasma concentration can
cause cardiovascular collapse.
Contra-indications and undesirable effects:
• The contra-indications are as follows:
o Hyperthyroidism
o Bronchial asthma
o Peptic ulcer
o Myocardial infarction
• The undesirable effects include CNS stimulation, myosis, spasm of accommodation
for distant vision, broncho-constriction, abdominal cramps, flushing, sweating and
salivation.
Bethanechol is available as 25 mg tablet.
3. Natural alkaloids
o Muscarine
o Nicotine
o Arecoline
o Pilocarpine (Trade name: PILOCAR, PILAGAN, PILOPRESS, LOCARP)
Muscarine, nicotine and arecoline are not used clinically. Muscarine is obtained from
poisonous mushroom Amanita muscaria. Nicotine is present in tobacco and Arecoline is
the main alkaloid present in betel nuts.
Pilocarpine is the main alkaloid obtained from leaves of the shrub Piolcarpus jaborandi. It
is a tertiary amine and crosses blood-brain barrier. It has a primary muscarinic action on
M3 receptors. It has also a mild nicotinic action on NN receptors of ganglia. It is too toxic
for systemic use. One of the important adverse reactions of systemic use of pilocarpine
is pulmonary oedema. It has following therapeutic uses:
• Ophthalmic use
As a 0.5-4% solution, it is instilled in to the eye, it is used for initial treatment of open
angle glaucoma. It reduces intra-occular pressure within few minutes and lasts for 4-8
hours.
It produces miosis and counteracts mydriasis produced by atropine.
It breaks adhesion between the iris and the lens, as in iridocyclitis, as a local solution.
• Salivary secretion
It promotes salivary secretion and acts as sialagogue. In oral dose of 5-10 mg, it can be
used to stimulate salivary secretions in patients after laryngeal surgery and to treat
xerostomia resulting after radiotherapy.
It is available as eye drops of 1%, 2% or 4%.
• Miscellaneous
o Tremorine
o Oxotremorine
Tremorine and oxytremorine are synthetic tertiary amines. Oxotremorine is an active
metabolite of tremorine. They are not used clinically. They are used as research tools
to stimulate Parkinson-like symptoms in animal models.
o Cevimeline
In a oral dose of 30 mg, it is used to treat xerostomia in patients undergoing cancer
chemotherapy or those suffering from Sjogren syndrome. Adverse effects include
decreased visual acuity in central field and diarrhoea.
[II] Indirectly Acting Parasympathomimetics:
These agents inhibit the enzyme acetyl cholinesterase (AChE), located in synaptic cleft.
The enzyme is responsible for rapid hydrolysis of ACh. As a result, these drugs prolong the
action and increase indirect availability of ACh at muscarinic and /or nicotinic receptors.
These drugs do not show any activity on dennervated organs because there is no inherent
release of ACh in them.
During degradation, ACh combines with AChE through electrostatic attraction at two
points: anionic site and esteratic site. See Fig. 3.9. In structure of ACh, there is one
quarternary ammonium and there is one ester. Quarternary ammonium binds to anionic site
and ester binds to hydroxyl group of serine residue of AChE at the esteratic site. Initially, an
enzyme-substrate complex (AChE-ACh) is formed. This is the first step of the reaction
(step I). It is followed by cleavage of the ester linkage (O-CO-CH3) with generation of
choline. This is called as step II. In the last step III reaction, remaining acetylated enzyme
(AChE) reacts with water to regenerate the active enzyme AChE. See Fig. 3.9.
-
O O
(CH3)3 N CH2 CH2.O.C.CH3 (CH3)3 N CH2 CH2.O C CH3

+
O H +
+O H
- -
AChE Step I
Anionic site Esteratic site AChE - ACh complex
Step II
Acetic acid
(CH3) C - OH + (CH3) C O
-
(CH3)3 N CH2 CH2 OH
O O H Choline O +
+ H2O
- - -
AChE Step III
Fig. 3.9: Mechanism of acetylcholine hydrolysis by acetylcholinesterase
The reversible anticholinesterase drugs bear structural similarity with ACh. They combine
with the anionic and the esteratic sites of ACh. This complex is less easily hydrolysed as
compared to AChE-ACh complex. As a result, the enzyme is temporarily inhibited and
prolongs the action of ACh. The action is due to slow recovery of AChE. Reversibility of
anticholinesterase with AChE and its renal elimination after detachment of AChE account for
its duration of action.
Following drugs belong to this category:

• Physostigmine (ESERINE)
• Neostigmine (PROSTIGMINE, TILSTIGMIN, MYOSTIGMIN)
• Pyridostigmine (PIRIDO, DISTINON, MYESTIN)
• Edrophonium
• Ambenonium
• Demecarium
• Rivastigmin
• Distigmin
Amongst these drugs, only physostigmin is a naturally occurring alkaloid. All other drugs
are synthetic quarternary ammonium compounds. They exist in ionised form and do not
cross blood-brain barrier. As a result, synthetic drugs have very limited action on CNS.
(i) Physostigmine (Eserine)
It is an alkaloid obtained from the dried ripe seeds of Physostigma venenosum. It is a
tertiary amine; it is highly lipid soluble. It shows better absorption in the body and shows
action even on CNS. It has marked muscarinic effects on M1 and M3 receptors and it also
stimulates ganglia. However, its nicotinic effects on motor end plate (NMJ) are negligible.
Because of its systemic toxicity, it is preferred for local use.
Uses:
• Ophthalmic uses of physostigmin resemble to uses of pilocarpine. It is used for following
conditions:
o For reversal of mydriasis
o To prevent adhesions between pupil and lens
o For the treatment of open angle glaucoma
It is highly lipid soluble, relatively toxic and poorly tolerated. Its ophthalmic preparations
are not used in India; however it is available as 0.25% and 0.5% eye drops elsewhere.
• Belladona (atropine) poisoning:
o Physositgmine is a specific antidote for atropine (datura) poisoning or for poisoning
by any other parasympatholytic/anticholinergic drug. It is useful for poisoning by
tricyclicantidepressants, like imipramine which shows anticholinergic action as an
adverse effect. Physostigmine, being a tertiary amine alkaloid passes blood-brain
barrier and can antagonise central as well as peripheral toxicity of atropine. 2 mg of
physostigmine is given either intravenously or intramuscularly. Parenteral
preparation of physostigmine is not available in India.
(ii) Synthetic Quaternary Compounds
This group includes all reversible anticholinesterases under the category of indirectly
acting parasympathomimetics. It includes:
• Neostigmine,
• Pyridostigmine,
• Erophonium,
• Ambienonium,
• Demecarium,
• Rivastigmine and
• Distigmine.
All synthetic compounds mentioned above are quartenary ammonium compounds. They
are least absorbed and do not cross blood-brain barrier. These drugs are useful on
neuromuscular junction as skeletal muscle relaxants. Low doses of these drugs prolong and
intensify the actions of physiologically released ACh at motor end plate. It results in
strengthening of muscles weakened by curare-like drugs or by a disease called as
myasthenia gravis. In addition, these drugs possess dire weakened by curare-like drugs or by
a disease called as myasthenia gravis. In addition, these drugs possess direct action at
nicotinic receptors of NMJ (NM) which also contributes to their effectiveness in treatment of
myasthenia gravis.
Uses:
Their therapeutic uses are as follows:
o Treatment of myasthenia gravis
It is discussed under Section 3.6.1.
o Paralytic ileus and atony of urinary bladder
Reduced peristalisis in GIT can lead to paralytic ileus. Atony (loss of tone) of urinary
bladder leads to urinary retention. These effects can be relieved by 0.5-1 mg sub-
cutaneous dose of neostigmine. A longer acting drug, distigmine can be used in a
dose of 5 mg orally every second day after neostigmine.
o Glaucoma
0.25-0.5% solution of demecarium is applied topically, in the eye, twice a week. The
drug has longer duration of action.
o Post operative decurarization (treatment of curare poisoning)
0.5-1 mg intravenous neostigmine or 10 mg intravenous edrophonium, along with
atropine, rapidly reverses muscle paralysis induced by d-tubocurarine given during
anaesthesia.
o Paroxysmal atrial and supra-ventricular tachycardia
Edrophonium is preferred; however it is now replaced by calcium channel blockers.
o Treatment of snake bites (as accessory drug)
The classical treatment for poisoning by snake bite is use of anti-snake venom (ASV).
The final cause of death by snake poisoning is respiratory paralysis. Hence reversible
anticholinesterases can be used for a temporary reversal of respiratory paralysis.
Neostigmine is available as 15 mg tablet and 0.5 mg/ml injection. Pyridostigmine is
available as 60 mg tablet.
Irreversible inhibitors of AChE

Irreversible AChE blockers are organo-phosphorous compounds. They phosphorylate
esteratic site of AChE irreversibly by forming a covalent bond. They have no clinical use. They
are known for their toxicological effects and their toxicity is treated by oximes.
3.4.3 Parasympatholytics
ACh has got two receptors: muscarinic and nicotinic. The drugs which block muscarinic
receptors are discussed in this sub-section. In addition, drugs which block nicotinic (NN)
receptors are called as ganglion blockers, while drugs blocking synaptic transmission at NMJ
are called as neuromuscular blocking drugs or skeletal muscle relaxants.
Classification and examples of muscarinic receptor antagonists are shown below:
1. Natural alkaloids
Atropine (dl-hyoscyamine) and Scopalamine (l hyoscine)
2. Semi-synthetic derivatives
Homatropine and its salts, Atropine methonitrate, Hyoscine methylbromide,
Benztropine, Ipratropium bromide, Tiotropium bromide
3. Synthetic derivatives
Eucatropine, Cyclopentolate, Tropicamide, Dicyclomine, Flavoxate, Oxybutinin,
Pirenzepine, Telenzepine, Trihexyphenidyl, Procyclidine, Propantheline, Drotaverine,
Oxyphenonium, Glycopyrrolate, Clinidium, Tolterodine, Pipenzolate, Valethamate
4. Other drugs showing anti-muscarinic action
Anti-histamines: Diphenhydramine, Promethazine, Orphenadrine
Anti-psychotics: Phenothiazines: Chlorpromazine, Thioridazine
Butyrophenone: Haloperidol
Tricyclic-antidepressants: Amitriptyline, Imipramine
Chemistry of Antimuscarinic Drugs (Parasympatholytics)
Atropine and Scopolamine are naturally existing alkaloids obtained from the family of
solanaceae plants. Atropine is obtained from Atropa belladonna or from Datura stramonium.
Naturally occurring atropine is l-hyoscyamine but is racemised immediately to di-hyoscy-
amine (commercial atropine). The anti-muscarinic activity resides only in l-hyoscyamine.
Scopolamine is obtained from Hyoscyamus niger and also from Scopolia carniolica.
Scopolamine is l-hyoscine and is several more potent than its d-isomer.
Chemically, both atropine and scopolamine are organic esters formed by combination of
an aromatic acid-tropic acid - and an organic base which is either tropine (in atropime) or
scopine (in scpolamine). Scopine differs from tropine in having an epoxide group (i.e.
oxygen bridge) between carbon atoms C6 and C7. See Fig. 3.10.
(Tropine) (Scopine)
N CH3
N CH3
CH2OH
7 CH2OH
O O CO CH
6 O CO CH
C6H5
C6H5
Atropine Scopolamine
N CH3(Tropine)
C 2H 5
OCOCH2CH2N
OH
C 2H 5
O CO CH
C6H5
Homatropine Dicyclomine
(Semisynthetic tertiary amine) (Semisynthetic tertiary amine)
C3H7
+
COOCH2CH2N C3H7 Br
Propantheline bromide CH3
(Synthetic quaternary derivative))
Fig. 3.10: Chemical structures of some antimuscarinic drugs (Parasympatholytics)
2. Semi-synthetic derivatives are obtained by combining natural organic base (tropine
or scopine) with any organic acid (e.g. mandelic acid as in homatropine).
3. Synthetic derivatives do not have tropine/scopine portion in their chemical structure.
Both semi-synthetic and synthetic derivatives are either tertiary amines or quartenary
amine salts.
Pharmacology of Antimuscarinic Agents
Pharmacokinetics
• Absorption
Atropine, scopolamine and other tertiary amines are well absorbed from GIT and can
easily cross conjunctival membrane. If prepared in a suitable vehicle, the drugs can be
absorbed by transdermal route (e.g. scopolamine transdermal patch). Quaternary amine
salts are poorly absorbed and do not cross blood-brain barrier because of their poor
lipid solubility.
• Distribution
Except for quaternary compounds, other anti-muscarinic drugs get widely distributed in
all compartments of body. Scopolamine is rapidly and fully distributed in CNS and has
greater effects in CNS.
• Metabolism
About 50% of atropine and 80% of scopolamine is metabolised in the liver as
conjugates. Rabbits are resistant to action of atropine because they possess an enzyme
called atropine esterase which degrades atropine at a faster rate.
• Excretion
About 50% of atropine is excreted unchanged in urine. Half-life (t1/2) is about 3 hours.
Atropine effects decline rapidly in all organs except the eye, where the effects last for
about 72 hours or even longer.
Pharmacodynamics
Atropine and related drugs compete with ACh or other muscarinic agonists on the
muscarinic receptor (M1, M2, M3). Thus, these drugs are competitive antagonists of ACh. The
antagonism is reversible in nature. When atropine binds to muscarinic receptors, it blocks all
actions of ACh (e.g. release of IP3 from M1 and M3, activation and inhibition of adenylate
cyclase from M2 receptor activation). Both atropine and scopolamine are non-selective
antagonists and block all (M1, M2, M3) muscarinic receptors. From among synthetic drugs,
selective antagonists for each of these sub-types of receptors are now available. Pirenzepine
and Telenzepine block M1 receptors. Tripitramine blocks M2 receptors while Tolterodine
blocks M3 receptors.
The effectiveness of anti-muscarinic drugs varies according to the tissues. The sensitivity
of tissues varies as follows: sweat, bronchial and salivary glands have highest sensitivity
followed by heart and eye followed by urinary bladder and GIT, followed by gastric glands.
The most likely determinant for sensitivity seems to be the extent of parasympathetic tone
by which the particular organ is governed. Higher the tone, more will be the sensitivity of
the organ.
Effects on different organs are described below:
1. Central Nervous System (CNS):
Atropine has no detectable CNS effects in low doses. In therapeutic doses, it has mild
stimulant effect on medullary centres. In higher doses, it stimulates higher cerebral centres
and in toxic doses it causes restlessness, irritability, disorientation, hallucinations and
delirium. With still higher doses, the stimulation is followed by depression leading to
circulatory collapse, paralysis, respiratory failure leading to death.
Scopolamine has greater permeability through blood-brain barrier. Scopolamine in low
as well as therapeutic doses normally causes CNS depression. In therapeutic doses, it
produces drowsiness, amnesia, fatigue, dreamless sleep and depression of vomiting centre
(anti-emetic effect) by suppressing vestibular excitation. In toxic doses, scopolamine causes
agitation, excitement and hallucinations. With still higher doses, the stimulation is followed
by depression leading to coma and respiratory failure.
Therapeutic uses
• Motion sickness
Whenever the body is rotated or its equilibrium is disturbed, the vestibular apparatus
sends nauseating signals to vomiting centre. ACh serves as an excitatory neurotransmitter in
such emesis. It is called as motion sickness. Scopolamine in doses of 0.6-1.0 mg given sub-
cutaneously is effective. Transdermal patches of scopolamine are also available. When
applied on skin behind the ear, it provides 0.5 mg of scopolamine over a period of 3 days.
Hyoscine (scopolamine): BELLOID, BUSCOPAN, HYOSPAN is available as 10 mg tablet,
20 mg/ml injection.
• Parkinson’s disease
Tremors and rigidity in Parkinson’s disease is due to domination of cholinergic system
over dopaminergic system in basal ganglia. Hence, muscarinic receptor antagonists are
used to treat extra-pyrimidal side effects associated with anti-psychotic drug therapy.
Centrally acting anti-cholinergic drugs like Benztropine (1-5 mg/day), Benzhexol
(trihexyphenidyl, 2-10 mg/day), procyclidine (5-15 mg/day), Biperiden (2-10 mg/day) are
given orally.
Trihexephenidyl: PACITANE, PARKIN, PARKITANE is available as 2 mg tablet and
Procyclidine: KEMADRIN, DINE is available as 5 mg tablet.
• Diagnosis of Alzheimer’s disease (AD)
Administering a low dose of short acting anti-muscarinic drug Tropicamide in eyes,
causes marked dilation of the pupil due to changes in receptor sensitivity associated
with AD. The observation is used to diagnose AD.
2. Eye:
Circular muscle of iris, ciliary muscle and lachrymal glands possess M3 receptors.
Atropine or other tertiary amine block M3 receptors and produce mydriasis due to
unopposed sympathetic dilator activity, caused by α1-receptors located on radial muscle of
iris. The wide pupillary dilatation causes photophobia. Blockade of M3 receptors abolishes
responses of cholinergic stimulation. As a result, suspensory ligaments get tightened,
resulting in less convex lens and the eyes get set for distant vision. See Fig. 3.8. This is called
as paralysis of accommodation or cycloplegia. It also weakens drainage of aqueous humour
through canal of Schlemm. Hence, patients receiving large doses of atropine or tertiary
amines complain of dry or sandy eyes.
Therapeutic uses
• Mydriatic
Opthalmoscopic examination of the retina is greatly facilitated by mydriasis. Accurate
measurement of refractive error needs ciliary paralysis. Hence, anti-muscarinic drugs are
given as eye drops during examination of retina. Drugs like Tropicamide, Eucatropine or
Cyclopentolate are preferred for this purpose. The details are given in table 3.3.
Table 3.3 Characters of anti-muscarinic drugs for ophthalmic use

Sr. Mydriasis Cycloplegia
Drug % concentration
No. duration duration
1 Atropine 1 7-10 days 7-12 days
2 Scopolamine 0.5 3-7 days 3-7 days
3 Homatropine 1-2 1-3 days 1-3 days
4 Eucatropine 2-5 12-24 hours -
5 Cyclopentolate 0.5-1 24 hours 6-18 hours
6 Tropicamide 0.5-1 6-8 hours 6-8 hours
• To prevent adhesions in inflammatory conditions of eye
Anti-muscarinic mydriatics can be alternated with myotics like Pilocarpine to prevent
adhesions between the iris and anterior surface of the lens to treat conditions like
iridocyclitis, iritis, uveitis. A longer acting drug like Homatropin with Pilocarpine is useful in
this condition.
Tropicamide: OPTIMIDE, TROMIDE, TMIDE and Cyclopentolate: CYCLATE, CYCLOGIK,
DILATE are available as 1% eye drops; Homatropine: HOMIDE is available as 2% eye drops.
3. CVS
Atropine in a dose of 0.4-0.6 mg by IM/SC route causes transient bradycardia initially. It
is caused by blockade of presynaptic M1 receptors causing release of ACh on SA node.
However, additional doses of atropine cause tachycardia due to blockade of vagal effects on
M2 receptors on SA node. Atropine induced tachycardia is notable in teenagers because
their vagal tone is high. Ventricles are less affected by atropine.
Although all blood vessels contain muscarinic receptors, they are devoid of
parasympathetic innervation. Hence, atropine causes very little effect on blood pressure.
Higher doses of atropine dilate cutaneous blood vessels, especially of the face. This is called
as atropine flush. Atropine also induces fever but it is not associated with sweating.
Therapeutic uses
Adequate doses of atropine can abolish reflex vagal cardiac slowing or acysto. In some
cases, atropine may reduce the degree of heart block. Atropine should be given cautiously
to patients of sinus bradycardia, because low doses aggravate bradycardia. Higher doses
causing tachycardia may extend the infarct by increasing oxygen demand.
4. Respiratory System
Both smooth muscle and secretory glands of pulmonary airway receive vagal
parasympathetic innervation and have M3 receptors. Atropine-like drugs inhibit secretions of
nose, mouth, pharynx and bronchi causing dryness. These drugs reduce laryngospasm
during general anaesthesia. Drying of mucus secretions and suppression of mucociliary
clearance are the adverse effects of atropine-like drugs. Anticholinergic drugs like
Ipratropium/Tiotropium/Oxitropium antagonise broncho-constriction induced by histamine,
bradykinin and PGF2α. They block indirect effects of inflammatory mediators and have lesser
drying effect on sputum. They do not inhibit mucociliary movements.
Bronchial asthma and chronic obstructive pulmonary disease (COPD)

Ipratropium-like drugs are preferred for COPD, because of advantages mentioned
earlier. Ipratropium can be given as a nebulised broncho-dilator in acute attack of asthma
along with β2 adrenoceptor agonists like Salbutamol. Tiotropium has a longer duration of
action than Ipratropium.
Ipratropium: IPRAVENT, IPRATOP is available as 20 µg/puff metered dose inhaler.
Tiotropium: TIATE, TIOVA is available as 18 µg rotocaps (1 rotocap/inhalation).
• Pre-anaesthetic medication
Due to reduced bronchial secretions and to prevent excessive vagal effect on heart,
drugs like atropine, scopolamine and glycopyrrolate are sometimes used as pre-anaesthetic
agents. Non-irritating anaesthetic agents like Halothane/Enflurane have reduced use of
atropine-like drugs. But, Scopolamine has an advantage because of its CNS depressant
effects. Glycopyrrolate, in a dose of 0.1-0.3 mg IM causes less tachycardia and reduces
bronchial and salivary secretions more effectively.
Glycopyrrolate: GLYCOP, VAGOLATE is available as 0.2 mg/ml IV/IM injection. Atropine:
ATROPINE SULPHATE, TROPINE is available as 0.6 mg/ml IM injection. Scopolamine is
available as 10 mg tablet and 20 mg/ml IM injection. It is advised to give these drugs 30
minutes before aneathesia.
5. GIT
Anti-muscarinic drugs can reduce basal secretions of gastric HCl by 40-50%. Basal
secretions are blocked more effectively than that stimulated by food, alcohol or nicotine.
–
Not only the volume of secretion but the total amount of H+, HCO3, pepsin and mucin are
also reduced. The effects on salivary secretions are more marked. Due to dry mouth,
swallowing and talking becomes difficult.
Anti-muscurinic drugs effectively reduce the tone and motility of GIT, right from
stomach to colon. It results in prolongation of gastric emptying time, closure of sphincters,
decrease in tone, amplitude and frequency of peristalitic movements. The drugs also
increase transit time in the intestine. Some drugs can relax the gut in absence as well as
presence of cholinoceptor stimulants. These drugs also relax bile duct and gall bladder.
Therapeutic uses
• Peptic ulcer
Anti-muscarinic drugs are non-selective muscarinic receptor blockers and exhibit
adverse effects like blurred vision, dry mouth, constipation and urinary retention. Due to
introduction of histamine H2-receptor blockers like Ranitidine/Famotidine and proton pump
inhibitors like Omeprazole/Pantoprazole, anti-cholinergic drugs are less preferred for
treating peptic ulcers. Amongst anti-cholinergics, Propantheline and Glycopyrrolate do not
cross blood-brain barrier and do not cause effects on CNS. Development of Pirenzepine and
Telenzepine has renewed interest in use of anti-muscarinic agents for peptic ulcer; because
they are comparable to Ranitidine. These drugs act by blocking M1 receptors at paracrine
cells and thereby prevent release of histamine.
• Anti-spasmodics
Semi-synthetic drugs like methyl-atropine and Hyoscine methylbromide, Tertiary amine
derivatives like Dicyclomine and Quartenary ammonium compounds like Propanthelene,
Oxyphenonium, Glycopyrrolate, Clidinium bromide and Pipenzulate methylbromide are used
to treat hyper motility of the gut. The related conditions are intestinal colic, traveller’s
diarrhoea, irritable bowel syndrome, mild dysentery and diarrhoea associated with
diverticulitis. The drugs can also be used for treating biliary colic.
Dicyclomine: COLINET, CYCLOPAM, is available as 10 mg tablet, 10 mg/ml injection; it is
also available as combination with paracetamol (dicyclomine 20 mg + paracetamol 20 mg) or
with mefanamic acid (dicyclomine 10 mg + mefanamic: MEFTAL-SPAS acid 10 mg).
PROBANTHINE is available as 15 mg tablet. Oxyphenonium is available as 5, 10 mg tablets.
Clidinium is available as a combination product: ANTRENYL (clidinium bromide 2.5 mg +
chlordiazepoxide: LIBRAX 5 mg) tablet and Pipenzulate methylbromide is available as a
combination product in the form of drops (pipenzulate 4 mg + phenobarbitone: PIPLAR
6 mg/ml).
• To reduce excessive salivation
Beladona alkaloids and synthetic tertiary amine derivatives like dicyclomine are effective
in excessive salivation with heavy metal poisoning or Parkinsoniasm. Dose adjustment is
necessary to avoid dryness of mouth.
6. Genito-urinary Tract
The smooth muscle of ureters and urinary bladder wall is relaxed by antimuscarinic
drugs. As a result, voiding is slowed causing urinary retention. These drugs cross placental
barrier; however the foetus is not affected.
Therapeutic uses
Dicyclomine (10-20 mg BD oral) and oxybutinine (5 mg BD oral) are used in the
treatment of renal colic. Oxybutinine has selective action on M3 receptors and is used to
relieve bladder spasm after urologic surgery. It is also useful in reducing involuntary voiding
in neurological disorders. When given orally, or instilled by catheter in to bladder,
oxybutinine improves the bladder capacity. Valethamate (10 mg BD oral) is useful in delayed
dilatation of cervix during delivery. Flavoxate (200 mg TDS oral) is useful in urinary
incontinence and for suprapubic pain in cystitis and urethritis. Drotaverin (80 mg BD/TDS
oral) acts on spastic sites by inhibiting phosphodiesterase IV enzyme and corrects cAMP and
calcium ion imbalance to relieve smooth muscle spasm. Tolterodine (2 mg ND oral) and
Fasoterodine are selective M3 anti-muscarinic drugs for treating urinary incontinence in
adults. Propaverine is one more drug with negligible CNS effects.
The anti-muscarinic drugs used to relieve bladder spasm should be used with caution in
elderly patients having prostatic hyperplasia.
Drotaverine: DOTARIN is available as 80 mg tablet. It is also available as a combination
product (drotaverin 80 mg + mefanamic acid: BANALGAN-DM, DOTARIN-MF 250 mg) in
the form of tablet. Flavoxate: FLAVOSPAS is available as 200 mg tablet. Oxybutinine:
OXYSPAS, CYSTRAN is available as 2.5 mg and 5 mg tablet. Tolterodine: TOLTER-OD,

FLOWCHEK is available as 2 mg or 4 mg tablet. Valethamate: EPIDOSIN is available as 8 mg
tablet or 8 mg/ml injection.
7. Sweat Glands
Thermoregulatory sweating (sweating to reduce elevated body temperature) is
suppressed by atropine. Sweat glands have M3 receptors and are innervated by cholinergic
nerves which are sympathetic in origin. In adults, the skin may become dry and hot but the
rise in body temperature, called as atropine fever, occurs only in toxic doses. In infants and
children (below 5 years) even therapeutic doses may cause atropine fever.
Therapeutic uses
• Hyperhydrosis is sometimes treated with anti-muscarinic drugs like Darifenacin, which is
a selective M3 receptor blocker. These drugs are not much effective because apocrine
glands are involved in sweating.
Miscellaneous uses
• Treatment of mushroom poisoning.
• Treatment of muscarinic side effects of neostigmine (used for treating myasthenia
gravis).
• Treatment of organo-phosphorous poisoning, along with Pralidoxime.
Adverse effects and toxicity
The most common adverse effects are dryness of mouth, blurred vision and
photophobia, constipation, urinary retention, decreased sweating and precipitation of
glaucoma.
Atropine toxicity or poisoning usually results due to accidental or suicidal intentions.
Oral doses above 80 mg are toxic. Infants and young children may show toxicity, even with
10 mg oral dose.
Symptoms of poisoning include dry skin, hyperpyrexia, flushing of face (red face),
mydriasis, photophobia, dry mouth, slurred speech, difficulty in micturition, confusion,
delirium, restlessness, hallucinations and tachycardia. It is followed by coma, cardiovascular
collapse and respiratory paralysis. Scopolamine is more toxic than atropine.
The poisoning is treated with 2 mg (IV/IM) phyostigmine initially. The dose of
physostigmine may be repeated later. Adverse effects on CNS can be controlled by small
doses of diazepam, given intramuscularly.
Table 3.4 summarises therapeutic uses of anti-muscarinic drugs.
Table 3.4: Summary of therapeutic uses of anti-muscarinic drugs
Sr. No. System Clinical condition Drugs used
1. CNS Motion sickness Scopolamine (SC
injection/transdermal)
2. CNS Parkinson’s disease Trihexyphenidyl, Benztropine,
Procyclidine
3. CNS Diagnosis of Alzheimer’s Tropicamide (as eye drops)
disease
contd. …
4. CNS Amnesia with twilight sleep Scopolamine (with morphine;

rare)
5. Eye As mydriatic Tropicamide, Eucatropine,
Cyclopentolate, Homatropine
6. Eye Iridocyclitis, iritis, uveitis Homatropine (with
Pilocarpine)
7. CVS To abolish reflex vagal cardiac Atropine (rare use)
slowing or asystole
8. CVS Second degree heart block as Atropine (rare use)
with digitalis toxicity
9. Respiratory Bronchial asthma and chronic Ipratropium (in nebulised
system obstructive disease form along with salbutamol);
Tiotropium
10. GIT Pre-anaesthetic medication Glycopyrrolate, Atropine,
Scopolamine
11. GIT Peptic ulcer Pyrenzepine, Telenzepine,
Propantheline
12. GIT Anti-spasmodics Dicyclomine, Clidinium
bromide, Pipenzolate,
Oxyphenonium,
Glycopyrrolate
13. GIT To relieve excessive salivation Dicyclomine
14. Genito-urinary Renal colic Dicyclomine, Oxybutinin
tract
15. Genito-urinary Delated dilatation of cervix Valethamate
tract during delivery
16. Genito-urinary Urinary incontinence Flavoxate, Drotaverin,
tract Tolterodine
17. Genito-urinary Nocturnal inuresis Propaverine
tract
18. Sweat glands Hyperhydrosis Dicyclomine, Darifenacin
3.5 SYMPATHOMIMETICS AND SYMPATHOLYTICS
3.5.1 Endogenous Sympathomimetics
Sympathomimetics are categorised in two sub-types: Endogenous and synthetic. They
are discussed below:
3.5.1.1 Endogenous
Nor-epinephrine/nor-adrenaline (NE/NA) is the major neurotransmitter of SNS.
Epinephrine/adrenaline (E/A) is the primary hormone secreted by adrenal medulla. Nor-
epinephrine is precursor of epinephrine. Dopamine (DA) is the precursor of nor-epinephrine.
All these three (epinephrine, nor-epinephrine and dopamine) together are called as
catecholamines.
Adrenergic Neurotransmitters (NE, E and DA)

The steps in biosynthesis of dopamine, nor-adrenaline and adrenaline are indicated in
Fig. 3.11.
HO CH2 CH · NH2
COOH
Phenylalanine
Hepatic hydroxylase
Tyrosine
Tyrosine hydroxylase
Dopa
L-Aromatic aminoacid decarboxylase
Dopamine
Dopamine-b-hydroxylase
Norepinephrine
Phenyle thanolamine N-methyl transferase

HO
H
HO CH · CH2· N· CH3
OH
Epinephrine
Fig. 3.11: Biosynthesis of catecholamines
Biosynthesis
Biosynthesis of catecholamines starts with the dietary amino acid L-phenyl alanine which
is absorbed from GIT. In liver phenyl alanine gets oxidised by the enzyme phenyl alanine
hydroxylase (hepatic hydroxylase) to form L-tyrosine. The circulating L-tyrosine is actively
transported to the cytoplasm of nor-adrenergic neurons. Within the neuronal cytoplasm,
L-tyrosine is hydroxylated by the enzyme tyrosine hydroxylase to l-dopa (dihydroxyphenyl
alanine). Conversion of tyrosine to dopa is the rate limiting step in the biosynthesis of
nor-adrenaline. Increase in cytoplasmic concentration in NE inhibits the activity of enzyme
tyrosine hydroxylase through negative feedback mechanism, which in turn limits conversion
of L-tyrosine to L-dopa. Thereafter L-dopa is converted to dopamine by cytoplasmic enzyme
L-amino acid decarboxylase (dopa decarboxylase). In the dopaminergic neurons, within CNS,
this is the last biosynthetic step. In SNS, dopamine is actively transported to storage vesicles
of axon terminals, where it is oxidised to nor-epinephrine by the enzyme dopamine-β-
hydroxylase, located in synaptic vesicles. NE is stored in synaptic vesicles and works as a
neurotransmitter in SNS. The adrenal medulla has two distinct types of catecholamine
containing cells: one for NE and another for E. An enzyme called phenyl ethanolamine-N-
methyl transferase converts NE to E. After its synthesis, E re-enters the chromaffin granules
where it is stored till its release. In adults, 80% of catecholamines are present as E in adrenal
medulla, while remaining 20% is NE.
Storage
The endogenous NE, located in the nerve terminal is stored in the synaptic vesicles as a
complex with ATP (4 molecules of ATP complex with 1 molecule of NE) along with a soluble
binding protein called as chromogranin-A. Inside the storage vesicles, there is acidic pH
which provides a positive charge on amino group of NE. This prevents outside diffusion
through the vesicle membrane.
Release
The release occurs either due to action potential or due to a spontaneous effect.
(i) Action potential induced release
An action potential after reaching to the synaptic vesicles causes changes in membrane
permeability. As a result sodium, calcium and chloride ions enter the synaptic vesicle while
potassium ions come out. Influx of calcium ions disrupts the storage vesicle to release NE,
ATP, chromogenin along with small amounts of dopamine β-hydroxylase enzyme in to
synaptic cleft by the process of exocytosis.
(ii) Spontaneous release
The random migration of storage vesicles towards the end of neuron can result in
spontaneous discharge of NE. This release is very small and the process is of less
importance.
Action on Different Receptors
The liberated NE, then stimulates different post-synaptic adrenoceptors as mentioned
below. Epinephrine (E) activates all five sub-types, while NE primarily activates all sub-types
except β2. Out of five sub-types, α2 and β2 receptors are located on pre-synaptic terminals.
Other sub-types are located on post-synaptic sites. See Fig. 3.12.
Noradrenergic nerve terminal
NE
ACh
M1 ACh
AT1 _
_ _
_
_ a2 Cholinergic nerve terminal

_
_
a2
NE
b2
Key: _ - Increase of neurotransmitter release

_
_ - Decrease of neurotransmitter release
AT1- Angiotensin Receptor-1

b1 b2 b3
a1
Fig. 3.12: Modulation of NE release indicating different receptors
(i) α1-Receptors
These receptors are present post-synaptically and when activated produce excitatory
effects in organs like vascular smooth muscles, salivary glands, bronchi, uterus, radial muscle
of iris and liver cells. In the intestine, they produce inhibitory effects leading to relaxation.
(ii) α2-Receptors
These receptors are located on pre-synaptic terminals of sympathetic post-ganglionic
neurons. Stimulation of these receptors by NE decreases further release of NE. when these
receptors are activated by NE, release of ACh is also decreased. In the brain stimulation of
these receptors decrease sympathetic out flow.
(iii) β 1-Receptors
These are located post-synaptically. They are found primarily in heart where they
produce positive ionotropic and positive chronotropic effect, after activation by NE or E. the
receptors are also present in kidneys where they promote release of rennin. E exhibits
moderate and NE exhibits strong actions on these receptors.
(iv) β 2-Receptors
These are present post-synaptically, primarily on bronchi, blood vessels supplying to
skeletal muscle, coronary arteries, uterus, GIT and cardiac smooth muscle. Except in
myocardium, their activation causes an inhibitory effect leading to relaxation of smooth
muscles. E exhibits stronger affinity to these receptors. Comparatively, NE has very less
affinity for them. The receptors have also been identified pre-synaptically on adrenergic
nerve terminals. Activation of pre-synaptic β2 receptors by NE/E, facilitates release of the
neurotransmitter.
(v) β 3-Receptors
These receptors are present on adipocytes. Their activation promotes lipolysis (rise in
blood free fatty acids) and thermogenesis (rise in temperature). NE has stronger action as
compared to E on these receptors.
Responses of Effector Organs to Sympathetic Stimulation
As indicated in table 3.2, receptors related to neurotransmitters of SNS are located in
different organs. As a result, stimulation of SNS results into different effects on various
organs as indicated below:
(i) Eye
The radial papillary dilator muscle of iris contains α1-receptors. Sympathetic stimulation
or activation by sympathomimetic drugs like phenylephrine causes mydriasis. NE, if
administered locally does not cause mydriasis because it does not cross conjunctival
membrane. In contrast to atropine, phenylephrine causes an active mydriasis. Active
mydriasis (more light) with no cycloplegia (no blurred vision) is one of the desired responses
of SNS to prepare the body to fight or run away from emergency situations. Circular muscles
of iris and lachrimal glands have no sympathetic innervation; and there are no tears at the
time of emergency.
(ii) Salivary glands

Activation of SNS produces thick salivary secretions. Reduced salivary secretion is a
consequence of reduced blood flow caused by vasoconstriction.
(iii) Lungs
Bronchial smooth muscles possess β2-receptors and cause relaxation leading to
bronchodilation. The blood vessels of mucus membrane of nasal and bronchial mucosa get
constricted by E and hence SNS stimulation causes decongestion. Both bronchodilatation
and mucosal vasoconstriction increase diameter of the lumen of respiratory tract and
decrease bronchial resistance. Both these effects are desirable to meet emergency
conditions. E also inhibits release of allergic mediators from the mast cells and help in
reducing congestion in bronchial muscles.
(iv) Heart
Direct effects of SNS stimulation on the heart are primarily due to β1-receptor. The
effects lead to increase in heart rate due to activation of β1-receptors at SA node, enhanced
conduction and decrease in effective refractory period due to effect on β1-receptors at AV
node. It also increases automaticity by activation of Purkinje fibres and increased force of
contraction due to effects on ventricular myocardium. All these effects help the body in
preparing for fight or flight.
(v) Blood vessels
Vascular smooth muscle tone is controlled by presence of α1 and β2-receptors. While
α1-receptors increase arterial resistance, β2-receptors promote smooth muscle relaxation.
There are major differences in the types of receptors present in different vascular beds. The
skin, mucosa, splanchnic and renal blood vessels have predominantly α1-receptors. As a
result, these muscles constrict because of SNS stimulation. Coronary arteries have
predominantly β2, α2 and D1 receptors and therefore exhibit vasodilatation. SNS stimulation
increases myocardial contractility and increases its oxygen demand producing local hypoxia.
This hypoxia in turn dilates the coronary arteries. The innervation to skeletal muscle blood
vessels is sympathetic in origin but cholinergic in character. The overall effect of SNS
stimulation is vasodilatation and reduced peripheral vascular resistance. Pulmonary blood
vessels contain both α1 and β2 receptors with the net result of pulmonary vasoconstriction
leading to decongestion. There is no change in cerebral vascular resistance and that of
systemic veins.
Thus, SNS stimulation leads to coronary dilatation leading to increased blood supply to
the heart. Skeletal muscle blood vessels get dilated to meet the demand of exercising
muscles. Blood supply to brain is not altered. Veins are not affected; renal perfusion is not
compromised. Pulmonary vasoconstriction leads to decongestion. This is accompanied by
broncho-dilatation. All these effects help the body to adjust to the needs of fight and flight.
(vi) GIT
Smooth muscles of stomach and intestines have α2- and β2-receptors. Out of these,
α2-receptors are located pre-synaptically at cholinergic neurons; their stimulation reduces
the tone as well as motility due to reduction in ACh. β2-receptors are located on smooth
muscles and cause relaxation via hyperpolarisation. α2-receptors also decrease salt and
water influx in to lumen of intestine. Sphincters have α1-receptors and get contracted by
SNS stimulation. α1 receptors located on GIT smooth muscle are inhibitory in nature. SNS
stimulation causes relaxation of GIT smooth muscles. Thus, decrease in tone and motility of
GIT, closure of sphincters and decrease in influx of salt and water in to the lumen of
intestine, all together prepare the body for fight or flight.
(vii) GUT
SNS stimulation causes urinary retention by relaxing the detrusor muscle (β2 effect) and
contracting the trigone and sphincter of the urinary bladder (α1 effect). The response of
uterus varies with the state of gestation. Uterine muscles of non-pregnant uterus are
contracted while muscles of pregnant uterus are relaxed. Ejaculation is facilitated by
activation of α1-receptors located in vas deferens, seminal vesicles and prostate.
(viii) Skin
Secretion of sweat from sweat glands located on palms, sole and fore-head is increased
due to SNS stimulation. Piolmotor muscles are contracted leading to piloerection; which
increases the perception to the surrounding and helps the body to cope up with situations
of fight or flight.
Metabolic Effects
The major metabolic effects are increased blood concentration of glucose, lactic acid
and free fatty acids. See Fig. 3.13 for illustration.
Liver Muscle
Glycogen Glycogen
Glycogen Phosphorylase (b2) Glycogen Phosphorylase (b2)
synthase synthase
Glucose-1-P Glucose-1-P
Glucose-6-P Glucose-6-P
Phosphorylase (b2) Glycolysis (b2)
+ +
Glucose + K K Lactic acid
Calorigenic effect
Fat
Free fatty acids Lactic acid

Glucose
Free fatty
Oxidation (b3) Lipase (b3) acids
Triglycerides
Blood vessel
Fig. 3.13: Metabolic effects of catecholamines

In adipocytes, stimulation of β2-receptors activate lipase enzyme which catalyses

breakdown of triglycerides to free fatty acids in the fat cells. In liver, β2 stimulation catalyses
phosphorylase enzyme and thus promotes glycogenolysis and gluconeogenesis. Release of
glucose from liver is accompanied by efflux of potassium ions. Later potassium ions released
from liver are taken up by skeletal muscles. In skeletal muscles and heart, glycogenolysis and
glycolysis produces lactic acid. This effect is mediated through β2-receptors. The net result is
hyperglycemia.
In pancreas, the prominent effect of SNS stimulation is on α2-receptors of the pancreatic
β-cells leads to reduction of insulin secretion. Simultaneously, there is increase in glucagon
secretion from the pancreatic α-cells through activation of β2-receptors. All these effects
further contribute to hyperglycemia.
(ix) Skeletal muscles
There is facilitation of neuromuscular transmission by a pre-synaptic α-receptor action
leading to increase in ACh at neuromuscular junction. Stimulation of β2-receptor improves
the blood flow to skeletal muscles. The net result is anti-fatigue effect during stressful
conditions.
(x) CNS
Effects of CNS stimulation are not very important. However during stress, there may be
anxiety, apprehension, arousal, restlessness and rarely tremors. These are the effects of
stress.
(xi) Kidney
There is release of renin from the juxta glomerular apparatus in the kidney; the effect is
mediated through β1-receptors. In addition, there is increase in motility and tone of ureter;
this effect is mediated through α1-receptor.
Other Effects
Following additional effects are caused by SNS stimulation:
• Inhibition of histamine release from mast cells leading to low incidence of itching
• Inhibition of lymphocytic activity
• Uptake of potassium ions from extracellular fluid to intracellular fluid resulting in
hypokalemia, which may precipitate cardiac arrhythmia due to stress.
Inactivation of NE and E
The actions of NE and E are terminated by following mechanisms:
• Active uptake in to nerve terminals (neuronal re-uptake; up to 80%) and then by re-
uptake by storage vesicles (vesicular re-uptake) (uptake 1)
• Uptake in to post-synaptic non-neuronal cell membrane (uptake-2)
• Metabolic degradation by two enzymes: MAO and COMT
Both MAO and COMT are widely distributed throughout the body. They are located in
intestines, liver, kidney and brain. However, only MAO is located in adrenergic neurons.
COMT is mainly located in the cytoplasm. MAO converts catecholamines (NE, E, DA) in to
corresponding carboxylic acids by oxidative deamination. See Fig. 3.14. COMT converts
catecholamines in to their O-methyl derivatives by O-methylation of one of the catechol-

hydroxyl group. Due to action of MAO and COMT, the final metabolite of catecholamines
(NE and E) is vanillyl mandelic acid (VMA). Dopamine, after interaction with MAO and COMT
gets converted in to homovanillic acid (HVA).
HO HO
HO CH CH2 NHCH3 HO CH CH2 NH2

OH OH
Epinephrine Norepinephrine
MAO MAO
Oxidative HO Oxidative
deamination deamination
COMT O-methylation HO CH COOH

O-methylation COMT
OH
3, 4-Dihydroxymandelic acid CH3O
H 3C
HO CH CH2 NH2
HO CH CH2 NHCH3 COMT
OH
OH
Metanephrine Normetanephrine
Oxidative CH3O Oxidative

MAO MAO
deamination deamination
3 2
HO 4 1 CH COOH
5 6
OH
3-Methoxy-4-hydroxymandelic acid (Vanillyl mandelic acid; AMV)
HO
HO CH2 CH2 NH2
Dopamine
MAO COMT
HO CH3O
HO CH2 COOH HO CH2 CH2 NH2
3, 4-dihydroxyphenylacetic 3-Methoxytyramine
acid (DOPAC)
COMT CH3O MAO
HO CH2 COOH
Homovanillic acid (HVA)

