UNIT-II

Age related drug therapy: Concept of posology, drug therapy for neonates, pediatrics,
geriatrics, Drugs used in pregnancy and lactation

TOPIC-12

Class-12 Age related drug therapy- Concept of posology, Drug therapy for neonates

Age related drug therapy

Advancing age is characterized by impairment in the function of the many regulatory processes
that provide functional integration between cells and organs. Therefore, there may be a failure
to maintain homeostasis under conditions of physiological stress. The reduced homeostatic
ability affects different regulatory systems in different subjects, thus explaining at least partly
the increased interindividual variability occurring as people get older. Important
pharmacokinetic and pharmacodynamic changes occur with advancing age. Pharmacokinetic
changes include a reduction in renal and hepatic clearance and an increase in volume of
distribution of lipid soluble drugs (hence prolongation of elimination half-life) whereas
pharmacodynamic changes involve altered (usually increased) sensitivity to several classes of
drugs such as anticoagulants, cardiovascular and psychotropic drugs. This review focuses on the
main age-related physiological changes affecting different organ systems and their implications
for pharmacokinetics and pharmacodynamics of drugs.

Ageing is the progressive accumulation of more or less random changes. This limits the average
life expectancy to about 85 years, maximum life span to around 122 years, and lowers the
ability to cope with external stresses. Moreover, the inter individual variability in the
physiological responses increases with age. Ageing is not a single entity but a collective term
representing the sum of cumulative local effects at the molecular, cellular and tissue level.
Ageing is the effect of these underlying changes and not the cause. Although an all-
encompassing definition of ageing is not possible, several characteristics are recognized. The
most consistent is the time-related loss of functional units. These units are the smallest
structures still capable of performing the specific physiological activities characteristic of the
organ of which they are a part (e.g. nephrons, alveoli or neurons). A further characteristic is the
disruption of some of the regulatory processes that provide functional integration between
cells and organs. Consequently, there is a failure to maintain homeostasis under conditions of
physiological stress. This loss of functional reserve is associated with a decrease in viability and
an increase in vulnerability. Ageing is not solely a progression of functional decline but
produces anatomical and physiological changes which might lead to decompensation of the
relevant system when they progress beyond a threshold. Some important age-related
physiological changes are discussed. This is followed by a detailed description of the age-related
changes in pharmacokinetics (drug absorption, distribution, metabolism, and excretion) and
pharmacodynamics (the effect of a drug on its target site).

Concept of Posology

Posology: It is the branch of pharmacology dealing with the determination of dosage. Study of
dosage of medications.

Young’s formula = Age in years/Age+ 12 × Adult dose

Dilling’s formula = Age in years/20 × Adult dose

Fried’s formula = Age in months/150 × Adult dose

Clark’s formula = Weight (pounds)/150 × Adult dose

Body surface area = Body surface area of child/Body surface area of adult × Adult
dose

Body surface area = Height (mts) × Weight (kgs)/3600

Goubin’s formula = Less than 1 year – 1/12 × adult dose

1-2 years- 1/8 × adult dose

2-3 years- 1/6×adult dose