Fig. 3.14: Metabolism of catecholamines by COMT (Catecol-o-methyl transferase) and
MAO (Monoaminotransferase)
These metabolites are excreted through urine as their sulphate or glucuronide water-
soluble conjugates.
3.5.1.2 Synthetic Sympathomimetics
These drugs mimic the actions of endogenous catecholamines. They are classified in to
three sub-groups as follows:
1. Directly acting sympathomimetics
2. Indirectly acting sympathomimetics
3. Mixed action sympathomimetics
3.5.1.2.1 Directly Acting Sympathomimetics
They have following characteristics:
• They act directly on pre-and/or post-synaptic α- and β- adrenergic receptors and
produce various pharmacological effects.
• They can exhibit effects even after dennervation of post-ganglionic adrenergic
neurons.
• Repeated doses of these drugs do not lead to tachyphylaxis.
These drugs can be primarily classified as catecholamines and non-catecholamines.
Catecholamines are further sub-classified as endogenous and synthetic.
(i) Endogenous catecholamines
Drugs in this category have following characteristics:
• They have high potency.
• They are rapidly inactivated. Hence, they have a short duration of action. They are
ineffective when given orally, because of being polar and inactivation by
metabolising enzymes.
• They have poor penetration in to CNS. However, they produce anxiety, tremors and
headache in high doses.
(a) Epinephrine (adrenaline)
80-90% of epinephrine (E) is secreted from adrenal medulla along with 10-20% NE.
The relative affinity of E towards adrenoceptors is β2 > β1 = α1 = α2. However, at low doses
β-effects predominate over α-effects. At high doses α effects are stronger.
Cardiovascular effects
Epinephrine is a very potent vasoconstrictor and cardiac stimulant.
There is increase in heart rate and force of contraction which is followed by reflex
bradycardia due to compensatory vagal discharge due to increase in blood pressure. The
stroke volume increases leading to increase in cardiac output and rise in systolic BP.
However, myocardium becomes more succeptible to arrhythmias.
E constricts aretrioles in skin, mucus membrane, viscera and renal beds; these effects are
mediated through α-receptors. Dilatation predominates in skeletal muscle, liver and
coronaries; these effects are mediated through β2-receptors. Total peripheral resistance
decreases. The cumulative effect is an increase in systolic BP coupled with slight decrease in
diastolic BP.
Moderate doses of E produce biphasic response i.e. initial rise in BP (α1 effect) followed
by fall in BP (β2-effect) later. The effects alter because of pre-treatment with respective
blockers. Pre-treatment with α-blockers causes reduction in BP only; while pre-treatment
with β-blocker causes increase in BP only. The effects are illustrated in Fig. 3.15.
a1 + b1 effect
E
a-blocker
E b2-effect
b1-effect
(low doses)
(a) (b)
E
b-blocker (c)
(a) Normal effect of epinephrine on BP; (b) Dale's Vasomotor Reversal Phenomenon,
(c) α-Effect (↑
↑ BP) seen after β -blockade
Fig. 3.15: Effects of epinephrine altered by α/β
β blockers
Effects on smooth muscles
E causes powerful broncho-dilatation (β2-effect) and decrease in bronchial secretions
(α1-effect). Cumulatively, there is decrease in bronchial resistance.
E causes relaxation of GIT muscles (α2- and β-effects) along with constriction of
sphincters (α1-effect). These effects have no clinical significance.
On urinary tract E causes relaxation of detrusoe muscle (β2-effect) along with contraction
of trigone and sphincter (α1-effect). As a result, micturition is hindered leading to urinary
retention.
On non-pregnant human uterus, E causes constriction; while on pregnant human uterus
it causes relaxation.
Metabolic effects
• Hyperglycemia due to glycogenolysis in liver (β2) and skeletal muscle (α1 and β2).
• Increase in free fatty acids due to lipolysis in adipose tissue (α and β3).
• Inhibition of insulin release (α2).
• Caloriegenic effect; rise in basal metabolic rate and effects on CVS causing rise in
temperature (β3).
Miscellaneous effects
• Active mydriasis in eye due to contraction of radial muscle of iris (α1).
• Thick salivary secretions (α1).
• Piloerection and sweating of palms and soles (α1).
• Inhibition of histamine release by stabilization of mast cells.
• Anxiety and tremors (CNS effect).
Therapeutic uses
• Allergy (anaphylactic shock)
It is a drug of choice for type I hypersensitivity reactions like acute anaphylactic attack. It
relieves broncho-spasm, angioneurotic edema of larynx, prevents release of histamine
from mast cells and maintains BP in anaphylactic shock. It is given intra-muscularly as
0.3-0.5 ml; 1:1000 solution. In an anaphylactic shock, sub-cutaneous absorption of
adrenaline is very low.
• Bronchial asthma
It causes bronchodilatation and decongestion of bronchial mucosa. It is given sub-
cutaneously 0.3-0.5 ml as 1: 1000 solution as aerosol.
• Cardiac resuscitation
Intracardiac injection of 0.1 mg/ml adrenaline can be used to reverse sudden cardiac
arrests caused by drowning and electrocution. Ventricular fibrillation is a contra-
indication in this condition.
• To prolong duration of local anaesthetic (LA) action
Adrenaline, because of its vasoconstricting effect, antagonises vasodilating effects of LA
and retards their systemic absorption from the site of injection. As a result, not only
duration of LA action is prolonged but their systemic toxicity is also decreased. It is given
sub-cutaneously or intradermally in combination with any LA.
• To control epistaxis (as a local hemostatic)
It is used to control bleeding as in epistaxis and in ENT surgery. It is used as a spray to
have clear vision.
Adverse effects
• Increase in BP can lead to cerebral hemorrhage.
• Increase in cardiac work and contractility may lead to coronary insufficiency - it may
precipitate angina, palpitation and even arrhythmia (in patients taking digitalis).
Adrenaline may cause pulmonary edema.
• CNS side effects may include tremors, anxiety and headache.
Contra-indications and interactions
• Hyperthyroidism: Due to up-regulation of α-receptors on the vessels and
β-receptors in heart, a patient with hyperthyroidism may become hyper-responsive
to adrenaline. In such cases, dose of adrenalin should be reduced.
• Angina and hypertension.
• Tricyclic anti-depressants like Imipramine prevent re-uptake of E in to neurons. As a
result, action of adrenaline may be excessively enhanced.
• Anaesthetics like Halothane increase the sensitivity of myocardium towards
catecholamines.
• Inhibitors of MAO increase concentration and availability of adrenaline. Hence, its
effects are excessively enhanced.
Adrenaline: VASOCON is available as 1 mg/ml injection.
(b) Nor-epinephrine (Nor-adrenaline) (NE/NA)

Endogenous NE is the l-isomer which is more potent than d-isomer. NE predominantly
acts on α-receptors with relative receptor affinity as α1 = α2>β1>>β2. It also possesses
significant β3 actions.
Cardiovascular actions
NE raises both systolic and diastolic BP, due to cardiac stimulation (β1) and rise in
peripheral vascular resistance (α1). Cardiac output is unchanged. Reflex bradycardia is
caused, secondary to hypertension. The coronary blood flow increases due to rise in mean
arterial pressure. NE has predominant α-action and does not exhibit Dale’s vasomotor
reversal.
Therapeutic uses
It is carefully used to treat cardiogenic shock, since the shock increases vascular
resistance and decreases blood flow to vital organs. Dopamine is preferred in this condition,
since it does not reduce blood flow to kidney. It is not suitable for sub-cutaneous, intra-
muscular or undiluted IV injection because of possibility of necrosis at the site of action.
Vasoconstriction is the cause of necrosis.
Adverse effects, precautions and contraindications
These are similar to that of adrenaline. Infusions of NE should be tapered off gradually
to avoid sudden fall in BP. Extravasation in to sub-cutaneous tissue should be carefully
watched to avoid tissue necrosis at the site of infusion.
NE: ADRENOR, NODRESOL, NORAD, NOREPIRIN is available as 2 mg/2ml injection.
(c) Dopamine
It is an endogenous catecholamine. When given parenterally, it does not cross blood-
brain barrier and exhibits no effect on CNS. When given intravenously in therapeutic doses
(2-5 µg/kg/min), it acts on D1-receptors and causes dilatation of renal vessels resulting in
increased GFR, renal blood flow, and excretion of sodium. At a dose of 5-10 µg/kg/min IV, it
also stimulates β1-receptors resulting in an increase in cardiac output but the total
peripheral resistance and mean BP are unchanged due to simultaneous vasodilatation of
renal and splanchnic vessels. In still higher doses of 10 µg/kg/min IV, it can cause
vasoconstriction by activating α-receptors, thus nullifying beneficial effects of low doses of
dopamine.
Therapeutic uses
It is used in conditions of low cardiac output with compromised renal functions, such as
cardiogenic shock due to myocardial infarction, trauma or surgery. It is also used in the
treatment of congestive heart failure, renal and liver failure. Dopamine is given as a infusion
at a rate of 5-10 µg/kg/min. The BP, HR and urine flow should be continuously monitored
for dose adjustment to get beneficial effects.
Adverse effects
They include nausea, vomiting, tachycardia, ectopic beats, hypertension (only in high
doses) and cardiac arrhythmia (low incidence).
Dopamine: DOPACARD, DOPAR, DOPASOL, DOPINGA is available as injection of
200 mg/5 ml ampule.
(ii) Synthetic catecholamines

These are synthetic catecholamines containing two adjacent hydroxyl groups in the
benzene nucleus.
(a) Isoprenaline
It predominantly stimulates β1- and β2-adrenoceptors. It has negligible α-receptor
action. The structure of isoprenaline is shown in Fig. 3.16.
HO
H
HO CH CH2 N CH3
OH CH
CH3
Fig. 3.16: Structure of isoprenaline
Pharmacological / Cardiovascular effects
It exerts positive ionotropic and chronotropic effect on heart causing an increase in
cardiac output (β1-effect). Due to cardiac stimulant action, it may slightly increase systolic BP
but mean arterial pressure and diastolic BP are greatly reduced. It dilates the arterioles of
skeletal muscle (β2-effect) resulting in decreased peripheral resistance.
Isoprenaline relaxes bronchial as well as GIT smooth muscles. It relieves broncho-
constriction mainly due to stimulation of β2-receptor and partly due to inhibition of induced
histamine release.
Pharmacokinetics
It is readily absorbed when given parenterally or as an aerosol. Compared to E and NE, it
is taken up to a lesser extent by neurons. It is stable to MAO degradation; but it is
metabolised by COMT present in liver and other tissues.
Therapeutic uses
It is used only in emergency situations to increase heart rate in patients with bradycardia
or heart block, prior to insertion of an artificial pace maker.
Adverse effects
Its cardiac stimulant actions can lead to palpitations, sinus tachycardia or even serious
arrhythmias.
Isoprenalilne: ISOLIN, ISOPERIN, ISOSOL, NEO-EPININE is available as 2 mg/ml
injection and 20 mg sub-lingual tablet.
(b) Dipivefrine
It is a pro-drug for epinephrine with enhanced corneal permeability. 0.1% solution is
used for the treatment of glaucoma. Ocular side effects may include photosensitivity and
conjunctival hyperaemia.
It is available as 0.1% eyedrops: PROPINE.
(c) Dobutamine
It is used clinically as a racemic mixture of two enantiomers. The l-form is a potent
agonist of α1-receptor while d-form is a potent antagonist of α1 and also powerful agonist
of β1-receptor. As a result, the net cardiovascular effects of dobutamine are mixed. On heart
it has more selective ionotropic than chronotropic effects without any significant change in
peripheral vascular resistance and BP.
It increases cardiac output and stroke volume without affecting heart rate, peripheral
resistance or blood pressure. Its half-life is about 2 minutes; hence it is given as a IV infusion.
Therapeutic uses
It is used as IV infusion in a dose of 2-5 µg/kg/min to treat patients of heart failure
associated with myocardial infarction, cardiac surgery and for short term management of
acute congestive heart failure.
Adverse effects
There is a sharprise in BP and heart rate in patients with hypertension. Being an
ionotropic agent, myocardial oxygen demand increases and hence angina may be
precipitated or myocardial infarction may be aggrevated. Tolerance may develop on
prolonged use. Since it increases AV conduction, it should be used with caution in atrial
fibrillation.
It is available as 250 mg/5 ml vial as IV injection in the form of a drip: DOBUTREX,
DOBIER, DOBUCARD, KARDIA.
(d) Dopexamine
It stimulates β2 receptors and peripheral dopamine receptors and it inhibits neuronal
uptake of NE. It results in an increased cardiac output, peripheral vasodilatation and an
increase in renal and mesenteric blood flow. It is used to provide haemodynamic support in
patients with congestive heart failure and shock. The most common side effect is
tachycardia, transient hypotension and dyspnea. It should not be used in patients with
phaeochromocytoma.
(e) Fenoldopam
It is a selective D1-receptor agonist. It has no α- or β-agonist activity. It is a peripheral
arteriolar dilator and causes vasodilatation ion coronary, renal and mesenteric arteries. It is
useful in short term management of severe hypertension in patients with impaired renal
functions where rapid reduction in BP is desired. Oral bioavilability of fenoldopam is poor;
hence it is usually given by intravenous route.
Adverse effects include reflex tachycardia, increase in intra-occular pressure and
headache. Hypokalemia may be caused due to diuretic action.
(iii) Non-catecholamines
The drugs having only one hydroxyl group and a substituted amine on the benzene
nucleus are not catecholamines in nature. Still they show agonistic activity to α-receptor.
Since there are two kinds of α-receptors, the drugs are discussed under the category of
α1-agonists and α2-agonists.
1. α1-agonist drugs
Phenylephrine and methoxamine are two prototype drugs in this category.
(a) Phenylephrine
It is a α1-selective agonist. It lacks hydroxyl group on benzene; hence it is a non-
catecholamine. It is not metabolised by COMT and hence has got a relatively longer duration
of action. See Fig. 3.17. Activation of α1-receptor results in increase in peripheral vascular
resistance and BP; which is associated with reflex bradycardia. It is used as a nasal
decongestant and a mydriatic. It may be useful in some patients of hypotension or shock.
HO CH3
CH CH2 N H
OH
Fig. 3.17: Chemical structure of phenylephrine
It is available as 10% eye drops: DROSYN and 0.20% nasal drops. In combination, it is
available as 5% eye drops along with 0.8% Tropicamide: DROSYN-T. It is also available as
nasal drops of 0.25% phenylephrine with 0.025% Naphazoline: FENOX. It is also available as a
tablet having composition as 5 mg phenylephrine with 2 mg chlorpheneramine: COZYPLUS,
500 mg paracetamol and 30 mg caeffine.
(b) Methoxamine, Midodrine
It is similar to phenylephrine in pharmacological effects and uses. Midodrine is a pro-
drug. Its active metabolite desglymidodrine has a selective α1-receptor activity. It is used to
treat postural hypotension. The adverse effect is hypertension in supine position; hence
dosing at bed time should be avoided.
(c) Naphazoline, Oxymetazoline and Xylometazoline
These drugs are used as nasal decongestants in rhinorrhoea and to check epistaxis. They
are predominantly α1-agonists. Oxymetazoline has some α2-agonist action and may cause
hypotension.
Naphazoline is available as 0.1% nasal drop and 0.01% eye drops: PRIVINE, OCUCEL,
FENOX.
Oxymetazoline is available as 0.05% and 0.5% nasal drops: XYNOSE, SYNAREST.
Xylometazoline is available as 0.1% nasal drops: OTRIVIN.
(d) Pseudoephedrine, Phenylpropanolamine
Pseudoephedrine is a stereo-isomer of ephedrine. Both drugs are used to treat nasal
congestion. Because of possibility of haemorrhagic stroke in young women and
hypertensives, local administration of Phenylpropanolamine has been banned.
Phenylpropanolamine is available as a tablet: ALERID-COLD either as a combination
product of 25 mg along with 5 mg Cetrizine and 500 mg Paracetamol; or 25 mg
phenylpropanolamine along with 2.5 mg of Triprolidine: ACTIFED.
Pseudoephedrine is available as a expectorant of 30 mg along with 2 mg
Chlorphenyramine and 4 mg of Bromhexine/5 ml of product: CHESTON.
2. α2-agonist drugs
α2-receptors are located pre-synaptically on sympathetic post-ganglionic neuron and
post-synaptically on blood vessels and brain. See Fig. 3.12. Stimulation of these receptors by
NE or any α2-agonists decreases further release of NE. In the brain, stimulation of
α2-receptors decrease central sympathetic outflow. Hence, they are primarily used for the
treatment of hypertension. Many blood vessels possess post-synaptic α2-receptors, which
cause vasoconstriction on stimulation; hence their stimulation causes hypertension. Thus
α2-agonists like Clonidine, when given by IV infusion, may initially cause hypertension
followed by a more prolonged hypertension due to decreased central sympathetic outflow.
(a) Clonidine
It belongs to imidazoline group chemically. After IV injection, it produces a transient rise
in BP. However on oral administration, it produces only fall in BP. It causes the effect by
following mechanisms:
• Is stimulates α2-receptors present at vasomotor centre. As a result, central
sympathetic outflow is reduced, resulting in fall in BP and heart rate.
• In addition, Clonidine also activates the pre-synaptic α2-receptors present on post-
ganglionic neurons and thus suppresses further release of NE from peripheral nerve
endings.
The decreased central sympathetic discharge to the kidney also reduces renin release
and decreases renal vascular resistance. Hence, clonidine is useful in hypertensive patients
with poor renal functions.
Pharmacokinetics
It is well absorbed after oral administration with a bioavailability of 100%. A transdermal
delivery patch permits continuous administration as an alternative to oral therapy. The patch
releases drug at a constant rate for about a week. After removal of the patch, plasma
concentration of the drug remains stable for 8 hours and then declines gradually in several
days.
Therapeutic uses
• Moderate hypertension
It is given orally as 100 µg - 300 µg twice daily. It is usually given with a diuretic in order
to avoid sodium and water retention. It has a limit of rebound hypertension after withdrawal.
Hence, it is not used as a first line of therapy.
• To control diarrhoea in diabetic patients with autonomic neuropathy
Stimulation of α2-receptors in GIT increases sodium and water retention, inhibits
bicarbonate secretion and reduces intestinal motility by inhibiting release of ACh. However,
oral clonidine causes orthostatic hypotension, limiting its utility.
• Prophylaxis of migraine
It reduces cerebral blood flow. Hence, earlier it was used for prophylaxis of migraine in
doses of 25-75 µg. It is not preferred now for this indication.
• Management of Nicotine, Alcohol and Opiate withdrawal

It controls some of the adverse sympathetic effects associated with withdrawal of
opiods, alcohol and smoking. It also decreases craving for these drugs.
• Pre-anaesthetic medication
Due to its sedative, anxieolytic and analgesic effects it is used before surgery to provide
hemodynamic stability. Dexmedetomidine is a selective α2-agonist which is used as a pre-
anaesthetic medication. It reduces bronchial secretions in addition to other effects
mentioned earlier. It is used in ICU for patients requiring mechanical ventilation for longer
period. It reduces need for frequent opiod use in cancer patients for controlling pain.
• Menopausal hot flushes
Transdermal patches of Clonidine are used for treating menopausal hot flushes.
Adverse effects
Major adverse effects are as follows:
• Rebound hypertension after abrupt withdrawal
• Dry mouth
• Sedation
• Nasal stuffiness
• Constipation
• Impotence
• Contact dermatitis, when used as a trans-dermal patch
It is available as tablet of 150 µg: ARKAMIN, CATAPRESS.
Moxonidine and Rilmenidine are congeners of Clonidine with longer plasma half-life.
Rebound hypertension is less common with them.
Apraclonidine and Brimonidine are selective α2-agonists used for treatment of
glaucoma. They are primarily used to prevent acute rise in intra-occular pressure. They do
not cross blood-brain barrier and have least systemic side effects. They reduce formation of
aqueous humor.
(b) α-methyldopa
It is a centrally acting anti-hypertensive drug. It exerts its action through a metabolite,
α-methyl NE. It has two major advantages:
• It reduces renal vascular resistance. Hence, it is useful in hypertensive patients with
renal insufficiency.
• It reduces ventricular hypertrophy. It is well tolerated by patients with diastolic
dysfunction in whom it reduces left ventricular mass.
Due to potential adverse reactions, immunological and hepato-toxicity, it is no longer a
drug of choice for long term management except for hypertension during pregnancy. It is
safe both for mother as well as fetus.
Adverse reactions
It causes sedation, dryness of mouth, involuntary movements, gynaecomastia in males
and galactorrhoea in females due to interference with dopaminergic suppression of pro-
lactin release. Hepato-toxicity is associated with fever. It also causes hepatic dysfunction. It is
advised that methyldopa should be avoided in patients with hepatic disease. It can cause
haemolytic anaemia and Coombs test.
It is available as 250 mg tablet: EMDOPA, ALFADOPA, ALDOPAM.
Guanfacine and Guanabenz are similar to Clonidine in mechanism of action and
adverse effects. These drugs are rarely used because of lack of advantage over Clonidine.
(iv) Non-catecholamine β 2-selective agonists
These drugs have preferential affinity for β2-receptors. They are administered by
inhalation, in the form of aerosol, leading to effective activation of β2-receptors in bronchi.
There is less potential to stimulate β2-receptors in skeletal muscle which can cause
palpitation and tremors when administered orally. They activate β2-receptors located on
airway smooth muscle and enhance the release of cAMP by activating the enzyme adenylyl
cyclise. The mast cells also have β2-receptors which respond to them.
They exert following actions:
• Relax airway smooth muscle.
• Inhibit the release of broncho-constricting mediators from mast cells.
• Inhibit micro-vascular leakage.
• Increase the muco-ciliary transport by increasing the ciliary activity.
The drugs under this category are as follows:
(a) Salbutamol
It is a fairly selective β2-agonist with relaxant effects on smooth muscles of bronchi and
uterus. It has minimal cardiac stimulant effects. It is not metabolised by COMT and exhibits
longer duration of action as compared to isoprenaline. For immediate relief of asthma, it is
given by oral inhalation from a metered dose inhaler (100 µg/dose). It can also be given
orally (2-4 mg TDS), intra-muscularly or by slow intravenous injection. Sustained release
tablets are also available. Inhalation causes fewer side effects in comparison to systemic
administration. It can also be used for the arrest of uncomplicated pre-mature labour
between 24-34 weeks of gestation by giving an intravenous infusion.
It is associated with nausea and vomiting with a risk of developing pulmonary edema.
Other side effects are tremors in hands, palpitation, headache and hypokalemia (after large
doses).
It is available as 2 mg, 4 mg tablet, 100 µg metered dose inhaler, 2 mg/5 ml syrup; 4 mg,
8 mg controlled release tablet: ASTHALIN, VENTORLIN, DERIHALER.
(b) Metaproterenol (orciprenaline)
It has lesser β2 selective action than salbutamol and terbutaline. It is resistant to
methylation by COMT. Its side effects are similar to that of salbutamol.
It is available as 10 mg tablet or 10 mg/5 ml syrup: ALUPENT.
(c) Terbutaline
It is a resorcinol derivative. It is not metabolised by COMT and hence has a longer
duration of action. It is effective when given orally, sub-cutaneously or by inhalation. It is
used to relieve acute broncho-spasm in asthma, as a metered dose aerosol whenever
required. As with other β2-agonists, tolerance may develop towards it, if used regularly. With
oral doses, onset of action is slow. It can also be used for treatment of COPD. It is also used
in the treatment of unresponsive urticaria along with Ketotifen. Its inhaled powder
formulations should be avoided, as they may harm tooth enamel and cause tooth erosion.
Its side effects are similar to that of salbutamol. Oral dose is 2.5-5 mg BD/TDS; 250 µg by
inhalation, as and when required.
It is available as 2.5 mg, 5 mg tablet; 1.5 mg/5ml syrup and 250 µg/puff metered dose
inhaler: BRICANYL.
(d) Bambuterol
It is a prodrug of Tebutaline. It is slowly metabolised (24 hours). It has only limited use in
chronic asthma. Oral dose is 10-20 mg once a day in the evening.
It is available as tablet of 10, 20 mg and a syrup of 1 mg/ml: BETADAY, BAMBUDIL,
ROBUROL.
(e) Salmeterol
It has prolonged duration of action (12 hours) but a slow onset of action. It is ineffective
in acute attacks of asthma. It is preferred for management of nocturnal asthma. Dose is
25-100 µg by inhalation twice a day. It has an anti-inflammatory action also.
It is available as inhalation with a dose of 25 µg/puff: SALMETER, SEROBID.
(f) Formoterol
It has quicker onset of action (within 5 min) with a longer duration of action (12 hours). It
is preferred to prevent nocturnal attacks of asthma, prophylaxis of exercise-induced
bronchospasm and COPD. It has an anti-inflammatory action also. Dose is 12-24 µg by
inhalation twice a day.
It is available as inhalation with a dose of 12 µg/puff: FORATEC.
(g) Pirbuterol
It has properties similar to Salbutamol. Following inhalation, it exerts its effects within 10
minutes, which lasts for about 5 hours.
(h) Clenbuterol
It increases the rate and force of contraction of skeletal muscle to a varying extent. It
possesses anabolic properties and therefore used illicitly by sports person to improve
performance.
3.5.1.2.2 Indirectly Acting Sympathomimetics
They have following characteristics:
• They do not have direct stimulant effect on adrenoceptors. They are taken up by
neuronal membranes; they displace NE from their stores. The displaced NE causes
pharmacological actions.
• Dennervation of post-ganglionic adrenergic neuron prevents their action.
• Repeated dosing at short intervals leads to tachyphylaxis due to depletion of stores
of NE.
These drugs are more lipid soluble than NE or E. Hence, they have better penetration in
CNS and are better absorbed by GIT.
Their common characteristics are, to replace catecholamines from the storage site. They
cross blood-brain barrier and have notable effects on CNS. Drugs in this category are as
follows:
(a) Tyramine
It is not used clinically. It is found in cheese, beef, wine, beer, banana, yeast and yoghurt.
It is metabolised by MAO present in liver, GIT and other parts of body. If the patient is taking
any inhibitor of MAO, then any substance containing Tyramine can precipitate serious
hypertensive crisis by profusely releasing NE from storage sites.
(b) Amphetamine
It has a powerful CNS stimulant action in addition to peripheral α- and β-adrenoceptor
effects.
Mechanism of action
It enters the nerve ending by active transport and displace DA and NE from storage
vesicles by altering pH. To some extent, they also inhibit DA metabolism by inhibiting MAO-
B in nerve ending. As a result, concentration of intra-neuronal DA increases. It reverses the
direction of transport mechanism resulting in release of DA by reverse transport in addition
to exocytosis. In totality, total DA concentration in the synaptic cleft increases.
Pharmacokinetics
It is well absorbed after oral administration and penetrates blood-brain barrier. A sizable
portion of un-metabolised drug is excreted through urine. By acidifying urine with ascorbic
acid or ammonium chloride reduces re-absorption of Amphetamine and enhances its
clearance.
CNS effects
d-isomer of Amphetamine, called as Dextro-amphetamine is 3-4 times more potent than
l-isomer in exhibiting CNS stimulant effects. It stimulates cortical region and reticular
activating system. It also stimulates the medullary respiratory centre, lessens CNS depression
by other drugs and produces wakefulness, alertness and decreased sense of fatigue. The
need for sleep may be postponed but cannot be avoided indefinitely. The performance of
simple mental tasks is improved but it is of no advantage because of increase in number of
errors. Physical performance in athletes is improved and the drug is often abused for the
purpose.
If Amphetamine is taken repeatedly over a period of few days, a state of Amphetamine
psychosis develops which closely resembles schizophrenia and is associated with paranoid
ideas along with auditory and tactile hallucinations. Higher doses can lead to aggressiveness
and violent behaviour; death may occur due to violence, accident, murder or even suicide.
CVS effects
The l-isomer is more potent than d-isomer on CVS. Amphetamine raises both systolic
and diastolic BP and produces tachycardia followed by bradycardia. In large doses,
arrhythmia may occur.
Effects on smooth muscle
Sphincter of urinary bladder constricts resulting in difficulty for micturition. It causes
relaxation of gut and increases tone of uterus.
Other effects
It suppresses appetite by depressing lateral hypothalamic feeding centre. Tolerance to
appetite suppression develops rapidly. It is not advised to use this drug for appetite
suppression.
Therapeutic uses
It is used for following indications:
• Narcolepsy
Amphetamine in small doses improves narcolepsy and prevents attacks of day time
sleep. It is advised that the drug should not be given after 4.00 pm, because it will
disturb the nocturnal sleep resulting in compulsions to have day time sleep.
• Attention Deficit Hyperactivity Disorder (ADHD)
This syndrome is observed in children. It is characterised by impulsiveness, impaired
inter-personal relationship, excitability and difficulty in sustaining attention resulting in
loss of academic achievements. Surprisingly, some children with ADHD respond well to
low doses of Amphetamine.
Adverse effects
Following types of adverse effects are observed:
• Restlessness, tremors, hyperactive reflexes, irritability, insomnia, euphoria,
hallucinations and sweating. High doses cause psychosis. These adverse effects are
related to CNS.
• Palpitation, headache and arrhythmia.
• Dry mouth, metallic taste, anorexia, abdominal cramps and difficulty in micturition.
• Dependence and tolerance: Psychological dependence develops after prolonged
use. Tolerance develops to its appetite suppressant effect but not for narcolepsy.
Withdrawal effects include CNS depression, insomnia and tremors.
Treatment of toxicity
Amphetamine toxicity can be treated by acidification of urine by ammonium chloride or
ascorbic acid, it prevents re-absorbtion of Amphetamine from renal tubule and promote
excretion. Diazepam may be given to limit adverse effects on CNS.
(c) Methamphetamine
It is closely related to Amphetamine in chemical structure. Low doses have
predominantly CNS stimulant effects without significant peripheral actions. It has a high
potential for abuse.
(d) Methylphenidate
It is also related chemically to Amphetamine. It is a mild CNS stimulant; but it has more
prominent action on mental functions. It is more effective than Amphetamine in treating
narcolepsy and ADHD. Abuse potential is similar to that of Amphetamine. In large doses, it
produces convulsions. It is contra-indicated in patients with glaucoma. Its d-isomer,
dexmethylphenedate is better tolerated and preferred for use in ADHD.
(e) Pamoline
It is structurally similar to methylphenetate. It has prominent CNS stimulant effects with
minimal effects on CVS. It has a longer plasma half-life. Hence, it is used in treatment of
ADHD. Its prolonged use is associated with dependence and hepatic damage.
(f) Modafanil
It is not an analog of Amphetamine. It blocks uptake of both NE and DA. It is used to
treat narcolepsy. It does not produce insomnia, but improves wakefulness. It has no abuse
potential.
3.5.1.2.3 Mixed Action Sympathomimetics
As in case of indirectly acting sympathomimetics, these drugs act by replacement of
stores of NE. In addition, they have a direct action on α- and β-receptors (like NE and E).
Following drugs are considered under this category:
(a) Ephedrine
It is a non-catecholamine alkaloid obtained from Ephedra vulgaris. Its racemic form is
used clinically. It has a direct action on both α- and β-receptors. In addition, it enhances
release of NE from sympathetic neuron. It is not destroyed by MAO and COMT and
therefore it has longer duration of action than E and NE. It crosses blood-brain barrier and
has a powerful stimulant action on CNS. It increases heart rate, cardiac output and BP.
Activation of β2-receptors in lungs promotes broncho-dilation. Stimulation of α1-receptor
produces mydriasis without cycloplegia. It is used to treat hypotension, subsequent to spinal
anaesthesia. It can be used orally to treat mild chronic asthma; but selective β2-agonists are
preferred for this purpose. Adverse effects include hypertension, (when given parenterally)
insomnia and tachycardia. Repeated doses at short intervals produce tachyphylaxis.
(b) Pseudoephedrine
It is a stereo-isomer of ephedrine and is used as a nasal decongestant in oral
formulation.
(c) Mephentermine
Its pharmacological actions are similar to that of ephedrine. Its use is restricted to
maintain BP in hypertensive states e.g. following spinal anaesthesia by giving slow injection.
Adverse effects include CNS stimulation, hallucinations and convulsions (only in
overdosage). The oral dose is 10-20 mg twice a day or as an IV infusion of 15-60 mg in 5%
glucose.
It is available as 10 mg tablet or 15 mg/ml injection: MEPHENTINE.
3.5.2 Sympatholytics
Sympatholytics are also termed as adrenergic receptor antagonists. They abolish (lyse)
the response to stimulation of sympathetic nerves. They are devoid of any intrinsic activity
on adrenoceptors but they exert their actions by blocking the interaction of catecholamines
or other sympathomimetics with adrenergic receptors; which are of three types: Alpha (α),
Beta (β), and Dopamine (D). The drugs which block D-receptors peripherally are of no
clinical significance; while those which block D receptors centrally are of clinical importance.
The α and β adrenoceptors have been classified in to five categories: α1, α2, β1, β2, and β3.
Blockers related to these receptors, which are of clinical importance are discussed below.
3.5.2.1 α-Adrenergic Blockers
On the basis of their selectivity and mode of action, α-adrenoceptor antagonists can be
classified as mentioned below. See Fig. 3.18.
a-Receptor antagonists
Non-selective Selective Miscellaneous

(block a1 and a2)
Ergot alkaloids
Reversible Irreversible a1 blockers a2 blockers
Phentolamine Phenoxybenzamine Prazosin Yohimbine

Tolazoline Terazosin Idazoxan
(Priscoline) Doxazosin
Alfuzosin
Bunazosin
Tamsulosin
Silodosin
Fig. 3.18: Classification of α-blockers
(i) Reversible non-selective α-blockers
These drugs are competitive antagonists at α-adrenergic receptors and have similar
affinities for α1- and α2-receptors. Two drugs viz. Phentolamine and Tolazoline deserve
discussion in this category.
(a) Phentolamine
Blockade of vasoconstrictor α1-receptors in the periphery by Phentolamine leads
to vasodilatation, decrease in peripheral vascular resistance leading to hypotension.
The resultant fall in BP stimulates baroreceptor reflex causing sympathetic discharge. Since
α1-receptors are blocked, the sympathetic discharge stimulates β1-receptors on the heart
producing tachycardia. Being non-selective, it also blocks pre-synaptic α2-receptors limiting
neuronal release of NE to produce more tachycardia and palpitation. The patients may suffer
from events of postural hypotension. In absence of efficient peripheral vasoconstriction in
erect posture, there is a peripheral pooling of blood leading to cerebral hypoxia, vertigo and
fainting, which are important features of postural hypotension.
Other effects
Following effects are observed with Phentolamine:
• Nasal stuffiness results due to vasodilatation and congestion of nasal mucosa.
• Myosis, due to loss of tone of radial muscles of iris and unopposed contraction of
circular muscle.
• Improved urine flow rates due to relaxation of smooth muscles of urinary bladder
neck and prostate.
• Failure of ejaculation and impotence due to inhibition of contractions of vas
deferens and ejaculatory ducts.
• Nausea, vomiting and diarrhoea due to partial inhibition of relaxant sympathetic
influences on GIT, and increase in gastric secretions due to agonistic action on
histamine H2 receptors.
Pharmacokinetics
It is poorly absorbed from GIT. It is administered intravenously. It has an immediate
onset and shorter duration of action.
Therapeutic uses
• For diagnosis and management of Phaeochromocytoma.
• For peripheral vascular disorders: It is used to treat Raynaud’s syndrome and
frostbite.
• To prevent dermal necrosis: It is used sub-cutaneously to prevent dermal necrosis
after incidental extravasation of NE from intravenous infusion.
• To prevent hypertensive crisis following abrupt withdrawal of Clonidine and those
resulting from ingestion of tyramine-containing food with MAO inhibitors.
It is available as 10 mg/ml injection: FENTANOR, FENTOSOL.
(b) Tolazoline
It is similar to Phentolamine; but it is less potent. It is better absorbed from GIT. It is
rarely used.
(ii) Irreversible non-selective α-blockers
The only drug in this category is Phenoxybenzamine.
(a) Phenoxybenzamine
It binds covalently to α1- and α2-receptors causing irreversible blockade of the receptors
with a longer duration of action (20-48 hours). It inhibits reuptake of released NE by
adrenergic nerve terminals. It also crosses blood-brain barrier. It causes vasodilatation,
progressive decrease in peripheral resistance and tachycardia. Cardiovascular effects of
overdose of Phenoxybenzamine cannot be reversed by catecholamines due to covalent
binding with the receptors, making it the drug a choice for Phaeochromocytoma. It causes
marked postural hypotension due to impairment of compensatory vasoconstrictor
responses. Tolerance to it develops later. Other toxic effects include reversible inhibition of
ejaculation, salt and water retention, cardiac arrhythmia, sedation, fatigue and nausea.
Therapeutic uses
• Treatment of Phaeochromocytoma in an intravenous dose of 1 mg/kg, controls
severe hypertension during surgery for Phaeochromocytoma.
• To treat peripheral vascular disease like Raynaud’s syndrome and frostbite. It is used
in a oral dose of 10 mg three times a day.
It is available as 10 mg capsule or 50 mg/ml injection: FENOXENE.
(iii) Reversible, selective α1-blockers
The primary drug in this category is Prazosin. Few derivatives of Prazosin are also
available.
(a) Prazosin
It is a selective α1-receptor antagonist. It causes peripheral vasodilatation and a fall in
arterial pressure with lesser tachycardia probably because of lack of α2-receptor blocking
actions, limiting release of NE. It also decreases cardiac preload and it suppresses
sympathetic outflow from CNS.
It is a potent inhibitor of the enzyme cyclic phosphodiesterase leading to increase in
cAMP. It also causes rise in the concentration of HDL and decrease in LDL and triglycerides.
Being an α1-selective antagonist, it relaxes smooth muscles of urinary bladder neck, prostate
capsule and prostatic urethra leading to improvement of urine flow in cases of benign
prostatic hypertrophy.
Pharmacokinetics
It is well absorbed after oral administraton. Its plasma half-life is about 4 hours.
Therapeutic uses
• Treatment of hypertension: Titration of dose is needed to limit postural hypotension.
Initially, a dose of 1 mg may be given orally at bed time.
• In the treatment of benign prostatic hyperplagia (BPH). Oral dose of 1-5 mg twice
daily is useful.
• In patients of Raynaud’s disease, calcium channel blockers are preferred over
Prazosin.
Adverse effects
• The major adverse effect is postural hypotension (Syncopal attack).
• Impotence, nasal congestion, GIT upset, sodium and water retention are additional
adverse reactions.
It is available as tablet of 1 mg, 2 mg or 5 mg: MINIPRESS, PRAZOPRESS.
(b) Terazosin and Doxazosin
Both are α1-blockers like Prazosin but have longer duration of action. Both are well
absorbed after oral administration. Plasma half-life of Tetrazosin is 12 hours; and that of
Doxasosin is 20 hours. One daily dose is preferred for treatment of hypertension and BPH.
Terazosin in a dose of 2-5 mg or Doxazosin in a dose of 1-4 mg, once daily is useful to
improve urine flow. It may be combined with another drug Finasteride, which inhibits
conversion of testosterone to dihydrotestosterone. The combination is useful in reducing
progress of BPH.
Terazosin: HYTRIN, TERAPRESS, TERALFA, OLYSTER is available as tablet of 1 mg,

2 mg, 5 mg; Doxasosin: DOXACARD, DURACARD is available as tablet of 1 mg, 2 mg and
4 mg
(c) Bunazosin and Alfuzosin
Both are orally effective α1-blockers similar to Prazosin. Alfuzosin is given in a dose of
2.5 mg three times a day. It has a shorter half-life of 4 hours and hence needs frequent
administration. It should be avoided in patients with hepatic impairment, due to extensive
metabolism by liver. Bunazosin has slightly longer half-life. Both drugs are used to treat BPH.
Alfuzosin: ALFOO, FUAL, AFFUSIN, PROFUZO is available as 10 mg extended release
tablet.
(d) Tamsulosin and Silodosin
These are selective α1-blockers. Tamsulosin is more effective for BPH than for
hypertension. It has a plasma half-life of 8 hours and better bioavailability than Prazosin.
Abnormal ejaculation and intra-operative floppy iris syndrome (which causes problems
during cataract surgery) are major adverse reactions. Silodosin is a weaker but long acting
analog of Tamsulosin.
Tamsulosin: CONTIFLO-OD, URIPRO, VELTAM, URIMAX is available as 0.2 mg, 0.4 mg
tablet.
(iv) α2-receptor blockers
The only drug in this category is Yohimbine.
(a) Yohimbine
It is a natural alkaloid available from Pausinystalia yohimbe. It is lipid soluble. It crosses
blood-brain barrier. It has antagonistic action to 5-HT. It can be used to treat autonomic
insufficiency by promoting NE release by blocking pre-synaptic α2-receptor. It can also be
used to treat male sexual dysfunction and to treat diabetic neuropathy and postural
hypotension. It can abruptly reverse anti-hypertensive effect of clonidine, which is a notable
drug interaction. Its clinical role needs to be established.
(v) Miscellaneous non-selective α-blockers
Ergot alkaloids fall in this category.
(a) Ergot alkaloids
Alkaloids from ergot like Ergotamine and Dihydroergotamine exhibit complex
pharmacological actions. They block both α1- and α2-receptors. In addition, they act as
partial agonists to α-receptors and 5-HT2 receptors. Some of them are Oxytocics and
dopamine receptor agonists. Methysergide, a synthetic compound is related to ergot
alkaloids. It is a potent 5-HT antagonist and was used for migraine prophylaxis.
Ergonovine/Ergometrine is an ergot alkaloid. Its derivatives methyl-ergonovine and
dihydroergonovine are used for their uterine relaxant (tocolytic) action.
3.5.2.2 β -Adrenergic Blockers

These drugs block β1- or β2-receptors and antagonise effects of catecholamines which
are mediated through the receptors. In addition, some of these drugs also exert membrane-
stabilising effect leading to local anaesthetic action. Some of them have intrinsic
sympathomimetic activity. Based on their selectivity towards receptors, they can be classified
as shown in Fig. 3.19.
b-Blockers
Non-selective Selective Mixed

(b1 and b2 blockers) (a and b blockers)
Propranolol Labetalol
Timolol Carvedilol
Sotalol
Nadolol b1 blocker b2 blocker
Pindolol Metaprolol Butoxamine
Oxprenolol Atenolol
Esmolol
Acebutalol
Celiprolol
Betaxolol
Bisoprolol
Nebivolol
Fig. 3.19: Classification of β -blockers
(i) Non-selective β -blockers
Propranolol is the prototype drug in this category. Hence, it is discussed in detail. In
addition, Timolol, Sotalol and Nadolol are derivatives of Propranolol.
(a) Propranolol
It is a non-selective β-antagonist. It is primarily used to treat hypertension and ischaemic
heart disease. It has little effect on normal resting heart, but exhibits profound action when
the sympathetic drive to the heart if high, as during physical exercise or stress.
It causes decrease in heart rate, myocardial contractility, conduction velocity and cardiac
output. Because of decrease in the work-load by heart, the myocardial oxygen demand is
also reduced. The automaticity of heart is suppressed because of the inhibition of latent
pace makers. Subsequently there is fall in blood pressure. The total peripheral vascular
resistance tends to rise initially because the vasoconstricting α1-adrenoceptor response is no
longer opposed by dilator effects on β2-receptors. Further, asreflex vasoconstriction is
preserved, postural hypotension is not very troublesome. Patients with hypertension show a
gradual fall in BP after chronic use of Propranolol. In addition to β1-receptor blockade, it
shows following additional effects.
• Decrease in renin release, further reducing production of angiotensin II and
aldosterone from adrenal cortex.
• Decrease in central sympathetic outflow.
• Chronic decrease in cardiac output.

• Blockade of facilitatory effect of pre-synaptic β2-receptors on release of NE.
Cardiovascular effects of Propranolol can be overcome by Isoprenaline; however it
cannot counteract cardiac stimulant action of Digoxin, calcium ions, Theophylline and
Glucagon, which indicates its selective action on β-receptors only.
Plasma lipid profile is worsened after long-term use of Propranolol:
• Total triglycerides and LDL tend to increase.
• HDL cholesterol levels fall.
It has a membrane stabilising (local anaesthetic) action and direct cardiac depressant
(quinidine like) actions. However, it does not contribute to anti-arrhythmic effects in usual
doses.
Respiratory effects
In asthmatic patients, Propranolol can cause severe bronchoconstriction. This is because
of its non-specific effect. Cardio-selective β1-blockers are less prone for it.
Metabolic effects
Propranolol inhibits stress-induced or adrenaline-induced glycogenolysis, which acts as a
safety device during episodes of hypoglycaemia, especially in insulin-induced hypo-
glycaemia in diabetic patients. The drug also blocks adrenergically induced lipolysis and has
an adverse effect on lipid profile. It also masks sympathetic manifestations of hypoglycaemia
like palpitations, tremors, sweating etc.
CNS effects
Besides decreasing central sympathetic outflow, which contributes to anti-hypertensive
effects, Propranolol also produces sedation, lethargy and disturbances in sleep after long-
term use. It suppresses performance anxiety e.g. anxiety prior to examination; but this is due
to peripheral action. In high doses it causes anti-psychotic effects; but they are not clinically
useful due to adverse cardiovascular effects.
Ocular effects
Propranolol decreases formation of aqueous humour and thus decreases intra-occular
pressure, especially in patients of glaucoma. Still it is not preferred for this clinical purpose
because it is less potent and its local anaesthetic action is undesirable.
Miscellaneous effects
• Propranolol increases synthesis and release of prostaglandins in selected vascular
beds, as the hypotensive effect of the drug can be reversed by aspirin-like drugs
which cause analgesic effects by virtue of effects on prostaglandin synthesis.
• It prevents platelet aggregation and promotes fibrinolysis to some extent.
• It reduces portal vein pressure in patients with cirrhosis.
Pharmacokinetics
It is completely absorbed when given orally, but has low bioavailability because of
extensive first-pass metabolism. It is highly lipid soluble and crosses blood-brain barrier. It
has shorter plasma half-life (4-6 hours). It exists in two isomeric forms. l-propranolol is 80-
100 times more potent than d-propranolol in blocking β-adrenoceptors. d-propranolol
exhibits more quinidine-like and membrane stabilising effects as compared to l-form.
Commercial preparations are in racemic forms. Sustained-release preparations of
Propranolol are available.
Therapeutic uses
Key word to remember therapeutic uses is 2H-2A-MI. 2H refers to Hypertension and
Heart failure; 2A refers to Angina and Arrhythmias and MI refers to Myocardial infarction.
• Essential hypertension
Singularly or in combination with a diuretic or α-adrenergic blocker, Propranolol is used
primarily to reduce elevated blood pressure. When used alone, fall in BP is gradual and
without postural hypotension. The oral dose is 20-40 mg three times a day or 80 mg
sustained release tablet once a day.
• Congestive heart failure (CHF)
When introduced gradually with slow advancing doses over time and maintained for a
long term, Propranolol retards progression of CHF and prolongs life. The benefit arises
from antagonism of damaging effects of cardiac β1-receptor over-activity, which
promotes unfavourable re-modelling of myocardium.
• Angina pectoris
As Propranolol decreases overload on heart, diminishes myocardial oxygen demand and
increases exercise tolerance, it benefits patients having angina of effort. The drug should
be given continuously and not merely when there is an attack.
• Cardiac arrhythmia
Propranolol is effective in all supra-ventricular tachycardias associated with high levels of
circulating catecholamines. The condition occurs in digitalis toxicity, phaeochromo-
cytoma, thyrotoxicosis or with general anaesthetics like halothane. The ventricular
ectopic beats are also controlled. The effects are due to increase in refractory period of
AV node and direct membrane stabilising effect. The drug also reduces drive to cardiac
pace-makers.
• Myocardial infarction
Propranolol significantly decreases incidence, recurrence and mortality in cases of
myocardial infarction after long term use. The benefit increases due to prevention of
platelet aggregation and promotion of fibrinolysis. The drug also prevents sudden
ventricular fibrillation due to second attack of myocardial infarction.
Other uses
Key word to remember other effects are MAGH-Paw-EVB. MAGH refers to Migraine,
Anxiety, Glaucoma and Hyperthyroidism. Paw refers to Phaeochromocytoma, Alcohol
withdrawal. EVB refers to Esophageal Variceal Bleeding.
• Migraine
It is useful in prophylaxis of migraine. The dose is 20 mg three times a day.
• Anxiety-provoking situations
It can be used in situations like examination, interview etc. It blocks symptoms of anxiety
like palpitation, tremors and sweating. The oral dose is 10-20 mg twice/thrice a day.
• Glaucoma
Other selective blockers like Timolol and Betaxolol are preferred for this purpose.
• Hyperthyroidism
The drug reduces unpleasant symptoms of sympathetic over-activity. It reduces
tachycardia, irregular cardiac rhythm, tremors, sweating and elevated basal metabolic
rate (BMR). The oral dose is 20 mg twice a day.
• Phaeochromocytoma
The drug is given along with α-blockers during surgery for removal of adrenal tumour. It
antagonises β-agonistic effects of circulating catecholamines. The oral dose is 20 mg
three times a day, three days before surgery.
• Alcohol withdrawal
It is useful by reducing central sympathetic over-activity during the phase of withdrawal
of alcohol. The oral dose is 20 mg twice/thrice a day.
• Esophageal variceal bleeding
The drug reduces cardiac output and induces splanchnic vasoconstriction leading to
reduction of bleeding from esophageal varices. Portal pressure is reduced by 40%. The
oral dose is 10-20 mg twice a day.
Adverse effects and complications
Key word to remember is 2B-2C-2H-RH & ALP. 2B refers to Broncho-constriction,
Bardycardia. 2C refers to Cold extremities, CNS side effects. 2H refers to heart failure and
hypoglycemia. RH refers to Rebound Hypertension and ALP refers to Adverse Lipid Profile.
• Broncho-constriction
In patients with asthma and chronic obstructive lung disease, the effect can be life
threatening.
• Bradycardia
The drug can cause life threatening bradyarrhythmias and heart block.
• Cold extremities
It is due to cutaneous vasodilatation. The drug is contra-indicated in Raynaud’s disease.
• CNS side effects
The effects include sleep disturbances, bad dreams, depression and sexual dysfunction
(only in males).
• Heart failure
AV nodal depression can lead to AV dissociation and can precipitate heart block. It is
contraindicated in heart failure.
• Hypoglycaemia
It is contra-indicated in patients receiving insulin and oral hypoglycaemic drugs. It is due
to possibility of hypoglycaemic coma.
• Rebound hypertension
Withdrawal of β-blockers should be slow; otherwise it may cause re-bound
hypertension.
• Adverse lipid profile
LDL-cholesterol tends to increase while HDL-cholesterol levels fail due to β-blockers.
Drug interactions
The drug interactions are sub-classified as pharmacokinetic and pharmacodynamic.
(i) Pharmacokinetic drug interactions
• Aluminium salts, cholestyramine and colestipol decrease absorption of β-blockers.
• Cimetidine and Hydralazine may increase bioavailability of β-blockers.
• β-blockers impair clearance of lignocaine and may increase bioavailability of
lignocaine.
(ii) Pharmacodynamic drug interactions
• Digitalis and Verapamil cause additive depression of SA node and AV conduction
leading to cardiac arrest.
• Indomethacin and Aspirin (other NSAIDs) can antagonise anti-hypertensive effects of
β-blockers.
• Hypertensive patients receiving Propranolol are very sensitive to pressor responses
of adrenaline.
Propranolol is available as tablets of 10 mg, 40 mg, 80 mg or slow release 40 mg, 80 mg. It
is also available as 120 mg time-release capsule: INDERAL, CIPLAR, BETACAP-TR.
(b) Timolol
Timolol is orally absorbed. It shows moderate first-pass metabolism. It crosses blood-
brain barrier. It's uses and side effects are similar to that of propranolol.
Therapeutic uses
It is used as eye drops to decrease raised intra-occular pressure, in case of wide angle
glaucoma. It is devoid of membrane stabilising activity. From ocular formulations, some
amount may be absorbed systemically to exhibit side effects.
It is available as 0.25% or 0.5% eye drops: OCUPRES, GLUCOMOL, IOTIM, TIMOLET.
Other β-blockers used for the same purpose are Betaxolol: OPTIPRESS, BULOL, IOBET,
OCUBETA and Levobunolol: BETAGAN both as 0.5% eye drops.
(c) Sotalol
Sotalol has low lipid solubility. It shows lesser CNS effects and has negligible first-pass
metabolism. Its uses and side effects are similar to that of propranolol. It has potassium
channel blocking activity and anti-arrhythmic activity also. Its oral dose is 80-320 mg twice a
day.
It is available as 40 mg or 80 mg tablet: SOTAGARD, SOLET.
(d) Nadolol
Nadolol has longer plasma half-life (20 hours). It does not cross blood-brain barrier. It
has least first-pass metabolism. Its dose is 40 mg once daily. Its effects are similar to that of
propranolol.
It is available as 40 mg tablet.
(ii) Cardio-selective β 1-blockers
These drugs are more selective towards heart and exert lesser side effects on respiratory
system. Their selectivity is in comparison to Propranolol. The examples in this category are
Metoprolol, Atenolol, Blisoprolol, Nebivolol, Esmolol and Betaxolol.
Advantages over non-selective β -blockers
• They are safer in asthmatic patients in comparison to Propranolol.
• They are safer in diabetes since they cause less inhibition of glycogenolysis during
hypoglycaemia. Tachycardia in response to hypoglycaemia is blocked.
• They are safer in patients with peripheral vascular disease since they do not cause
β2-blockade.
• They have less adverse effects on lipid profile.
Disadvantages
• They cause rebound hypertension after abrupt withdrawal.
• They are ineffective in controlling essential tremors.
Following drugs are discussed in this category:
(a) Metoprolol
It is completely absorbed after oral administration. Due to first-pass metabolism, its
bioavailability is low. Its plasma half-life is 4 hours. For treating hypertension, usual dose is
50-100 mg daily. Extended release formulations are available for once daily administration.
Its uses are similar to that of Propranolol.
It is available as a tablet with 25 mg, 50 mg or 100 mg content. It is also available as
1 mg/ml injection: BETALOC, METOLAR, LOPRESOR.
(b) Atenolol
It does not cross blood-brain barrier. It has relatively longer half-life in comparison to
Metaprolol. It can be given once daily in dose of 25-50 mg. Its uses are similar to that of
Metoprolol.
It is available as 25 mg, 50 mg or 100 mg tablets: BETACARD, TENORMIN.
(c) Bisoprolol
It is commonly used for hypertension and angina. Its dose is 2.5-10 mg once daily. When
used with ACE inhibitors, it lowers mortality in chronic heart failure.
It is available as 2.5 mg, 5 mg or 10 mg tablets: ZAVESTA, CORBIS, BISELECT.
(d) Nebivolol
It enhances production and release of Nitric Oxide (NO) in addition to β-blockade. It
lowers arterial blood pressure and reduces peripheral vascular resistance. It is used for
treating hypertension. Usual oral dose is 5-10 mg once daily.
It is available as 2.5 or 5 mg tablet: NEBICARD, NUBETA, NODON, NEBISTAR.
(e) Esmolol
It is an ultra-short acting β1-antagonist. It has a plasma half-life of 8-10 minutes. It is
given intravenously in conditions to terminate supra-ventricular tachycardia, episodes of
atrial fibrillation and to control heart rate and blood pressure during surgery or in critically ill
patients in whom the drug can be withdrawn immediately. Adverse effects include
bradycardia, hypotension and heart failure.
It is available as 10 mg/ml injection: CARDESMO, NEOTACH, MINIBLOCK.
(f) Betaxolol
It is less effective than Timolol because 80% of β-receptors on ciliary body epithelium
are of β2 sub-type. It is better tolerated. It has no membrane stabilising (local anaesthetic)
effect. It has cyto-protective action on retinal neurons. It is safer in asthmatic and diabetic
patients. Oral formulations are used for hypertension and angina. It facilitates drainage of
aqueous humour.
It is available in the form of eye drops.
(iii) Non-selective β -blockers with intrinsic sympathomimetic activity
Drugs under this category possess some intrinsic sympathomimetic activity on β1 and β2
receptors in addition to non-selective β-blockade. Drugs under this category are: Pindolol
and Oxprenolol. Their advantages and disadvantages are mentioned below:
Advantages:
• They cause lesser bradycardia and myocardial depression. Hence, they are more
useful in patients prone to bradycardia or with low cardiac reserve as in cases of
congestive heart failure.
• They are relatively better in patients of asthma because of β2-agonistic action.
• Rebound hypertension after withdrawal is less likely.
• Lipid profile is less worsened in comparison to Propranolol.
Disadvantages:
• These drugs cannot be used in migraine prophylaxis since β2 agonistic activity dilates
cerebral blood vessels.
• It is less suitable for secondary prophylaxis of myocardial infarction.
(a) Pindolol and Oxprenolol

Daily doses are 10 mg for Pindolol, once daily and 20 mg twice or thrice a day for
Oxprenolol.
Pindolol: VISKEN is available as 10 mg, 15 mg tablet and Oxprenolol: TRASICOR is
available as 40 mg and 80 mg tablet.
(iv) Selective β 1-blockers with intrinsic sympathomimetic activity
Drugs under this category offer combined advantages of Pindolol and Atenolol. They
also have membrane stabilising action. Drugs under this category are Acebutolol and
Celiprolol.
(a) Acebutolol
It is well absorbed orally. It undergoes first-pass metabolism and is converted to an
active metabolite, called diacetolol which has a longer half-life (10-12 hours). It is given as a
single oral dose of 400 mg/day. It is used for treating ventricular arrhythmia.
It is available as 200 mg or 400 mg tablet: SECTRAL.
(b) Celeprolol
It is well absorbed with a bioavailability of 75%. It has partial agonistic action on
β2-receptors. It also causes some direct vasodilatation by releasing nitric oxide (NO). It is
preferred for hypertensive patients with asthma in a oral dose of 200-400 mg once a day.
It is available as 100 mg or 200 mg tablet: CELIPRES.
(v) Mixed (α
α + β ) antagonists
Drugs under this category block α- and β- receptors. The examples are Labetalol and
Carvedilol.
(a) Labetalol
It acts as a competitive antagonist at both α1- and β-adrenergic receptors. It exhibits
optical isomerism and has four diastereomers. The racemic mixure exhibits following
activities:
• Selective blockade of α1-adrenergic receptors,
• Blockade of β1-receptors,
• Blockade of β2-receptors, and
• Partial agonistic activity at β2-receptors.
The α1- and β1-blocking actions of Labetolol lead to fall in BP. The intrinsic
sympathomimetic activity (ISA) at β2-receptors may contribute to peripheral vasodilatation
and bronchodilatation. Heart rate remains unaffected. It is orally effective but it has only
30% bioavailability due to first-pass metabolism. Plasma half-life is 4-5 hours. It is used to
treat hypertension of elderly people. It is also useful in phaeochromocytoma for controlling
rebound hypertension after Clonidine withdrawal. Postural hypertension and hepatotoxicity
are main adverse reactions. Usual oral dose is 100 mg once a day which is increased to 200
mg twice daily for 7-10 days.
It is available as 50 mg or 100 mg or 200 mg tablets: NORMADATE, LABESOL.
(b) Carvedilol
It is orally effective. It undergoes significant first-pass effect with 30% bioavailability.
It has a half-life of 6-8 hours. It is a β1-, β2- and α1-adrenoceptor blocker. Its β1- and
β2- receptor blocking actions are more prominent than α1- actions. It also inhibits free
radical-induced lipid peroxidation and also inhibits mitogenesis of vascular smooth muscle.
It also blocks L-type voltage-gated calcium channels. All these effects lead to cardio-
protective action in patients with congestive heart failure. It is used to treat essential
hypertension. Along with conventional therapy it is also useful to reduce mortality in
myocardial infarction. Adjustment of dosage is not necessary. For hypertension/angina,
usual oral dose is 6.25 mg twice a day which is increased to 12.5 mg if needed.
It is available as 6.25 mg or 12.5 mg or 25 mg tablet: ORICAR, CONPRESS, CEVAS,
CARVIMED, CARDIVAS.
3.6 NEURO-MUSCULAR BLOCKING AGENTS AND SKELETAL MUSCLE

RELAXANTS (PERIPHERAL)
There is a need of skeletal muscle relaxants to facilitate surgery. Hence, these drugs are
used along with surgical anaesthesia. They relax skeletal muscles, particularly of abdominal
wall and lower limbs so that operative manipulations become easier. This situation minimises
the risk of respiratory and cardiovascular depression and also reduce post anaesthetic
recovery period because in presence of skeletal muscle relaxants, a lighter anaesthesia is
sufficient. The drugs block post-synaptic actions of ACh at motor end plate. Some muscle
relaxants simply reduce spasticity in few painful conditions like chronic back pain and
myalgia. On the basis of their site and mechanism of action, skeletal muscle relaxants are
broadly classified as neuromuscular blocking agents and peripheral muscle relaxants.
3.6.1 Neuromuscular Blocking Agents
Whenever a nerve joins a muscle, there is no anatomical continuity between them. There
is a small gap between a nerve and a muscle. It is called as neuromuscular junction (NMJ).
These drugs act at NMJ. At NMJ, ACh works as a neurotransmitter through nicotinic
receptors. Hence, drugs blocking nicotinic actions of ACh perform as neuromuscular
blocking agents.
They are sub-classified in to two sub-categories: Non-depolarising blockers (competitive
blockers) and Depolarising blockers (persistent depolarisers).
(i) Non-depolarising Blockers
The first NMJ blocker was curare, which native hunters of South America were using for
paralysing an animal before hunting. Curare was a plant extract and d-Tubocurarine (d-TC)
was isolated and used in clinical practice from 1940s. Structure of d-TC and related
derivative are depicted in Fig. 3.20. There are several derivatives of d-TC. Some are long
acting e.g. Metocurine, Doxacurium, Pancuronium and Pipecuronium and some others are
short acting e.g. Atracurium, Cis-atracurium, Mivacurium, Vecuronium, Rocuronium and
Rapacuronium. See table 3.5 and 3.6. Their common features are presented below:
CH3 CH3 O OCH3

N
CH2 OH
O CH2 +
N
CH3O OH H CH3
Fig. 3.20: Structure of d-Tubocurarine (Isoquinoline derivative)
Mechanism of action
d-TC and other non-depolarising blockers are quaternary compounds with two
positively charged nitrogen in their structure. (see Fig. 3.19). These drugs have an affinity for
NM cholinergic receptors at the motor end plate but have no intrinsic activity over them.
They block the NM receptor and prevent binding of ACh to the site. As a result, necessary
conformational change in the NM receptor, needed for opening of sodium channel is
prevented. In absence of end plate potential, the motor nerve impulses cannot induce
contractions in the skeletal muscle. The net result is relaxation of skeletal muscles. They do
not cause depolarisation by themselves but prevent depolarisation by ACh. The antagonism
is competitive in nature. Anticholinesterase drugs like Physostigmin/Neostigmincan reverse
the NMJ block due to increase in concentration of ACh. At higher concentrations, these
drugs block sodium channels directly, which adds to the strength of blockade. This leads to
further weakening of NMJ transmission and reduce ability of drug like Physostigmin/
Neostigmin to reverse the actions of non-depolarising muscle relaxants.
Pharmacokinetics
• These drugs are not absorbed when given orally. They are given intravenously but
they differ in potency, rate of onset and duration of action. See table 3.5 and 3.6.
• They have relatively small volume of distribution (Vd). None of them cross blood-
brain barrier. Hence, they do not produce CNS toxicity.
• These drugs do not cross placental barrier and hence do not affect the newborn if
used during caesarean section.
• The route of elimination controls duration of action. Drugs excreted by kidney have
longer duration of action. Drugs eliminated by liver have intermediate duration of
action and drugs inactivated by plasma cholinesterase have shorter duration of
action. See table 3.5 and 3.6.
• Steroidal NMJ blockers (Vecuronium, Rocoronium and Rapacuronium) may show
accumulation and cause prolonged paralysis.
• Artracurium is chemically unstable at alkaline pH and has shorter duration of action
during respiratory alkalosis caused by hyperventilation.
• There is no pharmacogenetic variation in metabolism in case of these drugs.
Table 3.5: Pharmacokinetics of long acting non-depolarising NMJ blockers;

(Duration of action 35-100 minutes or more
Sr. No. Drug Onset Relative potency Elimination mechanism
(min) to d-TC
1. d-TC 4-5 1 Kidney 50%; Bile 50%
2. Metocurine 4-5 4 Kidney 80%; Bile 20%
3. Doxacurium 4-8 6 Mainly kidney 90%
4. Pancuronium 4-6 6 Kidney 80%; Liver 20%
5. Pipecuronium 2-4 6 Kidney 80%; Liver 20%
Table 3.6: Pharmacokinetics of short acting non-depolarising NMJ blockers
(Duration of action 25-50 min)
Sr. No. Drug Onset Relative potency Mechanism of elimination
(min) to d-TC
1. Atracurium 2-4 1.5 Spontaneous non-enzymatic,
plasma ChE
2. Cis-atracurium 3-6 1.5-2 Spontaneous non-enzymatic
100%
3. Mivacurium 2-3 4 Plasma ChE
4. Vecuronium 2-4 6 Liver 80%; Kidney 20%
5. Rocuronium 1-2 0.8-1 Liver 80%; Kidney 20%
6. Rapacuronium* 1-2 0.5 Mainly liver 90%
*the drug has been withdrawn due to severe adverse reaction.
Pharmacodynamics
After intravenous injections of d-TC like drugs, motor weakness gives way to progressive
flaccid paralysis. The fast moving smaller muscles like those of eyes, jaw, toes and larynx are
affected initially. Larger muscles like that of limbs and trunk are affected next. Finally, the
inter-costal muscles and then diaphragm are paralysed. Recovery of muscles usually occurs
in the reverse order.
Some derivatives of d-TC have a tendency to liberate histamine from mast cells.
Steroidal derivatives of d-TC like Pancuronium, Vecuronium, Pipecuronium, Rocuronium and
Rapacuronium cause least histamine release.
At common clinical doses, d-TC and Metocurine exhibit partial blockade of autonomic
ganglia. Other derivatives like Doxacurium, Mivacurium, Atracurium and cis-atracurium
exhibit least blockade. Steroidal derivatives do not block autonomic ganglia.
Only Pancuronium has vagolytic action due to blockade of M2 receptors leading to
tachycardia. Other drugs are devoid of vagolytic action.
d-TC and drugs like Metocurine, Mevacurium and Atracurium produce hypotension
partly due to histamine release and partly due to ganglionic blockade. Only Pancuronium
causes tachycardia; other drugs do not.
Only d-TC can cause broncho-spasm due to release of histamine from mast cells.
d-TC like drugs decrease the tone and motility of GIT. Recovery is followed by
constipation.
Reversal of blockade
Neostigmine and Pyridostigmine antagonise or reverse the non-depolarising
neuromuscular blockade caused by d-TC like drugs. The effect is due to increase in
concentration of ACh at motor end plate. Reversal of the blockade becomes necessary if
long-acting or intermediate-acting d-TC like drugs are used. Short-acting drugs do not need
such reversal.
Adverse effects
These are either related to skeletal muscle paralysis, histamine release, ganglionic
blockade or vagolytic actions.
• Hypoxia and respiratory paralysis may be caused by d-TC like drugs. It may be
accompanied with bronchospasm, hypotension and bradycardia.
• Pancuronium may cause tachycardia.
Synergists and antagonists
• Anticholinesterases like Neostigmine are antagonists to non-depolarising
neuromuscular blockade caused by d-TC like drugs.
• Hypothermia enhances the depolarising action of ACh. Hence, it antagonises the
action of non-depolarising blockers.
• Inhalational general anaesthetics like halothane decrease the sensitivity of post-
junctional membrane to depolarisation and therefore act synergistically with d-TC
like drugs. Hence, their doses should be reduced, when used along with inhalational
anaesthetics.
• Aminoglycoside antibiotics like Gentamycin cause neuromuscular blockde by
decreasing ACh release. Other antibiotics like Polymyxin-B, Clindamycin, Lincomycin
and Tetracycline group of antibiotics may also cause neuromuscular blockade. All
these drugs can act synergistically when used with d-TC like drugs.
• In large doses, most local anaesthetics block neuromuscular transmission and can
act synergistically with d-TC like drugs. Other drugs like Quinidine, Propranolol,
Diltiazem, Digitalis, Diuretics and Chloroquinine can also show synergism with d-TC
like drugs.
• Myasthenia gravis markedly adds to neuromuscular blockde caused by d-TC like
drugs. Conversely, patients with burns and those with upper motor neuron disease
require larger doses of d-TC like drugs.
Atracurium: ATRELAX TRACRIUIM is available as injection of 10 mg/ml.
Pancuronium: PANCURONIUM BROMIDE, PANCONIUM is available as 2 mg/ml injection.
Pipecuronium: ARDUAN is available as 4 mg/2 ml injection. Recuronium: CUROMID is
available as 50 mg/ml injection and Vecuronium: VERUNIUM, VECURON is available
10 mg/2 ml or 4 mg/2 ml injection.
(ii) Depolarising Blockers (persistent depolarisers): Succinyl Choline (SCh)

Only one depolarising neuromuscular blocker is available in clinical practice. It is Succinyl
choline (SCh). Actions of SCh are detailed below;
Mechanism of action
SCh is an analog of ACh. SCh is hydrolysed by pseudocholinesterase but not by true
AChE. As a result, only a small intravenous dose of SCh reaches NMJ after being hydrolysed
by pseudocholinesterase. At NMJ, it acts like an excess of ACh and its actions persist for
longer duration because it is not degraded by true AChE. SCh reacts with NM receptors of
motor end plate, open up sodium channel causing depolarisation which then spreads and
causes repetitive excitation of muscle motor unirts leading to transient muscle fasciculations.
Effectively, SCh continues to keep muscles next to NMJ in a polarized state. The action
results in flaccid paralysis, which cannot be reversed by AChE inhibitors like Neostigmine.
This is called as phase I block.
With higher doses of SCh or its prolonged infusion, phase I block can get converted in to
a non-depolarising type phase II block. The phase II block resembles to that of d-TC and can
be reversed by Neostigmine. Conversion from phase I to phase II is slow. During long
surgeries, d-TC like drugs are preferred over SCh because of uncertainty of phase I/phase II
in case of SCh. Only during short operative procedures, SCh is preferred because of muscle
relaxation in phase I.
Pharmacokinetics
SCh possesses two quaternary groups in its structure (Fig. 3.21). It is not absorbed if
given orally and does not cross bold-brain barrier or placental barrier. It is administered
intravenously in a dose of 0.75-1.5 mg/kg. The duration of action is very short (5-10
minutes). It is primarily due to hydrolysois by pseudocholinesterase present in plasma. Its
action is terminated by its diffusion from motor end plate to extra-cellular fluid. NMJ
blockade by SCh may be prolonged in patients with genetic variation having atypical
pseudocholinesterase. Ability of the enzyme pseudocholinesterase to metabolise SCh is
expressed as “dibucaine number”. For a normal person, dibucaine number is 80 and a
number less than 80 indicates proportionate concentration of atypical enzyme.
CH3 O O CH3
+ +
H3C N CH2 CH2 O C CH2 CH2 C O CH2 CH2 N CH3
CH3 CH3
Fig. 3.21: Structure of Succinylcholine
Pharmacodynamics
After a single intravenous dose of SCh fasciculations over chest and abdomen occur
briefly. Complete relaxation occurs within 1-2 minute and disappears within 5-10 minutes.
Twitches on cheek and abdomen appear first. Paralysis then spreads to neck, limbs, face,
trunk and then to respiratory muscles. The onset and recovery being rapid, the sequence of
paralysis is not distinguishable.
SCh stimulates ganglia due to agonistic action on NN receptor. Histamine release is less
than that of d-TC. Initial bradycardia due to stimulation of vagal ganglia is followed by
tachycardia and hypertension due to stimulation of sympathetic ganglia. However, blood
pressure is not affected much due to vasodilatation caused by muscarinic actions.
Adverse effects
• Hyperkalaemia
Efflux of potassium leads to hyperkalaemia. In susceptible patients like cases of burns,
spinal injury and uraemia, hyperkalaemia can precipitate arrhythmia or cardiac arrest.
• Malignant hyperthermia
It is a genetically inherited condition caused by mutation of calcium releasing channels
of sarcoplasmic reticulum. In susceptible individuals, persistent release of calcium leads
to persistent muscle contraction and increased heat production due to skeletal muscle
contraction. The condition may be aggrevated if general anaesthetics like Halothane are
used along with SCh.
• Muscle rigidity
It is yet another genetic abnormality caused by mutation of voltage sensitive sodium
channel. In such individuals SCh may complicate endotracheal tube insertion.
• Prolonged apnoea
Persons with atypical pseudocholinesterase show prolonged apnoea.
• Increased intra-gastric pressure
Nausea and vomiting with SCh occur due to increase in intra-gastric pressure as a
consequence of fasciculations.
• Rise in intra-occular pressure
The rise in intra-occular pressure is only for a short while (5-10 minutes). It occurs due to
contractions of myofibrils and partly due to transient dilatation of related blood vessels.
• Muscle soreness
Some patients show myoglobinuria following use of SCh. Hence, muscle soreness after
recovery is a common observation in such patients.
Synergists and antagonists
• Neostigmine potentiates phase I block caused by SCh.
• Hypothermia potentiates the action of SCh.
• Calcium channel blockers like Verapamil or Diltiazem enhance NMJ blockade caused
by SCh.
• Duration of action as well as toxicity of SCh increases in infants below 1 year,
patients with collagen disease, thyrotoxicosis and in patients with atypical pseudo-
cholinesterase.
SCh is available as injections of 50 mg/ml: SCOLINE, ENTUBATE, MIDARINE.
Therapeutic uses of NMJ blockers

• Adjuvant to general anaesthesia
All NMJ blockers (d-TC like drugs and SCh) are used to provide skeletal muscle
relaxation during abdominal or thoracic surgery and for endotracheal intubation. They
are also used to counteract laryngospasm during barbiturate anaesthesia. They are also
used to prevent muscle contractions during surgery. SCh is preferred for brief
procedures. For relatively long term use, d-TC like drugs are preferred based on their
pharmacokinetics.
• To prevent trauma during electro-convulsive therapy (ECT)
SCh with Diazepam is used to prevent injuries or fractures due to excessive convulsions
caused by ECT. The combination can also be used for reduction of fractures and other
orthopaedic surgeries.
• In different spastic conditions
In spastic conditions like tetanus or status epilepticus, NMJ blockers are used when
Diazepam alone is not sufficient.
• To control ventilation
In patients with obstructive airway disease, NMJ blockers eliminate chest wall resistance
and eliminate ineffective spontaneous ventilation.
3.6.2 Peripheral Skeletal Muscle Relaxants
There are some drugs which relax skeletal muscles because of their direct action. These
are called as peripheral muscle relaxants, directly acting muscle relaxants or spasmolytics.
Dantrolene is the only drug in this category.
Mechanism of action
Dantrolene acts directly at the contractile mechanisms of voluntary muscles by reducing
depolarisation-induced calcium release from sarcoplasmic reticulum. The contractile
responses are not absolutely abolished by Dantrolene. The drug facilitates action of GABA
resulting in depression of functions of brain stem and efferent motor neuron activity.
Cardiac muscles are not affected.
Pharmacokinetics
When given orally, it is poorly absorbed but absorption is consistent with rise in
proportionate plasma levels. Plasma half-life is 9-12 hours. It is given intravenously with a
dose of 1 mg/kg and repeated if necessary to a maximum of 10 mg/kg.
Pharmacodynamics
It is useful to treat spasticity resulting from upper motor neuron lesions caused by spinal
cord injury, multiple sclerosis and cerebral palsy. It is not useful in spasticity resulting from
musculo-skeletal injury or rheumatoid disorders.
Therapeutic uses
It is a drug of choice for the treatment of malignant hyperthermia which is a genetic
abnormality. Dantrolene is also used to treat neurolept-malignant syndrome.
Adverse effects
Generalised muscle weakness, sedation, diarrhoea and occasional hepatitis after
prolonged use have been reported.
3.7 LOCAL ANAESTHETIC AGENTS

Local anaesthetics (LA) reversibly block the impulse conduction and produce a transient
loss of sensation in a restricted region of the body. These drugs are preferred for performing
minor surgery. Unlike general anaesthetics, they neither cause a loss of consciousness nor
need a proper maintenance of vital functions during surgery.
Classification
LAs are classified as follows: (few examples are indicated in every category)
• Amide type
o Longer acting: Bupivacaine, Dibucaine
o Intermediate acting: Lidocaine, Mepivacaine
• Ester type
o Longer acting: Tetracaine
o Intermediate acting: Cocaine
o Short acting: Procaine, Benzocaine
• Miscellaneous: Pramoxine, Oxethazaine
Chemistry
Esters have part of carboxyl group (–COO) in its structure. Amides have amide group
(– NHCO) in its structure. Fig. 3.22 depicts structures of a representative ester and amide.
LAs are weak bases and exist in the form of acid salts. They have aromatic part in their
structure which are lipophilic in nature. They also have basic amine side chain, which is
hydrophilic in nature. Lipophilic component is necessary for penetration through nerve
membrane. Once inside the axon, it is the ionized form of LA which is active at the receptor
site. At physiological pH, Las remain partly ionized.
Ester/Amide
O C2H5
Procaine H 2N C O CH2 CH2 N
C2H5
Ester
O
Benzocaine H2N C O CH2 CH3
Ester
CH3
O C 2H 5
Lidocaine H 2N NH C CH2 N
Amide C 2H 5
CH3
Fig. 3.22: Chemical structures of few local anaesthetics
Mechanism of action
LAs block the voltage-gated sodium channels and consequently block the nerve
conduction by reducing permeability of sodium ions during depolarisation.
The blocking action of LA is favoured by depolarisation. A resting membrane is much
less sensitive to LA than one that is repetitively stimulated. The phenomenon is voltage-
dependent. The voltage-dependence of sodium channel opening reflects conformational
changes which results from voltage sensors due to difference in trans-membrane potential.
These voltage sensors are called as gates. Hence, these channels are referred as “voltage-
gated sodium channels”.
The sodium channels have an activation gate (AG) on its extracellular site and an
inactivation gate (IG) on its intracellular site. The voltage-gated sodium channels can exist in
three functional states as mentioned below:
• The resting or the closed state which prevails at the normal resting potential. In this
state the activation gate is closed.
• The activated or the open state which is favoured by brief depolarisation, which
opens the activation gate to allow sodium ions to flow inside along concentration
gradient.
• The inactivated or blocked state resulting from a trap-door like occlusion of the
channel by a floppy part of the intracellular region of the channel protein.
The flow of sodium ions ceases as soon as inactivation gate closes. After the action
potential, many sodium channels are in the inactivated state. They revert to their resting
state in a time-dependent manner and become available for activation once more. Fig. 3.23
depicts all these three states.
+
+
Na +
Extracellular Na + Na
BH B
AG
AG AG
IG IG IG
+
Intracellular LA receptor + LA receptor B BH
Na
Fig. 3.23: A model of voltage-gated sodium channel
The LA-receptor is located in the trans-membrane pore of sodium channel in its
intracellular half. The LA diffuses through the membrane in its unionised lipophilic form (B).
It then re-ionises as BH+ and binds to the LA receptor. The binding of LA to its receptor
stabilises the channel in its inactivated state. Then IG gets closed and sodium ion flow
ceases. (See Fig. 3.21). Thus, LAs prevent the initiation and propagation of the nerve impulse
by reducing the passage of sodium ions through voltage-gated sodium channels.
Effect of pH on LA action
Action of LAs is strongly pH-dependent. LA action is more in alkaline pH and less in
acidic pH. These drugs are weak bases and remain partly ionised and partly unionised at
physiological pH. The unionised form is needed for its diffusion through axonal membrane.
Once inside the axon, it is re-ionised and is in the cationic form (see Fig. 3.21) which binds to
LA receptor inside the channel. LAs are less effective in infected tissue, because in infected
area, the extracellular pH is acidic in nature. As a result, LA remains predominantly ionised
resulting in its poor diffusion through the nerve.
Prolongation of action by vasoconstrictors
Anything which delays absorption of LA in to the circulation will prolong its action and
reduce its systemic toxicity. Adrenaline, because of its vasoconstrictor action, prolongs the
duration of action of LAs. It is used in the concentration of 1 : 100,000 to 1 : 200,000 for
general purpose. In dentistry, the concentration range is 1 : 50,000 to 1 : 100,000. These
concentrations double the duration of LA action. Nor-epinephrine is usually not preferred
for the purpose.
Sometimes adrenaline may cause cardiac complications. In such cases an alternative
vasoconstrictor named Felypressin (a synthetic vasopressin) may be used as an alternative.
Pharmacokinetics
The presence of ester or amide bond in a LA molecule governs its biotransformation and
the possibility of causing hypersensitivity reactions.
• The ester-type LAs (e.g. Tetracaine, Chloroprocaine) are usually hydrolysed by
pseudocholinesterase or by liver esterases. Hence, they have a shorter duration of
action, in case of patients having genetic deficiency of the enzyme, the duration of
action of LAs may be prolonged.
• The amide type of LAs (Lidocaine, Bupivacaine) are degraded by hepatic micro-
somes. As a result they have a longer duration of action.
• Hypersensitivity reactions are common with ester type of LAs; because they are
hydrolysed to para-amino-benzoic acid (PABA). PABA or its derivatives are known to
be potential allergens.
• Since PABA antagonises actions of sulphonamides, LAs can antagonise anti-bacterial
action of sulphonamides.
• After oral ingestion, both Procaine and Lidocaine undergo significant first-pass
metabolism. Hence, they are not used to correct cardiac arrhythmia.
Therapeutic uses
The local anaesthesia induced by LA is designated according to the technique or
anatomical site where it is injected or applied. Thus, it is sub-classified in to following five
types:
(i) Topical anaesthesia
It is also termed as surface anaesthesia. It is restricted to mucus membranes, damaged
skin surface, wounds or burns. Surface anaesthetics do not work well on intact skin. The
corneal surface, mucosa of mouth, nose, pharynx, trachea and urethra are easily
anaesthetised. Surface anaesthetics can also be used to facilitate endoscopic procedures and
to reduce pain of haemorrhoids or anal fissures. Solutions, ointments or creams of LAscan
be applied to produce surface anaesthesia. The names of anaesthetics and their respective
concentrations used for topical/surface anaesthesia are:
Tetracaine: AMETHOCAINE, ANETHANE (2%), Lidocaine (2-5%), Benzocaine:
MUCOPAIN, ZOKEN (5%), Dycyclonine (0.5-1%), Proparacaine (0.5-1%) and Eutectic mixture
of Lidocaine (2.5%) and Prilocaine (2.5%).
(ii) Infiltration anaesthesia
In this case, the dilute solution of LA is injected under the skin to reach sensory nerve
terminals. Infiltration is used for minor surgical procedures like incisions or excisions.
Adrenaline or Felypressin may be added to retard absorption.
The available preparations are:
Lidocaine (1-2%): LIGNOCAINE, GESICAINE, XYLOCAINE, Bupivacaine (0.25%):
MARCAIN, BUPIVAN, Ropivacaine (0.5-1%), Mepivacaine (1-3%) and Prilocaine (1-4%):
PRILOX, ASTHESIA.
(iii) Conduction block anaesthesia
In this case, LA is injected around the nerve trunk so that the distal area around the site
of injection gets anaesthetised. It is of two types: Field block or Nerve block.
In case of field block, the LA is injected sub-cutaneously in the surrounding area of the
nerve so that all other nerves coming to a particular field are blocked. Field blocks are
applied to the scalp and interior abdominal walls where the nerve travels superficially to
supply the area.
In case of nerve block, the LA is injected around anatomically localised nerve trunks
i.e. close to the mixed nerve. The block is usually described like radial nerve block, ulnar
nerve block indicating name of the anaesthetised nerve. Nerve block lasts longer than field
block or infiltration anaesthesia.
In both the types, the LA is injected around the nerve and not in to the nerve. Any
injection in nerve is painful and can cause nerve damage. In both, field block and nerve
block same anaesthetics are used. Choice of anaesthetic depends on duration of action.
For duration of action of 2-4 hours, intermediate acting LAs like Lidocaine (1.5%) or
Mepivacaine (1.5%) are used. For longer duration, Bupivacaine (0.25-0.35%) is used.
Addition of epinephrine prolongs duration and reduces the plasma concentration of
intermediate acting LAs.
(iv) Central nerve block anaesthesia
It is further divided in to epidural and spinal block anaesthesia.
(a) Epidural block anaesthesia
It is also named as peri-dural block. It is widely used to provide analgesia or anaesthesia
in surgical or obstetric practice. It involves injecting a LA like Lidocaine, Bupivacaine or
Ropivacaine either alone or in combination with a small dose of opioid analgesic in to the
epidural space in the lumbar, thoracic or cervical regions to provide segmental analgesia.
One of these types is called as Caudal block which is administered in the caudal (sacral)
region.
(b) Spinal block anaesthesia
It is also named as sub-arachnoid or intra-thecal block anaesthesia. It can also be used
as spinal analgesia. It is produced by injecting a suitable LA in the spinal sub-arachnoid
space between L2 and L3 or L3 and L4. It is used to anaesthetise lower abdomen and hand
limbs. In this case, addition of vasoconstrictors like adrenaline is not preferred due to risk of
restricting blood supply. During late pregnancy, lesser amounts of LA are required.
Fig. 3.24 depicts various sites of application for local anaesthetics.
Infiltration
Spinal (subarachnoid space)
Nerve block
Dura
or conduction Topical or
surface
Arachnoid space
Sympathetic axon
Vertebra Muscle
Epidural
Fig. 3.24: Sites of application of local anaesthetics

Available preparations are Lidocaine (3-5%), Tetracaine (0.3-0.5%) or Bupivacaine (0.5-
0.7%).
(v) Intravenous regional anaesthesia
It is also named as Bier’s block. It is mainly used for the upper limb and for orthopaedic
procedures. In this case, the limb is first elevated to ensure venous drainage and then tightly
wrapped by an elastic bandage. Tourniquet is then applied proximally. Later, the elastic
bandage is removed and Lidocaine (0.5%) is injected intravenously, distal to the tourniquet.
Bupivacaine is avoided due to higher cardiac toxicity.
Available preparations are Lidocaine (0.5%) and Prilocaine (0.5%).
Following preparations are available for the purpose of different types of LAs:
Lidocaine: 2% jelly, 2% viscous preparation, 2% or 4% solution, 1% or 2% injection, 10% or
15% spray and combination product as (Lidocaine 53.3 mg/ml + dextrose 75 mg/ml) or with
adrenaline (Lidocaine 21.3 mg/ml + adrenaline 0.005 mg/ml): GESICAINE WITH
ADRENALIN, XYLOCAINE WITH ADRENALIN, injection or with Prilocaine as eutectic
mixture of (Lidocaine 2.5% + Prilocaine 2.5%).
Other available preparations are Bupivacaine (0.5%, 1%) injection, Tetracaine (1%)
cream.
Adverse effects
In general, adverse effects of all types of LAs are similar. They are mentioned below:
• CNS
At low doses, LAs cause tongue numbness, sleepiness, mild headache, visual and
auditory disturbances. At high concentrations they cause nystagmus and muscular
twitching. Profound CNS stimulation can cause convulsions. Cocaine may produce long
lasting CNS stimulation and euphoria. Cocaine is a drug of abuse and it is rarely used as
LA.
• CVS
LAs block sodium channels and depress abnormal cardiac pace-maker activity,
excitability and conduction. Most LAs produce hypotension. Bupivacaine is cardiotoxic
and can cause ventricular tachycardia and fibrillation. Lignocaine has a quinidine-like
action on heart and is used in the treatment of cardiac arrhythmia.
• Blood
Large doses of Prilocaine can cause accumulation of its metabolite called ortho-
toluidine, which oxidises haemoglobin to methaemoglobin. Higher levels of
methaemoglobin can cause cyanosis. Methylene blue or ascorbic acid can be a remedy
to restore haemoglobin.
• Allergic reactions
The ester type of LAs are metabolised to PABA or its derivatives, which are responsible
for allergic reactions in some individuals. The result is contact dermatitis, rashes and
asthma. Amide group of LAs do not cause allergic reactions.
Drug interactions
• Hypertensive patients receiving therapy of propranolol are sensitive to hypertensive
responses of adrenaline, present in few formulations of LA. Simultaneous blockade of
β1- and β2-receptors leads to an unopposed vasoconstriction by adrenaline because of
action on α1-receptors. Drugs like Haloperidol having α1-receptor blocking activity may
cause hypotension, if administered along with Xylocaine and adrenaline.
• Persons with acute alcohol intoxication need a higher dose of Xylocaine and adrenaline
combination for getting proper LA effects. As a result, availability of Xylocaine at the
desired site of action is reduced.
• Special care should be taken while giving injection of Xylocaine and adrenaline to a
patient of cardiac failure taking Digoxin because of possibility of developing cardiac
arrhythmias.
• In coronary care units, where Xylocaine is infused in large doses to treat ventricular
arrhythmias, co-administration of Propranolol can cause Xylocaine toxicity. This is
because Propranolol inhibits metabolic oxidation of Xylocaine. Propranolol also
decreases hepatic blood flow and thus diminishes its delivery to liver for metabolic
degradation.
3.8 DRUGS USED IN MYASTHENIA GRAVIS AND GLAUCOMA

Diseases like myasthenia gravis and glaucoma have different Pathophysiology as mentioned
below. Anti-cholinesterases are useful for treating myasthenia gravis. Glaucoma is treated by
different kinds of drugs. Drugs belonging to both these categories are discussed below:
3.8.1 Drugs for Myasthenia Gravis
Etiology and Symptoms
Myasthenia gravis is an acquired auto-immune disorder causing fatigue and weakness of
skeletal muscles. The disease is associated with production of IgG type of antibodies to ACh
receptors (NM) at the post-junctional motor end plate. In 90% of patients having this disease,
anti-ACh antibody titre is raised. Reduction in number of NM receptors results in reduction in
amplitude of the end plate potential which in turn fails to trigger an action potential.
The symptoms include weakness of muscle and fatigue which worsens after excersice
but goes off after rest. The weakness in muscles is not associated with pain. In early stages
of disease, the fast moving muscles are affected first. Hence, symptoms start with ptosis,
diplopia, slurring of speech, difficulty in swallowing and weakness of extremities.
Subsequently, all muscles are progressively affected including respiratory muscles. The
thymus shows abnormality in about 75% cases of myasthenia gravis.
Treatment of Myasthenia Gravis
Any reversible anti-AChE drug of intermediate duration of action is useful for treatment
of myasthenia gravis. Initially, the doses are given on an empirical basis but later titrated for
prolonged therapy.
Initially Neostigmine is given in a oral dose of 15-30 mg/day in divided doses or
0.5-2.5 mg as intramuscular or sub-cutaneous injection with gradual increment till
therapeutic goals are achieved. Alternatively oral Pyridostigmine 60 mg three times a day is
followed by gradual increase till satisfactory response. Another alternative is oral
Ambenonium 2.5-5 mg, every 6 hours.
Sustained release preparations of Pyridostigmine are also available, which can be given
at bed time. Longer acting AChE inihibitors like organophosphates are not used.
During prolonged therapy, titration of the dose is done. The patient’s condition may
swing between myasthenia gravis (due to lower doses of drugs) or cholinergic crisis (due to
toxicity of drugs). Both the conditions can end up in to muscular weakness. In such cases,
doses of anti-AChE drug need to be adjusted. Prior to such dose adjustments, Edrophonium
is given intravenously in a dose of 2 mg. If the condition worsens due to Edrophonium, the
muscular weakness is due to overdosing of AChE dose like Neostigmine. On the contrary, if
the condition of the patient improves after Edrophonium dose, the muscle weakness is due
to myasthenia gravis. Based on the response to Edrophonium, the dose of anti-AChE drug is
adjusted.
Drugs Causing Myasthenia Gravis

Following drugs are known to aggravate myasthenia gravis. See table 3.7. Doses of these
drugs should be reduced or these drugs may be withdrawn during treatment of myasthenia
gravis.
Table 3.7: Drugs which aggravate myasthenia gravis
Sr. No. Category of drug Examples
1. Antibiotics Aminoglycosides (Streptomycin, Gentamycin),
Polymixins, Colistin
2. Anti-arrhythmics Procainamide, Quinidine and Propranolol
3. CNS depressants Morphine (respiratory depression)
4. Miscellaneous d-TC, Quinine, Methoxyflurane and Lithium
Since etiology of myasthenia gravis originates in auto-immunity, drugs like
glucocorticoids (Prednisolone), immune-supperssants (Azathioprine, Cyclosporine) are used
to treat myasthenia gravis. In addition, techniques like thymectomy or plasmapheresis are
also used to treat myasthenia gravis.
3.8.2 Drugs for Glaucoma
Glaucoma is characterised by an increase in intra-occular pressure (IOP) which, if
persistent, can lead to damage to optic disc resulting in blindness. Usually glaucoma is
caused by impaired drainage of aqueous humour, produced by the ciliary epithelium in the
posterior chamber of the eye. Refer to Fig. 3.8. Normally, aqueous humour flows in to the
anterior chamber by passing between the lens and the iris and then out through the pupil.
Finally, it leaves the anterior chamber by flowing through the trabecular mesh work and in to
the canal of Schlemm (Fig. 3.8) which lies at the base of an angle formed at the intersection
of cornea and the iris. This region is called the ocular angle.
There are three types of glaucoma: primary, secondary and congenital. Treatment is
available for primary glaucoma and certain types of secondary glaucoma (after trauma or
after cataract operation). There is no treatment for congenital glaucoma.
The primary glaucoma is associated with a direct disturbance in outflow of aqueous
humour. It is divided in to two sub-types: narrow angle glaucoma and wide angle glaucoma.
(i) Narrow angle glaucoma (closed angle, acute congestive or angle closure glaucoma)
In this case, the pressure from the posterior chamber pushes the iris forward, closing the
ocular angle and preventing the drainage of aqueous humour. The iris may also physically
block the passage of aqueous humour through tne canal of Schlemm. This is medical
emergency. Patients present with a painful red eye, sweating, headache with nausea and
vomiting as a result of rise in IOP. The drugs may control the acute attack but the long range
treatment involves surgery.
(ii) Wide angle glaucoma (open angle, chronic simple glaucoma)
In this case, the ocular angle remains wide but the trabecular mesh work starts losing
patency due to progressive degeneration. As a result, the outflow of aqueous humour gets
impeded. In this type, the surgical intervention is not much helpful. Control of IOP is usually
dependent on long range drug therapy.
The cholinomimetic (parasympathomimetic) drugs decrease the IOP in both types of

glaucoma; however the mechanisms are different. In closed angle glaucoma, the papillary
constriction lowers the IOP by pulling the iris away from the trabecular mesh work with
consequent opening of the ocular angle. In wide angle glaucoma, it is the contraction of the
longitudinary ciliary muscle which stretches the trabecular mesh work and opens the tubules
to facilitate the drainage of aqueous humour leading to decrease in IOP.
The treatment is started with 0.5% Pilocarpine, three times a day as eye drops. If it is not
effective, Physostigmine may be added. The drugs used to treat glaucoma, along with their
mechanism and dosage is listed in table 3.8.
Table 3.8: Drugs used in treatment of glaucoma
Sr. Group Mechanism Drugs Dosage regimen
No.
1. Directly acting Contraction of Pilocarpine 0.5-4% topically
cholinomimetics ciliary muscle, thrice a day; or as
papillary sustained release
constriction, pulling ocular inserts
of iris, drainage of
aqueous humour,
decrease in IOP
2. Reversible anti- -do- Physostigmine 0.25-5% topically
AChE thrice a day
3. Reversible anti- -do- Demecarium 0.25-5% topically
AChE twice a week
4. Irreversible anti- -do- Ecothiophate 0.05-0.25%
AChE topically once in
two weeks
5. Irreversible anti- -do- Isoflurophate 0.03% topically
AChE
6. β-blockers Reduce formation Timolol 0.25-0.5% twice a
of aqueous humour day
7. β-blockers -do- Betaxolol 0.25-0.5% twice a
day
8. β-blockers -do- Levobunolol 0.25-0.5% once a
day
9. β-blockers -do- Carteolol 1% solution
topically
10. Non-selective Facilitate outflow of Epinephrine 0.5-2% topically
α-agonists aqueous humour
contd. …
11. Non-selective -do- Dpipvefrine 0.1% twice or

α-agonists thrice a day
12. Selective α2- Reduce formation Apraclonidine 0.5-1% topically
agonists of aqueous humour
13. Selective α2- -do- Brimonidine 0.2% topically
agonists
14. Carbonic Reduce formation Acetazolamide 250-500 mg three
anhydrase of aqueous humour times a day orally
inhibitors
15. Carbonic -do- Dorzolamide 2% solution twice
anhydrase a day topically
inhibitors
16. Carbonic -do- Brinzolamide 1% solution twice
anhydrase a day topically
inhibitors
17. Hypertonic Reduce IOP by Mannitol 20% Infused
solutions osmotic action intravenously
18. Hypertonic -do- Glycerol Given orally
solutions
19. Prostaglandins Reduce IOP by Latanoprost 0.005% solution
increasing outflow once daily
of aqueous humour
20. Prostaglandins -do- Bimatoprost 0.03% solution
once daily
QUESTIONS
1. Comment on organisation of nervous system.
2. Describe the role of autonomic nervous system.
3. Give a summary of effects of stimulation of sympathetic nervous system.
4. Give a summary of parasympathetic nervous system.
5. Compare and contrast parasympathetic nervous system with sympathetic nervous
system.
6. Discuss distribution and functions of adrenergic receptors.
7. Classify neurotransmitters with suitable examples.
8. Discuss the process of biosynthesis, storage and release of Ach.
9. Discuss the process of biosynthesis, storage and release of adrenaline/nor-
adrenaline.
10. Comment on metabolism of caecholamines.
11. Classify muscarinic receptors.

12. Classify α-receptors.
13. Classify β-receptors.
14. Give a summary of therapeutic uses of anti-muscarinic drugs.
15. Comment on clinical uses of blockers of α-receptors.
16. Comment on clinical uses of β-receptors.
17. Comment on non-catecholamine sympathomimetics.
18. Write pharmacological actions, mechanism of action, clinical uses and adverse
reactions to Clonidine.
19. Write pharmacological effects of Amphetamine.
20. Write pharmacological actions, clinical uses and adverse effects of Prazosine.
21. Describe pharmacological actions of Propranolol.
22. Classify β-blockers with suitable examples.
23. Comment on mechanism of action of neuromuscular blocking agents.
24. Discuss pharmacodynamic effects of dTC.
25. Comment on pharmacokinetics and pharmacodynamics of succinyl choline.
26. Classify local anaesthetics and elaborate their mechanism of action.
27. Comment on etiology, symptoms and treatment of myasthenia gravis.
28. With suitable examples comment on drugs aggravating myasthenia gravis.
29. What is pathophysiology and treatment for glaucoma.
• Neurotransmission
• Neuromodulation
• Neuromediation
2. Write short nots on:
• Effects of ACh on eye.
• Muscarinic receptors
• Nicotinic receptors
• α-receptors
• β-receptors
• Physostigmin
• Neostigmine
• Beladona poisoning
• Pilocarpine
• Glaucoma
• Atropine
• Dicyclomine
• Endogenous catecholamines.
• Dale’s vasomotor reversal
• Isoprenaline
• Clonidine
• Ergot alkaloids
• dTC
• Succinyl choline
• Dantroline
• Pharmacokinetics of local anaesthetics
• Drug interactions of local anaesthetics
• Adverse effects of local anaesthetics
Unit ... 4
PHARMACOLOGY OF
CENTRAL NERVOUS SYSTEM - I
• Neurohumoral transmission in CNS with special emphasis on GABA, Glutamate, Glycine, 5-HT,
Dopamine
• Pharmacology of general anaesthetics/pre-anaesthetics
• Pharmacology of sedatives, hypnotics and centrally acting muscle relaxants
• Pharmacology of antiepileptics
• Pharmacology of alcohol
4.1 ORGANISATION OF CNS

The brain works through chemical neurotransmission. It is concerned with all processes
in the body like circulation, digestion, respiration, movements, psychic processes like
emotional feelings, attitude, thoughts, memory including balanced co-ordination. It also
secretes certain hormones which control various functions in the body. The brain is
protected by a specialized system of capillary endothelial cells known as blood-brain-barrier
(BBB). The role of BBB is as follows:
• To preserve the internal environment of the brain.
• To maintain the desired concentration of nutrients and to regulate the levels of
circulating neurotransmitters such as E, NE ACh, 5-HT, and DA.
• To protect the brain tissue, both from toxic substances which may circulate in blood
and also from neurotransmitters like E, NE, ACh and DA, which are released
peripherally but can also bind to CNS receptors to cause adverse effects.
The BBB does not cover all parts of the brain. The organs of CNS not covered by BBB
include the following:
• Area posterma (beneath the floor of fourth ventricle i.e. CTZ) and vomiting centre.
• Pineal gland
• Pituitary gland
• Median eminence
• Choroid plexus capillaries
(4.1)
Pharmacology - I (B.Pharm. Sem. IV) 4.2 Pharmacology of Central Nervous System - I
Cerebral cortex
Thalamus
Hypothalamus
Amygdala
Hippocampus
Pons Cerebellum
Medulla
Spinal cord
(a) Anatomical structures in the brain

Central sulcus Primary somatosensory
Primary motor cortex
cortex area
Parietal lobe
Frontal lobe
Occipital lobe
Prefrontal cortex
Cerebellum
Temporal lobe Spinal cord
(b) Regions of cerebral cortex

Fig. 4.1
The major anatomical divisions of the brain (Fig. 4.1) are as follows:
• Cerebrum (cerebral cortex of cerebral hemispheres)
• Sub-cortical region including thalamus and hypothalamus (diencephalon)
• The mid-brain (the upper segment of brain stem)
• The hind-brain composed of pons, medulla and cerebellum.
• The spinal cord
The cerebrum (cerebral cortex) is the largest part of the human brain and is divided in to
left and right hemispheres. Left hemisphere is associated with logic and reasoning while the
right hemisphere is related to creativity. The cerebral cortex consists of four regions as
mentioned below (Fig. 4.1):
• The frontal cortex, which is associated with higher cognitive functions and long-term
memory storage. The posterior part of the frontal cortex, called as primary motor
cortex controls fine movements.
• The parietal lobe integrates and processes sensory information from touch, muscle
stretch receptors and joint receptors. Hence, it is called as somato-sensory cortex.
• The temporal lobe is involved in auditory functions and language and also processes
sensory information originating from ears and vestibular organs.
• The occipital lobe is involved in visual processing and receives information from
visual pathways. It is also referred as visual cortex.
Major cholinergic and dopaminergic pathways pass through cerebral cortex region.
The thalamus has both sensory and motor functions. It is a relay centre for sensory
pathways to the cortex. It is related to appreciation of pain, temperature and crude touch
sensation. The hypothalamus located below thalamus is involved in homeostasis, emotion,
thirst, hunger, circadian rhythm and control of autonomic functions. It also controls pituitary
gland. The limbic system consists of hippocampus (involved in learning and memory), the
amygdale (associated with emotions, fear and memory) and the ventral tegmental area or
nucleus accumbens (involved in addiction). Thus, the limbic system consists of structures
below the cerebral cortex which control emotions and instincts along with motor and
visceral activities. The basal ganglia is a part of extra-pyramidal system consisting of corpus
striatum (caudate nucleus + putamin + globus pallidus) and substantia nigra. It provides
extra-pyrimidal control of skeletal muscle tone and its co-ordination with posture. Its
degeneration produces tremors and rigidity. It contains the major dopaminergic pathway of
the CNS.
The reticular formation is a heterogenous mass of cell bodies embedded in a network of
dendrites and axons located in the central core of medulla, pons and mid-brain. It is a
diffused multi-synaptic system. A complex interrelated group of pathways passing through
the reticular formation is called as reticular activating system (RAS). It is intimately related to
sleep-wakefulness cycle and co-ordination of gaze and eye movements. All sensory
information is rooted through the RAS. It also controls the muscle tone, posture and vital
functions like respiration and circulation. It has major monoamine containing neurons of the
brain.
The medulla and pons (including mid-brain) are called as brain stem and are involved in
vision, hearing and in body movements. The medulla regulates vital functions like breathing
and heart rate. The pons control motor and sensory functions and plays a vital role in
consciousness and sleep. The cerebellum is associated with the control of vestibular
functions, body posture and balance. Cerebellum and brain stem relay information from the
cerebral cortex and the limbic system to the spinal cord. The spinal cord integrates the
sensory and motor reflexes and also controls the muscle tone.
4.2 NEURO-HUMORAL TRANSMISSION IN THE CNS, SPECIAL EMPHASIS
ON IMPORTANCE OF VARIOUS NEUROTRANSMITTERS LIKE GABA,
GLUTAMATE, GLYCINE, SEROTONIN, DOPAMINE
4.2.1 Neurohumoral Transmission in the CNS
Four processes occur in relation to nerve transmission within the CNS. These processes
are mediated through different transmitters. They are as follows:
• Neurotransmission occurs through neurotransmitters, which are released in to
synaptic cleft to rapidly stimulate or inhibit the post-synaptic neurons.
• Neuro-modulation occurs through neuromodulators, which are releasd by neurons
and by astrocytes and act either to slow or enhance the pre- or post-synaptic
responses.
• Neuromediation occurs through neuromediators, which are second messengers like
cAMP, cGMP and IP3.
• Neurotropic effects occur through neurotropic factors, which are secreted by

neurons, astrocytes, microglia and act over a longer time to regulate the growth and
morphology of neurons.
Some of the major neurotransmitters are discussed beolow:
4.2.2 GABA
GABA (Gamma-Aminobutyric Acid) is a major inhibitory neurotransmitter in mammalian
CNS. It is present fairly uniformly in the brain. Very little amount exists in the periphery.
GABA is synthesised from glutamate by the action of enzyme L-glutamic acid-1-
decarboxylase (GAD). (Fig. 4.2). It is further metabolised by GABA transaminase (GABA-T) to
succinic semi-aldehyde and succinic acid. Glutamate needed for synthesis of GABA is formed
mainly from the TCA cycle product (α-oxaglutarate) by the action of enzyme GABA-T. Two
types of GABA receptors have been identified: GABAA and GABAB.
Glutamate a-oxoglutamate
GAD
GABA Succinic
semialdehyde
+
Succinic acid
Fig. 4.2: Synthesis and Metabolism of GABA

4.2.2.1 GABAA Receptors
These are ionotropic receptors. They are most prevalent receptors. They are located
post-synaptically and are directly linked with chloride ion channel opening which causes
hyper-polarisation and reduction in the membrane excitability. Muscimom is an agonist of
GABAA receptors, while Bicuculline is its antagonist. The receptor has several different
accessory binding sites as shown in Fig. 4.3. The sites are as follows:
• GABA binding site.
• The modulatory sites to bind Benzodiazepines (BZDs); their antagonists like
Flumazenil and inverse agonist like carbolins also bind to the same site.
• The modulatory as well as blocking site at chloride ion channel as for barbiturates
and picrotoxin. -
Cl Modulatory site
GABA binding sites
_
+ Benzodiazepines
GABA _ Flumazenil (antagonist)
_
Inverse agonist
(b-carbolines)
Membrane
_ +
Picrotoxin - Barbiturates channel
Cl modulators
channel blockers
(a) Hypothelical model of GABAA receptor-chloride ion channel complex
-
Cl
GABA binding site GABA binding site
b
Muscimol b a a
Bicuculline Benzodiazepines
g
Flumazenil
Inverse agonist
Outside Barbiturates
Picrotoxin Membrane
Inside
Neurosteroids
Ion chennel
-
Cl
(b) Sites of various drugs action
Fig. 4.3
These receptors have a pentameric structure assembled from five sub-units selected
from seven polypeptide classes, named as α, β, γ, δ, ε, θ, ρ (alpha, beta, gamma, delta,
epsilon, theta and rho respectively). The major isoform of GABAA receptor in the brain
consists of five sub-units, namely two α1, two β2 and one γ2 sub-units. It is known that
binding of GABA with its site, located between α1 and β2 sub-units, triggers chloride channel
opening with resultant membrane hyper-polarisation. Binding sites for BZDs lies between α1
and γ2 sub-units which facilitates GABA binding to its receptor sites and increases the
frequency of chloride channel opening.
The adjacent site between α and β sub-units of GABAA receptors are the functional
receptional receptors which respond to barbiturates but not to BZDs. Convulsants like
Picrotoxin block the chloride ion channel directly. Sites of action for few other drugs have
been indicated in Fig. 4.3.
4.2.2.2 GABAB Receptors
Unlike GABAA receptor, GABAB receptor is not modulated by BZDs or barbiturates. It is
not linked to chloride channel. It is a G-protein coupled receptor. Its activation decreases
formation of cAMP. These receptors cause pre- and post-synaptic inhibition (hyper-
polarisation) by inhibiting calcium channel opening and increasing K+ conductance. The
peripherally acting skeletal muscle relaxant, Baclofen, is a GABAB receptor agonist and is
used to treat spastic disorders. The competitive antagonist for GABAB receptor is Saclofen,
which has no clinical use.
4.2.3 Glutamate
In brain, glutamate (GLU) is synthesised in the nerve terminals from two sources: from
glucose via Krebs cycle and transamination of oxaglutarate (Fig. 4.2) and from glutamine
which is synthesised in the glial cells (Fig. 4.4). GLU is stored in synaptic vesicles and released
by calcium dependent exocytosis. After release and action, GLU is recaptured by neuronal
GLU-transporters (GTn) in to the neuron and by glial type transporters (GTg) in to the glial
cells. Glial glutamate is then converted to glutamine by the enzyme glutamine synthetase.
Later, glutamine enters the adjacent neuron to replenish the glutamine after hydrolysis by
mitochondrial glutamase. (Fig. 4.4). Thus, glutamine serves as a pool of inactive transmitter
within glial cells.
Neuron Glial cell
GTM GTM GTM

2 1
GTn
GLU
GLU
GTg
GLU
GLU-R
Key: GLU-R – glutamate receptor; GTM – glutamine; GTn – glutamate transporter neuronal
type; GTg – glutamate transporter glial type; (1) glutamine synthetase; (2) glutaminase
Fig. 4.4: Synthesis, Storage, Release and Metabolism of GLU
GLU and aspartate (ASP) are the excitatory neurotransmitters widely concentrated in
cortex, basal ganglia and sensory pathway. Five different types of glutamate receptors have
been identified. Out of these five types, three (NMDA, AMPA and Kainate)are ionotropic
receptors. The other two are metabotropic receptos. Role of metabotropic receptors is being
unfolded by new research. Ionotropic receptors are discussed below.
4.2.3.1 NMDA Receptors
NMDA refers to N-methyl-D-aspartate. The receptors are involved in a wide range of
diverse functions like memory acquisition, development of synaptic plasticity, epilepsy and
the neuronal excitotoxicity due to cerebral ischaemia. NMD receptor is a pentamer,
composed of two different sub-units called as NR1 and NR2. It is ligand-gated ion channel
receptor with high permeability to calcium and sodium ions. It has a wider distribution in
brain (hippocampus, cerebral cortex, glial cells) and spinal cord. The receptor has atleast six
binding and modulatory sites. The model of receptor is shown in Fig. 4.5.
2+ Glycine
Ca +
Glutamate Na
+
+
2+ _
Zn Polyamines
_ _
2+
Mg PCP/Ketamine
Fig. 4.5: Hypothetical model of NMDA receptor
4.2.3.2 AMPA and Kainate Receptors

AMPA refers to α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid. Both AMPA
and Kainate receptors mediate fast excitatory synaptic transmission associated with influx of
sodium ions through sodium channels. Both are different than NMDA receptor.
AMPA receptors are pentamers consisting of GLUR1-4 sub-units. Kainite receptors are
also pentamers but consist of GLUR5-7 and KA1-2 sub-units. Domoate and Kainate are the
preferred agonists to kainite receptors.
Both NMDA and metabotropic receptors play an important role in long-term adaptive
changes (synaptic plasticity) as well as pathological changes (excitotoxicity) in the brain.
Normal stimulation of glutamate receptor plays a central role in learning and memory but
over-stimulation of glutamate receptor, particularly NMDA type results in excitotoxicity in
brain leading to neuro-degeneration and apoptosis.
4.2.4 Glycine
It is an inhibitory neuro-transmitter, enriched in medulla, spinal cord, the lower brain
stem and retina. It is structurally and functionally similar to GABAA receptor and is directly
linked to chloride ion channel. Strychnine-sensitive glycine receptor is a pentameric
structure, α sub-unit of which binds both to glycine and strychnine. Strychnine is a
competitive antagonist at glycine receptor.
Activation of NMD receptors requires low concentration of glycine along with glutamine.
Binding sites of glutamate and glycine are different but both have to be occupied; only then
the receptor channel opens.
4.2.5 Serotonin (5-Hydroxytryptamine, 5-HT)
5-HT has diverse pharmacological and physiological roles which include as a
neurotransmitter in CNS, as a regulator of smooth muscle function in CVS and GIT and as
regulator of platelet function, besides other subsidiary roles in several functions.
(a) Distribution, Biosynthesis, Release and Metabolic Degradation
5-HT is formed by dietary tryptophan which is converted to 5-hydroxy tryptophan by the
enzyme Tryptophan hydroxylase. 5-hydroxy tryptophan is further converted to 5-HT by a
non-specific aromatic L-amino acid decarboxylase (dopa decarboxylase). (Fig. 4.6). 5-HT is
stored in specialised cells like enterochromaffin cells and neurons as co-transmitter together
with various peptide hormones like somatostatin, vasoactive intestinal peptide (VIP) and
substance P.
Tryptophan
Tryptophan 5-Hydroxytryptophan
(from diet) Hydroxylase
Aromatic L-amino
acid decarboxylase
5-Hydroxytryptamine
(5HT/serotonin)
MAO
5-Hydroxyindole Aldehyde 5-Hydroxyindole

acetic acid dehydrogenase acetaldehyde
(5 - HIAA)
Fig. 4.6: Biosynthesis and Metabolism of 5-HT
Degradation of 5-HT occurs through oxidative deamination by MAO, to 5-hydroxy

indole acetaldehyde followed by its oxidation to 5-hydroxy indole acetic acid (5-HIAA),
which is excreted in urine.
(b) Pharmacological Actions of 5-HT
Various actions of 5-HT, evident on different systems are indicated below:
(i) CNS
5-HT is involved in the regulation of mood, behaviour, sleep, depression, pain
perception, sexual activity, thermo-regulation and in the hypothalamic control of the release
of pituitary hormones. 5-HT is also synthesised in pineal gland where it is precursor for the
synthesis of melatonin, a melanocyte stimulating hormone, which influences sleep. Externally
injected 5-HT does not cross BBB.
(ii) CVS
5-HT directly causes contraction of vascular smooth muscle (including intra-cranial
vessels), except in skeletal muscles and heart where it causes vasodilatation and bradycardia.
When injected intravenously, it produces a typical triphasic response. There is an early sharp
fall in heart rate and blood pressure. The bradycardia is mediated by vagal outflow to the
heart and can be blocked by atropine. The hypotension is a consequence of decrease in
cardiac output caused by bradycardia. Thereafter there is a rise in blood pressure due to
peripheral vasoconstriction and increase in cardiac output. Finally, there is a sustained
hypotension due to dilatation of blood vessels of skeletal muscles. Still, 5-HT is not involved
in physiological regulation of blood pressure.
5-HT causes blood platelets to aggregate by activating 5-HT2A receptors and the
aggregation is followed by further release of 5-HT. If the endothelium is damaged, the
release from adherent platelet causes vasoconstriction which impairs blood flow. Platelet-
derived 5-HT plays an important role in vascular diseases.
(iii) GIT
5-HT stimulates peristalisis and gastric secretions via 5-HT4 receptors. Activation of 5-HT4
receptors in CNS causes increased release of ACh, which mediates a pro-kinetic (motility
enhancing) effect of 5-HT. Some of the 5-HT4 receptor agonists like Cisapride and
Mozapride are also pro-kinetic. Overproduction of 5-HT, as in carcinoid tumour (a tumour of
enterochromaffin cells) is associated with severe diarrhoea.
(iv) Miscellaneous Effects
• 5-HT, like Histamine, stimulates perception of pain and itch by activating 5-HT3
receptors on afferent nerve endings.
• 5-HT constricts bronchial smooth muscles by facilitating ACh release from bronchial
nerve endings. It may result in hyperventilation due to stimulation of bronchial
sensory nerve endings by 5-HT.
• 5-HT reduces food intake and also has an anorexigenic effect.
(c) Location and Importance of 5-HT

Serotonergic neurons are found near the middle raphe nuclei of the brain stem and
project to the cortex, cerebellum and the spinal cord. About 90% of the serotonin in the
body is found in enterochromaffin cells in the GIT and remaining 10% is shared by platelets
and the brain. Serotonergic system plays an important role in schizophrenia, depression,
temperature regulation and eating disorders. In addition, serotonin is synthesised in the
pineal gland where it serves as a precursor for the synthesis of melatonin.
(d) 5-HT Receptors
5-HT acts on more than a dozen receptor sub-types. Mainly there are seven main types
of receptors (5-HT1, 5-HT2,…5-HT7). Of these, 5-HT1 and 5-HT2 are sub-divided further.
Except for 5-HT3 sub-type which is ionotropic, all others are metabotropic (G-protein
coupled) receptors. 5-HT1A agonists (Buspirone) are used to treat anxiety disorders; 5-HT1D
receptor agonists (Sumatriptan) are used to treat migraine and cluster headaches; 5-HT2A/2C
antagonists (Clozapine) are used to treat schizophrenia, while 5-HT reuptake inhibitors
(SSRIs Fluoxetine) are used to treat depression and obsessive-compulsive disorders.
(i) 5-HT Receptor Agonists
5-HT has no clinical application as drug. However, following selective agonists have
therapeutic value:
• Bispirone group of anti-anxiety drugs are partial agonists of 5-HT1A receptors in CNS.
• Sumatriptan and its conginers are selective agonists of 5-HT1D receptors, which being
cerebral vasoconstrictors are useful to treat acute migraine attacks.
Dosage of Sumatriptan is 25-100 mg as a single oral dose. It is less effective orally. Sub-
cutaneous injection is repeated once in 24 hours. It is also given as 5-20 mg nasal spray
to a maximum of 40 mg in 24 hours.
Other drugs in this category are Almotriptan, Eletriptan, Naratriptan, Zolmitriptan and
Rizatriptan.
• Cisapride and Renzapride are selective 5-HT4 receptor agonists which increase GIT
motility and are used to treat gastro-esophageal reflux disease (GERD). Tegaserod is a
new addition in this category.
• Dexfenfluramine is a non-selective 5-HT receptor agonist. It blocks 5-HT transporter
and inhibits 5-HT uptake. It was earlier used as appetite suppressant. It is withdrawn due
to cardio- and neurotoxicity. Sibutramine also acts similar to Dexfenfluramine, and is
used to treat obesity.
• d-Lysergic acid diethyl amide (LSD) is another non-selective 5-HT receptor agonist.
It is a potent hallucinogen and a drug of abuse.
Sumatriptan is available as tablets of 25 mg, 50 mg and 100 mg. It is also available as
6 mg/ml injection.
(ii) 5-HT Receptor Antagonists

Clinically useful 5-HT antagonists are discussed below:
Ketanserin and Ritanserin are antagonists of 5-HT2A receptors. Ketaneserin is an anti-
hypertensive drug due to its α1- adrenoceptor blocking action. In addition, due to blockade
of 5-HT2A receptors, they antagonise platelet aggregation caused by 5-HT. This action
provides symptomatic relief in conditions like Raynaud’s disease. Ritanserin is a conginer of
Ketanserin. It is more selective 5-HT2A antagonist and has insignificant α1 blocking action. It
reduces thromboxane formation and increases bleeding time by inhibiting platelet
aggregation time.
Ondansetron, Dolasetron and Granisetron are 5-HT3 receptor antagonists and are
used for treating chemotherapy-induced emesis.
Clozapine, Olanzapine, Quetiapine and Risperidone are 5-HT2A and 5-HT2C receptor
antagonists. In addition, they are also dopamine receptor antagonists and are used as a
typical anti-psychotic agents.
Methysergide is one of the ergot alkaloids. It is a potent 5-HT2A-2C antagonist with some
non-selective action on 5-HT1 receptors. Earlier it was used for prophylaxis of migraine. Its
use is declining.
Cyproheptadine has 5-HT2A receptor antagonist action along with histamine H1
blocking effect. It has a mild anti-cholinergic activity and CNS depressant effect. It is useful
in controlling skin allergies and in cold urticaria.
(iii) 5-HT Receptor Partial Agonists/Antagonists
Ergot alkaloids possess partial agonist-antagonist actions on 5-HT receptors. The most
important alkaloids in this group are Ergotamine and Dihydroergotamine. Both are partial
agonists/antagonists on 5-HT1 receptors. Ergometrine is a uterine stimulant and 5-HT2
receptor agonist. It is used in obstetric practice to prevent post-partum haemorrhage. Ergot
alkaloids are contraindicated in pregnancy, peripheral vascular disease, coronary artery
disease and hypertension.
4.2.6 Dopamine (DA)
It is the most important of the biogenic neurotransmitters in CNS. Parkinson’s disease is
characterised by a marked reduction in the concentration of DA in basal ganglia, while in
schizophrenia there is dopaminergic overactivity in the pathway of brain which controls
behaviour. DA is primarily an inhibitory neurotransmitter. Its deficiency causes extra-
pyramidal disturbances.
Five types of DA receptors (D1 ro D5) have been identified. Among them D1 and D5
belong to one group, while D2, D3 and D4 belong to another group. D1 and D5 stimulate
release of cAMP by activation of adenylyl cyclase and also stimulate phosphatidyl inositol
(PIP2) hydrolysis. These receptors are coupled to GS protein (metabotropic rececptors). Its
inhibition causes extra-pyramidal disorders. Unlike this, D2, D3 and D4 receptors inhibit cAMP
release, block calcium ion channels and open potassium ion channels. These are coupled to
G1 proteins and are involved in control of behaviour, voluntary movements, prolactin release
and in other endocrine consequences. Some of the atypical neuroleptics possess
antagonistic properties D3 and D4 receptors.
4.3 GENERAL ANAESTHETICS AND PRE-ANAESTHETICS

The distinguishing features of general anaesthesia include varying degree of analgesia,
amnesia, loss of all sensations, reflexes and consciousness. In addition, it also involves
relaxation of muscles with partial loss of homeostatic control over respiratory and
cardiovascular functions. General anaesthesia develops in to four different stages after
administration of general anaesthetics. The stages are as follows:
4.3.1 Stages of Anaesthesia
Stage I
It is the state of analgesia, because sensory transmission in spino-thalamic tract is
inhibited. There is no amnesia. Consciousness and sense of touch are present, while sense of
hearing is enhanced.
Stage II
It is the state of excitement and delirium. The patient shows violent behaviour and is
amnesic. There is irregular rise in blood pressure and respiratory rate. To avoid these
symptoms, a short acting barbiturate like thiopental sodium is given intravenously before
administration of inhalation anaesthetic.
Stage III
It is the stage of surgical anaesthesia. Regular respiration and relaxation of skeletal
muscle occurs during this stage. It is divided in to following four planes:
• Plane 1: During this plane, there are revolving movements of eye balls which while
attaining plane 3 get fixed. Respiration and skeletal muscle tone are normal.
• Plane 2: Most surgical procedures are performed during this plane. There is
progressive loss of corneal, light and laryngeal reflexes. Respiration is slow but
regular.
• Plane 3: It is a plane of marked muscle relaxation. Respiration is abdominal. Eye ball
movement is absent. Pupils are dilated. Light, corneal and laryngeal reflexes are
absent.
• Plane 4: It is a plane of complete muscle relaxation. Pupils are dilated. There is
complete loss of light, corneal and laryngeal reflexes. Respiration is abdominal.
Stage IV
It is a stage of medullary paralysis. It appears due to overdose of the general anaesthetic.
During this stage, there is severe depression of respiratory centre and vasomotor centre in
medulla. The stage is fatal causing death of the patient.
The most reliable index for attainment of stage III is loss of corneal reflex and
establishment of regular respiratory pattern. A fall in BP, cardiac and respiratory depression
are the signs of deep anaesthesia. As against this, resistance to insertion of endotracheal
tube is the sign of light anaesthesia. Monitoring of vital signs reduces the dose requirement
of general anaesthetic which contributes to rapid recovery from general anaesthesia.
4.3.2 General Anaesthetics

They are classified as inhalation anaesthetics and intravenous anaesthetics. Their names
are given below:
• Inhalation Anaesthetics
They exist in two forms: gas or liquid. The only gas used for the purpose is nitrous oxide.
The halogenated liquids are Halothane, Methoxyflurane, Enflurane, Isoflurane,
Sevoflurane and Desflurane.
• Intravenous Anaesthetics
They are sub-classified as fast inducers, slow inducers and dissociative anaesthetics.
o Fast inducers are either barbiturates or non-barbiturates. Examples of barbiturates
are Thiopental and Methohexital. Examples of non-barbiturates are Propofol and
Etomidate.
o Examples of slow inducers are Benzodiapines like Diazepam, Lorazepam and
Midazolam.
o Ketamine is the only dissociative anaesthetic.
Pharmacokinetic Principles
There are three factors which need attention. They are induction, maintainence and
recovery. The principles of pharmacokinetics should be understood in the context of these
factors.
• Induction
It means the time interval between the administraton of anaesthetic drug and the
development of stage of surgical anaesthesia. Lipophilicity is the key factor governing
pharmacokinetics of inducing drugs. Being highly lipophilic, after a single intravenous
bolus injection, these drugs preferentially enter in the brain. Redistribution out of CNS in
to muscle, viscera and lipophilic adipose tissue are the main causes for termination of
action.
• Maintainence
It is the period during which the patient remains in a sustained stage of surgical
anaesthesia (stage III, plane-2). During this stage, the anaesthesiologist monitors the
patient’s vital signs and response to various stimuli by controlling concentration of
anaesthetic to be inhaled or infused based on depth of anaesthesia. The factors which
influence uptake and distribution of the anaesthetic, govern the rate at which an
effective concentration of the anaesthetic reaches the brain. This requires transfer of
anaesthetic from alveolar air to the blood and then to the brain. The rate of transfer
depends on following factors:
o Alveolar wash-in
o Solubility characteristic of anaesthetic drug
o Concentration of the drug in the inspired air
o The pulmonary ventilation rate
o Cardiac output
o The partial pressure gradient of the drug between arterial and venous blood before
its redistribution
• Recovery
The recovery phase starts when the anaesthetic drug is discontinued. During this phase,
the anaesthesiologist has to ensure that there are no delayed toxic reactions. Frequently,
oxygen is given during last few minutes of anaesthesia and in early post-anaesthetic
period. Metabolism of anaesthetic is an important factor during recovery. The gradation
of metabolism of anaesthetics by liver is as follows: methoxyflurane > halothane >
enflurane > sevoflurane > isoflurane > desflurane > nitrous oxide. Nitrous oxide is
almost totally washed out by exhalation.
Potency of Inhaled Anaesthetics
The potency of inhaled anaesthetics is quantified by the term Minimum Alveolar
Concentration (MAC). MAC is the minimum concentration of the anaesthetic which is
required to prevent movement in 50% of patients in response to a standard surgical skin
incision. MAC values are expressed as percentage of anaesthetic gas in the inspired mixure.
Smaller MAC values indicate greater potency of anaesthetic. Higher the lipid solubility of the
anaesthetic, lower is its MAC value.
MAC value of an anaesthetic decreases with age, hypothermia and by concurrent use of
CNS depressant drugs like sedative-hypnotics, anxieolytics and narcotic analgesics. Sex,
species, acid-base balance and changes in arterial blood pressure do not influence MAC. The
rank order of MAC values (%) of different inhalation anaesthetics is: methoxyflurane (0.16%)
< halothane (0.75%)< isoflurane (1.2%) < enflurane (1.7%) < sevoflurane (1.9%) < desflurane
(6%) < nitrous oxide (> 100%). The MAC value of nitrous oxide indicates that it is least
potent. It indicates that even if 100% of nitrous oxide gas is inspired, its potency is still not
equal to 1 MAC.
Mechanism of Action
Inhalation anaesthetics are non-selective in their action. At molecular level, anaesthetics
interact with hydrophobic regions of neuronal membrane proteins which are on interface
with membrane lipids. Inhaled anaesthetics like barbiturates, benzodiazepines, etomidate
and propofol facilitate GABA-mediated inhibition and there by increase chloride ion flux
through its channel. Ketamine blocks the action of glutamate on NMDA receptor. Inhalation
anaesthetics like enflurane and isoflurane decrease the duration of opening of nicotine
receptor activated sodium ion channels leading to decrease in excitatory effects of ACh at
cholinergic synapses. By influencing neuronal membrane proteins, general anaesthetics
disrupt neuronal firing and sensory processing in the thalamus, causing loss of
consciousness and analgesic effects. In addition, motor activity reduce because they
decrease neuronal output from the internal pyramidal layer of cerebral cortex.
4.3.2.1 Specific Inhalation Anaesthetics
(i) Nitrous Oxide
It has a mild sweetish smell. It is neither inflammable nor explosive. It is used to maintain
surgical anaesthesia with 30% oxygen and other volatile anaesthetics like halothane,
isoflurane or propofol and a muscle relaxant if required.
It has a strong analgesic action. Inhalation of 50% nitrous oxide and 50% oxygen has
effects comparable to standard dose of morphine. Induction is rapid and recovery takes only
4 minutes. It has no adverse effects on CVS, respiratory system, kidney and liver.
It is less potent; does not cause bronchodilation and has no muscle relaxant effects. The
incidence of post anaesthetic nausea and vomiting increases with the duration of
anaesthesia. Exposure for more than 4 hours can cause megaloblastic changes in bone
marrow.
(ii) Halothane
It is a halogenated volatile anaesthetic. It is relatively inexpensive. It has a mild sweetish
odour, non-irritant and non-inflammable. It is a poor analgesic and poor muscle relaxant.
It may be used along with nitrous oxide/opioids and skeletal muscle relaxants.
It is pleasant to breathe and not hepato-toxic to children. It is preferred for paediatric
use. It is a potent anaesthetic. It abolishes pharyngeal and laryngeal reflexes. It is a
bronchodilator and is preferred for asthmatic patients. It inhibits intestinal and uterine
contractions and can be used for assisting external or internal version of foetus during late
pregnancy. Recovery from halothane is smooth except for shivering, nausea and vomiting.
Its induction and recovery is relatively slow. It is poor analgesic and muscle relaxant.
It causes bradycardia and transient fall in BP. It reduces cardiac output and sensitizes
myocardium to arrhythmic effects of catecholamines. It is metabolised to trifluroethanol and
bromide ion. This may induce delayed fever, anorexia, nausea, vomiting and occasional
hepatitis. Repeated administration can cause severe hepatic necrosis; hence it is not
repeated within 2-3 weeks. Its use during labour can prolong delivery and can cause
post-partum haemorrhage. Normalisation of mental function takes several hours after
recovery. It can cause malignant hyperthermia in genetically predisposed cases. Succinyl
choline, if used as a muscle relaxant, can worsen the condition. Dantrolene in a dose of
1 mg/kg is given intravenously to treat the condition.
Halothane is available as liquid in a pack of 30 ml, 50 ml, 200 ml: FLUOTHANE
HYPNOTHANE.
(iii) Methoxyflurane
Because of slow induction, slow recovery, hepatotoxicity and nephrotoxicity, it is not
used in clinical practice now.
(iv) Enflurane
It is non-irritating, non-inflammable liquid with mild odour. It decreases heart rate,
cardiac output and blood pressure. It also causes uterine relaxation. Unlike halothane, it
does not sensitize the heart to catecholamines; hence arrthmia is rare. It causes
bronchodilation and is a better skeletal muscle relaxant in comparison to halothane. It has a
rapid induction and rapid recovery.
It is contraindicated in epileptic patients due to CNS excitation. It has a greater
respiratory depressant action. About 5-8% of the drug is metabolised to fluoride ions with a
possibility of polyuric renal failure. Hence it is contraindicated in renal failure. Incidence of
hepatotoxicity is relatively low.
(v) Isoflurane
It is a structural derivative of enflurane. It is more potent than enflurane. It is non-
inflammable liquid with pungent odour. It exhibits rapid induction and recovery. It is
relatively expensive.
It does not cause dilation of pupils and light reflex is not lost. It undergoes minimal
metabolism and less fluoride is produced. Hence, hepatotoxicity and nephrotoxicity is less. It
does not induce cardiac arrhythmia. Low concentrations of isoflurane do not increase
cerebral blood flow or intracranial pressure. It depresses cortical EEG activity and is preferred
for neurosurgery. It is also a muscle relaxant. It is a potent coronary vasodilator. It irritates
upper airway, but it is a bronchodilator.
It has a pungent odour and causes bronchial irritation. Hence, induction is unpleasant. In
patients of coronary artery disease, it may cause redistribution of blood from the area of
inadequate perfusion to one of normal perfusion. Being a vasodilator, it causes hypotension
and reflex tachycardia.
Isoflurane is available as inhalant liquid in a pack of 30 ml, 100 ml or 250 ml: FORANE,
ISORANE, SOFANE.
(vi) Desflurane
It is structurally similar to isoflurane. It is non-inflammable, non-explosive but irritant
anaesthetic. It has a rapid induction and recovery. It is preferred for out-patient surgery.
Recovery from anaesthesia, psychomotor and cognitive skills is rapid. It undergoes
negligible metabolism; hence there is less generation of fluoride ions. Thus, it is relatively
safer. It is preferred for prolonged anaesthesia. It rarely precipitates malignant hyperthermia
and does not sensitize myocardium to catecholamines. Muscle relaxation is equal to
isoflurane and seizure provoking potential is negligible.
It is irritant to airways and may provoke breath holding apnea, laryngospasm, coughing
and increased salivation. It is not suitable for children. Depth of anaesthesia fluctuates
rapidly with change in inhaled concentration. Incidence of post-operative nausea and
vomiting is relatively larger.
(vii) Sevoflurane
It is a non-pungent, non-inflammable anaesthetic. Induction is rapid and smooth.
Recovery is also faster than halothane. Being non-pungent, it does not cause respiratory
irritation. It is better accepted by children. Induction and recovery are fast. It is a good
muscle relaxant. Sensitization of myocardium is relatively less. It is a good choice for
inhalation, particularly in children.
It is not a bronchodilator. It may trigger malignant hyperthermia in susceptible patients.
About 2% of the drug is metabolised; hence generation of fluoride is less. Thus, it is
relatively safe. It is degraded by contact with CO2 absorbants like soda lime. It is avoided in
patients with renal failure. Reported adverse effects are shivering, nausea and vomiting. It is
a relatively safe anaesthetic.
4.3.2.2 Specific Intravenous Anaesthetics

Unlike inhaled anaesthetics, intravenous agents do not need specialised vapouriser
equipment for their delivery. Intravenous anaesthetics are classified based on their induction
time: fast or slow.
(i) Fast Inducers
Drugs like thiopental, methohexital, etomidate and propofol are used because of their
fast onset. Recovery also is sufficiently rapid. For short surgical procedures, these agents are
used alone. In case of surgery with longer duration, intravenous anaesthetics may be
followed by inhalation anaesthetics.
(a) Thiopental
It is a ultra-short acting thiobarbiturate. It induces anaesthesia smoothly within less than
a minute. Following an intravenous bolus injection, it crosses BBB rapidly. Due to high lipid
solubility, brain equilibrium is attained swiftly. Subsequently, it diffuses rapidly from brain to
body fats, muscles and other tissues. Because of rapid removal from brain, it is short acting.
Induction dose is 3-5 mg/kg. It is metabolised in liver at a rate of 12-15% per hour. It
reduces cerebral blood flow and intracranial pressure. Hence, it is a drug of choice for
patients with cerebral edema and brain tumours.
Laryngospasm may be caused if anaesthesia is light. It has no muscle relaxant action. It
has no analgesic activity. Shivering and delirium may occur during recovery. Barbiturates
precipitate acute intermittent porphyria by inducing the enzyme ALA synthetase. Since pH of
intravenous thiopental is 11, it may cause local tissue damage. It also reduces respiratory
rate and tidal volume.
Thiopental: INTRAVAL, PENTOTHAL sodium is available as 500 mg, 1 gm powder in a
vial for making fresh injection.
(b) Methohexital
It is a thiobarbiturate similar to thiopental with a short terminal half-life (4-5 hours). Its
use has declined due to restlessness, coughing and hiccups during recovery.
(c) Propofol
Induction of anaesthesia occurs with a dose of 1.5-2.5 mg/kg within 30 seconds.
Induction is smooth and pleasant with low incidence of excitation. Recovery is rapid with low
incidence of nausea and vomiting. On stopping the drug, plasma concentration falls rapidly
due to redistribution and metabolism. It is non-irritant to respiratory airways. It has no
analgesic or muscle relaxant effects.
It causes dose-dependent cortical depression and has anti-convulsant action. Risk of
laryngospasm is low. It is preferred for out-patient surgery.
Apnoea and pain at the site of injection are common adverse effects. It produces
marked decrease in systemic blood pressure during induction. It decreases peripheral
resistance and can cause bradycardia.
Propofol: CRITIFOL, PROPOFOL, PROPOVAN is available as injection of 1% in 10 ml,
20 ml, 50 ml; 10 mg/ml and 20 mg/ml.
(d) Etomidate
It has a shorter duration of action (5-10 minutes) and produces much less cardiovascular
and respiratory depression. It causes pain on injection; excitatory muscle movements are
common on induction and incidence of nausea and vomiting are frequent after recovery. It
is a poor analgesic and causes adrenocortical suppression. Hence, it is not preferred for
prolonged use. It is occasionally used for emergency anaesthesia because it causes relatively
lesser hypotension.
(ii) Slow Inducers
Benzodiazepines (BZDs) are preferred for endoscopies, cataract operations, cardiac
catheterisation, angiographies, fracture settings and electro-convulsive therapy (ECT). In
addition, they are used as pre-anaesthetics and also for inducing and maintaining
anaesthesia. When injected intravenously, they produce sedation, muscle relaxation and
amnesia.
Diazepam (0.2-0.5 mg/kg), Lorazepam (0.04 mg/kg) and Midazolam (0.07-0.08 mg/kg)
are used intravenously for causing anaesthesia. BZDs are slow inducers but they produce
amnesia which is clinically useful. Midazolam is frequently used because it produces higher
(> 50%) amnesia. It has a rapid onset and shorter elimination half-life (2-4 hours). It is
relatively more water soluble and produces lesser irritation. BZDs do not depress respiration
or cardiac functions. They do not cause post-operative nausea or vomiting. They are poor
analgesics. An opioid or nitrous oxide is added if analgesia is needed.
Lorazepam: ATIVAN, LARPOSE, LORVAN, TRAPEX, LOPERZ is available as 1 mg, 2 mg
tablet or 2 mg/ml injections. Midazolam: MIDAZ, MEZOLAM, FULSED is available as
1 mg/ml or 5 mg/ml injections. Diazepam: VALIUM, CALMPOSE is available as 5 mg, 10 mg
tablet or 5 mg/ml injection.
4.3.2.3 Dissociative Anaesthetic - Ketamine
Ketamine is characterised by a feeling of dissociation from surrounding, profound
analgesia, immobility and amnesia with light sleep. Its primary site of action is cortex and
limbic system. It acts by blocking the action of glutamate at NMDA receptor. It is a highly
lipophilic drug. After its diffusion into brain, it is redistributed in different body
compartments with simultaneous hepatic metabolism and both urinary as well as biliary
metabolism. Its usual intravenous induction dose is 1-2 mg/kg.
It is the only intravenous anaesthetic with significant analgesic properties and CNS
stimulation. It increases heart rate, blood pressure and cardiac output. It increases cerebral
blood flow and intracranial pressure. It is contraindicated in patients of hypertension,
ischaemic heart disease, schizophrenia and epilepsy. It is useful in patients of hypovolaemic
shock. Recovery is associated with delirium characterised by frightening dreams and
disorientation. Intravenous use of Diazepam or Midazolam, prior to ketamine minimises
these adverse effects. It is also used with Propofol for outpatient anaesthesia and in children
for burn dressing. It is also useful in asthmatic patients because of its bronchodilator effect.
4.3.3 Pre-Anaesthetics
The aim of pre-anaesthetic medication is to ensure comfort to the patient and minimise
adverse effects of anaesthesia. The drugs given before anaesthesia and surgery reduce
anxiety, apprehension, provide analgesia, reduce chances of emesis and autonomic effects
during anaesthesia and induce amnesia.
Following drugs are used as preanaesthetics:
(a) Antianxiety Drugs
Benzodiazepines (BZDs) like diazepam (5-10 mg oral) or lorazepam (2 mg IM) are used.
Midazolam (70-100 µg/kg IV) may also be given.
(b) Sedative Hypnotics
In addition to BZDs, promethazine (25 mg IM) is widely used. It is an antihistamine with
sedative, antiemetic and anticholinergic actions. It causes neglible respiratory depression
and is useful for children.
(c) Opioid Analgesics
Morphine (8-12 mg IM) or pethidine (50-100 mg IM) is used for the purpose. Fentanil
(50-100 µg IM/IV) may also be used.
(d) Anticholinergics
Atropine (0.5 mg IM) or hyoscine (0.5 mg IM) or glycopyrrolate (0.1-0.3 mg IM) are used.
They reduce salivary, bronchial secretions; produce bradycardia and hypotension. They
also prevent laryngospasm.
(e) Antiemetics
Metoclopramide (10 mg IM), domperidone (10 mg oral) or ondansetron (4-8 mg IV) are
used for gastric emptying prior to emergency surgery. These drugs may be combined
with histamine H2 receptor blockers.
(f) H2 Receptor Blockers
Ranitidine (150-300 mg oral) or famotidine (20-40 mg oral) are given in night before and
in the morning before surgery. Proton pump inhibitors like omeprazole (20 mg) may be
given with H2 blockers.
4.4 SEDATIVES, HYPNOTICS AND CENTRALLY ACTING MUSCLE
RELAXANTS
4.4.1 Sedatives and Hypnotics
Sedation indicates decrease in alertness and a decreased responsiveness to any level of
stimulation without inducing sleep. During hypnosis, a person becomes passive, highly
suggestive and obeys the commands. Hypnosis resembles natural sleep but the person can
be aroused by strong stimuli like pin prick or the sound of alarm clock.
The sequence of events during non-specific CNS depression starts from anxiety followed
by disinhibition, sedation, hypnosis, anaesthesia, coma and ultimately death. The effects of
drugs depend on their dose, route of administration and their physico-chemical characters.
Drugs under this category are classified as follows:

[I] Benzodiazepines (BZDs)
Although BZDs were introduced after barbiturates, they are preferred drugs for hypnotic
and sedative activities. A comparison between BZDs and barbiturates is listed below:
o BZDs do not provide anaesthesia even in high doses and the patient can be aroused.
Barbiturates can cause loss of consciousness and have lower margin of safety.
o BZDs are not enzyme inducers and do not cause metabolic tolerance. Drug
interactions are less.
o BZDs have a very low abuse liability; barbiturates cause psychic and physical
dependence.
o BZDs do not affect REM sleep and cause less disturbance of normal sleep while
barbiturates cause marked suppression of REM sleep.
o BZDs show no hyperalgesia while barbiturates may increase sensitivity to pain.
o BZDs exhibit amnesia without automatism while barbiturates cause amnesia with
automatism. Automatism can lead to accidental poisoning.
o BZDs can be used as day-time anxiolytic-sedative in sub-hypnotic doses while
barbiturates cause drowsiness.
o BZDs, in hypnotic doses do not affect respiration or cardiovascular functions while
barbiturates cause respiratory depression and hypotension.
o Flumazenil is a specific antagonist for BZDs; there is no specific antagonist to
barbiturates.
Characteristics of BZDs are discussed below:
Site of Action
BZDs exhibit relatively greater depressant action on limbic system which regulates
thoughts and mental functions. They have relatively lesser depressant action on mid-brain
ascending RAS which maintains wakefulness. Hence, they exhibit anxieolytic action with less
sedative effects. At higher doses they depress RAS and induce sedative-hypnotic action. This
effect differs qualitatively with individual BZD. Muscle relaxation is produced due to action
on medulla, by inhibiting polysynaptic reflexes in the spinal cord. They also cause ataxia due
to action on cerebellum.
Mechanism of Action
BZDs facilitate action on GABAA receptors. GABAA receptor has different binding sites.
(Fig. 4.7). The sites are as follows:
• GABA-binding site
• The modulatory sites to bind BZDs, their antagonists and inverse agonists
• The modulatory as well as blocking site at chloride ion channel
Benzodiazepines
Modulatory site
_ Flumazenil
-
Cl (antagonist)
GABA _
_
Inverse
GABA agonists
binding (b-carbolines)
site
_ + Channel
Channel
blockers modulators
(picrotoxin) (barbiturates)
-
Cl
Fig. 4.7: Main sites of drug action at GABAA receptor
BZDs selectively bind with high affinity to the modulatory site on GABAA receptor in such
a way that the binding of GABA to GABAA receptor is facilitated. This modulatory site is
distinct from the GABA binding site and is specific for BZDs; hence it is also called as
“benzodiazepine receptor”. BZDs neither substitute for GABA, nor activate GABAA receptor
but enhance binding of GABA to the binding site of GABAA receptor. BZDs appear to
increase the frequency rather than duration of GABA-gated chloride channel opening.
BZD Inverse Agonists and Antagonists
Inverse agonist to BZDs is β-carbolene which exerts opposite signs to that of BZDs
leading to anxiety and convulgence. β-carbolene has no therapeutic use. Antagonist to BZDs
is flumazenil. It is clinically useful to treat overdose toxicity of BZDs. It undergoes significant
first pass metabolism in liver. Hence, it is preferred by intravenous route in a dose of 0.5 mg.
It is given at the rate of 0.2 mg/minute up to maximum dose of 5 mg. It is given till the
patient recovers. Its half-life is 1-2 hours.
Pharmacokinetics
There are marked variations in pharmacokinetics of BZDs. Only Midazolam is given
either by IM or IV route. All other BZDs are given orally. BZDs like diazepam, oxazepam and
chlordiazepoxide are more than 90% bound on proteins. There is no significant
displacement reaction. They have high volume of distribution, they cross placental barrier
and are to be used cautiously in pregnancy. Many of the phase I metabolites of BZDs are
pharmacologically active; hence their half-life is extended. Active metabolites of parent
drugs are as follows:
• Midazolam: hydroxymethyl midazolam
• Diazepam: oxazepam, nordiazepam (clorazepate)
• Flurazepam: dismethylflurazepam and hydroxymethyl flurazepam
• Alprazolam: alpha-hydroxyalprazolam
• Chlodiazepoxide: dismethyldiazepam and oxazepam
Accumulation, with multiple dosing is not clinically significant with short acting BZDs but
it is significant with intermediate acting and long acting BZDs. Withdrawal effects are milder
with long acting BZDs.
Therapeutic Uses
• To treat anxiety neuroses: BZDs like alprazolam, lorazepam, oxazepam, diazepam
and chlordiazepoxide are commonly used for this purpose.
• To treat insomnia: BZDs are the hypnotic drugs of choice. Rapidly acting and rapidly
eliminated BZDs like triazolam (0.1-0.25 mg) or temazepam (15-20 mg) are preferred
for transient insomnia caused by jet-lag, shift work, new place or overnight journey.
For short term insomnia, drugs like temazepam (15-30 mg), flurazepam (15-30 mg)
or estazolam (1-2 mg) are given at bed time. For long-term chronic insomnia, long
acting BZDs like flurazepam (15-30 mg) or nitrazepam (5-10 mg) are preferred.
• For pre-anaesthetic medication and induction of anaesthesia: diazepam, lorazepam
and midazolam are generally used. Intravenous midazolam is preferred due to high
degree of amnesia, rapid onset and shorter duration of action.
• As skeletal muscle relaxants: diazepam is preferred for the purpose if the spasticity
has origin in CNS.
• As anti-convulsants: slow intravenous diazepam or clonazepam is used to treat
status epilepticus. Clonazepam is used for myoclonic/petit mal seizures. Tolerance
develops to these drugs. Continuous, slow infusion of diazepam can be used to
prevent titanic spasm.
• Treatment of alcohol withdrawal: diazepam, oxazepam and chlordiazopoxide are
used to control withdralwal effects of alcohol.
Adverse Reactions
Following adverse effects are observed with BZDs:
• BZDs cause dose dependent drowsiness, fatigue, disorientation, lethargy and
impairment of psychomotor skills. Fast IV injection can precipitate cardiac arrest.
• Tolerance develops slowly. There is no induction of hepatic microsomal enzymes.
• Dependence is mild. Withdrawal effects include anxiety, insomnia, impaired
concentration, headache, irritability, tremors, palpitation and vivid dreams.
• Advancing age retards rate of phase I metabolism. Hence, effects of long-acting
BZDs tends to increase in elderly people resulting in increased confusion and
forgetfulness.
• Paradoxical stimulation may occur rarely, especially with flurazepam.
• Flunitrazepam is a tasteless BZD which is misused in sexual assaults. It has been
misused to obliterate memory of events to escape judicial punishment for sexual
assaults.
Drug Interactions
Following drug interactions are observed with BZDs:
• BZDs potentiate effects of other CNS depressants like alcohol, hypnotics and
neuroleptics.
• Smoking decreases the activity of BZDs.
• Aminophylline antagonises sedative effects of BZDs.
• Enzyme inhibitors like cimetidine and ketoconazole enhance BZD action.
Alprazolam: ALPRAX, ALZOLAM, RESTYL, TRIKA is available as 0.25 mg, 0.5 mg. 1 mg
tablets or 0.5 mg, 1 mg, 1.5 mg SR tablets. Chlordiazepoxide: LIPRIUM, ODIP is available as
10 mg, 25 mg tablets. Diazepam is available as 5 mg, 10 mg tablets or 5 mg/ml injection.
Midazolam: MEZOLAM, FULSED is available as 1 mg/ml, 5 mg/ml injection. Lorazepam:
ATIVAN, LARPOSE, LORVAN, TRAPEX, LOPERZ is available as 1 mg, 2 mg tablets or
2 mg/ml injection. Oxazepam: SEREPAX is available as 15 mg, 30 mg tablet.
Nitrazepam: HYPNORIL, NITROSUN is available as 5 mg, 10 mg tablet. Flurazepam:
NINDRAL, FLURAZ is available as 15 mg capsule. Clonazepam: LONAZEP, RIVOTRIL,
EPITRIL is available as 0.5 mg, 1 mg, 2 mg tablet.
[II] Non-benzodiazepine Hypnotics
Two types of BZD receptors have been identified: BZ1 and BZ2. BZ1 receptors are found
throughout the brain and in large concentrations in the cerebellum. They are responsible for
antianxiety, sedative and hypnotic effects. BZ2 receptors are found mainly in the cerebral
cortex, hippocampus and spinal cord and are associated with muscle relaxation,
anticonvulsant action and amnesia. Non-benzodiazepines like Zolpidem, Zaleplon, Zopiclone
and Eszopiclone act on BZ1 receptors only. Benzodiazepines like Clobazam act preferably on
BZ2 receptors and exert muscle relaxant anticonvulsant actions.
As hypnotic, Zolpidem (half-life 2-3 hours) and Zaleplon (half-life 3-4 hours) have faster
onset of action with shorter duration of action. Drugs like Zopiclone (half-life 6-8 hours) and
Eszopiclone (half-life 6 hours) are slightly longer acting. In therapeutic doses they hardly
alter REM sleep and have minimal day time sedation. The problem of rebound insomnia is
minimal. Their effects can be blocked by Flumazenil.
These drugs have minimal muscle relaxant and anticonvulsant action. The risk of
tolerance and dependence is less. Side effects and safety in overdoses are similar to that of
BZDs. Dose reduction is needed in hepatic disease and in elderly patients. Adverse reactions
like day time drowsiness and night mares occur only in high doses.
Zolpidem: NITREST, ZOLPIGEM, ZOLPINITE is available as 10 mg tablet. Zaleplon:
ZAPLON, ZASO is available as 5 mg or 10 mg tablet. Zopiclone: ZOLINOX, ZOPICON,
ZOLIUM is available as 7.5 mg tablet and Eszopiclone: FLUNITE is available as 1 mg, 2 mg
tablets.
[III] Barbiturates
The general structural formula of barbiturates is shown in Fig. 4.8. If R1 and R2 are
aliphatic alkali groups, then the resultant barbiturate or thiobarbiturate (if X is sulphur)
possesses sedative hypnotic properties. If R1/R2 is phenyl group, then the resultant drug has
anticonvulsant-sedative action (e.g. Phenobarbital). Thiobarbiturates are more lipid soluble
and are ultra-short acting. X
General structure of Barbiturates: C
2
If X → O; it is barbiturate. 1 3 NH
If X → S; it is thiobarbiturate. 6 4
O 5 O
R1 and R2 are substituents.
R1 R2
Fig. 4.8: General structure of barbiturates
Mechanism of Action
Barbiturates act on the channel modulatory site of GABAA receptor and potentiate the
GABA mediated inhibitory effects by increasing the duration of chloride channel opening
(Fig. 4.7). At higher doses, barbiturates directly increase chloride ion conductance and
exhibit GABA-mimetic action and not a GABA-facilitatory action.
Classification
Barbiturates are classified based on their duration of action. Thiopental and
Methohexital are ultra-short acting barbiturates with duration of action ranging from
15-20 minutes. Pentobarbital and Amobarbital are shorter acting barbiturates with 3-8 hours
as duration of action. Phenobarbital and Mephobarbital are longer acting barbiturates with
12-24 hours as duration of action.
Pharmacokinetics
• The rate of absorption of barbiturates depends on their lipid solubility. The pH of
solutions of sodium salts is usually alkaline. Hence, IM/SC injections can cause
necrosis and pain at the site of injection. They remain unionised in acidic pH and
fully ionised at alkaline pH.
• They are widely distributed depending on lipid solubility and regional blood flow.
The action of ultra-short acting barbiturates is terminated due to redistribution from
brain to other tissues, muscles and fat/adipose tissue.
• They are metabolised both by phase I and phase II processes. Phase I involves
microsomal oxidation while phase II involves glucuronyl conjugation.
• On prolonged use, they cause induction of liver microsomal enzymes resulting in
development of metabolic tolerance.
• They are excreted through urine; but are readily reabsorbed from renal tubules.
Alkalinisation of urine promotes their excretion.
Pharmacological Effects
• The ultra-short acting barbiturates exhibit dose-dependent CNS depressant action.
The long acting barbiturates possess sedative-anticonvulsant actions. These two
actions are independent. They disrupt the balance between REM: Non-REM sleep by
decreasing the duration of REM sleep. Hence, on withdrawal of barbiturates, there is
a rebound increase in REM sleep which leads to a feeling of disturbed sleep.
• They may show hyperalgesic action i.e. they may increase reaction to painful stimuli.
• Sedative-hypnotic doses have no effect on cardiovascular system. High doses
decrease blood pressure, heart rate and depress myocardium.
• Sedative hypnotic doses do not affect respiration. Higher doses depress respiration
and cause shallow berathing, pulmonary edema and laryngeal edema.
• Prolonged use increases the size and weight of smooth endoplasmic reticulum
leading to enzyme induction.
• Higher doses have relaxant effect on GIT, bladder and uterus and decreases urine
flow from kidneys due to decrease in renal blood flow, increase in ADH release and
relaxation of bladder.
Therapeutic Uses
• As sedative-hypnotics: These days BZDs have superseded barbiturates.
• In anaesthesia: Ultra-short-acting barbiturates like thiopental are used as intravenous
fast inducing anaesthetics.
• As anticonvulsants: Long-acting barbiturates like Phenobarbital are used for the
purpose.
• To treat hyperbilirubinaemia: They increase activity of enzyme glucuronyl transferase
by induction. Hence, bilirubin gets conjugated faster and excreted through bile. They
also increase the bile flow.
Adverse Effects
• Repeated use of barbiturates causes metabolic tolerance due to enzyme induction.
This leads to accelerated metabolism of several concommittantly administered
drugs.
• They can cause psychic as well as physical dependence on withdrawal after
prolonged use. Withdrawal symptoms include tremors, insomnia, headache,
restlessness and delirium.
• They cause hangover, impairment of judgement and drug automatism.
• They cause respiratory depression, laryngeal edema and hypersensitivity reactions
causing skin rash, swelling of lips and eyelids.
Drug Interactions
Barbiturates reduce effectiveness of drugs like oral contraceptives, anticoagulants,
tolbutamide and theophylline due to induction of enzymes.
Contraindications
• They are contraindicated in liver dysfunctions, kidney disease and severe pulmonary
insufficiency.
• Patients with family history of porphyria or in case of acute intermettant porphyria.
This is because barbiturates cause induction of the enzyme ALA-synthetase which is
responsible for synthesis of porphyrins. The net effects are porphyria and
neurotoxicity.
Acute Toxicity and Treatment
Barbiturate poisoning is mostly suicidal and rarely accidental. It leads to respiratory
failure, cardiovascular collapse, coma and renal failure. The treatment includes gastric lavage,
artificial respiration and forced alkaline dialysis.
[IV] Miscellaneous Drugs
(i) Melatonin and Ramelteon
Melatonin is a hormone produced in the pineal gland from the amino acid tryptophan.
Normally, it is involved in skin colouration, but it is also secreted during hours of darkness
and affects sleep pattern. The light stimulates the retina and transmits the signal to pineal
gland to inhibit release of melatonin. Darkness promotes melatonin secretion. It is primarily

used to elevate symptoms of jet lag and other disorders resulting from delay of sleep. It has
been found useful in elderly hypnotic-dependent insomniacs. Food increases its
bioavailability. It undergoes first pass metabolism and is excreted by kidney. It decreases
serum luteinizing hormone and increases prolactin levels. It is contraindicated in patients
taking corticosteroids like dexamethasone.
Ramelteon is a selective agonist to receptors of melatonin. It has been approved for
treatment of insomnia in which there is difficulty in falling asleep. Adverse effects include
fatigue, dizziness and somnolence.
Melatonin: MELOSET, ZYTONIN is available as 3 mg tablet.
(ii) Triclofos
It is similar to chloral hydrate; both get converted in to trichloroethanol. Triclofos is more
palatable, causes less GIT upset and is better tolerated. Its onset of action is less than 30
minutes and duration of action is 8-12 hours. It is used for short term management of
insomnia in children for sedation during recurrent colic. Dose is 1 gm at bed time.
Triclofos: PEDICLORYL, TRICLORYL is available as 500 mg tablet/5 ml syrup.
(iii) Hydroxyzine
It is an antihistamine with antiemetic, sedative, anticholinergic and local anaesthetic
action. It is used for short term management of anxiety, pre-anaesthetic sedation and
pruritus. Its onset of action is 15-30 minutes and duration of action is 6 hours. Usual oral
dose is 50-100 mg three times a day. Its active metabolite is cetrizine.
Hydroxyzine: ATARAX is available as 10 mg, 20 mg tablet or 6 mg/ml syrup.
(iv) Promethazine
It is a sedative antihistamine with antiemetic and anticholinergic properties. It is used for
night time sedation in a dose of 25 mg at bed time. Its onset of action is one hour and
duration of action is 10-12 hours. Its longer duration of action may cause hangover the next
day. It is also used in children as sedative hypnotic.
Promethazine: AVOMINE, PHENERGAN is available as 10 mg, 25 mg tablet or 5 mg/5 ml
syrup.
4.4.2 Centrally Acting Skeletal Muscle Relaxants (Spasmolytics)
These drugs reduce skeletal muscle tone by a selective action in the cerebrospinal axis
without altering consciousness. Spasticity is characterised by an increase in tonic stretch
reflexes and flexor muscle spasm along with muscle weakness. It is associated with disease
like cerebral palsy and multiple sclerosis. It involves abnormal function of bowel, bladder and
skeletal muscle. Antispastic drugs control the symptoms of spasticity either by enhancing
the activity of inhibitory neurons of the reflex arc (e.g. diazepam, baclofen) or by interfering
directly with skeletal muscle excitation-contraction coupling (e.g. dantrolene). Components
involved in these processes and sites of action of drugs are shown in Fig. 4.9. Mephenesin
group drugs are also used to relieve acute local muscle spasm. Their mode of action is non-
specific and is described as depressants of polysynaptic reflexes at spinal level. Both spinal
and supra-spinal polysynaptic reflexes are involved in the regulation of the muscle tone.
Monosynaptic pathways mediate stretch reflex. All these drugs have some sedative side
effects.
Polysynaptic pathway
Monosynaptic pathway
Afferent neurons
Internuncial
neuron
e
++ len
Ca ro
nt
Da
Actin
Diazepam
Baclofen
Myosin
Muscle
Efferent neuron
Fig. 4.9: Cross-section of spinal cord showing components involved in stretch reflex arc with
postulated sites of action of diazepam, baclofen and dantrolene
[I] Mephenesin Group
It involves drugs like Carisoprodol, Chlorzoxazone, Chlormezanone and Methocarbamol.
These drugs are spinal neuron blocking agents at the level of brain stem. They preferentially
inhibit polysynaptic reflexes without affecting monosynaptic tendon reflexes like knee jerk.
They are used to treat muscle spasm of local origin such as resulting from spondylitis,
sprains and lumbago. Sedation and GIT upset are the most common side effects.
Chlorzoxazone has longer duration of action (8-12 hours) and a slower onset of action
(1.5 hour). It is well tolerated orally. Carisoprodol has duration of action of 4-6 hours. It is
also analgesic, antipyretic and has antimuscarinic action. It causes blurred vision. It is
converted to meprobamate, as an active metabolite. Hence, tolerance and dependence may
develop after prolonged use. Chlormezanone has some hypnotic action as well.
Methocarbamol is preferred by parenteral route because of extensive first pass metabolism.
Carisoprodol: CARISOMA is available as 350 mg tablet. Chlorzoxazone: NEW PANAZOX,
UNIDIC-MR is available as 500 mg tablet. Methocarbamol: ROBINAX FLEXINOL is available
as 500 mg tablet.
These drugs are usually combined with paracetamol and anti-inflammatory drug like
diclofenac or ibuprofen.
[II] Benzodiazepine Group

Diazepam and chlorazepam have antispastic action. They enhance GABA-ergic
transmission in brain as well as other GABA synapses. They inhibit both monosynaptic as
well as polysynaptic reflexes and produce marked sedation. They reduce muscle spasm of
almost any origin including local muscle trauma. They are particularly useful in spinal
injuries, tetanus and rheumatic disorders associated with muscle spasm. Sedation is their
major side effect.
Diazepam is available as 2 mg, 5 mg tablet. Clonazepam is available as 1 mg, 2 mg and
5 mg tablet.
[III] GABA Derivative
Baclofen is an orally active GABA-mimetic drug which acts as a agonist on GABAB
receptors. The receptors are G-protein coupled receptors which hyperpolarise neurons by
increasing potassium ion conductance and reducing calcium ion conductance. At spinal
level, it inhibits both monosynaptic and polysynaptic responses. Activation of GABAB
receptors in brain results in hyperpolarisation which interferes with release of excitatory
neurotransmitters. It also reduces pain associated with spastic conditions.
It is used to relieve painful spasticity in multiple sclerosis. It is not much useful in cerebral
palsy. It can be used to treat trigeminal neuralgia and tardive dyskinesia.
Its adverse reactions are sedation, drowsiness, muscle weakness and ataxia. Sudden
withdrawal may precipitate anxiety, tachycardia and hallucination. It is teratogenic and
should be avoided during pregnancy.
Baclofen is available as 10 mg and 25 mg tablet: LIOFEN, LIORESAL, BACMAX.
[IV] Central α2- agonist
Tizanidine is a α2-agonist with action on CNS and alters neuronal activity in the spinal
cord. It antagonises spasticity at doses which have minimal effect on blood pressure in
comparison to clonidine. It inhibits release of excitatory amino acids in spinal interneurons. It
is widely used to treat spasticity in multiple sclerosis. It is effective in patients with
amyotrophic lateral sclerosis. It is useful in spasticity due to neurological disorders and
painful muscle spasm of spinal origin. Adverse effects include drowsiness, dry mouth,
asthenia and hypotension. It is well tolerated orally but undergoes first-pass metabolism.
Tizanidine is available as 2 mg and 4 mg Tablet.
4.5 ANTI-EPILEPTICS
Epilepsy is a common neurological abnormality characterised by occurrence of seizures.
A seizure means a paroxysmal abnormal discharge at high frequency, from an aggregate of
neurons in cerebral cortex. Epilepsy involves recurrent seizures. Convulsions are involuntary,
violent and spasmodic or prolonged contractions of skeletal muscle. A patient may have
epilepsy without convulsions.
4.5.1 Classification of Seizures
Broadly, the seizure activity is either generalised or partial. In addition, there is one more
category of unclassified seizures.
(i) Generalised Seizures

These seizures arise from both cerebral hemispheres and diencephalon simultaneously,
involving the entire body, and have characteristic bilateral pattern in EEG recording. These
are of following types:
(a) Grand mal or Tonic-Clonic Seizures
These are usually associated with an aura prior to seizures. The patient falls to the
ground in stiff tonic phase (legs extended) with an epileptic cry, caused by tonic
contraction of laryngeal muscles. This is followed by clonic convulsions (repeatitive
bilateral muscle jerking) and then to coma which may last for 15-30 minutes.
Recovery is associated with stupor, amnesia, mental confusion and post-ictal
depression, incontinence and exhaustion. EEG shows a bilateral diffused pattern of
high voltage polyspikes of 10-30 Hz/sec in tonic-clonic phase.
(b) Petit mal or Absence Seizures
There is no aura associated with this disorder and attack appears without warning.
There is no loss of consciousness. The seizure lasts for few seconds without loss of
postural control. There is no post-ictal confusion or amnesia. The seizures are
characterised by subtle bilateral symptoms such as rapid blinking of eyelids, chewing
movements or small amplitude clonic jerks of hands for few seconds. EEG shows
generalised symmetric 3 Hz spikes and wave pattern of discharge per second which
begins and ends suddenly. These are responsive to pharmacotherapy.
Atypical absence seizures are of slower onset and of longer duration. These are non-
responsive to pharmacotherapy and are associated with other neurologic
complications like mental retardation.
(c) Myoclonic Seizures
These are bilateral epileptic myoclonus characterised by sudden and brief skeletal
muscle contraction which may involve the entire body or one part of the body. Most
commonly the patient complains of sudden jerking movements appearing during
sleep. EEG shows 2 Hz spikes and wave pattern per second.
(d) Akinetic (Atonic) Seizures
These are characterised by sudden loss of postural tone. The head may sag to
oneside or the patient may fall all of a sudden. The consciousness may be impaired
for a brief period but there is no post-ictal confusion. EEG shows brief generalised
spike and wave discharge followed by diffused slow waves which correlate with loss
of muscle tone.
(e) Clonic Seizures
These are characterised by repetitive muscle jerks. EEG shows fast activity (10 Hz or
more) slow waves.
(f) Tonic Seizures
These are characterised by rigid, violent muscular contraction with stiff and fixed
extended limbs. EEG shows low-voltage fast-activity waves.
(ii) Partial Seizures (Localised/Focal)
These are the most common seizures. The seizure activity is restricted to a discrete area
belonging to one cerebral hemisphere only. These are of three types:
(a) Simple partial seizures (Jacksonian seizures)

These are characterised by unilateral clonic movements which begin in one group of
muscles and spread gradually to adjacent group reflecting the march of epileptic
activity (e.g. mouth, thumb, great toe). Alternatively, the patient may have
somatosensory symptoms such as auditory, visual or olfactory hallucinations. There
is no loss of consciousness in simple partial seizures.
(b) Complex partial seizures (Psychomotor Epilepsy)
These originate in the temporal or the frontal lobe and are accompanied by partial
loss of consciousness. It is a dreamy state of psychic seizures where the patient
behaves as partially conscious with automatism. The patient may get up, put on his
clothes, start walking or even driving a vehicle but does not follow your commands
and does not recollect the events after the attack is over. The attack is usually
associated with auditory, visual or olfactory aura. Sometimes patient shows other
types of automatisms like lip smacking, fumbling and searching of which the patient
has no memory.
(c) Partial seizures evolving to secondary generalised seizures
These are the type when partial seizures progress to generalised/tonic/clonic/tonic-
clonic seizures. Patients usually report aura before the event.
(iii) Unclassified Seizures
It covers undetermined epilepsies and epileptic syndromes like febrile seizures or
infantile spasm. In febrile seizures, young children frequently develop seizures with illness
accompanied by hyper-pyrexia. In infantile spasm, there is progressive mental retardation.
These are generalized tonic-clonic convulsions of short duration which may appear
frightening but are usually benign.
4.5.2 Mechanism of Action of Anti-Epileptic Drugs
Anticonvulsant drugs act by different mechanisms to suppress repetitive firing action
potentials by an epileptic focus in the brain. The mechanisms are classified in two types:
(i) Mechanisms in Grand mal and Partial Seizures:
They are further sub-classified into following sub-types:
o Inhibition of Use-Dependent Sodium Ion Channels. Drugs like Phenytoin,
Carbamazepine, Valproate, Lacosamide and Lamotrigine block voltage-gated sodium
channels.
o Enhancement of GABAergic action. Drugs like Phenobarbital and Benzodiazepines
activate GABAA receptors to facilitate opening of chloride channels.
o Blockade of NMDA or AMPA receptors. Drugs like Felbamate block NMDA receptors.
Drugs like Phenobarbital, Topiramate and Lamotrigine block AMPA receptors.
o Blockade of voltage-gated N type calcium channels. Drugs like Lamotrigine and
GABApentin decrease synaptic release of glutamate.
o Selective blocking of synaptic vascular protein. Drug like Levetiracetam decrease
synaptic release of glutamate and increase release of GABA.
o By blocking effects of neurotropic factors, drug like Lacosamide inhibit specific
proteins involved in genesis of epilepsy.
(ii) Mechanisms in Petit mal (Absence Seizures)
It involves inhibition of T-type calcium channels. Drug like Ethosuximide inhibit calcium
channels. Valproic acid also shows this kind of action.
4.5.3 Individual Drugs

Following drugs are used to treat epilepsy. Types of epilepsy and drugs used to treat
them are depicted in Fig. 4.10.
Absence Etho-
(petit mal) suximide*,
Ganaxolone
Myoclonic
Generalised
seizures Atonic Clonazepam
Clobazam
Vigabatrin,
Clonic Topiramate,
Felbamate,
Zonisamide
Tonic
Grand mal Valproate*,

(tonic-clonic) Lamotrigine*
Diazepam
Simple Carbamazepine*,
partial Phenytoin*,
Phenobarbitone,
Primidone
Levetiracetam,
Partial Complex Oxcarbazepine,
seizures partial Gabapentin,
Tiagabine,
Clorazepate
Secondary
generalised
Infantile ACTH,
spasm Vigabatrin,
Ganaxolone
Unclassified
Febrile Midazolam,
seizures Rectal
Diazepam*
* Drugs of first choice, rest are 'add-on' drugs
Fig. 4.10: Therapeutic spectra of antiepileptic drugs

(i) Phenytoin
It is an oldest non-sedative antiepileptic drug. Chemically, it is diphenylhydantoin. It
provides a good example of application of pharmacokinetics for successful prescribing.
• Mechanism of action
In therapeutic plasma levels of 10-20 µg/ml, it blocks use-dependent sodium channels
and thus inhibits generation of repetitive action potentials. At higher doses it also
reduces influx of calcium and suppresses repetitive firing of neurons. Both these actions
decrease glutamate release.
• Therapeutic uses and plasma levels
o Antiepileptic use
It is the drug of choice for psychomotor seizures. As a second choice, it is used to
treat generalised tonic-clonic and status epilepticus. Fosphenytoin is its pro-drug.
Phenytoin is contraindicated in Petit mal (absence) and myoclonic seizures.
o Non-antiepileptic use
It is used to treat trigeminal neuralgia, ventricular arrhythmia and also for wound
healing.
• Pharmacokinetics
Its oral absorbtion is slow but complete (80-90%). Phenytoin is not given by IM or IV
route. Its pro-drug Fosphenytoin is administered by slow IV route. IM phenytoin precipitates
in muscle and causes intense pain. IV phenytoin causes thrombophlebitis and hypotension.
It is 90-92% protein bound. It is a potent enzyme inducer both for CYP3A4 and
glucuronyl transferase. Metabolites are eliminated through urine. The drug is excreted
through saliva. Its elimination is dose-dependent and follows saturation kinetics. Up to
10-20 µg/ml, its elimination obeys first order kinetics. Hence, its plasma levels remain steady,
up to 20 µg/ml. Beyond 20 µg/ml, its elimination follows zero-order kinetics and hence a
slight increase in dose results in to larger increase in plasma concentration leading to
toxicity.
Periodic assessment of plasma concentrations and subsequent dose adjustments are
necessary in neonates and in patients with kidney disease, liver disease and
hypoproteinaemia. Its plasma half-life is about 24 hours. Five days are needed to attain
steady state.
• Adverse reactions
Following adverse effects are observed with chronic toxicity:
o Gingival hyperplagia and coarsening of facial features.
o Megaloblastic anaemia
o Vitamin K deficiency
o Vitamin D deficiency
o Hirsutism (in females) and acne
o Hyperglycemia, decrease of ADH release
o Congenital malformation like cleft lip, cleft palate and heart disease
o Hypersensitivity reactions like skin rashes, fever, hepatitis, vertigo, nausea, tremors
o Withdrawal seizures, if discontinued abruptly
• Drug interactions
o It increases metabolism of Corticosteroids, Oral contraceptives, Doxycycline,
Rifampicin, Theophylline, Levodopa, Vit. K and Vit. D due to enzyme-induction.
o Enzyme-inhibitors like Disulfiram, Cimetidine, Isoniazid and Chloramphenicol
decrease metabolism of Phenytoin leading to increase in plasma concentration.
o Carbamazepine and Phenytoin or Phenobarbital and Phenytoin increase each other’s
metabolism.
o Sodium valproate displaces protein bound Phenytoin and inhibits its metabolism.
Hence, plasma level of phenytoin increases.
Phenytoin: DILANTIN, EPSOLIN, EPTOIN is available as 100 mg capsule, 100 mg tablet,
150 mg tablet, 300 mg ER tablet, 25 mg/ml suspension, 30 mg/5 ml suspension and 50 mg/ml
injection. Fosphenytoin: FOSOLIN is available as 75 mg/ml injection.
(ii) Phenobarbital and Primidone
Barbiturates having an aromatic ring at position-5 exhibit anticonvulsant action.
Primidone is a deoxyphenobarbital. It is metabolised to Phenobarbital and phenylethyl
malonamide and all these three agents have anticonvulsant action.
Phenobarbital binds to GABA receptor and enhances GABA-mediated inhibitory effect
by increasing the duration of chloride channel opening. It also inhibits glutamate
mediated excitatory effects by blocking AMPA receptor. Both the increase in GABA-
mediated inhibition and decrease in glutamate mediated excitation are observed with
Phenobarbital and primidone. At higher doses they block calcium and sodium channels.
• Therapeutic uses
Both are effective against partial seizures and generalised tonic-clonic seizures but are
less effective than Phenytoin and Carbamazepine. Combination of them works better
than individual drugs alone. Both are enzyme inducers. They competitively inhibit each
other’s metabolism. Tolerance develops to its sedative action but not anticonvulsant
action. Phenobarbital, if discontinued suddenly, precipitates withdrawal seizures. These
drugs are contraindicated in Petit mal (absence) seizures and in porphyria.
Oral absorption is slow but almost complete (85-90%). It is metabolised by liver and is
potent enzyme inducers for CYP2A, CYP2B, CYP2C, CYP3A and CYP6A isoforms of
cytochrome P450 and also for glucuronyl transferase enzyme. Plasma half-life of
Phenobarbital is around 100 hours; hence after steady state, there is less fluctuation in
plasma for 24 hours.
Therapeutic levels for Phenobarbital range from 10-40 µg/ml. In febrile seizures, levels
below 15 µg/ml are ineffective. Usual doses for Phenobarbital are 60-180 mg daily orally
at night. For Primidone initially, 125 mg daily at night can be slowly increased to 250 mg
twice a day.
• Adverse effects
Adverse effects due to enzyme induction are same as that of phenytoin. Phenobarbital
does not cause gingival hyperplasia, coarsening of facial features and hirsutism. It can
cause irritability and hyper-excitability in children. The chances of dependence are less. It
is less teratogenic; but when given with phenytoin, teratogenecity increases.
Phenobarbital: GARDENAL, PHENOBARB, PHENYTAL is available as 30 mg, 60 mg
tablet or 20 mg/5 ml syrup. Primidone: MYSOLINE is available as 250 mg tablet.
(iii) Carbamazepine and Oxcarbazepine
Carbamazepine is structurally related to tricyclic antidepressants and Oxcarbazepine is a
derivative of Carbamazepine.
Like Phenytoin, Carbamazepine blocks sodium channels and inhibits high frequency-
repetitive firing.
Like Phenytoin, Carbamazepine blocks sodium channels and inhibits high frequency-
repetitive firing of the neurons in brain, at therapeutic levels.
o Antiepileptic use
It is a drug of choice for partial and generalised tonic-clonic seizures. It is contra-
indicated in absence seizures.
It is a drug of choice for trigeminal neuralgia and in other neuropathic pain. It is not
an analgesic. It is also effective in treating manic depressive psychosis.
Oral absorption is slow. It should be given after meals. It is distributed mainly in brain,
liver and kidneys. It is metabolised by CYP3A4 and is its enzyme inducer. It also induces
glucuronyl transferase. Its metabolites are excreted through kidney. Oxcarbazepine is a poor
enzyme inducer. It is converted to hydroxyl-metabolite which has itself anticonvulsant
action.
Optimum therapeutic levels are 4-8 µg/ml. The usual adult oral dose is 100-200 mg twice
or thrice daily which can be increased to maximum of 200-400 mg twice or thrice daily. For
Oxcarbazepine usual oral dose is 300 mg twice daily which can be increased to 450 mg twice
daily.
• Adverse effects
o Dose-dependent adverse effects start with drowsiness followed by dizziness,
headache, slurred speech, vertigo, ataxia and diplopia.
o Allergic reactions like rashes and fever are observed. Other idiosyncratic reactions
are blood dyscrasias, aplastic anaemia, leukopenia, hepatitis and systemic lupus
erythematosis.
o It stimulates ADH secretion and can cause water retention and hyponatremia.
o Risk of teratogenecity is low, but can induce finger nail hypoplasia and delayed
development of foetus.
o Oxcarbazepine shows lesser hypersensitive reactions and has milder side effects.
o Erythromycin, Fluoxetine and Isoniazid inhibit metabolism of Carbamazepine and
precipitate toxicity.
o Carbamazepine and Phenytoin increase each other’s metabolism.
o It is an enzyme inducer and reduces plasma concentration of Haloperidol and Oral
contraceptives.
Carbamazepine: MAZETOL, TEGRITAL, TEGRITOL is available as 100 mg, 200 mg,
400 mg tablets; 200 mg and 400 mg SR tablets; 100 mg chewable tablet; 100 mg/5 ml syrup.
Oxcarbazepine: OXCARB, OXETOL, OXEP is available as 150 mg, 300 mg and 600 mg tablets.
(iv) Ethosuximide
It belongs to succinimide group of anticonvulsants. It is a drug of choice for Petit mal
(absence) seizures. It inhibits the low threshold T-type calcium channels. The therapeutic
plasma levels are 60-100 µg/ml. For this purpose, oral dose of 20-30 mg/kg/day is adequate.
It is secreted in saliva and can reflect plasma concentration effectively.
Its absorption is almost complete after oral administration. It is metabolised in liver and
the metabolites are excreted in urine. It follows first order elimination kinetics.
It causes GIT distress, headache, dizziness, hiccups, lethargy and euphoria. Idiosyncratic
adverse effects include skin rashes, fever, eosinophilia and bone marrow depression. It is
lesser teratogenic and can be given during pregnancy.
Valproic acid inhibits Ethosuximide metabolism and clearance and increases its plasma
levels.
(v) Trimethadone
It is similar to Ethosuximide. It is no longer used now. It is a serious teratogenic drug.
(vi) Valproic acid (sodium valproate)
It is used either as valproic acid or as its sodium salt.
It is known to block sodium channels, increase GABA activity by activating the enzyme
glutamic acid decarboxylase (GAD) and by inhibiting the enzyme GABA transaminase. It
decreases release of glutamate and blocks T-type calcium channels.
o Antiepileptic use
It is effective against absence seizures. It is preferred if the patient has con-
committent generalised tonic-clonic attacks and myoclonic seizures. It is used in
combination with clonazepam to treat cortical myoclonus. It is used for infantile
spasm. It should be withdrawan gradually.
Enteric coated tablet of Semi-sodium valproate is used to treat manic depressive
bipolar disorder. It is also used for prophylaxis of migraine and tension type cluster
headache. It is used with Metyrapone in the treatment of Cushing’s syndrome. Due
to its GABAergic action it is used to treat tardive dyskinesia. It is also useful to treat
trigeminal neuralgia as an alternative to Carbamazepine.
It is well absorbed (80%) following oral dose. Food delays its absorption, but the toxicity
is reduced if the drug is given after meals. It is 90-95% bound to plasma proteins. It is a
potent enzyme inhibitor and can inhibit its own metabolism as well as that of
Phenobarbital. The therapeutic plasma concentration of 50-100 µg/ml can be attained
by an oral dose of sodium valproate as 300 mg twice a day. It can be slowly increased to
500 mg to 1 gm twice a day.
• Adverse effects
Adverse effects include weight gain, increase in appetite, GIT distress, tremors and
reversible alopecia. Idiosyncratic toxicity is limited to fatal hepatotoxicity. The risk is
greater in children below 3 years and those taking a combination of Valproate with
Phenobarbital. Rarely, it may cause pancreatitis and thrombocytopenia. Its use in
pregnancy results in a higher risk of spina bifada.
o It is not a CNS depressant, but it potentiates depressant actions of Phenobarbital
and BZDs.
o It increases plasma concentration of Phenobarbital.
o It decreases metabolism as well as displaces Phenytoin resulting in toxicity of
phenytoin.
Valproic: ENCORATE, TORVATE, VALTEC acid/sodium valproate is available as 200 mg,
300 mg, 500 mg, 750 mg, 1000 mg tablets or 200 mg/5ml syrup. It is also available as 500 mg
CR tablet and 300 mg capsule.
(vii) Benzodiazepines (BZDs)
Although BZDs have anticonvulsant action, it has two limitations: pronounced sedative
effects and development of tolerance to anticonvulsant action. They enhance the frequency
of GABA-mediated chloride channel opening. At higher doses they block sodium channels
which have an advantage in controlling generalised status epilepticus.
Diazepam as a slow IV injection in a dose of 20-30 mg is used to treat seizures. It is also
useful for controlling local anaesthetic induced seizures. In addition, Clonazepam,
Clorazepate and Clobazam are also used for treating convulsions.
Clobazam: COBAZAM, CLOBA, CLOBATOR is used as 5 mg, 10 mg and 20 mg tablet.
Diazepam and Clonazepam formulations are listed under BZDs.
(viii) Vigabatrin
It is an irreversible inhibitor of GABA transaminase and thus elevates GABA levels in
brain. It is useful in the treatment of simple and complex partial seizures as well as
generalised seizures. It is also useful in treating drug-refractory epilepsy and infantile spasm.
It should not be used in cases of absence epilepsy or myoclonic seizures. The usual dose is
2 gm per day, to be taken in equally divided doses.
Adverse effects include behavioural changes, sedation, amnesia and weight gain. Rarely,
it may cause irreversible visual field defects due to peripheral retinal atrophy. It should be
used with caution in patients with visual field defects and in children suffering from infantile
spasm, in whom visual field monitoring is difficult.
(ix) Tiagabine
It inhibits GABA uptake by neurons and increases its content in brain. It is used for
treatment of partial complex seizures, and as an adjunct for refractory complex epilepsy.
Adverse reactions include dizziness, fatigue, sedation, tremors and confusion. Usual doses
for adults are 20-60 mg/day in 3-4 equally divided doses.
(x) Gabapentin and Pregabalin
Both are GABA analogs and can cross BBB and increase GABA concentration in brain.
They inhibit calcium channels and decrease synaptic release of glutamate. They also function
as GABAB receptor agonist.
The absorption of Gabapentin from the intestine depends on carrier system and shows
saturation. Hence increasing dose may not increase absorption proportionately. It is neither
metabolised nor bound to plasma proteins and is excreted unchanged by kidneys. Drug
interactions are minimal.
It is useful in treating drug resistant partial seizures and generalised tonic-clonic seizures.
Usual adult dose is 200-300 mg orally three times a day. It is useful in treating diabetic
neuropathy, post-herpetic neuralgia, trigeminal neuralgia and pain associated with multiple
sclerosis in doses of 1800 mg/day in divided doses. Adverse reactions include drowsiness,
fatigue, dizziness, weight gain and ataxia. Dose of Pregabalin is 200-600 mg three times a
day orally.
Gabapentin: GABANTIN, GABAPIN, GABATOR, GABANEURON is available as
100 mg, 300 mg, 400 mg capsule. Pregabalin: MAXGALIN, NEUGABA, PREGEB, PREEGA-M
is available as 50 mg, 75 mg and 150 mg capsule.
(xi) Topiramate
It is a broad spectrum anticonvulsant drug acting by multiple mechanisms like blockade
of sodium channels, activation of GABAA receptor and inhibition of AMPA receptors for
glutamate. It is most useful for generalised tonic-clonic, partial and absence seizures. Usual
adult oral dose is 300-600 mg/day in divided doses. Adverse reactions include sedation,
somnolence, amnesia, urolithiasis and teratogenic risk.
Topiramate: TOPEX, TOPIROL is available as 25 mg, 50 mg or 100 mg tablet.
(xii) Zonisamide
It is a broad spectrum anticonvulsant drug with multiple actions including blockade of
sodium channels and inhibition of calcium channels. It has good bioavailability, linear
elimination kinetics, negligible protein binding and renal excretion. It is effective against
partial, generalised tonic-clonic and myoclonic seizures. It is also useful against infantile
spasm. Usual adult oral dose ranges from 100-600 mg/day in 2-3 equally divided doses.
Adverse reactions include drowsiness, amnesia, skin rash and kidney stones.
Zonisamide: ZONISEP, ZONICARE, ZONIMID is available as 50 mg, 100 mg capsule.
(xiii) Lamotrigine
It is a broad spectrum antiepileptic drug. It blocks voltage-gated sodium channels as
well as calcium channels and inhibits release of glutamate. It is effective in treating partial,
generalised tonic-clonic, secondary generalised, absence and atonic seizures. It is effective in
myoclonic seizures in children. Usual adult oral dose is 100-300 mg/day in divided doses. It
is effective in treating bipolar disorder as a additional drug. Adverse reactions include
dizziness, ataxia, diplopia and skin rash, especially in children. Enzyme inducers like
Phenytoin and Carbamazepine decrease while enzyme inhibitors like Valproic acid increase
the half-life of Lamotrigine.
Lamotrigine: LAMITOR, LAMOGIN, LAMEPIL, LAMETEC is available as 25 mg, 50 mg
and 100 mg tablet.
(xiv) Felbamate
It is a wide spectrum of antiepileptic activity. It is less preferred because of unpredictable
toxicity. It is useful in drug refractory epilepsies. It is also useful in atonic seizures, atypical
absence seizures, partial seizures and generalised tonic-clonic seizures. Usual adult oral dose
is 2000-4000 mg/day in 3-4 equally divided doses. It has been withdrawn from some
countries due to aplastic anaemia and hepatotoxicity.
(xv) Levetiracetam
It is used specifically for treating partial seizures. The elimination kinetics is linear and
hence drug interactions are minimal. Usual adult oral dose is 500 mg twice daily. Adverse
reactions include somnolence, asthenia and dizziness.
Levetiracetam: LEVROXA, TORLEVA, LEVTAM is available as 250 mg, 500 mg and
750 mg tablet and 100 mg/ml syrup.
(xvi) Lacosamide
It is useful for treatment of partial seizures. Usual oral dose is 50 mg twice daily and can
be increased by 100 mg every week till 300 mg. Adverse reactions include headache, nausea
and dizziness. Oral bioavailability is 100%. It is neither enzyme inducer nor inhibitor. No
clinically important drug interactions are reported.
4.6 ALCOHOL AND DISULFIRAM

4.6.1 Alcohol (Ethyl Alcohol/Ethanol)
The pharmacological effects of alcohol on different organs are to be considered as acute
and chronic.
4.6.1.1 Pharmacological Effects (Acute)
Ethanol is rapidly absorbed from GIT. Food, especially milk delays absorption of alcohol
by slowing gastric emptying. Distribution is rapid with Volume of distribution (Vd) of 0.5-0.7
litres/kg. It crosses BBB as well as placental barrier; but the concentration in brain is very
close concentration to that in blood. It is because the brain receives large proportion of
blood flow.
About 95% of absorbed alcohol is metabolised and remaining 5% is excreted through
breath, urine and sweat. Alcohol in alveolar air is in equilibrium with that in pulmonary
capillary blood and this ratio is relatively constant. 80 mg/100 ml of ethanol in blood is
equivalent to 35 µg/100 ml of ethanol in expired air.
A sizable fraction of ethanol is cleared by first-pass hepatic metabolism, which follows
zero-order kinetics. A fixed amount of 8-12 ml or 7-10 gm of alcohol is metabolised per
hour irrespective of its blood concentration. Hence, when stomach is empty, greater
absorption produces higher pharmacological effects.
Ethanol is metabolised first to acetaldehyde and then to acetic acid. Two major pathways
of alcohol metabolised to acetaldehyde, which take place in liver have been identified.
(Fig. 4.11)
Aldehyde dehydrogenase
Alcohol dehydrogenase (75%)
pathway (75%)
Disulfiram
Disulfiram
CO2 + H2O
ACETAL- ACETIC
ETHANOL
DEHYDE ACID
Mixed function Aldehyde oxidase

oxidase pathway (75%)
(25%)
HEDATIC EXTRAHEDATIC
Fig. 4.11: Metabolism of ethanol
o Metabolism of alcohol to acetaldehyde

The enzyme alcohol dehydrogenase, found mainly in liver, stomach and intestine
oxidises about 75% ethanol to acetaldehyde (Fig. 4.10). The metabolism follows zero
order kinetics.
Another enzyme, mixed function oxidase (CYP450) system is responsible for
remaining 25% of ethanol metabolism. At concentration of ethanol above 100
mg/dl, this pathway is more important for metabolism. During chronic alcohol use,
there is induction of this enzyme system and therefore metabolism of steroids, oral
anticoagulants and paracetamol is increased.
o Metabolism of acetaldehyde to acetic acid
About 75-80% of acetaldehyde is converted to acetate in the liver by enzyme
aldehyde dehydrogenase (ALDH). Only 20-25% of acetaldehyde is converted to
acetic acid outside liver by an enzyme aldehyde oxidase. This leads to formation of
acetate which is further metabolised to CO2 and water.
• CNS
Alcohol enhances the action of GABA at GABAA receptors similar to that of
benzodiazepines (BZDs). BZDs also intensify acute effects of alcohol. BZD antagonist,
Flumazenil reverses CNS depressant action of alcohol; however it is not used to reverse
ethanol intoxication. Ethanol also inhibits ability of glutamate to activate NMDA receptor
and thus inhibit opening of calcium channel linked to NMDA receptor.
The acute effects of alcohol on CNS are sedation, relief from anxiety, loss of inhibitions
and impaired judgement as well as driving skills. These effects occur at alcohol blood
levels between 50-100 mg/dl. Blood levels of 120-160 mg/dl lead to effects like ataxia,
slurred speech, mental clouding and grossly impaired motor functions. These effects are
identified as “gross drunkenness”. Levels between 200-300 mg/dl produce emesis and
stupor, while levels above 300 mg/dl lead to coma, respiratory and cardiovascular
depression. Levels above 500 mg/dl are lethal. Concommittent administration of drugs
like BZDs, Phenothiazines, Tricyclic antidepressants and opiates causes additive
depression.
• Heart
At blood concentrations of 100 mg/dl, ethanol decreases myocardial contractility.
Acetaldehyde may cause cardiac abnormalities by altering myocardial stores of
catecholamines. Large doses depress vasomotor centre leading to fall in BP.
• Smooth muscles and other effects
o Ethanol causes cutaneous vasodilatation, which leads to feeling of warmth, but
actually increases heat loss.
o It produces relaxation of uterus only at high doses.
o Diuresis is associated with alcohol intake. It is caused by inhibiton of antidiuretic
hormone secretion and partly because of increased water intake. However, tolerance
develops rapidly to diuresis.
o Aggressive sexual behaviour is due to loss of inhibitions; however performance of

the sexual act is hampered.
o Moderate amounts of ethanol causes catecholamine release and reduce glucose
uptake by the tissues resulting in hyperglycemia. However inhibition of gluco-
neogenesis can also cause hypoglycaemia.
o It requires no digestion and instantly supplies 7 cal/gm. This energy cannot be
stored or utilised for body building. Thus, alcohol serves as an expensive as well as
nutritionally worthless food.
4.6.1.2 Pharmacological Effects (Chronic)
Chronic ethanol intake adversely affects functions of several vital organs.
(a) Nervous system
Tolerance and dependence are major effects on CNS. Tolerance develops to the
subjective and behavioural effects of alcohol. Chronic alcoholics may function normally
even above 180 mg/dl levels as compared to occasional drinkers. The reduced rate of
absorption and faster metabolism is responsible for pharmacokinetic tolerance.
Chronic alcohol drinkers, if forced to abstain, experience distressing withdrawal
symptoms with physical dependence. The symptoms include hyper-excitability, toxic
psychosis, delirium tremens and seizures. The withdrawal effects are observed around
8-24 hours after abstinence. The symptoms are tremors, nausea and sweating. This
phase is followed by seizures and in next three days delirium tremens develop, which is
characterised by confusion, agitation, aggressiveness and hallucination. Psychological
dependence is characterised by compulsive desire to drink.
(b) Neurotoxicity
Chronic/heavy drinkers show ataxia, demensia and peripheral neuropathies. It is
associated with thiamine (vitamin B1) deficiency. The syndrome is characterised by ataxia,
confusion and paralysis of extra-occular muscles. Prompt treatment with IV/IM thiamine
is necessary. Alcohol also impairs visual acuity with painless blurring of vision on chronic
consumption.
(c) Liver and GIT
Chronic excessive ethanol consumption causes fatty liver with inflammation. It leads to
irreversible hepatic necrosis, fibrosis and failure. Another factor causing liver damage is
malnutrition. Women appear to be more susceptible to alcohol hepatotoxicity. It is one
of the most common causes of chronic pancreatitis. Irritation, inflammation, bleeding,
scaring or even induration of gut mucosa occurs after chronic alcohol use. Defective
absorption leads to deficiency of water soluble vitamins.
(d) Cardiovascular system
Chronic alcohol consumption leads to dilated cardiomyopathy, ventricular hypertrophy
and fibrosis. Alcohol also interferes with therapeutic benefits of β-blockers and ACE
inhibitors. It is also associated with ventricular arrhythmia, which may lead to syncope. It
is also a contributory factor for hypertension.
(e) Blood lipoprotein and platelet functions

Moderate alcohol intake increases HDL and decreases LDL, which may account for
observed protective effect against ischaemic heart disease. Alcohol inhibits platelet
aggregation; it results from inhibition of arachidonic acid formation from phospholipids.
Chronic alcoholics show megaloblastic anaemia due to alcohol related folic acid
deficiency. Iron deficiency anaemia may be caused by gastro-intestinal bleeding.
(f) Endocrine effects and electrolyte balance
Chronic alcoholism can produce testicular atrophy, gynaecomastia and impotence.
“Pseudo-Cushing’s syndrome” is observed in chronic alcoholics. Alcoholics with cirrhotic
liver may show ascites, edema and effusions due to decreased protein synthesis and
portal hypertension. Secondary aldosteronism in chronic alcoholics can cause
hypokalemia and muscle weakness. Some alcoholics may exhibit ketosis caused by
increased lipolytic factors like cortisol and growth hormone.
(g) Effects on foetal development
Consumption of about 6-10 units of alcohol per day during pregnancy causes foetal
alcohol syndrome. It is characterised by microcephaly, mental retardation, flattened face,
retarded growth and cardiac or other malformations of eyes and ears as congenital
abnormalities.
Another lesser degree of impairment is “alcohol-related neuro-developmental disorder”.
It is characterised by behavioural as well as cognitive and motor defects.
(h) Miscellaneous effects
o There are effects on immune system. Chronic alcoholics are pre-disposed to lung
infections and may suffer from pneumonia.
o Its chronic use is associated with increased incidence of neoplastic disease like breast
and liver carcinoma.
o Ethanol alters uric acid metabolism by increasing uric acid metabolism and
decreasing renal secretion. Hence, gout may be precipitated due to hyperuricaemia.
4.6.1.3 Treatment of Acute and Chronic Alcoholism
Intoxication due to acute intake of ethanol is managed by maintainence of vital signs
and prevention of aspiration of vomitus. Treatment of hypoglycaemia and ketosis can be
made by giving IV glucose. IV/IM thiamine and correction of electrolytes may also be
required.
The abstinence syndrome is managed by administration of a long acting sedative –
hypnotic like Chlordiazepoxide or Diazepam. Intensity of withdrawal syndrome may be
reduced by Clonidine and Propranolol. Once the withdrawal phase is over, BZDs may be
withdrawn with gradual reduction of dose. Several months may be needed for restoration of
normal sleep, and decrease of tremors and anxiety.
Alcohol dependence is followed by following means:

(a) The first effort is to render ethanol consumption unpleasant. It is discussed under
use of Disulfiram.
(b) Another approach is to reduce craving or to blunt the pleasurable outcome of
renewed drinking. Naltrexone, an opioid antagonist in a dose of 50 mg once a day is
used to treat alcohol dependence. It reduces craving for alcohol.
Another approach is to use anticonvulsant drug like Topiramate. The drug
potentiates inhibitory effects of GABA but acts at a site different than BZDs or
barbiturates.
(c) Selective serotonin uptake inhibitors (SSRIs) like Fluoxetine can increase serotonergic
activity in CNS. Alternatively, Ondansetron, a 5-HT3 antagonist has been successfully
used to treat alcohol dependence.
(d) To reduce craving for alcohol Acamprosate has been tried. It reduces excitatory
effect of glutamate on NMDA receptor and also facilitates GABA neurotransmission.
It also possesses some opioid antagonist activity and increase serotonin levels in
synapses.
4.6.2 Drug Interactions
• Chronic consumption of alcohol increases risk of hepatotoxicity by Paracetamol. It
involves CYP2E1 mediated conversion of paracetamol to reactive hepatotoxic
metabolite N-acetyl-p-benzo-quinone imine.
• All cerebral depressants like hypnotics, sedatives, phenothiazines and anti-histamines
can have synergistic effect with ethanol. It can have serious consequences during
driving.
• Chronic alcoholics are relatively tolerant to use of general anaesthetics like
halothane.
• Alcohol enhances the hypoglycaemic effects of insulin and sulfonylureas.
• Some alcoholic drinks like beer or wine contain tyramine, which is sufficient to cause
hypertensive crisis in patients taking MAO inhibitors.
4.6.3 Clinical Uses of Ethanol
It is used for following purposes:
• As a skin antiseptic (76% v/v), alcohol is most effective.
• It has astringent action and hardens the skin to prevent the bed sores.
• It is used to treat methanol poisoning.
4.6.4 Disulfiram
The enzyme aldehyde dehydrogenase is inhibited by Disulfiram and by other drugs
including metronidazole, oral hypoglycemics, some cephalosporins like Cifotetan and
Cefoperazone and urinary antiseptics like Nitrofurantoin. When alcohol is consumed in
presence of Disulfiram, conversion of acetaldehyde to acetic acid is significantly reduced.
Hence, acetaldehyde accumulates to cause effects like facial flushing, nausea, vomiting,
dizziness and headache. The reaction is extremely unpleasant, but not life threatening.
Hence, Disulfiram can be used as an aversion therapy to discourage people from consuming
alcohol. Disulfiram is rarely used as an aversion therapy of alcohol dependence. Adverse
reactions of Disulfiram include skin rashes, metallic taste and abdominal upset. Its dose is
1 gm on first day which is to be reduced by 250 mg daily until 250 mg once daily
maintainence dose is adjusted.
Disulfiram: ANTADICT, SUFITAL, ESPERAL is available as 250 mg tablet.
QUESTIONS
1. Describe neurohumoral transmission in CNS.
2. Comment on distribution, biosynthesis, release and metabolic degradation of 5-HT.
3. Describe various pharmacological actions of 5-HT.
4. Comment on actions of GABA on its receptors.
5. Comment on different agonists for 5-HT receptor.
6. Describe different stages of anaesthesia.
7. What are pharmacokinetic principles for using general anaesthetics.
8. Compare and contrast Benzodiazepines with Barbiturates.
9. Comment on pharmacokinetics of Benzodiazepines with reference to interrelation of
their metabolites.
10. Comment on adverse reactions and drug interactions of Benzodiazepines.
11. Write pharmacological effects, pharmacokinetics and therapeutic uses of
Barbiturates.
12. Elaborate on centrally acting skeletal muscle relaxants.
13. Classify types of seizures.
14. Comment on mechanism of action of antiepileptic drugs.
15. Give detailed account of Phenetoin.
16. Write pharmacological actions and pharmacokinetics of ethanol.
17. Discuss chronic effects of alcohol consumption.
• GABA
• Glutamate
• Glycine
• Serotonin (5-HT)
• Dopamine
• MAC value of anaesthetic
• Halothane
• Isoflurane
• Thiopental
• Pre-anaesthetics
• Non-benzodiazepine hypnotics
• Melatonin
• Ticlophos
• Promethazine
• Mephenesin
• Daclofen
• Adverse reactions to Phenetoin
• Pharmacokinetics of Phenobarbitone
• Carbamazepine
• Ethosuximide
• Sodium valproate
• Vigabatrin
• Gabapentin
• Lamotrigine
2. List three adverse reactions to Benzodiazepines
3. List three drug interactions of Benzodiazepines with other drugs.
4. Classify Barbiturates.
5. Name three adverse effects of Barbiturates.
6. Enlist contraindications of Barbiturates.
7. Comment on drug interactions of Barbiturates with other drugs.
8. How does Disulphuran act?
9. What are clinical uses of ethanol.
10. What are interactions of ethanol with other drugs.
Unit ... 5
PHARMACOLOGY OF
CENTRAL NERVOUS SYSTEM - II
• Pharmacology of Psychopharmacological Agents like Antipsychotics, Antidepressants, Antianxiety Agents,
Antimaniacs and Hallucinogens
• Pharmacology of Drugs used in ParkinsonÊs and AlzheimerÊs Disease
• Pharmacology of CNS stimulants and Nootropics
• Pharmacology of Opioid Analgesics and Antagonists
• Drug Addiction, Drug Abuse, Tolerance and Dependence
Drugs acting on CNS are classified in different categories. The first category belonging
to psychopharmacological agents is discussed below.
5.1 PSYCHO-PHARMACOLOGICAL AGENTS: ANTI-PSYCHOTICS,
ANTI-DEPRESSANTS, ANTI-ANXIETY AGENTS, ANTI-MANIACS AND
HALLUCINOGENS
Psychopharmacological agents are the drugs used to treat CNS – conditions related to
behaviour of a person. They are further sub-classified as antipsychotics, antidepressants,
antianxiety agents, antimaniacs and hallucinogens. Each sub-category is discussed below.
5.1.1 Antipsychotics
Antipsychotics are used to treat schizophrenia. Although, genetic predisposition is
considered to be one of the causes of schizophrenia, there are three hypotheses, based on
neurotransmitters used to explain pathogenesis of schizophrenia.
(a) Dopamine (DA) hypothesis
It is argued that DA abnormality is the basis for most of the manifestations of
schizophrenic patients. Excess of dopamine in some areas of brain is considered
responsible for schizophrenia. Typical antipsychotic drugs like Haloperidol bind to D2
receptors of DA. However, dopamine antagonists are not a cure for all schizophrenics.
Probably, other neurotransmitters are involved.
(b) 5-HT/Serotonin hypothesis
The role of 5-HT in schizophrenia is based on the finding that LSD, a central 5-HT2
receptor agonist produce hallucinations and sensory disturbances, which are symptoms
(5.1)
Pharmacology - I (B.Pharm. Sem. IV) 5.2 Pharmacology of Central Nervous System - II
observed in psychosis. Atypical neuroleptics like Clozapine and Olanzapine are potent
5-HT2A receptor antagonists. These receptors modulate release of DA in some areas of
brain. Hence, both 5-HT and DA hypotheses for schizophrenia are compatible.
(c) Glutamate hypothesis
Involvement of glutamate is based on the finding that glutamate-NMDA receptor
antagonists like Phencyclidine and Ketamine when administered to normal subject,
produces psychotic symptoms like hallucinations and thought disorders. In addition,
reduced glutamate densities have been reported in brains of schizophrenics. Drugs
which may enhance NMDA receptor activity may be useful in treating schizophrenia.
5.1.1.1 Classification of Antipsychotics
Antipsychotics are broadly classified as typical and atypical antipsychotics.
(i) Typical antipsychotics are further classified in to four categories as follows:
• Phenothiazenes: They are further sub-classified based on side chains attached to
phenothiazenes.
o Aliphatic side chain: Chlorpromazine
o Piperidine side chain: Thioridazine
o Piperazine as side chain: Trifluoperazine, Perfenazine, Fluphenazine
• Thioxanthenes: Flupenthixol, Thiothixene, Zuclopenthixol
• Butyrophenones: Haloperidol, Benperidol, Droperidol.
• Miscellaneous: Pimozide, Penfluridol, Molindone, Loxapine, Sulpiride, Amisulpride,
Remoxipride.
(ii) Atypical antipsychotics: Clozapine, Olanzapine, Quetiapine, Zotepine, Risperidone,
Ziprasidone, Paliperidone, Aripiprazole, Sertindole, Asenapine.
5.1.1.2 Mechanism of Action
All typical antipsychotic drugs act as antagonists at D2 and/or D3/D4 dopamine receptors.
Atypical antipsychotics block other monoamine receptors, especially 5-HT2A receptors.
Typical antipsychotics produce competitive blockade of post-synaptic D2 receptors in
mesolimbic system. Atypical antipsychotics have a high affinity for 5-HT2A receptors, but
they have antagonistic action on α1, ACh M1, Histamine H1 and Dopamine D2 receptors.
All antipsychotic drugs exhibit a latent period of 2-3 weeks for attaining therapeutic
effects. Majority of them are given orally; however their bioavailability increases ten fold
when given by IM route.
5.1.1.3 Therapeutic Uses
They are primarily used for three types of indications:
(a) Psychiatric indications
They are primarily used to treat schizophrenia. In addition, they are also used to treat
drug-induced psychoses like delusions associated with LSD, Amphetamine-induced
psychoses and delirium following infectious psychoses. They are also used to treat shizo-
affective disorders in which schizo refers to schizophrenia and affective refers to mania.
(b) Neuro-psychiatric indications

It involves use in Tourette’s syndrome which is marked by tics, grunts and vocalisations
which are frequently obscene. Haloperidol and Pimozide are preferred for this condition.
In addition, they are also useful for Huntington’s disease which involves progressive
choreoathetosis and dementia. Haloperidol and Chlorpromazine are preferred for this
condition.
(c) Non-psychiatric indications
All antipsychotics have antiemetic effects of varying degree. It is due to blockade of D2
receptor in CTZ as well as in GIT. Prochlorpromazine is preferred for this purpose.
Antipsychotic like Promethazine is used as pre-operative sedative since it has
antihistaminic, anticholinergic and antiemetic effects also. Droperidol is a short acting
antipsychotic with antiemetic, sedative and anticonvulsant effects.
Parenteral acaholrpromazine or Haloperidol is useful in controlling intractable hiccups.
5.1.1.4 Adverse Effects
Adverse effects to antipsychotics are categorised into following five types:
(a) CNS side effects
It involves behavioural effects, tolerance and dependence. Behavioural effects depress
the sensory inputs to reticular activating system and cause sedation as well as
psychomotor impairment in high doses. Toxic confusional states may occur with higher
doses of drugs having anticholinergic effects.
Tolerance develops to sedative and autonomic effects but not to antipsychotic action.
Withdrawal symptoms are manifested as dyskinesias. Physical dependence is not
observed.
(b) Neurological side effects
Dystonias, akathisia, parkinsoniasm and a rare neurolept-malignant syndrome appear
during treatment. Tardive dyskinesia and a rare peri-oral tremor appear later following
prolonged treatment for about a year.
Dystonia is characterised by spasm of muscles of tongue, face, neck and back.
Akathisia is characterised by uncontrollable motor restlessness without anxiety.
Parkinsoniasm is due to imbalance in dopamine-acetyl choline in basal ganglia due to
D2-receptor blockade.
Neurolept-Malignant Syndrome (NMS) is a life-threatening disorder observed in
extremely sensitive patients. It leads to hyperpyrexia, muscle rigidity, autonomic
instability with fluctuating BP, increased myoglobin and increased creatinine kinase
reflecting muscle damage.
Peri-oral tremors (Rabbit syndrome) shows rapid chewing movements just like that of
rabbits.
Tardive dyskinesia shows involuntary oro-buccal-lingual dyskinesia; as if the patients are
chewing gum.
(c) Autonomic side effects

It involves α-adrenergic blockage and anti-muscarinic effects. α-blockade leads to
postural hypotension and tachycardia. It also involves loss of libido and delayed
ejaculation. Anti-muscarinic effects cause dryness of mouth, constipation, urinary
retention, disturbed accommodation but no pupillary dilation.
(d) Endocrinal side effects
It results in hyperprolactinamia which is manifested as galactorrhea in females and
gynaecomastia in males. These drugs also inhibit release of FSH and LH leading to
amenorrhoea and inhibition of ovulation.
(e) Miscellaneous side effects
Drugs belonging to Phenotiazine groups are also known to cause jaundice,
photosensitivity, corneal opacity, epileptogenic effects and poikilothermic effects.
5.1.1.5 Drug Interactions
Drug interactions of antipsychotic drugs are presented in table 5.1.
Table 5.1: Drug interactions with antipsychotic drugs
Sr. No. Drug Effects
1. Antacids Decreased absorption of antipsychotic drugs
2. Anticholinergics Increased anticholinergic effects
3. Alcohol More sedation
4. Antithyroid drugs Increased risk of agranulocytosis (with Clozapine)
5. Barbiturates Decreased antipsychotic effects, more sedation
6. Carbamazepine/Phenytoin Decreased antipsychotic effects and lowering of
seizure threshold
7. Chloroquinine May precipitate extra-pyramidal symptoms with
Phenothiazines
8. Lithium Enhancement of neurotoxicity and precipitation of
NMS (Haloperidol)
9. Levodopa Decreased efficacy of neuroleptics
10. Oral contraceptives May potentiate hyperprolactinaemia
11. Cigarette smoking Increased metabolism of antipsychotics; higher
dose needed
Preparations of various antipsychotics are presented in table 5.2.

Table 5.2: Available preparations of antipsychotic drugs
Sr. No. Drug Formulations and strength Trade name
1. Chlorpromazine 25 mg, 50 mg, 100 mg, 200 mg Megatil, sunprazin
tablet; 25 mg/ml injection
2. Fluphenazine 25 mg/ml injection Anatensol decanoate,
Prolinate
3. Trifluoperazine 5 mg, 10 mg tablet Neocalm, Talecalm,
Trazine
4. Thioridazine 10 mg, 25 mg, 50 mg, 100 mg Melleril, Ridazin, Thioril
tablet
5. Flupenthixol 0.5 mg, 1 mg, 3 mg tablet; Fluanxol
20 mg/ml depot injection
6. Zuclopenthixol 200 mg/ml injection Clopixol depot
7. Haloperidol 1.5 mg, 5 mg, 10 mg, 20 mg tablet; Serenace, Trancodol,
2 mg/ml, 5 mg/ml injection, Senorm – LA, Gendol –
50 mg/ml depot injection LA
8. Penfluridol 20 mg tablet Flumap, Semap
9. Pimozide 2 mg, 4 mg tablet Mozep, Orap, Larap
10. Loxapine 10 mg, 25 mg capsule; 25 mg/ml Loxapac
liquid
11. Sulpiride 100 mg, 200 mg, 400 mg tablet Stride
12. Amisulpiride 50 mg, 100 mg, 200 mg tablet Sulpitac, Amipride,
Zulpride
13. Levosulpiride 25 mg tablet Lesuride
14. Clozapine 25 mg, 50 mg, 100 mg tablet Sizopin, Lozapin,
Skizoril
15. Olanzapine 2.5 mg, 5 mg, 7.5 mg, 10 mg, Oleanz, Olexar, Oliza,
15 mg, 20 mg tablet Tolaz
16. Risperidone 1 mg, 2 mg, 3 mg, 4 mg tablet; Sizodon, Risnia, Risdone
1 mg/ml syrup
17. Ziprasidone 20 mg, 40 mg, 80 mg tablet Zipsydon, Azona
18. Paliperidone 3 mg, 6 mg, 9 mg ER tablet Palica – OD
19. Aripiprazole 10 mg, 15 mg, 20 mg, 30 mg Arpizole, Schizopra,
tablet Aripra – MT
20. Quetiapine 25 mg, 50 mg, 100 mg, 200 mg, Placidin, Qutipin, Qutan,
300 mg tablet Q-pin
5.1.2 Anti-Depressants
Depression is a disorder of mood and hence it is classified as affective disorder. There
are two major types of depression: unipolar depression and bipolar depression. Unipolar
depression is further sub-divided as reactive depression and endogenous depression.
About 80% of depressed patients experience unipolar depression in which the mood
swings in one direction only i.e. either depression with a feeling of worthlessness or
depression with irritability. About 60% of unipolar depressed patients show reactive
depression manifested by feeling of sadness or grief and anxiety due to reasons like death
of a loved one, unemployment, physical illness or social problems. It is self-limiting and
responds to antianxiety drugs. About 25% of unipolar patients are having endogenous
depression with suicidal thoughts. It is not self-limiting, unless treated with an anti-
depressant drug or by electro convulsive therapy (ECT). It results either due to genetic
causes or due to disturbed neurotransmission of NE, 5-HT or DA in certain areas of brain.
5.1.2.1 Classification
Classification of antidepressant drugs is based on their mechanism of action.
Antidepressants are classified in to following seven sub-types:
• Drugs which block both NE and 5-HT reuptake: Tricyclic antidepressants (TCAs):
Imipramine, Clomipramine, Amitriptyline, Doxepin
• Selective 5-HT-NE reuptake inhibitors (SNRIs): Duloxetine, Venlafaxine, Milnacipram
• Drugs which block NE reuptake: Desipramine, Nortriptyline, Protryptyline,
Maprotiline, Amoxapine, Reboxetine
• Selective serotonin reuptake inhibitors (SSRIs): Sertraline, Fluoxetine, Fluvoxamine,
Paroxetine, Citalopram, Escitalopram
• Atypical antidepressants: Trazodone, Nefazodone, Bupropion, Mirtazapine, Mianserin
• Antidepressants of natural origin: St. John’s wort (Active principle: Hyperforin)
• MAO inhibitors: Non-selective: Tranylcypromine; Selective: Moclobemide
5.1.2.2 Mechanism of Action
A brief account of mechanism of action is presented below:
(a) Drugs which block NE and 5-HT reuptake: These are tricyclic antidepressants. They
block reuptake of NE and 5-HT into their neuron by inhibiting respective
transporters. It leads to more availability and a longer stay of NE and 5-HT at their
respective receptor sites. (Fig. 5.1).
(b) SNRIs: Besides the effects shown by tricyclic antidepressants, SNRIs lackα1-
adrenergic, histamine H1 and cholinergic receptor blocking properties of TCAs.
Hence, they have fewer side effects.
(c) Drugs blocking NE reuptake: These drugs predominantly inhibit NE reuptake which
results in increased concentration of NE in synaptic cleft.
(d) SSRIs selectively increase levels of serotonin in synaptic cleft. They are most
commonly prescribed antidepressant drugs.
All antidepressants described above exhibit a lag of 2-3 weeks to produce desirable
clinical effects.
Moclobemide Se
ron roto
neu n in
e rg
rgic ic n
rene Mianserin eu r
Norad on
Mirtazapine
MAO Metabolites
Metabolites MAO
5HT1
a2
a2
5HT1
5-HT
NE uptake uptake
5-HT
Imipramine NE SSRIs
desipramine etc.
a2 b1 b2 5-HT2
Fig. 5.1: Potential sites of action of some antidepressant drugs

(e) Atypical antidepressants have different mechanisms of action. Trazodone/
Nefazodone inhibit uptake of 5-HT, blocks 5-HT2A receptor and desensitizes
presymaptic 5-HT receptor. Mianserin blocks presynaptic α1-receptors and increase
release of NE in brain. Mirtazapine acts by increasing both NE and 5-HT release.
Bupropion is a weak inhibitor of neuronal reuptake of 5-HT, NE and DA.
(f) Active ingradients of St. John’s wort (Hypericum perforatum) are monoamine
reuptake inhibitors, mild MAO inhibitors and stimulants at GABA receptors.
(g) MAO inhibitors increase brain amine levels by inhibiting their metabolism, resulting
in increase of NE and 5-HT. There are two isoforms of MAO: MAO-A and MAO-B.
MAO inhibitors need a biological lag of 2-3 weeks to exert clinical effects.
5.1.2.3 Pharmacokinetics
Oral absorption of most antidepressant drugs is good; still the bioavailability is uncertain
because of their first pass metabolism. Bioavailability of Citalopram and Protryptyline is
> 90%. The plasma half-life of most antidepressants is long, hence plasma concentration is
built-up slowly. After reaching steady state, one daily dose at bed time is enough. Plasma
half-life for some antidepressants is low. Amoxapine (8 hours), Nefazodone (2-4 hours),
Trazodone (4-8 hours) and Venlafaxine (4-9 hours) are some of the examples. The half-life is
longer due to their metabolites except for Fluvoxamine, Paroxetine and Protriptyline. Among
MAO inhibitors, Moclobemide is readily absorbed but its first pass metabolism reduces
bioavailability; its half-life is 1-3 hours.
5.1.2.4 Therapeutic Uses

They are broadly classified as psychiatric uses and non-psychiatric uses.
(a) Psychiatric uses
The drugs are useful to treat endogenous depression. There are three phases of
treatment: acute phase, continuation phase and maintainence phase. In the initial phase,
objective is to resolve symptoms followed by prevention of relapse and prevention of
recurrence in the last phase. SSRIs like Mirtazapine, Nefazodone, Duloxetine and
Venlafaxine are considered best drugs of choice.
SSRIs like Paroxetine, Fluvoxamine and Fluoxetine, alone or with Alprazolam, can be used
to treat panic disorders. They need several weeks for stabilisation.
SSRIs like Fluvoxamine are useful for treating Obsessive-Compulsive Disorders (OCDs).
Alternatively, Clomipramine or Citalopram may also be used for the purpose.
Drugs like Imipramine or Desipramine are preferred to treat Attention Deficit
Hyperkinetic Disorders (ADHD). Alternatively, Atomoxetine is also used for the purpose.
SSRIs like Paroxetine or reversible MAO-A inhibitor Moclobemide are preferred for
school phobia and social phobia. Paroxetine with Alprazolam are preferred for post-
traumatic stress disorder. SSRIs are helpful in controlling impulse control disorder like
gambling.
(b) Non-psychiatric uses
Antidepressants with anticholinergic side effects like Amitriptyline, Desiprimine and
Imipramine are preferred for treating enuresis and bed-wetting in children. Older
patients are more sensitive to anticholinergic effects of TCAs.
TCAs like Imipramine, Amitriptyline or nortriptyline are preferred in treating neuropathic
chronic pain.
TCAs like Amitriptyline in low doses (10 mg at night), followed by increase in dose up to
50 mg within 2-3 weeks is effective in treating migraine headache.
5% topical Doxepin cream relieves itching in atopic dermatitis.
SSRIs like Fluoxamine and Fluoxetine are useful in treating bulimia nervosa.
Bupropion is used to treat nicotine dependence and smoking caessation.
Citalopram is used to treat ethanol abuse syndrome.
5.1.2.5 Adverse Effects
Adverse effects are dependent on the type of anti-depressant based on its mechanism
of action.
(a) TCAs which block uptake of NE or NE + 5-HT
TCAs with histamine H1 receptor blocking actions (Amitriptyline, Doxepin and
Trimipramine) cause more sedation. Drugs like Maprotiline, Bupropion and
Clomipramine lower seizure threshold and precipitate epileptic seizures. Drug like
Amoxapine can induce extrapyarmidal effects, gynacomastia (in males) and
galactorrhoea (in females).
Antidepressants with anticholinergic effects cause blurred vision, urinary retension,

constipation and increase in intra-occular pressure. Antidepressants with α-blockade
cause postural hypotension and tachycardia.
Some antidepressants altering endocrinal responses cause weight gain and sexual
disturbances. Some TCAs can cause QT-prolongation leading to arrhythmia.
(b) SNRIs
These drugs have serotonergic side effects like discontinuation syndrome.
(c) SSRIs
Some patients complain of agitation, anxiety and insomnia. Few others complain of
sexual dysfunction including decreased libido and delayed ejaculaton. Nausea and loose
stools are also experienced by few patients. Sudden withdrawal causes discontinuation
syndrome leading to dizziness, paresthesias and headache.
(d) MAO inhibitors
Their adverse effects include postural hypotension (in elders), weight gain, dizziness and
sexual dysfunction.
(e) Atypical antidepressants
Trazodone causes nausea, sedation, postural hypotension and priapism leading to
impotence. Bupropion causes agitation and insomnia. Mirtazapine and Mianserin cause
sedation due to histamine H1-blockade. Hepatotoxicity and blood dyscrasias have also
been reported.
5.1.2.6 Drug Interactions
They are classified under three categories:
(i) Interactions with TCAs and related drugs:
(a) TCAs potentiate effects of directly acting sympathomimetics causing rise in BP and
arrhythmias; but inhibit effects of indirectly acting sympathomimetics.
(b) Anticholinergic drugs aggravate toxicity of TCAs.
(c) Phenytoin, Chlorpromazine and Aspirine displace TCAs from their protein binding
sites leading to increased effect of TCAs.
(d) MAO inhibitors have synergistic action with TCAs causing hypertension, arrhythmias
and seizures.
(ii) Interactions with MAO inhibitors:
(a) Food articles containing tyramine, like cheese, beer, red wine, banana, yoghurt and
pickled meat when used with MAO inhibitors can cause hypertensive crisis.
(b) MAO inhibitors with TCAs or with directly/indirectly acting sympathomimetics can
cause hypertension, arrhythmias and seizures.
(c) MAO inhibitors inhibit degradation of DA. This can result in hypertension.
(d) MAO inhibitors retard metabolism of drugs like morphine causing severe respiratory
depression. It also retards metabolism of sulfonylureas causing hypoglycaemia and
that of chloroquinine causing toxicity of chloroquine.
(iii) Interactions with SSRIs:

(a) SSRIs inhibit metabolising enzymes like CYP2D6 and CYP3A4. As a result, plasma
levels and toxicity of TCAs, Haloperidol, Clozapine, Warfarin, Dextromethorphan,
Terfenadine, Astemizole and Cisapride are increased. Elevated levels of Terfenadine,
Astemizole and Cisapride can precipitate arrhythmias.
(b) SSRIs with MAO inhibitors result in elevated levels of 5-HT causing “serotonin
syndrome” leading to hyperthermia, muscle rigidity, tremors and rapid changes in
mental status along wirth cardiovascular collapse.
Preparations of various antidepressants are presented in table 5.3.
Table 5.3: Preparations of antidepressant drugs
Sr. Drug Formulations and strength Trade name
No.
1. Amoxapine 50 mg, 100 mg tablets Demolox, A-pine
2. Amitriptyline 10 mg, 25 mg, 75 mg tablets Amitone, Tryptomer, Tadamit
3. Clomipramine 10 mg, 25 mg, 50 mg tablets Clonil, Clofranil
4. Doxepin 10 mg, 25 mg, 75 mg capsule Doxetar, Doxin, Spectra
5. Imipramine 25 mg, 75 mg capsule Depsonil, Depsonil PM,
Imipramine
6. Nortriptyline 25 mg tablet Sensival, Nordep, Primox
7. Trimipramine 10 mg, 25 mg tablets Surmontil
8. Reboxetine 2 mg, 4 mg tablets Rebotin, Reboot
9. Duloxetine 20 mg, 30 mg, 40 mg capsule Delok, Dulane, Duzac
10. Venlafaxine 25 mg, 37.5 mg, 75 mg Dalium, Venlift, Veniz-XR,
tablets; 150 mg ER capsule Venlor-XR
11. Citalopram 10 mg, 20 mg, 40 mg tablets Citopam, Zetalo, Cytop
12. Escitalopram 5 mg, 10 mg, 20 mg tablets Articalm, Stalopam, S-Zetalo,
Nexito
13. Fluoxetine 10 mg, 20 mg, 60 mg tablet; F-udac, Prodep, hoftil, Flutinol
20 mg/ 5ml suspension
14. Paroxetine 10 mg, 20 mg, 30 mg, 40 mg Parotin, Pexep, Pari, Paxidep-
tablets; 12.5 mg, 25 mg, 37.5 CR
mg CR tablets
15. Sertraline 25 gm, 50 mg, 100 mg tablets Zosert, Sertil, Inosert, Serlift
16. Moclobemide 150 mg, 300 mg tablet/ Rimarex, Trima
capsule
contd. …
17. Bupropion 150 mg tablet, 150 mg SR Zyban, Smoqit-SR, Bupron-SR

tablet
18. Mianserin 10 mg, 30 mg tablets Depnon, Tetradep, Seridac
19. Mirtazepine 7.5 mg, 15 mg, 30 mg tablets Mirtaz, Mirtee, Mirazep
20. Trazodone 25 mg, 50 mg, 100 mg tablets Depryl, Trazonil, Tazodac,
Trazalon
21. Hypericum 300 mg capsule J-Wort, Jovin
(St. John’s wort)
5.1.3 Anti-anxiety Agents
Anxiety is an adaptive response which prepares a person to face the challenges of life. It
is characterised by psychological symptoms like tension, fear, apprehension and lack of
concentration. In addition, sympathetic somatic symptoms like tachycardia, tremors,
sweating and GIT distress are also observed. Fatigue and sleep disturbances are also
common. If anxiety persists, it impairs person’s ability to perform the job and often leads to
visceral organ dysfunction and neurological problems.
Anxiety neurosis is characterised by uneasiness, easily provoked irritable behaviour and
disproportionate concern and fear for future. It can result due to problems related to
examination, interview to performance related to sexual act or even problems at work place.
Manifestations of such anxiety are sweating, epigastric distress, tremors, dizziness,
congestion in chest and hyperventilation.
There are two types of drugs used to treat anxiety: typical and atypical.
[I] Typical antianxiety drugs are BZDs and are discussed under section 4.4.1.
[II] Atypical antianxiety drugs (anxiolytics) are Buspirone, Ipsapirone and Gepirone.
These drugs act through non-GABAergic system and have low chances of side effects in
comparison to BZDs. These drugs exert their anxiolytic effects by acting as a partial agonist
primarily at brain 5-HT1A receptors. By selective activation of the inhibitory presynaptic
5-HT1A receptor, they suppress 5-HT neurotransmission through neuronal system.
Useful anxiolytic effects of Buspirone are delayed for more than two weeks, which makes
it unsuitable for treating acute anxiety states. It has no muscle relaxant, anticonvulsant or
hypnotic action. It has minimal abuse liability and causes no withdrawal reactions on abrupt
discontinuation. It causes lesser impairment of psychomotor skills and does not potentiate
CNS depressant effects of alcohol. It can cause tachycardia, nervousness, GIT distress and
paresthesias. It causes dose-dependent papillary constriction.
Buspirone is available as 5 mg, 10 mg tablet: TAMSPAR, BUSCALM, BUSPIDAC.
Non-specific β-adrenergic blocker like Propranolol is also used to treat anxiety. Worrying
situations and apprehensions associated with examinations, job interviews or public address
may lead to palpitation, tremors, GIT upset or even hypertension die to sympathetic
overactivity. These symptoms, in turn, reinforce anxiety and thus the visicous cycle continues.
Propranolol breaks the visicious cycle. Through its β-blocking action, it decreases palpitation,
tremors, GIT upset, hypertension and blood lactic acid levels. However, because of its
cardiovascular actions, it is not a potential preferred anxieolytic.
Propranolol is available as 10 mg, 20 mg tablet in combination with 0.25 mg Alprazolam:
ALLTOP-P, ZOPAX PLUS.
5.1.4 Anti-maniacs
Mania is characterised by an excessive desire and too much of euphoria. Majority of
patients of mania experience cyclic episodes of mania followed by severe depression with
periods of normal mood in between. Thus, the patient’s condition moves between mania
and depression. Hence, it is called as manic-depressive psychosis (MDP).
Excessive NE/DA related activity precipitates mania and the drugs which reduce NE/DA
relieve mania. Balanced neurotransmitter levels help in stabilisation of mood. While manic
episode is believed to result from elevated NE, depressive phase is associated with decrease
in NE.
Lithium carbonate is considered to be a drug of choice for treating MDP. In addition,
Carbamazepine, valproate or olanzapine can be used as alternatives to Lithium carbonate.
Details about Lithium carbonate are presented here.
(a) Mechanism of Action
The mechanism of action of Lithium is related to second messenger involved in
α-adrenergic and muscarinic neurotransmission. Inositol triphosphate (IP3) is inactivated to
inositol diphosphate (IP2), inositol monophosphate (IP1) and then to inositol. Lithium
selectively inhibits signal transduction in overactive neurons by blocking conversion of IP2 to
IP1 and then to inositol. As a result, the supply of free inositol to regenerate phosphatidyl
inositol-diphosphate (PIP2) in hyperactive neurons is interrupted and ultimately release of IP3
and diacyl glycerol (DAG) is also reduced which decreases neuronal response to NE, DA and
5-HT.
In addition, Lithium may uncouple receptors from their G-proteins. Sodium ions are so
common for neurotransmission. Competition of lithium ions with sodium is also said to
contribute to the action of lithium.
(b) Pharmacokinetics
Lithium carbonate is readily absorbed from GIT. Distribution occurs throughout
extracellular fluid and body water with no evidence of either protein binding or metabolism.
The elimination half-life is 24 hours but the doses are given at 8 hourly interval. 96% of the
drug is excreted through kidney and remaining 4% through saliva and sweat. Na+ loading
enhances Li+ clearance while Na+ depletion promotes Li+ retention. This interrelation
explains association of lithium toxicity with diuretics and diarrhoea. Li+ has a low margin of
safety with a therapeutic window of 0.5-1.5 mEq/L. Frequent measurements of serum steady
state concentration are essential for optimum outcome. Toxicity appears when serum levels
exceed 1.5 mEq/L.
(c) Therapeutic Uses

Lithium is used as Lithium carbonate or citrate. Both are less hygroscopic and less irritant
to GIT than lithium chloride. However, in stomach any salt of lithium is converted to lithium
chloride. Usual dose is 300-600 mg three times a day. The dose should be adjusted based on
serum levels of lithium.
Lithium is primarily used for manic depressive bipolar psychoses. Abrupt discontinuation
can lead to rebound effect. Persistent long term treatment is of importance.
Leucocyte counts are increased with Lithium therapy. This property is used to treat
leukopenia and agranulocytosis associated with cancer chemotherapy.
Lithium is occasionally used to treat cluster headache and as an adjuvant to TCAs for
treating recurrent unipolar depression.
(d) Adverse Effects
• Tremors, confusion and slurred speech.
• Sub-clinical hypothyroidism is reported on long-term use. Lithium inhibits
TSH –activated adenylate cyclise causing lesser cAMP which in turn decreases T3 and
T4 secretion.
• On long-term use some patients develop nephrogenic diabetes insipidus
characterised by polyuria and polydipsia.
• Lithium causes diarrhoea. Diarrhoea causes sodium loss and the cycle continues.
• Oedema is a frequent adverse effect of lithium.
• Renal clearance of lithium increases during pregnancy but decreases immediately
after delivery. Dose adjustment is essential. Lithium is also secreted through breast
milk and should be avoided in lactating mothers.
(e) Drug Interactions
• Phenothiazine and Butyrophenone group of antipsychotics, when combined with
lithium may aggravate risk of extrapyramidal effects.
• Thiazide or loop diuretics lead to rise in lithium plasma levels.
• Except aspirin or paracetamol, other NSAIDs reduce renal clearance of lithium.
Lithium carbonate is available as 250 mg, 300 mg, 350 mg tablet; 150 mg, 350 mg capsule
and 400 mg SR/ER tablets: LITHOSUN, LITHOSUN – SR, LICAB, LICAB – XL, LITHOCAP.
Alternatives to Lithium
Nearly 50% of patients show incomplete or poor response to lithium. Hence, following
drugs are used as an alternative to treat MDP: Olanzapine, Risperidone, Quetiapine,
Ziprasidone, Lorazepam, Clonazepam, Bupropion, Paroxetine, Valproic acid, Carbamazepine,
Lamotrigine, Gabapentine or Topiramate. Alternative drugs have been discussed earlier.
5.1.5 Hallucinogens
Hallucinogens are also termed as psychedelics or psychotomimetics. After the use of
these drugs, a person feels that there is no boundary between him and the cosmos and that
his mind is able to see more than what he can tell. Drug abusers glorify them by the term
“mind expanders”. Pharmacologically, these drugs produce changes in sensory perceptions
(visual, auditory and olfactory), thoughts, behaviour and mood. Their actions mimic
psychoses.
Mood simply means a state of feeling at particular time. Percepts are such thoughts or
messages, which though originate from outside, have a high degree of agreement with
external reality or signals. These signals are not fantasies. If a fantacy is generated during
sleep, it is called as a dream. However, if a fantasy occurs during wakeful state, it is called as
hallucination. Thus, hallucination is a false perception without a true sensory stimulus. In
hallucination, the images are vague and disproportionate.
The drugs under this category are as follows:
(i) Lysergic Acid Diethylamide (LSD)
It is a lysergic acid derivative which occurs in the cereal fungus ergot. The drug produces
strong psychedelic effects in doses less than 1 µg/kg. It works as agonist of 5-HT2 receptors
and suppresses electrical activity in serotonergic raphe neurons which tonically inhibits the
visual and sensory inputs. As a result, the excitation threshold of retina is decreased and its
spontaneous electrical activity increases leading to visual hallucinations. Similarly, the
excitation threshold of mid-brain RAS is decreased producing a hyper-arousal state. The
drug also displays agonistic activity at 5-HT1A and 5-HT1C receptors.
A dose of 25-50 µg produces all effects of LSD. The onset of effect is fairly rapid but the
duration varies with the user and the dose. Effects normally vanish within 8 hours. The
effects start with somatic symptoms like tremors, blurred vision amd tachycardia. After one
hour, they are followed by perceptual symptoms. Visual perceptions are expressed as
distorted shapes with brilliant colours of changing intensities. Auditory perceptions include
sharp hearing with difficulty in locating the source of sound. Further auditory sense gets
fused with visual to provoke a strange feeling where one starts seeing the sound and
hearing the colours. Olfactory perceptions also get fused with auditory and visual senses.
The mood fluctuates in between joyous, sad to frightening. The sense of time is lost. After
two hours, psychic symptoms start appearing. They are characterised by dreamy state and
depersonalisation, as if the soul has come out of the body. A sense of union with cosmos is
felt. All such experiences are either terrifying or hilarious depending on the user’s personality
traits. Further flash backs of hallucinatory experiences can appear within a week or month
and may be precipitated by stress, fatigue or alcohol.
Adverse effects include hyper-pyrexia, nausea and muscular weakness. Hallucinatory
experiences may be accompanied with paranoid delusions, which may lead to homicide or
suicide. There is no physical dependence. Even psychic dependence is mild. Higher rate of
absorption is observed in women. Animal experiments have shown teratogenic effects.
Treatment of toxicity includes Diazepam for sedation and Haloperidol for psychotic
symptoms.
(ii) Mescaline
It is derived from a Mexican cactus and has a low potency. It has marked
sympathomimetic effects. It is less active than LSD and is lesser in use.
(iii) Phencyclidine (PCP; Angel dust)
It is an anticholinergic with mild hallucinatory effects like disorientation, distorted body
images, loss of the sense of time and impairment of the thought processes. Like LSD, it also
causes occasional bad experiences and recurrent psychotic episodes. Hence, it is less
abused. Ketamine is an annalog of PCP with much low hallucinogenic potential and is used
to produce anaesthesia. PCP may be smoked, mixed with tobacco, snorted or taken orally or
injected intravenously.
(iv) Cannabinoids (∆9-Tetrahydrocannabinol; ∆9 THC)
It is the active principle of the extracts of the hemp plant (Cannabis sativa and Cannabis
indica). It is the most popular drug of abuse and is used in following forms:
o The dried leaves are powdered, made a paste and then used as a drink called Bhang.
o The dried leaves and flowering tops of the plant are referred to as marijuana (grass,
pot, weed or reefer) and is smoked in pipes or rolled as cigarettes.
o Charas or hashish are resinous exudates of flower tops or leaves. It is very potent and
is usually smoked in a pipe.
The major psycho-active constituent is TCH. The TCH content in hashish is more than
that of marijuana. Its metabolite, 11-hydroxy-THC is also highly active.
(a) Pharmacokinetics
THC is readily absorbed when marijuana is smoked. The effects appear within 30 minutes
of the onset of smoking. On oral administration THC is absorbed more slowly. The terminal
half-life ranges from 18 hours to 3 days. The behavioural and physiological effects return to
normal within 6-8 hours. Being highly lipophilic, THC and its metabolites are sequestered in
body fat and adipose tissue. Hence, excertion continues several days after single dose.
(b) Pharmacological Actions
Initially there is CNS stimulation followed by sedation. During stimulatory phase there is
euphoria, increased talkativeness, increase in appetite and a feeling of confidence, relaxation
and well being. Many may laugh in an uncontrolled manner. During sedative phase, there
are mild LSD type effects. There is retention of fixed unnatural posture. Ability to
concentrate is impaired; sleepiness prevails. There is impairment of short term memory,
simple learning task and of motor co-ordination. The peripheral effects include tachycardia,
vasodilatation with reddening of conjunctiva, reduction in intraocular pressure and
bronchodilatation. Other CNS effects are analgesia and anti-emetic action. It has inhibitory
effects on immune function.
(c) Mechanism of Action and Clinical Use

Two types of cannabinoid receptors are known: CB1 and CB2. CB1 receptors are located in
brain while CB2 receptors are located in periphery. Both are G-protein coupled receptors
linked to inhibition of adenylate cyclise.
Anandamide, an arachidonic acid derivative, is an endogenous cannabinoid ligand for
CB1 receptor. Dronabinol and Nabilone are synthetic analogs of THC. They are used to
increase appetite in patients of AIDS. Dronabinol is used to prevent emesis caused by cancer
therapy. Rimonabant is approved for obesity. It is antagonist to CB1 receptor. It is also used
for smoking cessation.
CB2 receptors are located in lymphoid system and accounts for inhibitory effects on the
immune system.
(d) Adverse Effects
Cannabis is relatively safer than most abused substances like opioids and alcohol.
Psychological dependence is mild. There is no physical dependence. There are no
reports of fatal overdose. Withdrawal effects are mild and include irritability, decrease in
appetite and insomnia. Some tolerance may develop in heavy marijuana users.
Cannabinoids do impair cognitive and motor skills. They do not affect retrieval of
previously learned facts. THC causes impairment of short term memory. Heavy marijuana
smokers suffer with bronchitis. Endocrinal side effects include notable decrease in plasma
testosterone and a reduction in sperm count. THC produces teratogenecity in rats and
mutagenecity in white cells of human beings. Risk of foetal malformation is negligible.
Rimonabant is available as 20 mg tablet.
5.2 DRUGS USED IN PARKINSON’S DISEASE AND ALZHEIMER’S
DISEASE
5.2.1 Drugs for Parkinson’s Disease
Parkinson’s disease is a slowly progressive neuro-degenerative disease characterised by
following symptoms:
• Pill rolling tremors
• Akathesia: Inability to sit still
• Rigidity
• Kinesias (akinesia, bradykinesia)
• Instable (stooped) posture
• No arm swinging in rhythm with legs
• Sialorrhea: profused salivary secretion
• Masked facial expression
During functioning of brain, there is a functional balance between dopaminergic and
cholinergic system. In Parkinson’s disease (PD), there is a loss of dopaminergic neurons. It
indirectly leads to hyperactivity of cholinergic neurons. The mechanism of action of drugs
used in treating PD is shown in Fig. 5.2.
BRAIN
(Competes with
I-dopa for uptake
3-O-Methyldopa
Entacapone
Tolcapone COMT
Levodopa Levodopa
Dopa-
Carbidopa Dopa- decarboxylase
decarboxylase Blood brain barrier
Selegiline
Dopamine
Dopamine MAO-B
DOPAC
Does not cross BBB
Peripheral degradation Amantadine
DA
and adverse effects Bromocriptine
Tolcapone Ropinirole
Pramipexole
Peripheral tissues
and gut D2
CPMT
3-O-Methyldopa
Fig. 5.2: Mechanism of action of dopaminergic drugs used for treatment of PD

Drugs used for treating Parkinson’s disease are classified in to following four categories:
5.2.1.1 Drugs Which Increase Dopamine Levels
1. Levodopa with Carbidopa
DA itself does not cross BBB. Its peripheral effects do not provide any advantage to
patients of Parkinson’s disease. Levodopa is the precursor of DA. Levodopa can cross BBB
and it is decarboxylated to DA in brain. If administered alone, only about 1% of Levodopa
actually enters the brain. Remaining 97-99% Levodopa gets metabolised in GIT and
peripheral tissues by the enzyme dopa decarboxylase to DA, which cannot enter brain
because of its inability to cross BBB. To prevent its peripheral degradation, Levodopa is
usually coadministered with either Carbidopa or Benserazide, a peripheral dopa
decarboxylase inhibitor. This combination lowers the dose of Levodopa and reduces
incidence of peripheral side effects.
Levodopa is widely used for treatment of all types of Parkinsoniasm, except the one
which is associated with antipsychotic therapy. All clinical manifestations respond to the
combination of Levodopa with Carbidopa. Rigidity, bradykinesia, abnormalities of posture
and locomotion respond well to the combination while tremors are less responsive. The
therapy started with small dose of Carbidopa 25 mg + Levodopa 100 mg (1:4 ratio) three
times a day, 1 hour before meals. The dose of Levodopa is increased up to 250 mg (1:10
ratio) gradually. If necessary, a dopamine agonist like Bromocriptine may be added.
(a) Adverse effects

The response to combination of Levodopa + Carbidopa is not constant if the therapy is
continued for a long time. There is decrease of effect indicating reduction in duration of
benefit progressively. The treatment is characterised by “on-off phenonmenon” which
indicates positive and negative effects of the therapy.
During therapy, there are excessive and abnormal choreiform movements of limbs,
trunk, face and tongue. These effects are termed as dyskinesias, which disappear if the dose
of Levodopa is reduced; but this causes rigidity to return. The variation in response is
probably due to fluctuating levels of DA.
Other adverse reactions related to CNS are vivid dreams, delusions, hallucinations,
confusion and sleep disrturbances, especially in elderly people. Prolonged therapy of
Carbidopa + Levodopa may cause schizophrenia-like symptoms in elderly.
Postural hypotension may occur, but tolerance develops to this effect later. Occasionally,
cardiac arrhythmias may occur due to stimulation of adrenoceptors by DA.
Anorexia, nausea and vomiting may be caused due to accumulation of DA. It is much
less with the combination than with Levodopa alone. Tolerance develops to these effects
later.
Levodopa may cause mydriasis and may precipitate an attack of glaucoma in some
patients. Abnormalities in smell/taste, hot flushes and precipitation of gout may occur. Mild
but transient increase in blood urea, serum transaminases, alkaline phosphatise and bilirubin
may also be observed.
(b) Contraindications
Levodopa is contraindicated in psychoses, narrow angle glaucoma, cardiac arrhythmias
and melanoma.
(c) Drug interactions
• Pyridoxine (vitamin B6) enhances the extracerebral metabolism of Levodopa and
decreases its therapeutic effects.
• MAO-A inhibitors potentiate toxicity of Levodopa leading to hypertensive crisis.
• Proteins ingested with meals may produce sufficient amount of amino acids, which
compete with Levodopa transport both in GIT and brain; hence Levodopa should be
given 30 minutes before meals.
• TCAs decrease the absorption of Levodopa leading to hypertensive episodes.
Levodopa + Carbidopa: SYNDOPA, TIDOMET-FORTE, TIDOMET LS, SINEMET PLUS,
SYNDOPA PLUS, TIDOMET PLUS is available as a combination as either 250 mg/25 mg or
100 mg/10 mg. It is also available as 100 mg/25 mg combination. Levodopa + Benserazide:
BENSPAR is available as a combination of 200 mg/50 mg (tablet) or 100 mg/28.5 mg capsule.
2. COMT Inhibitors
COMT metabolises DA and its precursor Levodopa, producing the inactive metabolite.
Hence, inhibition of peripheral COMT will result in increase in plasma half-life of Levodopa.
Selective COMT inhibitors like Tolcapone and Entacapone, not only diminish metabolism of
Levodopa but also increase its bioavailability in brain. Pharmacological effects of Tolcapone
and Entacapone are similar. However, Tolcapone has both central and peripheral effects
while Entacapone is only peripheral blocker of COMT. Tolcapone is occasionally associated
with severe hepatotoxicity and death. Hence, Entacapone is preferred because of lack of
hepatotoxicity. Common side effects are dyskinesia, nausea, diarrhoea, postural hypotension
and sleep disturbances.
Tolcapone is available as 100 mg tablet; Entacapone is available as 200 mg tablet. Both
are given three times a day.
3. Amantadine
It is an antiviral drug. It prevents DA uptake, facilitates presynaptic DA release, possesses
weak antimuscarinic action and blocks glutamate NMDA receptor. The first two actions help
in treating Parkinson’s disease. Blocking of NMDA receptor contributes in reducing
excitation-induced neurotoxicity and dyskinesia. Amantadine alone or in combination with
Levodopa and Carbidopa is used to treat PD. Adverse effects include nausea, dizziness,
insomnia, confusion hallucinations, anke odema. Its anti-muscarinic actions are additive to
CNS effects.
Amantadine is available as 100 mg tablet: AMANTREL, COMANTREL.
5.2.1.2 Drugs Which Prevent Dopamine Degradation
Inhibitors of the enzyme MAO-B are useful to treat PD. Selegiline is an irreversible
inhibitor of MAO-B, an enzyme in dopaminergic neurons responsible for metabolism of DA.
It makes more DA available for stimulation of its receptors. Initially, Selegiline may be used
alone. Later, it is used along with Levodopa + Carbidopa to minimise problem of dyskinesia
associated with long term use of Levodopa. Selegiline may retard progression of PD by
reducing oxidative damage due to formation of free radicals produced during metabolism
of DA. It may cause insomnia. It should not be coadministered with TCAs and SSRIs for the
risk of acute toxic reactions like hyperpyrexia, agitation, delirum and coma.
Selegiline is available as 5 mg tablet: SELGIN, SALERIN, ELEGELIN.
5.2.1.3 Drugs Which Stimulate Dopamine Receptors
1. Dopamine agonists
These drugs directly stimulate DA recptors and do not depend on the formation of DA
from Levodopa. They have following advantages:
(a) They do not require metabolic conversion to DA.
(b) They do not depend on the functional integrity of dopaminergic neurons.
(c) They have longer duration of action and lesser on-off phenonmenona as compared
to Levodopa.
(d) They are more selective than Levodopa on DA receptors.

(e) They are less likely to generate damaging free radicals.
Bromocriptine and Cabergoline are amine ergot derivatives. Ropinirole and Pramipexole
are synthetic non-ergot DA receptor agonists. Bromocriptine is a potent D2 receptor agonist
and a weak D1 antagonist. Cabergoline is similar to Bromocriptine, but with a longer
duration of action (half-life > 80 hours). Ropinirole and Pramipexole have more selective
action on D2-receptors. Pramipexole is excreted by kidney while Ropinirole is metabolised by
CYP1A2. Ciprofloxacin, which inhibits CYP1A2 can increase plasma concentration of
Ropinirole.
Bromocriptine and Cabergoline, being ergot derivatives cause following adverse
reactions: anorexia, nausea, vomiting, vertigo, postural hypotension, painless peripheral
vasospasm, peripheral oedema, pleural fibrosis and erythromelalgia. Erythromelalgia consists
of red, tender, painful swollen joints of feet and hands. These symptoms are less frequent
with Pramipexole and Ropinirole. Synthetic drugs are preferred. Pramipexole is given in a
dose of 0.125-0.75 mg once a day while Ropinirole is given as 0.25 mg once a day. One
more addition is of Rotigotine, which is used as a transdermal patch.
Bromocriptine: PROCTINAL SICRIPTIN, PARLODEL, BROM, ENCRIPT is available as
1.25 mg, 2.5 mg tablet. Cabergoline: CABGOLINE is available as 0.25 mg and 0.5 mg tablet.
Ropinirole: ROPITOR, ROPARK is available as 0.25 mg, 0.5 mg, 1 mg and 2 mg tablet.
Pramipexole: PARPEX is available as 0.5 mg, 1 mg and 1.5 mg tablet.
5.2.1.4 Drugs Which Restore DA-ACh Balance
The drugs under this category are centrally acting antimuscarinic drugs. In the absence
of inhibitory control of DA, the activity of cholinergic system becomes dominant. Blockade
of central muscarinic receptor by these drugs reduces cholinergic activity. The muscarinic
antagonists are most commonly used to treat following conditions:
(a) Early stages of the disease
(b) Late-stage PD as an adjunct to Levodopa + Carbidopa therapy
(c) Neuroleptic-induced extrapyrimidal side effects
The drugs in this category include: Trihexyphenidyl (benzhexol), Procycliydine,
Orphenadrine and Benztropine. These drugs correct tremors and rigidity of PD more
effectively than other symptoms. The adverse effects are related to their anticholinergic
action and include: dry mouth, blurred vision, urinary retention and constipation. In high
doses they cause confusion, delirium and hallucinations.
Trihexiphenidine is reported to have some abuse potential. The antihistamine
Diphenhydramine has anticholinergic action and is used to treat mild PD.
Trihexiphenidine: PACITANE, PARKITANE, PARKIN is available as 200 mg tablet.
Procyclidine: KEMADRIN, PRODINE is available as 2.5 mg and 5 mg tablet and
Orphenadrine: ORPHIPAL is available as 50 mg tablet.
5.2.2 Drugs for Alzheimer’s Disease (AD)

It is the most prevalent form of dementia which does not have any previous cause like
stroke, brain trauma or alcohol toxicity. The symptoms of AD are progressive loss of memory
and disordered cognitive functions, with loss of short-term memory that usually preceeds
loss of long-term memory. Patients of AD may not recognise their own family members.
Other signs include reduced verbal fluency and impairment of speech due to failure of
arranging words in proper sequence. Ultimately, patient may fall in to a vegetative state.
Death is usually associated with complications of immobility; e.g. pneumonia or pulmonary
embolism.
The loss of cholinergic activity in brain or patients with AD led to the use of
cholinesterase inhibiting drugs which can cross BBB. These drugs block degradation of ACh
and increase availability of ACh in synaptic cleft. The drugs used to treat AD are: Tacrine,
Donepezil, Rivastigmine and Galantamine. Tacrine is a long-acting reversible anticholine-
sterase. It can be used for treatment of mild to moderate patients of AD. It is orally active
and provides improvements in memory, cognition and general well being soon after
initiation. It facilitates release of ACh from cholinergic nerve ending. However, it produces
significant hepatotoxicity hence its use is restricted. Donepezil, Rivastigmine and
Galantamine have better penetration in CNS. They are less toxic and better tolerated in
comparison to Tacrine. Their clinical results are modest and temporary.
Their dosages are as follows:
o Donepezil: 5 mg once daily in evening increased maximum upto 10 mg once daily
after 4 weeks.
o Rivastigmine: 1.5 mg initially twice a day increased upto 3 mg twice a day after two
weeks.
o Galantamine: 4 mg twice initially, increased upto 8 mg twice a day after one to two
weeks. Transdermal Rivastigmine patch, to be applied once in a day is available. Use
of these drugs is not associated with hepatotoxicity except for peripheral cholinergic
side effects like disrrhoea, nausea, vomiting and increased urination.
It is also postulated that enhanced glutamate transmission via NMDA receptors also
contributes to Pathophysiology of AD. Memantine is a non-competitive antagonist of NMDA
receptor. It is better tolerated and less toxic than cholinesterase inhibitors. The drug is given
5 mg once daily, slowly increased to 10-20 mg /day which can be given in two divided
doses.
Donepezil: ALZIL, DONECEPT, DOPEZIL is available as 5 mg, 10 mg tablet. Rivastigmine:
RIVASMINE, RIVAMER, EXELON is available as 1.5 mg, 3 mg, 4.5 mg and 6 mg capsule.
Galantamine: GALAMER is available as 4 mg, 8 mg and 12 mg tablet. Memantine:
ADMENTA, MENTADEM is available as 5 mg, 10 mg tablet.
5.3 CNS STIMULANTS AND NOOTROPICS

5.3.1 CNS Stimulants
The drugs in this category have a marked influence on mental functions and behaviour
to produce excitement, euphoria, increase in motor activity and reduction in fatigue. They
are sub-classified as follows:
(I) Amphetamines/Non-amphetamines
• Amphetamine group: e.g. Amphetamine, Dexaamphetamine, Methamphetamine,
Methylenedioxy methamphetamine (MDMA), Methylphenidate and Fenfluramine.
• Non-amphetamine group: e.g. Modafinil, Atomoxetine, Sibutramine and Pemoline.
(II) Methylxanthines:
• Pharmacological effects of amphetamins and Non-amphetamines are almost same.
Hence, only methylxanthines are discussed separately.
These drugs enter the nerve ending by active transport and displace DA/NE from
storage vesicles by altering their pH. They have some property to inhibit DA metabolism by
inhibiting MAO-B in the nerve ending. Due to inhibition of the enzyme, concentration of
intraneuronal DA increases. This reverses the direction of transport mechanism so that DA is
now released in to synapse by reverse transport rather than by usual exocytosis. This further
increases DA concentration in the synaptic cleft.
(b) Pharmacological Effects
Following are main central effects of Amphetamine-like drugs:
• Increased motor activity
• Euphoria and excitement
• Anorexia
• Stereotyped and psychotic behaviour with prolonged administration.
In addition, their peripheral sympathomimetic actions include rise in BP and inhibition of
GIT motility. Amphetamines increase the wakefulness, capacity to work and euphoria.
Hence, there is unawareness of fatigue which can be dangerous. With large doses,
stereotyped behaviour occurs which consists of characteristic repeated actions. Subjects
become confident, talkative and hyperactive. Sex drive is said to be enhanced. Fatigue, both
physical and mental, is reduced but the improvement can be offset by mistakes committed
due to overconfidence. Amphetamine like drugs (Fenfluramine and Dexfenfluramine) cause
marked anorexia; but the effect is short lived. The effect occurs due to enhancement of
release of 5-HT.
If Amphetamine is taken repeatedly, psychoses can develop which resembles
schizophrenia. It is associated with paranoid ideas and auditory as well as tactile
hallucinations rather than visual. This is the main difference between Amphetamine and LSD.
Since higher doses lead to aggressiveness and violent behaviour, death may occur due to
violence, accident, murder or even suicide.
(c) Pharmacokinetics
All these drugs are well absorbed orally and freely penetrate BBB. A considerable portion
of unmetabolised drug is excreted through urine. It is possible to trap this weakly basic drug
by acidifying urine with ascorbic acid or ammonium chloride. Acidification reduces its
absorption from renal tubules and enhances its clearance.
(d) Clinical Uses
(i) Attention deficit hyperkinetic disorder (ADHD) with minimal brain
dysfunction: It is a childhood disease characterised by hyperactivity, inability to
concentrate and impulsive behaviour. Dexamphetamine, Methylphenidate and
Atomoxetine are quite effective in controlling hyperkinetic children. Atomoxetine is
a non-stimulant, non-addicting drug which is inhibitor of reuptake of NE. It is quite
safe but is contraindicated in glaucoma.
(ii) Narcolepsy: Narcolepsy is characterised by sleep attacks particularly during day
time, vivid nightmares which may persist even in awakening state and sudden loss
of muscle tone (catalepsy) which is usually reversible. Methylfenidate is particularly
useful to treat narcolepsy. Another non-amphetamine derivative called Modafinil is
useful to treat narcolepsy and is devoid of abuse liability.
(iii) Appetite suppression: Amphetamine has anorexic effect; but tolerance to this
action develops within few weeks and food intake returns to normal. In addition,
insomnia, pulmonary hypertension and abuse potentials are associated side effects.
Hence, their use is restricted. Fenfluramine and Dexfenfluramine were used to treat
obesity. Now, Sibutramine is used for the purpose. It blocks neuronal uptake of NE,
5-HT and DA which are involved in regulating food intake. It can be used in severely
obese patients with diabetes and dyslipidaemia. Adverse effects include dry mouth,
headache, insomnia, constipation, increase in heart rate and BP. It is contraindicated
in any cardiovascular disease. It should not be taken along with SSRIs like Fluoxetine
and 5-HT agonists like Sumatriptan.
(d) Adverse Effects
(i) Tolerance: Tolerance develops rapidly to peripheral sympathomimetic and anorexic
effects.
(ii) Psychic dependence: Amphetamine produces high psychic dependence and rarely
physical dependence. Withdrawal symptoms consist of prolonged sleep, extreme
hunger, and fatigue with long phases of depression.
(iii) Effects of amphetamine overdose: The effects include euphoria, dizziness,
tremors, hypertension, irritability and insomnia. Higher doses cause convulsions,
psychotic manifestations, cardiac arrhythmia and coma.
(iv) Sudden death: Sudden deaths have occurred with Methylenedioxy metham-
phetamine (MDMA) even after a single moderate dose. MDMA may cause
rhabdomyolysis and renal failure. It also causes inappropriate secretion of ADH
leading to water retention and hyponatraemia. It possesses hallucinogenic activity.
Besides inducing release of NE and DA, it also releases endogenous 5-HT and
activates 5-HT receptor.
(v) Psychotomimetic effects: Methylenedioxy amphetamine (MDA) is similar to

MDMA in its pharmacological profile. However, 75 mg of MDA produces
psychotomimetic effects with a feeling of closeness to each other. At a dose of 150
mg, it produces LSD-like effects and at 300 mg, it produces Amphetamine - like
psychotic manifestations. Adverse effects include tachycardia and hypertension. It
can cause arrhythmias at higher doses.
Modafinil: PROVAKE, MODALERT, MODAPRO is available as 100 mg, 200 mg tablets.
Atomoxetine: ATTENTROL, AXEPTA is available as 10 mg, 25 mg capsule. Fenfluramine:
FLABOLIN is available as 20 mg tablet and 40 mg capsule. Sibutramine: OBEGO,
OBESTAT, SIBUTREX is available as 5 mg, 10 mg capsule.
5.3.1.1 Methylxanthines
• The popularity of xanthine - containing drinks such as coffee, tea and coke appears to
be related to their CNS-stimulating effects. Xanthine derivatives are: Caffeine,
Theobromine, Theophylline and its derivatives like Aminophylline, Etophylline,
Acebrophylline and Enprophylline. Theophylline is found in tea, Theobromine in coca
while caeffine is found in coffee, tea and cola drinks.
Three important mechanisms of actions for methylxanthines are as follows:
• Methylxanthines inhibit the enzyme phosphodiesterase (PDE) resulting in increased
concentration of 3,5-c AMP causing bronchodilation.
• They inhibit the cell surface receptors for adenosine. Adenosine is a modulator. Its
actions are inhibitory, leading to drowsiness, motor inco-ordination, cerebral
vasodilation, CNS depression, anticonvulsant action and bronchoconstriction.
Methylxanthines antagonise all these effects.
• They enhance deacetylation of histones and prevent transcription of inflammatory
genes (acetylation of histones activate inflammatory genetranscription). It leads to
inflammatory action.
(b) Pharmacological Actions
(i) CNS effects: They act as CNS stimulants. The rank order is caeffine > Theophylline
> Theobromine. CNS stimulation causes wakefulness, alertness and increased
capacity to do intellectual work with better association of ideas. They produce equal
fatigue reduction, much less locomotor stimulation but produce no euphoria,
stereotyped behaviour or psychotic manifestations.
(ii) CVS effects: They produce increase in heart rate, peripheral vasodilation. BP is not
affected. Cardiac output is increased, which is an advantage in CHF patients.
Coronary blood flow is increased. Cranial blood vesels are constricted; oxygen
tension in brain is reduced. Caeffine is useful in migraine.
(iii) Kidney: They are mild diuretics, but the action is brief. The action is due to
increased filtration pressure at glomerulus and also due to increased cardiac
output.
(iv) Miscellaneous effects

o They stimulate medullary respiratory centre.
o They cause bronchodilation. Biliary spasm is reduced.
o They facilitate neuromuscular transmission by increasing release of ACh and
enhance contractile power of skeletal muscles. They are useful in dyspnoea.
o They increase gastric acid and pepsin secretion leading to gastric irritation.
o Theophylline inhibits release of histamine and other mediators in mast cells.
This is the basis of their action in bronchial asthma.
(c) Clinical Uses
o Caeffine is combined with aspirin for treatment of headache. It is also combined with
ergot alkaloids for treatment of migraine.
o Oral Theophylline is used in the treatment of COPD and mild to moderate asthma.
o Ceaffine citrate or Theophylline is used for short term management of apnoea in
premature infants in first few weeks of life.
o Aminophylline is useful in relieving paroxysmal dyspnoea, associated with ventricular
failure.
(d) Adverse Effects
Theophylline has a narrow margin of safety with 8-15 µg/ml as optimum plasma level.
Above 15 µg/ml, the adverse effects are: dyspepsia, headache, insomnia, restlessness,
vomiting, palpitations, agitation, tachypnoea, flushing, hypotension, extra-systoles,
arrhythmias, delirium, convulsions, coma leading to death. Children are more prone for the
toxicity.
(e) Drug Interactions
o Agents which decrease Theophylline concentration are: Smoking, Phenytoin,
Carbamazepine, Rifampin, Phenobarbital. Dose of Theophylline is to be increased
when used along with the above mentioned drugs/smoking.
o Drugs which inhibit Theophylline metabolism are: Erythromycin, Ciprofloxacin,
Cimetidine, Oral contraceptives and Allopurinol. Dose of Theophylline is to be
reduced when used in combination with the mentioned drugs.
o Theophylline enhances the effects of sympathomimetics, Digitalis, Furosemide,
Hypoglycemic agents and Oral anticoagulants.
(f) Abuse of Xanthenes
Caeffine-containing beverages cause habituation, but no dependence. Chronic coffee
drinkers suffer from headache and a feeling of fatigue after sudden abstention. Tolerance to
these drugs is not severe.
Theophylline: BRONCORDIL, THEODAY, THEODER, DERIPHYLLINE is available as 400
mg, 600 mg ordinary/SR tablet. Doxofylline: DOXOBID, DOXFREE, BESTOFYLINE is available
as 400 mg tablet or 100 mg/5 ml syrup. Aminophylline: MINOPHYL, AMINOPHYLLINE is
available as 100 mg tablet or 25 mg/ ml injection. Acebrophylline: AB-PHYLLINE,
BESTOPHYLLINE-A, UNOBRO is available as 100 mg capsule.
5.3.2 Nootropics
Nootropics are psychotherapeutic agents which facilitate the acquisition of learning and
enhance memory retention.
Learning is defined as, "the change in behaviour to a given situation brought about by
repeated experiences in that situation". It is acquired when a stimulus or a sequence of
stimuli are transmitted to the brain which is encoded in to a memory race. It involves
formation of new synaptic connections in brain area involved in forming and storing the
acquired information. The memory process involves three components: registration
(acquirement of learning), retention (memory storage) and retrieval (recall). Cognition is
defined as, "the process of acquiring, storing and utilising intellectual knowledge".
Impairment in memory, cognition, comprehension, problem solving, judgement and
learning is a normal consequence of ageing and is seen in many mental illnesses. Several
depressants including alcohol, scopolamine and hallucinogens can impair memory. There is
a loss of memory in Alzheimer’s disease. Nootropics can be useful to enhance memory.
Nootropics can overcome or retard cognitive decline occurring in old age and in some
diseased conditions. They can prevent the disruption of the process of memory
consolidation by hypoxia, trauma, seizures, hypoglycaemia and other aversive factors.
Nootropics should possess following properties:
o They should facilitate learning acquisition and memory consolidation and prevent or
mitigate impairment of memory induced by ageing, amnestic agents and other
aversive factors.
o They should facilitate inter-hemispheric transfer of information.
o They should improve tonic cortical control over sub-cortical centres.
o They should not induce any overt behavioural or autonomic effects on long term
administration.
Some nootropics may act mainly by improving cerebral citculation and cerebral
metabolism which are retarded in cerebro-vascular disease. Their use may be limited to
cognitive defects induced by cerebro-vascular insufficiency.
They belong to diverse chemical category. Some of them are listed below:
o Piracetam and its congeners: Aniracetam, Oxiracetam.
o Hydergine (dihydroergotoxin)
o Vincamine
o Meclofenoxate
o Pentoxifylline
o Pyritinol
o Cyclangate
o Nicergoline
o Herpestis monniera (Brahmi)
o Ginkgo biloba extract

Nootropics like Pentoxifylline, Pyritinol, Cyclandate and Nicergoline function like cerebral
protectors improving cerebral circulation. Actions of other drugs are more complex.
Improvement in brain metabolism and energy utilisation may be involved, as also effects on
central neurotransmitters. There is evidence that central cholinergic synapses may be part of
the intrinsic system controlling memory storage. Nootropics may induce environment of
neurotransmitters condusive to learning acquisition and memory retention. The mechanism
of action includes increase in central cholinergic, nonadrenergic and dopaminergic activity
with concommittent reduction in serotonergic function.
Piracetam
Piracetam is a cyclised derivative of GABA. It was first introduced as a nootropic agent. It
has been shown to be beneficial in cognitive deficit occurring in several types of brain
disorders. Mental performance is improved in children and ageing individual with memory
deficits. Piracetam is devoid of significant autonomic, motor or behavioural effects, even at
relatively high doses.
Piracetam has been proposed to augment energy utilisation and to increase resistance
to adverse cellular changes induced by anoxia. Changes induced by Piracetam on central
neurotransmitters may also contribute to its nootropic action. Aniracetam and Oxiracetam
are derivatives of Piracetam. The derivatives have actions similar to Piracetam. Dose of
Piracetam is 2-3 gm daily in divided doses.
Therapeutic Uses
o In cognitive defects associated with presenility (Alzheimer’s disease) and ageing.
o In children with learning and attention deficit.
o Amnesia following cerebral trauma, drug abuse including alcoholism, seizures.
o Coexisting memory deficits in neurological and psychiatric illnesses.
5.4 OPIOID ANALGESICS AND ANTAGONISTS
Pain is an ill-defined, disabling event associated with many medical conditions. It is often
evoked by an external or internal noxious stimulus. The sensation of pain is called as algesia.
Drugs which inhibit sensation of pain are termed as analgesics. Opium was the first natural
analgesic. Derivatives of opium are termed as Narcotic/Opioid/Morphine like analgesics.
Some background about pathophysiology of pain, endogenous opioid peptides and opioid
receptors is desirable before discussing opioid analgesics.
5.4.1 Pathophysiology of Pain
There are two components in pain perception: the nociceptive and the affective. The
nociceptive component is a disabling, unpleasant sensation evoked by noxious stimuli and
conveyed to CNS by ascending pathways. The affective component is the psychological
response towards the pain and is conveyed from CNS to dorsal horn by descending
pathway.
The physiological basis of pain and sites of action of drugs which relieve pain are
summarised in Fig. 5.3.
General
Sensory cortex
anesthetics
Thalamus
Opioid Midbrain Ascending spinal tracts Opioid

analgesics brain stem analgesics
Spinal dorsal horn

Inhibitory
pathways Local
(gating) Sensory nerves anesthetics
Pain receptors NSAIDs
Fig. 5.3: Neural pathways of pain and sites of action of drugs relieving pain
o Noxoious stimuli stimulate nociceptive receptors of sensory nerve endings in pain
sensitive tissues. The stimulation is mostly chemical in nature. The pain-inducing
endogenous substances are released during inflammation, tissue injury, ischaemia
and by thermal or mechanical stimuli. The endogenous substances include ACh,
histamine, bradykinin and kallidin. Of these, bradykinin is the most powerful algesic
substance. It acts by releasing prostaglandins (PGs). PGs do not induce pain
themselves but they sensitize pain receptors to the action of other algesic chemicals.
o The sensations from pain receptors are transmitted through sensory afferent nerves
to the dorsal horn of spinal cord. Substance P may be the neurotransmitter for relay
of nociceptive impulses. The signals are processed and transmitted via ascending
pathways in the spinal cord to different regions.
o The signals received in the thalamus, brain stem reticular formation and peri-
ventricular grey matter (pain centres) are processed and transmitted to the sensory
cortex where pain is finally perceived. These centres are depressed by opioid
peptides.
o Pain processing by the dorsal horn is subject to modulatory influences by “gate”
controlled mechanism. Thus, inhibitory influences are exerted by activity in other
peripheral sensory neurons and the descending pathways from mid brain and brain
stem.
o Opioid analgesics act on the spinal cord and brain, where they inhibit pain
processing at the dorsal horn and increase the threshold for pain perception by the
central pain centres. They may also act by altering the sensory cortical component of
pain.
5.4.2 Endogenous Opioid Peptides

Three types of endogenous peptides with analgesic activity have been identified. They
are endorphins, enkephalins and dynorphins. They are derived from distinct precursor
polypeptides. They are involved in modulating pain and form part of the complex pain-
inhibiting mechanisms in the brain and spinal cord. These peptides have also been involved
in genesis of psychiatric disorders and in control of autonomic and neuroendocrine
functions, both under normal and stressed conditions.
5.4.3 Opioid Receptors
Four major categories of endogenous opioid receptors have been identified. They are as
follows:
o µ (mu)
o ĸ (kappa)
o δ (delta)
o σ (sigma)
Of these, the µ, κ and σ receptors mediate the main pharmacological actions of narcotic
analgesics. µ and κ receptors are important for analgesia while sigma receptors are
responsible for psychotomimetic effects. The δ-receptors inhibit excitatory
neurotransmission in the brain and periphery. It is postulated that opioid receptor activation
leads to decrease in c AMP production in the brain, opening up of K+ channels and
inhibition of intraneuronal Ca++ transport, all of which induce inhibiton of neuronal activity.
Based on receptor activity, drugs acting on opioid receptors can be categorised as
follows:
• Agonists
They are sub-classified based on chemical modifications in the structure of morphine.
o Morphine analogs are: Heroin and Codeine.
o Methadone derivative is Dextropropoxyphene.
o Thebaine derivative is Etorphine.
o Phenylpiperidine derivatives are Pethidine, Fentanyl, Sufentanil and Diphenoxylate.
• Mixed agonists-antagonists
They are also sub-classified on chemical modifications in the structure of morphine.
o Benzomorphan derivatives: Pentazocine, Cyclazocine.
o Morphine analogs: Nalbuphine, Buprenorphine.
o Morphinan derivatives: Levollorphan, Meptazinol.
• Antagonists
These are discussed separately in section 5.4.6.
5.4.4 Opioid Analgesics
Drugs having agonistic activity, especially on µ-receptors are used as analgesics.
Morphine is the prototype drug in this category. Other morphine agonists and mixed
agonists-antagonists have actions similar to morphine with few modifications.
Actions of morphine are discussed below:

(a) Pharmacokinetics
Morphine is readily absorbed from GIT. However, because of extensive first-pass
metabolism, bioavailability is poor. The drug is usually administered by intramuscular route.
Half-life is 2.5 hours, peak effect is at 1 hour and duration of analgesia is 4 hours. Morphine
is metabolised by N-dealkylation and oxidation followed by glucuronide or sulphate
conjugation. It has relatively poor access through BBB. Its derivative, Heroin (diacetyl
morphine) crosses BBB easily. It is 2-2.5 times more potent than morphine, and is preferred
by addicts. Metabolites are excreted in urine.
(b) Mechanism of Action
Morphine acts through different receptors mentioned earlier. In addition, it influences
the activity of some neurotransmitters in brain. It increases cholinergic and 5-HT activity; and
inhibits nor-adrenergic, dopaminergic and GABAergic activity. It releases histamine but
inhibits release of substance P. These wide-ranging effects contribute to various
pharmacological actions.
(c) Pharmacological Actions
(i) Effects on CNS: Morphine has a wide variety of actions in CNS due to location of
related receptors.
o Analgesia: Besides raising pain threshold, morphine reduces emotional reaction
to pain. This eliminates distress caused by pain and helps the patients to
tolerate pain better. The analgesic action is due to effect on opioid receptors.
o Euphoria: Morphine induces a marked sense of well-being and relief from
anxiety which contributes to its analgesic action. Some patients may experience
restlessness and anxiety, termed as dysphoria. Tolerance is noted both to
euphoria (mu-receptors) and dysphoria (kappa receptors).
o Sedation: Morphine induces sedation in analgesic doses and is useful when
pain is accompanied by insomnia.
o Respiratory depression: Morphine depresses respiratory centre resulting in
increase in plasma carbon dioxide concentration. The sensitivity of respiratory
centre to CO2 is decreased, but the hypoxic drive is not affected. Morphine does
not depress vasomotor centre. The action on respiratory centre is mediated by
mu-receptors and is the cause of death in morphine poisoning. Some degree of
tolerance to respiratory depressant effect is observed in morphine addicts.
o Pupillary constriction: Miosis is induced by action of morphine on mu and
kappa receptors. Tolerance to pupillary constriction is not seen in addicts. Pin-
point pupils are indicative of morphine abuse.
o Nausea and vomiting: Nausea and vomiting, observed along with analgesic
effect of morphine are due to stimulation of CTZ. Higher doses of morphine
inhibit CTZ. Morphine emesis is not blocked by DA antagonists like
Prochlorperazine, but is inhibited by opioid antagonist, Naloxone.
o Antitussive effect: It depresses medullary cough centre. It is not used for

clinical benefit because its derivative, codeine is more effective. Tolerance is
noted for this activity.
o Neuroendocrine effects: It increases release of ADH, decreases release of
ACTH, growth hormone and gonadotrophins, together with increased plasma
prolactin levels.
(ii) Effects on GIT: It induces marked increase in tone and reduces motility in many
parts of GIT. It results in severe constipation. Gastric emptying is delayed. Intra-
biliary pressure is increased due to constriction of biliary sphincter and contraction
of gall bladder. Gastric, intestinal, pancreatic and biliary secretions are decreased by
morphine. The actions of morphine on GIT are blocked by Naloxone and Atropine.
(iii) Effects on CVS: Morphine causes hypotension and bradycardia. Hypotension is due
to dilation of peripheral veins and arterioles, histamine release and reduced
sympathetic activity. Bradycardia is due to vagal stimulation.
(iv) Other actions: Bronchoconstriction is due to release of histamine and increased
vagal activity. In addition, contraction of uterus, ureters and urinary bladder occurs
occasionally.
Immunosuppressant effect is probably due to actions on CNS. Morphine addicts
may have risk of AIDS.
(d) Therapeutic Uses:
(i) For analgesia: For relief of acute severe pain in trauma, burns, post-operative pain,
myocardial infarction, renal and intestinal colic. It may also be used in terminal
cancer patients for analgesia and euphoria.
(ii) In left ventricular failure: Morphine helps relief of symptoms by inducing marked
veno-dilatation and decrease in pre-load. In addition, reduced sensitivity of
respiratory centre to stimuli from congested lungs and increased CO2 levels also
contribute to decreased dyspnoea.
(iii) In anaesthetic pre-medication: Morphine sulphate (8-12 mg) or Pethidine (50-
100 mg) is given intramuscularly 1 hour before surgery to reduce pain during
surgery.
(e) Contraindications
(i) Acute abdomen: Morphine can mask the symptoms; hence it should not be given
in undiagnosed abdominal pain.
(ii) Head injury: Morphine induced respiratory depression and rise in intra-cranial
tension, together with miosis and vomiting may interfere with diagnosis.
(iii) Bronchial asthma: Morphine may aggrevate bronchial spasm and respiratory
depression.
(iv) Chronic lung disease: Respiratory insufficiency by morphine can aggrevate the
symptoms.
(v) Hypothyroidism: Slow metabolism of morphine can cause increased toxicity.
(vi) Hepatic failure: Reduced metabolism can cause higher toxicity leading to hepatic
coma.
(vii) Biliary colic: Morphine can cause constriction of biliary spincter. It is also to be
avoided after cholecystectomy.
(viii) Ulcerative colitis: Production of colonic dilatation by morphine can complicate
ulcerative colitis.
(ix) Enlarged prostate: Morphine may cause urinary retention.
(x) In obstetrics: There is a possibility of respiratory depression of neonate.
(f) Adverse Reactions
Acute toxicity symptoms are nausea, vomiting, drowsiness, sweating, prurites,
piloerection, bradycardia, hypotension, bronchospasm, urinary retention, dysphoria and
constipation. All these actions are related to pharmacological actions of morphine. Tolerance
and dependence of morphine are discussed in section 5.5.3 and 5.5.4.
(g) Drug Interactions
The respiratory depression caused by morphine is potentiated by all CNS depressants,
Chlorpromazine, TCAs and MAO inhibitors. Hypotension is aggrevated by anti-
hypertensives. Cimetidine inhibits metabolism of morphine and Pethidine.
5.4.5 Morphine Related Drugs (Opioids)
(i) Pethidine: It is less potent than morphine as analgesic but causes equal
respiratory depression and vomiting. It has shorter duration of action; it is less
sedative, antitussive and constipating agent. It has spasmolytic, mydriatic and
visual effects. It is used as an analgesic and preanaesthetic medicant.
(ii) Heroin: It is more effective than morphine as analgesic. It crosses BBB. It is
metabolised to morphine in brain. It is most addictive and is not used clinically.
(iii) Methadone: It is equipotent to morphine with an advantage of being oral active
and longer duration of action. It is used in the treatment of morphine deaddiction.
Its withdrawal syndrome is mild and more prolonged. Levomethadyl acetate, a
related agent has longer duration of action and is used for deaddiction from
Morhine or Heroin.
(iv) Fentanyl: Fentanyl and its derivatives Sufentanil, Afentanil, Remifentanil are more
potent than morphine but have shorter duration (30-60 minutes) of action. Their
uncontrolled use may lead to marked respiratory depression. They are used in
combination with Droperidol to induce neurolepanalgesia and in patient-
controlled analgesia because of shorter duration of action.
(v) Etorphine: It is an analogue of morphine with 1000 times more potency than
morphine. It is mainly used in veterinary medicine and for trapping wild animals.
(vi) Codeine: Codeine and its derivatives Oxycodone, Dihydrocodeine, Hydrocodone

are less effective as analgesics. Large doses can induce excitement. Tolerance and
physical dependence are less marked. It is mainly used for antitussive action. 10%
of administered codeine is metabolised to morphine. It is a constituent of many
cough syrups.
(vii) Buprenorphine: It is a partial agonist of morphine. It acts on mu receptors and
can precipitate morphine withdrawal. It is a potent analgesic with long duration of
action. It inuduces significant respiratory depression but is less euphoric than
morphine and less dysphoric than Pentaziocine. Bioavailability following oral
administration is unpredictable; hence sub-lingual route is preferred. In a dose of
0.4-0.6 mg IM, 0.3-0.6 mg IV, it is used as an analgesic and for treatment of
morphine addiction.
(viii) Nalbuphine: It has Pentazocine like actions but includes less sympathomimetic
effects. Hence, it is better tolerated in myocardial infarction. Respiratory
depression is not reversed by Naloxone.
(ix) Pentazocine: It has replaced Phenazocine. Pentazocine is an intermediate beween
morphine and Pethidine for its potency as an analgesic. It is an agonist at κ-
receptor and antagonist at µ-receptor. Its potency is much less than that of
Nalorphine or Naloxone. The importance of pentazocine in clinical medicine is
primarily due to ready non-availability of either morphine or Pethidine.
(x) Dextropropoxyphene: It is a dextro-isomer of Propoxyphene. It has less analgesic,
antitussive, respiratory depressant and addictive properties in comparison with its
conginer Methadone. It is rapidly absorbed and in low dose, can induce respiratory
arrest, severe hypotension and cardiac arrhythmia within one hour. It is usually
combines with Paracetamol for use as an analgesic. Levopropoxyphene has no
analgesic action; but is used as antitussive.
(xi) Nefopam: It is structurally different from known narcotic/non-narcotic analgesic. It
is devoid of respiratory depressant, constipating, emetic and addictive properties
of narcotic analgesics and is free from GIT-related side effects of NSAIDs. It
involves central cholinergic activity.
(xii) Tramodol: Its analgesic activity is partly mediated through µ-receptors. It is useful
in chronic neuropathic pain. Toxicity includes dependence, seizures and
anaphylactoid reactions.
(xiii) Diphenoxylate/Loperamide: Both are derivatives of morphine and are used to
control diarrhoea. Atropine is added to Diphenoxylate to enhance anti-diarrhoeal
effects and to limit addictive potential.
Preparations of morphine and its derivatives are listed in table 5.4.
Table 5.4: Preparations of Morphine and its Derivatives
Sr. No. Drug Strength and formulation Trade name
1. Morphine sulphate 10 mg, 20 mg, 30 mg, Vermor, Vermor – SR,

60 mg tablet/SR tablet; Rilimore
10 mg/ml injection
2. Pethidine 100 mg/2 ml injection Pethidine hydrochloride
3. Dextropropoxyphene 65 mg tablet in combi- Proxyvon, Dolopar plus,

nation with 400 mg/650 mg Walagesic, Sudhinol
Paracetamol
4. Fentanyl 25 µg/ml injection; 25 µg, Fent, Durogesic

50 µg, 75 µg, 100 µg/hour
transdermal patch
5. Tramadol 50 mg capsule; 50 mg/ml Domadol, Contramal,

injection Dolotram, Esgipyrin-T,
Domadol plus
6. Codeine 15 mg tablet; 15 mg/5 ml Codine sulphate, Codin

syrup linctus
7. Pentazocine 25 mg tablet; 30 mg/ml Fortiwin, Fortstar, Zocin,

injection Foracet, Fortagesic
8. Butorphanol 1 mg/ml, 2 mg/ml injection Butodol
9. Buprenorphene 0.2 mg tablet; 0.3 mg/ml Tidigesic, Norphin, Buprinor

injection
5.4.6 Opioid Antagonists
The substitution of N-methyl by a bulkier N-allyl group at piperidine nitrogen

(Fig. 5.4) changes an agonist to an antagonist. Naloxone, Naltrexone and Nalmefene are
pure opioid antagonists at µ, κ and δ receptors. However, they block µ receptors at lower
doses in comparison to doses required to block κ and δ receptors. Given alone to non-
addicts or opioid-free person, these antagonists exhibit no pharmacological effects, there is
no tolerance, dependence or withdrawal effects due to opioid antagonists. Individual opioid
antagonists are discussed below:
CH3
CH3 CH3 CH2 CH = C
CH3
N N N
10 17
1 16
8 CH3
3 6
CH3
OH OH OCH3 OH OH
O O
(a) Morphine Codeine Pentazocine
CH3
N N CH2CH = CH2
16
8 HO
CH3OCO OCOCH3 HO O
O O
Heroin Naloxone
N CH2
CH3O HO
N OCH3
CH3O
OCH3 HO O
CH2 O
(b) Papaverine Naltrexone
Note: The phenanthrene moiety (a) and benzylisoquinoline moiety (b) have been
highlighted with bold lines.
Fig. 5.4: Structures of morphine and related drugs
(i) Naloxone: Noloxone is a strong µ receptor antagonist; moderate antagonist at κ

receptor and a weak antagonist at δ receptor. It has a fast onset of action (within
minutes) with a plasma half-life of 1-2 hours. It has an extensive first-pass
metabolism which reduces its bioavailability. It is primarily used for the treatment
of opioid overdose. When given intravenously to a morphine toxicated person, it
drastically reverses the opioid effects within minutes. It also normalises respiration,
level of consciousness, pupil size, bowel activity and awareness of pain. However,
because of its shorter duration of action, within 1-2 hours, the patient may show
respiratory depression and coma, after immediate effects. Hence, it should be
given in an intravenous dose of 0.4-0.8 mg every 5 minutes, till the desired
parameters are normalised. Additional IV/IM doses may be given every 30-60
minutes till all the opioid is cleared from the body and no relapse is observed. It
can also be used to reverse the agonistic actions of mixed agonist-antagonists
overdose like that of Pentazocine. It also inhibits acupuncture analgesia because
effects of acupuncture are associated with release of endogenous opioid peptides.
If there is no response to respiratory depression, after administration of Naloxone,
it indicates that the poisoning is not due to opioids.
It can also be used as a diagnostic test for a case of opioid addiction, because of
instantaneous action. It is also used to revert neonatal respiratory depression, due
to opioid use during labour. Adverse effects to Naloxone are minor.
Naloxone is available as 400 µg/ml injection: NALOX, NARCOTAN, NEX.
(ii) Naltrexone: It is a strong antagonist to µ and κ receprtors and a weak antagonist
to δ receptors. It is 3-5 times more potent than Naloxone and has a longer
duration of action. Its half-life is 10-12 hours. It exhibits significant first-pass
metabolism in liver, but its major metabolite is equally active. It can be given orally.
It can be used for treatment of opioid dependence in an opioid-detoxified,
formerly addict patient. It is a good drug for treating morphine addicts. Before
initiating treatment, an opioid free period of 10 days is essential. A great
motivation is needed before starting the treatment. Doubts can be verified by
performing a Naloxone challenge test. Naltrexone is also reported to decrease
craving for alcohol in chronic alcoholics. Adverse reactions are minimal but high
doses are hepatotoxic.
Naltrexone is available as 50 mg tablet: NODICT, NALTIMA.
(iii) Nalmefene: It is a derivative of Naltrexone, but can be used only intravenously. It
has a quick onset of action (2 minutes), but plasma half life is longer than
Naloxone (10 hours). It can be used like Naloxone to treat opioid overdose. It lacks
hepatotoxicity. It is also approved for treatment of cholestatic pruritus with a dose
of 20 mg twice a day.
(iv) Alvimopan: It predominantly blocks peripheral µ receptors in the gut and does
not cross BBB. It has been approved for relieving constipation of an opium addict
without risking the precipitation of opiate withdrawal. It is also used to treat post-
operative paralytic ileus following bowel surgery.
5.5 DRUG ADDICTION, DRUG ABUSE, TOLERANCE AND DEPENDENCE

Whenever a person needs to take higher quantity of the same drug for its expected
effect, it is termed as addiction. The reason for addiction may be tolerance. An addictive
drug may cause dependence. All these causes lead to abuse of drugs, probably because of
euphoria caused by the drug. Features of these drugs are discussed below.
5.5.1 Drug Addiction

Drug addiction has following features:
• The detrimental effects of drugs not only harm the individual but the society as well.
• There is always an intense craving to procure the drug by any means.
• There is development of tolerance and hence a need to increase the dose to get the
same rewarding experience.
• There are life-threatening or alarming withdrawal effects after cessation of the drug
and hence there is a physical need to continue with use of the drug for the fear of
abstinence syndrome.
5.5.2 Drug Abuse
Drug abuse has following features:
• Recurrent substance use results in failure to fulfil his/her major obligations at work,
school or home, e.g. poor performance at work, expulsion from school.
• Recurrent substance use even in situations where it should not be used, e.g. during
driving, operating a machine or even operating on the patient.
• Recurrent substance use despite punitive action, e.g. punishment for disorderly
conduct.
• Recurrent substance use despite having interpersonal or family problems,
e.g. arguments or physical fight with spouse about consequences of abuse.
Drug abuse discards all other terms like misuse, habituation etc.
It does not apply to taking tea or coffee.
5.5.3 Drug Tolerance
Tolerance develops if, after repeated administration, a given dose of a drug produces a
decreased effect than expected. Conversely, larger doses are needed to obtain the same
effects with previous dose. It is classified as pharmacokinetic (e.g. Barbiturates) or
pharmacodynamic (e.g. opioids). There is another related term: cross-tolerance. When
tolerance to primary drug develops, the individual also exhibits cross-tolerance to related
classes of drugs, e.g. a patient with tolerance to morphine may show cross-tolerance to
heroin.
5.5.4 Drug Dependence
Dependence is a physiological state of neuroadaptation resulting from repeated
administration of the drug, necessitating its continued use to prevent the appearance of
distressing withdrawal syndrome which is manifested as opposite to the pharmacological
effects of drugs.
Withdrawal or abstinence syndrome is a term used for the adverse (sometimes life-
threatening) psychologic or physiologic reactions to an abrupt discontinuation of a
dependence-producing drug.
Rebound means an exaggerated manifestation of the original disease symptoms
experienced immediately after discontinuation of the drug providing clinical benefits.
Rebound should not be confused with withdrawal syndrome as there is no craving or
dysphoria after cessation of the drug.
Relapse refers to re-occurrence of the same disease symptoms, from which the patient
suffered, after discontinuation of the treating drug. Detoxification means slow tapering of
the drug that has caused dependence and would cause withdrawal if stopped suddenly.
The drugs of abuse which can endanger dependence are as follows:
• Drugs/agents having only mild psychological dependence. There are low withdrawal
symptoms and no physical dependence, e.g. coffee, tea.
• Drugs/agents with moderate to severe psychological dependence. There are low
withdrawal symptoms but slight physical dependence, e.g. Marijuana, Hashish, LSD,
Amphetamine, Coccaine, Nicotine.
• Drugs/agents having moderate to severe psychological dependence with mild
physical dependence, e.g. Benzodiazepines, Alcohol (moderate use).
• Drugs/agents having severe psychological and physical dependence, e.g. Opioids
Barbiturates and Alcohol (heavy use).
5.5.5 Treatment of Drug Dependence
The pharmacological approaches to treat drug dependence and withdrawal include
following:
• Short-term or long-term substitution of the abused drug by a similar drug having
longer plasma half life.
• An aversive therapy by using a drug which produces unpleasant response after an
intake of the abused drug.
• Use of a proper antagonist, to prevent relapse, once the drug free status is achieved.
• Use of such drugs which reduce craving for the abused drug.
• Rehabilitation and psychosocial interventions.
QUESTIONS

1. Comment on hypothesis for schizophrenia.
2. Discuss five interactions of anti-psychotics with other drugs.
3. Discuss mechanism of action and pharmacokinetics of tricyclic anti-depressants.
4. Write mechanism of action and interactions of other drugs with Tranylcypromine.
5. Comment on adverse effects and interactions with lithium carbonate.

6. Describe hallucinogens.
7. Write mechanism of action, contraindications and drug interactions of Livodopa.
8. What are symptoms of Parkinsoniasm?
9. Comment on pathophysiology of Alzheimer’s disease.
10. What is the treatment for Alzheimer’s disease.
11. Write mechanism of action, pharmacological effects and clinical uses of
Amphetamine.
12. What are adverse reactions to Amphetamine.
13. What are pharmacological actions and mechanism of action of Theophyline.
14. What are adverse effects and drug interactions with Theophylline.
15. Elaborate on nootropics.
16. Write pharmacological actions of opium.
17. What are features of drug addiction and drug abuse.
18. What is drug dependence? Discuss treatment with a suitable example.
1. Classify anti-psychotics.
• Chlorpromazine
• Haloperidol
• Selective serotonin reuptake inhibitors
• MAO inhibitors
• Mania
• Manic depressive psychosis
• LSD Cannabis
• COMT inhibitors
• Amantadine
• Selegiline
• Bromocriptine
• Piracetam
• Pethidine
• Codeine
• Pentazocine
• Buprenorphine
• Naloxone
• Naltrexone
3. Classify anti-depressants.
4. Write clinical uses of Theophylline.
5. What is mechanism of action of nootropics.
6. List opioid receptors.
7. What are endogenous opioid peptides.
8. What are therapeutic uses of opium.
9. List contraindications to opium.
Appendix
Appendix I: Abbreviations
• 5-AMP: Adenosine Mono Phosphate (Linear)
• 5-HT: 5-Hydroxy Tryptamine (Serotonin)
• A: Adrenaline
• AcCoA: Acetyl Coenzyme A
• ACE: Angiotensin Converting Enzyme
• ACh: Acetyl Choline
• AChE: Acetyl Cholinesterase Enzyme (Enzyme)
• ACTH: Adreno Cortico Tropic Hormone
• AD: Alzheimer’s Disease
• ADH: Anti Diuretic Hormone
• ADHD: Attention Deficit Hyperactivity Disorder
• ADME: Absorption, Distribution, Metabolism, Excretion
• ADR: Adverse Drug Reaction
• AG: Activation Gate
• AIIMS: All India Institute of Medical Sciences
• ALA: Amino Levulonic Acid
• AMC: ADR Monitoring Centre
• AMPA: Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid
• ANF: Atrial Natriuretic Factor
• ANS: Autonomic Nervous System
• ASICs: Acid Sensing Ion Channels
• ASP: Aspartate (Amoni acid)
• ASV: Anti-Snake Venom
• ATP: Adenosine Tri Phosphate
• AUC: Area Under Curve
• AV: Atrio-Ventricular
• B: Bronchoconstriction
• BBB: Blood Brain Barrier
• BP: Blood Pressure
• BPH: Beningn Prostatic Hypertrophy
• BZDs: Benzodiazepines
• c AMP: Cyclic Adenosine Mono phosphate
• c GMP: Guanosine Mono phosphate (Cyclic)
• CDSCO: Central Drug Standard Control Organisation
• CDT: Cholinergic Dependent Transporter
• ChAT: Choline Acetyl Transferase (Enzyme)
• ChE: CholinEsterase (Enzyme)
• CHF: Congestive Heart Failure
• CIOMS: Council for International Organisations of Medical Sciences
(A.1)
Pharmacology - I (B.Pharm. Sem. IV) A.2 Appendix
• CNS: Central Nervous System

• COMT: Catechol Ortho-Methyl-Transferase (Enzyme)
• COPD: Chronic Obstructive Pulmonary Disease
• CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on
Animals
• CTZ: Chemoreceptor Trigger Zone
• CYP: Cytochrome P450 enzymes, located in liver.
o Subclassified as CYP1:/2/3; CYP1:A/B/C/D; CYP1A:1/2/3/4 etc.
• CVS: Cardio Vascular System
• D/DA: Dopamine
• D: Defaecation
• DAG: Diacyl Glycerol
• DBD: DNA-Binding Domain
• DDT: Dichloro Diphenyl Trichloroethane, (A synthetic insecticide)
• DHR: Decreased Heart Rate
• DNA: Deoxyribo Nucleic Acid
• DRC: Dose Response Curve
• DRR: Dose Response Relationship
• d-TC: d-Tubocurarine
• DUS: Drug Utilisation Study
• EA: Episodic Ataxia
• ECG: Electro Cardio Gram
• ECT: Electro-Convulsive Therapy
• ED50: Effective Dose in 50% subjects
• EEG: Electro Encephalo Gram
• EMA: European Medicines Agency
• ENS: Enteric Nervous System
• Erb: Epidermal growth factor receptor
• FHM: Familial Hemiplegic Migraine
• FSH: Follicle Stimulating Hormone
• GABA: Gamma Amino Butyric Acid
• GAD: Glutamic-Acid-Decarboxylase (enzyme)
• GDNF: Glial Cell-Derived Neurotropic Factor
• GEFS: Generalised Epilepsy with Febrile Seizures
• GERD: Gastro-Esophageal Reflux Disease
• GIT: Gastro Intestinal Tract
• GLP: Good Laboratory Practice
• GLU: Glutamate
• GPCR: G-Protein Coupled Receptors
• GPvP: Good Pharmacovigilance Practices
• GTF: General Transcription Factor
• GTg: Glial Type Transporters
• GTn: GLU-Transporters
• HDL: High Density Lipoprotein
• HR: Heart Rate
• HSF: Heat Shock Factor
• HVA: Homovanillic Acid
• Hz: Hertz
• ICH: International Council for Harmonisation
• IG: Inactivation Gate
• IM: Intra-Muscular
• IND: Investigational New Drug
• IOP: Intra-Occular Pressure
• IP1: Inositol Monophosphate
• IP2: Inositol Diphosphate
• IP3: Inositol Triphosphate
• IPC: Indian Pharmacopoeia Commission
• ISA: Intrinsic Sympathomimetic Activity
• IV: Intra-Venous
• JAK: Janus Kinase (enzyme)
• JAK-STAT: Involving JAK enzyme and STAT protein
• L: Lachrymation
• LA: Local Anaesthetic
• LDL: Low Density Lipoprotein
• LH: Luetinising Hormone
• LSD: Lysergic Acid Diethylamide
• M: Muscarinic (Cholinergic receptor)
• MAC: Minimum Alveolar Concentration
• MAO: Mono Amino Oxidase (Enzyme)
• MDA: Methylene Dioxy Amphetamine
• MDMA: MethyleneDioxy Methamphetamine
• MFO: Mixed Function Oxidase (Enzyme)
• MI: Myosis
• NREM: Non-rapid Eye Movement (Sleep)
• N: Nicotinic (Cholinergic receptor)
• NA: Nor Adrenaline
• NDA: New Drug Application
• NMDA: N-Methyl-D-Aspartate
• NMJ: NeuroMuscular Junction
• NMS: Neurolept-Malignant Syndrome
• NO: Nitrogen Oxide
• NPR: Natriuretic Peptide Receptor
• NSAID: Non Steroidal Anti Inflammatory Drug
• NT: NeuroTransmitter
• OCD: Obsessive-Compulsive Disorder

• PABA: Para-Amino-Benzoic Acid
• PCP: Phencyclidine
• PD: Parkinson's Disease
• PDE: Phospho Di Esterase
• PDH: Pyruvate Dehydrogenase Enzyme (Enzyme)
• PGs: ProstaGlandins
• PIAS: Protein Inihibitors of Activated STAT
• PIP2: Phosphatidyl Inositol Diphosphate
• PK: Pharmacokinetic
• PNS: Peripheral Nervous System
• PSNS: Parasympathetic Nervous System
• QSAR: Quantitative Structure Activity Relationship
• RAS: Reticular Activating System
• RBC: Red Blood Cell
• REM: Rapid Eye Movement (Sleep)
• RNA: Ribo Nucleic Acid
• S: Salivation
• SA: Sino-Atrial
• SC: Sub-Cutaneous
• Ser: Serine (amino acid)
• SNRIs: Selective NE-Re-uptake Inhibitor
• SNS: Sympathetic Nervous System
• SOCS: Suppressors of Cytokine Signalling
• SOP: Standard Operating Procedure
• SSRIs: Selective Serotonin Re-uptake Inhibitor
• STAT: Signal Transducer and Activator of Transcription (Protein family)
• T1/2: Half-life of a drug
• TAL: Transcription Activator Like
• TCA: Tricyclic Antidepressant
• TD50: Toxic Dose to kill 50% subjects
• TF: Transcription factor
• THC: Tetra Hydro Cannabinol
• Thr: Threonine (amino acid)
• TI: Therapeutic Index
• TLR: Toll-Like Receptor
• TM: Trans-Membrane
• TRH: Thyroxine Releasing Hormone
• TTX: Tetrodo toxin
• TYK: Tyrosine kinase (Enzyme)
• Tyr: Tyrosine (Amino acid)
• U: Urination
• UMC: Uppsala Monitoring Centre

• USFDA: United State Food and Drug Administration
• Vd: Volume of Distribution
• VIP: Vasoactive Intestinal Polypeptide
• VLDL: Very Low Density Lipoprotein
• WHO: World Health Organisation
Appendix II: Explanation of Terms

• Abstinence syndrome: Physiologic changes in patients who have become physically
dependent on a drug.
• Acne/Acne vulgaris: Long term skin disease when hair follicles are clogged with dead
skin cells and oil from skin.
• Acute intermettant porphyria: Heriditary hepatic porphyria causing higher porphyrin
in blood.
• Agitation: A state of anxiety or nervous excitement.
• Akathisia: A feeling of internal motor restlessness.
• Akinesia: Inability to move.
• Aldosteronism: A condition with excessive secretion of aldosterone leading to high BP.
• Alopecia: Hair loss.
• Alveolar wash-in: A special procedure to treat a rare form of lung disease.
• Amenorrhoea: Absence of menstrual period in awoman of reproductive age.
• Amnesia: Deficit in memory caused by brain damage.
• Amyotrophic lateral sclerosis (ALS) (Motor neuron disease (MND); Lou Gehring’s
disease): Adisease causing death of neurons controlling voluntary muscles.
• Analgesia: Relief from pain.
• Angina pectoris: A condition marked by severe pain in chest.
• Angioneurotic edema: A genetic disease with lack of inhibitor protein (C1 esterase
inhibitor) leading to swelling.
• Anorexigenic: Causing loss of appetite.
• Antispasmodics: A drug used to relieve spasm of involuntary muscle.
• Aplastic anaemia: Deficiency of all types of blood cells due to failure of bone marrow
development.
• Apnoea: Temporary caessation of bleeding, especially during sleep.
• Apocrine glands: Sweat glands located in skin or eye lid.
• Aqueous humor: A transparent, watery fluid secreted from capillary epithelium in eye.
• Ascites: Abnormal accumulation of fluid in abdominal/peritoneal cavity.
• Asthenia: Abnormal physical weakness or lack of energy.
• Ataxia: Loss of full control of bodily movements.
• Athetosis: Repetitive involuntary, slow, gross movement.
• Atony: Loss of tone of a muscle.
• Atrial fibrillation: An irregular, rapid heart rate originating in atria.
• Attention deficit hyperactivity disorder (ADHD): A mental disorder of neuro

developmental type with difficulty in paying attention and controlling behaviour.
• Auditory hallucinations: A hallucination involving hearing of one or more talking
voices.
• Aura: A perceptual disturbance expected before seizures.
• Autoimmune disease: A condition in which immune system attacks own body.
• Autoimmune disorder: A disorder when body’s immune system attacks/destroys
healthy body tissue by mistake.
• AV node: Atrio-ventricular node controlling heart rate.
• Benign prostatic hypertrophy: Enlargement of prostatic gland caused by benign
overgrowth of glandular tissue causing constriction of urethra.
• Blood dyscrasia: A pathological condition with abnormal blood cells.
• Bradyarrhythmia: Arrhythmia of heart showing slow heart rate.
• Bradycardia: Abnormally slow heart action.
• Bradykinesia: Reduced movements of body.
• Bronchial asthma: Chronic inflammatory disease of airways causing periodic attacks of
coughing, wheezing, shortness of breath and chest tightness.
• Bronchodilation: Increase in calibre of bronchi and bronchioles due to drugs or
autonomic nervous activity.
• Bronchospasm: Spasm of bronchial muscle, producing narrowing of bronchi.
• Brugada syndrome: A genetic disorder resulting in abnormal electrical activity in heart.
• Bulimia nervosa: A serious, potentially life-threatening eating disorder characterised by
eating followed by purging.
• Caesarean section: Use of surgery to deliver a baby.
• Cerebellum: A part of brain performing co-ordination, precision and timing of body
movement.
• Cerebral haemorrhage: Bleeding in and around the brain.
• Cerebral ischaemia: A condition in which there is insufficient blood flow to brain.
• Cerebral palsy: A group of movement disorders appearing in early childhood.
• Chemokines: A family of cytokines, or signalling proteins secreted by cells.
• Chorea: A nervous disease with involuntary and irregular movements.
• Choreoathetosis: A morbid condition characterised by choraic and athetoid movement.
• Choroid plexus: A plexus of cells which produces cerebrospinal fluid in the ventricles of
brain.
• Chromaffin granules: Granules present in chromaffin cells of adrenal medulla
• Chromogenin: A substance which produces coloured pigments
• Chronotropic: A drug changing heart rate
• Cleft palate: Facial and oral malformation which occurs early in pregnancy while the
baby is developing.
• Coarsening of facial features: Constellation of facial features present as inborn error of
metabolism.
• Congenital malformation: A disorder which is present at or before birth.
• Conjunctiva: A clear thin membrane which covers part of the front surface of the eye
and inner surface of the eyelids.
• Constriction: The action of making a lumen narrower.
• Coombs test: A blood test used in immunohematology to detect antibodies on surface
of RBCs.
• Corneal opacity: A disorder of cornea which makes it appear clody or white.
• Cortical myoclonus: A type of epilepsy originating in cerebral cortex.
• Cushing’s syndrome: A collection of signs and symptoms due to prolonged exposure
to cortisol.
• Cycloplegia: Paralysis of ciliary muscle of the eye resulting in loss of accommodation.
• Cystic fibrosis: A genetic disorder causing difficulty in breathing and coughing of
mucus due to frequent lung infections.
• Cytochrome P450: Enzymes present in liver microsomes, which metabolise potentially
toxic compounds.
• Cytokines: A category of small proteins which are secreted by certain cells of immune
system.
• Dale’s vasomotor reversal: A phenonmena where prior administration of α-blocker
leads to only fall in BP after giving adrenalin (it was first observed by Dale).
• Delirium: An acutely disturbed state of mind characterised by restlessness, illusions and
incoherence.
• Delirium tremens: It shows rapid onset of confusion after withdrawal from alcohol.
• Delusions: An idiosyncratic belief or impression maintained despite being contradicted
by reality or rational argument.
• Dementia: Achronic or persistent disorder of mental processes caused by brain disease
or injury.
• Dendrotoxins: A class of pre-synaptic neurotoxins which block potassium channels in
neurons.
• Detrusor muscle: A smooth muscle found in the wall of the bladder which remains
relaxed to allow the bladder to store more urine.
• Diaphragm: A sheet of internal skeletal muscle separating thoracic and abdominal
cavity.
• Diastereomer: A stearic isomer where compounds have different configurations at one
or more asymmetric carbon atoms.
• Diencephalon: A part of forebrain containing thalamus, hypothalamus and the third
ventricle of brain.
• Dilatation: The action of dilating a vessel or opening or the process of becoming
dilated.
• Diplopia: Technical term for double vision.
• Disorientation: A condition of having lost one’s sense of direction/a mental disorder.
• Diverticulitis: A condition in which pouches are formed in the wall of colon.
• Dizziness: The feeling of being light headed or unbalanced.
• Duchenne muscular dystrophy: A genetic disorder of voluntary muscles related to hips,

pelvic area, shoulders and calves.
• Dyskinesia: Abnormality or impairment of voluntary movement.
• Dyslipidemia: Abnormal amount of lipids in blood.
• Dyspepsia: Indigestion.
• Dyspnoea: Difficult or laboured breathing.
• Dyspraxia: A developmental disorder of the brain in childhood causing difficulty in
activities requiring co-ordination and movement.
• Ejaculation: Discharge of semen from the male reproductive tract.
• Electro-convulsive therapy: A procedure, done under general anaesthesia, in which
small electric currents are psaased through the brain, intentionally triggering a brief
seizure.
• Enkephalin: A pentapeptide involved in regulating nociception in the body.
• Encephalitis: An acute inflammation of the brain, often due to infection.
• Endorphins: Indeginous opioid neuropeptides and peptide hormones in humans.
• Endotracheal tube: A flexible plastic tube placed in trachea through mouth to help
breathing.
• Enterochromaffin cells: A type of neuroendocrine cell in the gastric glands near parietal
cells which aid in production of gastric acid via histamine.
• Enuresis: Involuntary urination, especially by children at night.
• Episodic ataxia: A genetic disorder characterised by sporadic events of ataxia (severe
dis-co-ordination) with or without myokymia (continuous muscle movement).
• Epistaxis: Bleeding from nostril, nasal cavity or nasopharynx.
• Erythromelalgia: A condition characterised by intense burning pain of extremities,
severe redness and increased skin temperature.
• Esophageal variceal bleeding: Bleeding from esophagus when swollen veins (varices) in
lower esophagus rupture and bleed.
• Ethanol abuse syndrome: A condition in which an individual is physically and
psychologically dependent on alcohol.
• Euphoria: A feeling or state of intense excitement or happiness.
• Excitement: A feeling of great enthusiasm and eagerness.
• Excitotoxicity: A pathological process by which neurons are damaged and killed by
overactivations of NMDA/AMPA receptor.
• Extra-pyramidal symptoms: The symptoms including dystonia, akathesia, Parkinson,
bradykinesia, tremor and tardive dyskinesia, caused by stimulation of nerve-tracts other
than pyramidal pathways.
• Extra-systoles: A heart beat outside the rhythm.
• Extravasation: Leakage of fluid outside capillaries.
• Familial hemiplegic migraine: A genetic disease including weakness of half the body
which can last for hours, days or weeks.
• Familial hypercholesterolemia: A genetic disorder with defect in removing LDL from
blood.
• Fasciculation: A brief spontaneous contraction affecting a small number of muscle

fibres.
• Finger nail hypoplasia: Underdevelopment or incomplete development of nail.
• Flaccid paralysis: A paralysis with weakness and reduced muscle tone without other
obvious cause.
• Floppy iris syndrome: A complication which may occur during cataract extraction.
• Flushing: Becoming red and hot, as the result of illness or strong emotion.
• Foetal alcohol syndrome: Symptoms caused in children whose mothers consume
alcohol during pregnancy.
• Frostbite: Adverse effects of low temperature causing freezing of skin or other tissues.
• Galactorrhoea: It is a milky nipple discharge unrelated to the normal milk production of
breast feeding.
• Ganglia: A structure containing a number of nerve cell bodies, typically linked by
synapses, and often forming a swelling on nerve fibre.
• Gastro-esophageal reflux disease: It occurs when stomach acid frequently flows back
into esophagus.
• Gingival hyperplagia: Increase in the size of gingival (gums).
• Glaucoma: A disease of the eye in which fluid pressure in the eye rises.
• Glioblastoma multiforme: An aggressive cancer which begins within the brain.
• Gluconeogenesis: A metabolic pathway which results in generation of glucose from
non-carbohydrate sources.
• Glycogenolysis: It is the breakdown of glycogen to glucose.
• Glycolysis: A sequence of reactions for breakdown of glucose to pyruvic acid.
• Gout: A form of arthritis characterised by severe pain, redness and tenderness in joints.
• Grunts: A low short sound made by the person.
• Gynaecomastia: Enlargement of male breast tissue.
• Haemolytic anaemia: A condition involving destruction and removal of RBCs from
blood before their normal life span.
• Haemophilia: A genetic condition in which ability of the blood to clot is severely
reduced.
• Hallucination: An experience involving the apparent perception of something not
present.
• Heteropodatoxin: A peptide toxin from the venom of giant crab spider.
• Hirsutism: Unwanted male-pattern hair growth on a woman’s face, chest and back.
• Huntington’s disease: An inherited condition in which nerve cells in the brain
breakdown over time.
• Hyper excitability: An excessive reaction to stimuli.
• Hyperaemia: An excess of blood in the vessels supplying to an organ or other part of
the body.
• Hyperalgesia: Abnormally heightened sensitivity to pain.
• Hyperexia: Abnormally increased fever.
• Hyperhidrosis: Excessive sweating.
• Hyperkalemic periodic paralysis: Episodic muscle weakness caused due to elevated

potassium.
• Hyperprolactinaemia: Elevated serum prolactin.
• Hyperpyrexia: Abnormally increased fever.
• Hyperthyroidism: Overproduction of thyroxine.
• Hyperuricemia: Excess of uric acid in blood.
• Hypokalemia: A condition when blood potassium levels are too low.
• Hyponatremia: A condition which occurs when the level of sodium in blood is too low.
• Hypoxia: Deficiency in the amount of oxygen reaching the tissues.
• Iberiotoxin: An ion channel toxin from Indian scorpion.
• Impotence: Inability in a man to achieve an erection or orgasm.
• Impulse control disorder: It is a psychiatric disorder leading to failure to resist
temptation.
• Incontinence: Lack of voluntary control over urination or defaecation.
• Integrins: Proteins which function by attaching cell cytoskeleton to extracellular matrix.
• Intractable hiccups: A condition when hiccups last for more than a month.
• Ionotropy: Force of cardiac contraction.
• Iridocyclitis: Inflammation of the iris and ciliary body in eye.
• Iritis: Inflammation affecting coloured ring around the pupil of eye.
• Irritability: Excitatory ability to respond to the change in environment.
• Ischaemic heart disease: A heart disease caused by reduction of blood flow/oxygen to
heart.
• Islets of Langerhans: Tiny cluster of cells in pancreas responsible for insulin production.
• Jaundice: Yellow discolouration of skin, mucus membranes and whites of eyes.
• Juxta glomerular: A specialised structure in glomeruli and distal convulted tubule of
kidney.
• Laryngospasm: Sudden spasm of vocal cords.
• Laxatives: A substance which loosens stools.
• Leucopenia: Reduction in the number of white cells in the blood.
• Libido: Sexual desire.
• Li-Fraumeni syndrome: A genetic disorder which predisposes to cancer.
• Limb girdle muscular dystrophy: A group of disorders manifesting in proximal muscles
around the hips and shoulders.
• Lipolysis: Breakdown of fats and other lipids by hydrolysis.
• Lumbago: Pain in the muscles and joints of the lower back.
• Malignant hyperthermia: A severe reaction causing muscle rigidity, high fever and a
fast heart rate.
• Manic depressive psychosis: A mental disorder that causes periods of depression and
periods of abnormally elevated mood.
• Median eminence: A part of hypothalamus from which regulatory hormones are
released.
• Medulla (medulla oblongata): Apart of brain stem controlling ANS responses and
motor functions.
• Megaloblastic anaemia: A macrocytic anaemia which results from inhibition of DNA

synthesis during RBC production.
• Mental confusion: A change in mental staus in which a person is not able to think with
usual level of clarity.
• Mental retardation: The condition of having mental IQ below 70-75. The person lacks in
adaptive skills.
• Mesolimbic system: A dopaminergic pathway in the brain related to reward system.
• Metabotropic receptors: Receptors linked with ion channels through signal
transduction mechanisms, often G-proteins.
• Microcephaly: A condition in which a baby’s head is significantly smaller than expected.
• Micturition: The act of passing urine.
• Migraine: A headache of varying intensity, often accompanied by nausea and sensitivity
to light and sound.
• Miosis: Excessive constriction of the pupil of the eye.
• Mucosal vasoconstriction: Blockage of vessels to mucosa, especially in nasal passages
leading to nasal congestion.
• Multiple sclerosis: A disease in which the immune system eats away protective covering
of nerves.
• Muscarinic: Relating to a type of ACh receptor in nervous system capable of responding
to muscarine.
• Myasthenia gravis: Adisease causing weakness and rapid fatigue of muscles under
voluntary control.
• Mydriasis: Dilation of the pupil of the eye.
• Myocardial infarction: A condition in which blood flow to heart decreases or stops,
causing damage to heart muscle.
• Myoclonic/petit mal seizures: A kind of epilepsy when myoclonic jerks are associated
with abnormal brain wave activity.
• Myoclonus: Spasmodic jerky contraction of groups of muscles.
• Myoglobinuria: Presence of myoglobin in urine.
• Narcolepsy: A chronic sleep disorder which causes overwhelming daytime drowsiness.
• Neoplastic disease: It refers to both malignant and benign growths.
• Nephrogenic diabetes insipidus: A kind of diabetes insipidus caused due to pathology
of kidney.
• Neurolept analgesia: An intense analgesic and amnesic state.
• Neurolept-malignant syndrome: A rare, life-threatening condition characterised by
fever, muscular rigidity, altered mental status, caused by antipsychotic drug.
• Neuronal excitotoxicity: Toxicity caused by excessive stimulation by glutamate/similar
substances.
• Nicotinic: A channel protein which upon binding by ACh opens flow of cations, as in
case of nicotine.
• Nocturnal anuresis: An involuntary urination which happens at night while sleeping.
• Nystagmus: A condition of involuntary eye movement resulting in limited vision.
• Obsessive-compulsive disorders: Excessive thoughts (obsessions) that lead to
repetitive behaviours (compulsions).
• Oedema: A condition with excess of watery fluid in cavities or tissues of the body.
• Pancreatitis: An inflammation of pancreas causing abdominal pain.
• Paralytic ileus: Obstruction of intestine due to paralysis of intestinal muscles.
• Paranoid delusions: Fixed, false belief that one is being harmed or persecuted by a
person.
• Paranoid ideas: Thought process believed to be heavily influenced by anxiety or fear.
• Parasympatholytics: A substance or activity which reduces the activity of PSNS.
• Parasympathomimetics: A substance which stimulates PSNS.
• Paresthesia: Burning or prickling sensation, usually felt in hands, arms, legs or feet.
• Paroxysmal: A sudden recurrence or intensification of symptoms.
• Peptic ulcer: A break in the lining of stomach or duodenum.
• Phaeochromocytoma: A hormone-secreting tumour which occurs in the adrenal gland.
• Pheromones: A chemical produced by a mammal or insect, affecting the behaviour or
physiology of others of its species.
• Photophobia: A condition in which bright lights hurt eyes.
• Photosensitivity: An immune reaction triggered by Sunlight.
• Pill rolling tremors: A tremor in which index finger of hand tends to get in contact with
thumb and they perform a circular movement together.
• Piloerection: Involuntary erection or bristling of hairs due to a sympathetic reflex
triggered by cold, shock or fright.
• Plasmapheresis: A process which filters the blood and removes harmful antibodies.
• Plasticity: Ability of the brain to change throughout an individual’s life.
• Pleural fibrosis: A restrictive lung disease with high morbidity/mortality.
• Poikilothermic: Ability to change body temperature with environment.
• Polydypsia: Abnormally great thirst.
• Polyuria: Production of abnormally large volumes of dilute urine.
• Pons: A part of brain stem including neural motor pathways from brain to cerebellum
and sensory signals to thalamus.
• Porphyria: Disorder resulting from build up of porphyrin in blood.
• Positive ionotropic: Agents increasing strength of muscular contraction.
• Post-ictal depression: Feeling of depression before a seizure.
• Post-traumatic stress disorder: Stress observed after trauma.
• Priapism: Persistent and painful erection of the penis without sexual arousal.
• Presenility: Events earlier to mental deterioration associated with old age.
• Progressive choreoathetosis: Progressive movement disorder, cognitive and
behavioural changes with a myopathy.
• Prostatic hyperplasia: Age-associated prostate gland enlargement that can cause
difficulty in urination.
• Pseudocholinesterase: An enzyme present in blood and other organs which hydrolyses
ACh more slowly than acetyl cholinesterase.
• Pseudo-cushing’s syndrome: Cushing’s syndrome which is not associated with
hypothalamic-pitutary-adrenal axis.
• Psychedelics: Related to drugs which produce hallucinations and apparent expansion of
consciousness.
• Psychotomimetics: Relating to drugs which are capable of producing an effect on the

mind similar to a psychotic state.
• Ptosis: Grouping of the upper eyelid due to paralysis or disease.
• Purgatives: A medicine causing expulsion of unwanted waste from the body.
• Raphe neurons: Cluster of nuclei in brain stem, responsible for release of 5-HT to the
rest of brain.
• Raynaud’s syndrome: A condition in which spasm of arteries cause episodes of reduced
blood flow.
• Refractory complex epilepsy: A type of epilepsy which cannot be controlled by several
antiepileptics.
• Restlessness: The inability to rest or relax as a result of anxiety or boredom.
• Resuscitation: The process of correcting physiological disorders in an acutely unwell
patient.
• Rett syndrome: A rare genetic mutation affecting brain development in girls (6-18
months).
• Rhabdomyolysis: A breakdown of muscle tissues that releases a protein in to blood
which makes urine brown (myiglobinuria).
• Rhinorrhoea: A condition where the nasal cavity is filled with a significant amount of
mucus fluid.
• SA node: The heart’s natural pacemaker, located in upper part of right atrium.
• Saxitoxin: A potent neurotoxin from shell fish causing paralysis.
• Schizophrenia: A mental disorder that affects a person’s ability to think, feel and behave
clearly.
• Serotonin syndrome: A group of symptoms that may occur due to serotonergic drugs.
• Sialorrhea (drooling): Excessive salivation caused by poor oral and facial muscle
control.
• Sickle cell anaemia: A group of disorders that cause RBCs to alter their shape and
breakdown.
• Sjogren syndrome: An immune system disorder characterised by dry eyes and dry
mouth.
• Somnolence: A state of strong desire for sleep or sleeping for unusually long periods.
• Spasticity: A condition in which certain muscles are continuously contracted.
• Sphincter: A circular muscle which normally maintains constriction of a natural body
passage or orifice and which relaxes as per physiological need.
• Spina bifida: A birth defect in which a developing baby’s spinal cord does not develop
properly.
• Spino-thalamic tract: A sensory pathway from the skin to thalamus.
• Splanchnic vasoconstriction: Constriction of vessels supplying to spleen.
• Spondylitis: A form of arthritis which occurs in the spine.
• Sprain: A stretching or tearing of ligaments, the fibrous tissue which connects bones
and joints.
• Status epilepticus: A dangerous condition in which epileptic feets follow one another
without recovery of conscious between them.
• Stupor: A state of near-unconsciousness or insensibility.

• Sympatholytics: A drug which is antagonist to or inhbiting the transmission of nerve
impulses in SNS.
• Sympathomimetics: A drug producing physiological effects characteristic of SNS.
• Syncope: Atemporary loss of consciousness due to insufficient blood flow to the brain.
• Systemic lupus erythematosis (SLE): An autoimmune disease in which the immune
system mistakenly attacks healthy tissue in many parts of the body.
• Tachycardia: Increase in heart rate (> 100/minute).
• Tachyphylaxis: Rapidly diminishing response to successive doses of a drug, rendering it
less effective.
• Tachypnoea: Abnormally rapid breathing.
• Tactile hallucinations: False perception of sensory input that creates a hallucinatory
sensation of physical contact with an imaginary object.
• Tardive dyskinesia: A disorder which results in involuntary repeatitive body movements.
• Tetanus: A serious bacterial infection of Clostridium tetani spores causing painful muscle
spasm and can lead to death.
• Tetrodo toxin: A potent neurotoxin from a fish which blocks sodium channel.
• Thalassemia: A genetic disorder characterised by abnormal haemoglobin production.
• Theromogenesis: Production of heat in human body.
• Thrombocytopenia: A condition characterised by abnormally low levels of throm-
bocytes/platelets.
• Thrombophlebitis: Inflammation of a vein (phlebitis) related to blood clot (thrombus).
• Thymectomy: Surgical removal of the thymus gland.
• Tic: An involuntary, spasmodic contraction of muscle fibres.
• Tourette's syndrome: A neuro-psychiatric condition showing tics, grunts and
vocalizations.
Appendix III: Receptors and their Subtypes

• Dopamine (DA): D1, D2, D3, D4.
• Serotonin (5HT): 5HT-1, 5HT-1A, 5HT-1C; 5HT-2A, 5HT-2B
• Acetylcholine (AcH): Muscarinic: M1, M2, M3; Nicotinic: NM, NN
• Histamine (H): H1, H2.
• Adrenaline (A): α1, α2; β1, β2, β3.
• Noradrenaline (NA): α1, α2; β1, β2, β3.
• Cannabis: CB1, CB2.
Appendix IV: Trade-Names of Few Drugs
DRUG (GENERIC NAME) TRADE NAMES

Acebrophylline : AB-PHYLLINE, BESTOPHYLLINE-A, UNOBRO
Adrenaline : VASOCON
Alprazolam : ALPRAX, ALZOLAM, RESTYL, TRIKA, ALLTOP-P,
ZOPAX PLUS.
Amantadine : AMANTREL, COMANTREL
Aminophylline : MINOPHYL, AMINOPHYLLINE
Asebutolol : SECTRAL
Atenolol : BETACARD, TENORMIN
Atomoxetine : ATTENTROL, AXEPTA
Atracurium : ATRELAX TRACRIUIM
Atropine : ATROPINE SULPHATE, TROPINE
Baclofen : LIOFEN, LIORESAL, BACMAX
Bambuterol : BETADAY, BAMDULI, ROBUROL
Benzocaine : MUCOPAIN, ZOKEN
Betaxolo : OPTIPRESS, BULOL, IOBET, OCUBETA
Bisoprolol : ZAVESTA, CORLOIS, BISELECT
Bromocriptine : PROCTINAL SICRIPTIN, PARLODEL, BROM,
ENCRIPT
Bupivacaine : MARCAIN, BUPIVAN
Buspirone : TAMSPAR, BUSCALM, BUSPIDAC.
Cabergoline : CABGOLINE
Carbamazepine : MAZETOL, TEGRITAL, TEGRITOL
Carisoprodol : CARISOMA
Carvedilol : ORICAR, CONPRESS, CEVAS, CARVIMED,
CARDIVAS
Celeprolol : CELIPRES
Chlordiazepoxide : LIPRIUM, ODIP, LIBRAX
Chlorpheneramine : COZYPLUS
Chlorzoxazone : NEW PANAZOX, UNIDIC-MR
Clobazam : COBAZAM, CLOBA, CLOBATOR
Clonazepam : LONAZEP, RIVOTRIL, EPITRIL
Clonidine : ARKAMIN, CATAPRESS
Cyclopentolate : CYCLATE, CYCLOGIK, DILATE
Diazepam : VALIUIM, CALMPOSE
Dicyclomine : COLINET, CYCLOPAM

Dipivefrine : PROPINE
Disulfiram : ANTADICT, SUFITAL, ESPERAL
Dobutamine : DOBUTREX, DOBIER, DOBUCARD, KARDIA
Donepezil : ALZIL, DONECEPT, DOPEZIL
Dopamine : DOPACARD, DOPAR, DOPASOL, DOPINGA
Doxasosin : DOXACARD, DURACARD
Doxofylline : DOXOBID, DOXFREE, BESTOFYLINE
Drotaverine : DOTARIN
Esmolol : CARDESMO, NEOTACH, MINIBLOCK
Eszopiclone : FLUNITE
Fenfluramine : FLABOLIN
Flavoxate : FLAVOSPAS
Flurazepam : NINDRAL, FLURAZ
Formoterol : FORATEC
Fosphenytoin : FOSOLIN
Gabapentin : GABANTON, GABAPIN, GABATOR, GABANEURON
Galantamine : GALAMER
Glycopyrrolate : GLYCOP, VAGOLATE
Halothane : FLUOTHANE or HYPNOTHANE
Homatropine : HOMIDE
Hydroxyzine : MELOSET, ZYTONIN
Hyoscine (scopolamine) : BELLOID, BUSCOPAN, HYOSPAN
Ipratropium : IPRAVENT, IPRATOP
Isoflurane : FORANE, ISORANE, SOFANE
Isoprenalilne : ISOLIN, ISOPERIN, ISOSOL, NEO-EPININE
Labetalol : NORMADATE, LABESOL
Levobunolol : BETAGAN
Levodopa + Benserazide : BENSPAR
Levodopa + Carbidopa : SYNDOPA, TIDOMET-FORTE, TIDOMET LS,
SINEMET PLUS, SYNDOPA PLUS, TIDOMET PLUS
Lidocaine : GESICAINE WITH ADRENALIN, XYLOCAINE WITH
ADRENALIN, LIGNOCAINE, GESICAINE,
XYLOCAINE
Lithium carbonate : LITHOSUN, LITHOSUN – SR, LICAB, LICAB – XL,
LITHOCAP
Lorazepam : ATIVAN, LARPOSE, LORVAN, TRAPEX, LOPERZ
Mefanamic acid : MEFTAL-SPAS, BARALGAN-DM, DOTARIN-MF

Melatonin : ATARAX
Memantine : ADMENTA, MENTADEM
Mephentermine : MEPHENTINE
Metaproterenol (orciprenaline) : ALUPENT
Methocarbamol : ROBINAX FLEXINOL
Metoprolol : BETALOC, METOLAR, LOPRESOR
Midazolam : MIDAZ, MEZOLAM, FULSED
Modafinil : PROVAKE, MODALERT
Naloxone : NALOX, NARCOTAN, NEX
Naltrexone : NODICT, NALTIMA
Naphazoline : PRIVINE, OCUCEL, FENOX
Nebivolol : NEBICARD, NUBETA, NODON, NEBISTAR
Noradrenaline (NE) : ADRENOR, NODRESOL, NORAD, NOREPIRIN
Orphenadrine : ORPHIPAL
Oxazepam : SEREPAX
Oxcarbazepine : OXCARB, OXETOL, OXEP
Oxprenolol : TRASICOR
Oxybutinine : OXYSPAS, CYSTRAN
Oxymetazoline : XYNOSE, SYNAREST
Pancuronium : PANCURONIUM BROMIDE, PANCONIUM
Phemylephrine : DROSYN
Phenobarbital : GARDENAL, PHENOBARB, PHENYTAL
phenobarbitone : PIPLAR
Phentolamine : FENTANOR, FENTOSOL
Phenylpropanolamine : ALERID-COLD
Phenytoin : DILANTIN, EPSOLIN, EPTOIN
Pindolol : VISKEN
Pipecuronium : ARDUAN
Pramipexole : PARPEX
Prazosin : MINIPRESS, PRAZOPRESS
Pregabalin : MAXGALIN, NEUGABA, PREGEB, PREEGA-M
Prilocaine : PRILOX, ASTHESIA
Primidone : MYSOLINE
Procyclidine : KEMADRIN, DINE, PRODINE
Promethazine : AVOMINE, PHENERGAN
Propantheline : PROBANTHINE
Propofol : CRITIFOL, PROPOFOL, PROPOVAN

Propranolol : INDERAL, CIPLAR, BETACAP-TR
Pseudoephedrine : CHESTON
Recuronium : CUROMID
Rivastigmine : RIVASMINE, RIVAMER, EXELON
Ropinirole : ROPITOR, ROPARK
Salbutamol : ASTHALIN, VENTORLIN, DERIHALER
Salmeterol : SALMETER, SEROBID
Selegiline : SELGIN, SALERIN, ELEGELIN
Sibutramine : OBEGO, OBESTAT, SIBUTREX
Sotalol : SOTAGARD, SOLET
Succinylcholine (ScA) : SCOLINE, ENTUBATE, MIDARINE
Tamsulosin : CONTIFLO-OD, URIPRO, VELTAN, URIMAX
Terazosin : HYTRIN, TERAPRESS, TERALFA, OLYSTER
Terbutaline : BRICANYL
Tetracaine : AMETHOCAINE, ANETHANE
Theophylline : BRONCORDIL, THEODAY, THEODER,
DERIPHYLLINE
Thiopental : INTRAVAL, PENTOTHAL
Timolol : OCUPRES, GLUCOMOL, IOTIM, TIMOLE
Tiotropium : TIATE, TIOVA
Tolazoline : FENOXENE
Tolterodine : TOLTER-OD, FLOWCHEK
Topiramate : TOPEX, TOPIROL
Triclofos : PEDICLORYL, TRICLORYL
Trihexephenidyl : PACITANE, PARKIN, PARKITANE
Trihexiphenidine : PACITANE, PARKITANE, PARKIN
Triprolidine : ACITIFIED
Tropicamide : OPTIMIDE, TROMIDE, TMIDE, DROSYN-T
Valethamate : EPIDOSIN
Valproic : ENCORATE, TORVATE, VALTEC
Vecuronium : VERUNIUM, VECURON
Xylometazoline : OTRIVIN
Zaleplon : ZAPLON, ZASO
Zolpidem : NITREST, ZOLPIGEM, ZOLPINITE
Zonisamide : ZONISEP, ZONICARE, ZONIMID
Zopiclone : ZOLINOX, ZOPICON, ZOLIUM
α-methyldopa : EMDOPA, ALFADOPA, ALDOPAM

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What are some of the drugs mentioned in the appendix?

What are some of the drugs mentioned in the appendix?

What information is provided about the drugs?

What information is provided about the drugs?

A Text Book Of

Dr. S. B. Bhise Mrs. M. S. Bhise

The subject of Pharmacology has a different context for pharmacists in comparison to

1.1 INTRODUCTION TO PHARMACOLOGY

• Disability-Adjusted Life Years (DALYs)

• Fixed dose combination (FDC) product

• Internet pharmacy (Online pharmacy)

• Rational use of medicines

1.1.2 Historical Landmarks and Scope of Pharmacology

Early in the development of pharmacological techniques, it was found that an isolated

an extension of clinical pharmacology. Forensic toxicology addresses to medico-legal

1.1.4 Essential Drugs Concept

The broad classification is presented in Fig. 1.1.

Fig. 1.1: Routes of administration

Fig. 1.2: Injectable routes of drug administration

Brief characteristics of different routes of administration are presented in table 1.1.

4. Intramuscular Depends on • Suitable if drug • Affects certain lab

8. Sublingual Depends on the • Bypasses first- • Limited to certain

Efficacy and Potency

diffusion of molecules across the cell membrane by undergoing conformational alterations

Extracellular fluid Carrier protein

Fig. 1.6: Facilitated diffusion

Fig. 1.8: Plasma concentration of an oral/intravenous drug

products or antacids is an example. Absence of hydrochloric acid in stomach is called as

(a) Structure of endothelial cells in the liver

Slit injections Lipid

A few drugs that can be transported

1.2.6 Enzyme Induction

The classes of enzyme inducing drugs include following categories:

Table 1.4: Some examples of cross-induction

Slope = -Ko 0.5 Slope =

10. Half-life 0.5 C0 0.693

• General pharmacology consists of four main components: Pharmacodynamics, Adverse

Table 2.1: Some common disorders requiring gene therapy

transduction, often involving secondary messengers. Activity of secondary messengers is

Receptor Drug-receptor complex

generate a response involving hundreds to millions of molecules. The transduction of

Fig. 2.4: Signal transduction pathways

5 AMP cAMP ATP P3

EFFECTS EFFECTS EFFECTS

Out Ions Cell membrane

EFFECTS EFFECTS EFFECTS

• Autonomic nervous system transmission: Both sympathetic and parasympathetic

(iii) cGMP system

Fig. 2.6: Ion-channel diagram

2.1.10 JAK-STAT Binding Receptor

The pathway is negatively regulated on multiple levels. Protein tyrosine phosphatases

(ii) Differential enhancement of transcription

EC50 EC50 EC50

2.1.13 Therapeutic Index (TI)

in a number of classifications such as partial agonist, competitive/non-competitive agonist,

2.3 DRUG INTERACTIONS

2.3.1.3 Metabolism Interactions

2.3.1.4 Excretion Interactions

2.4 DRUG DISCOVERY AND CLINICAL EVALUATION OF NEW DRUGS

Primary assays Secondary assays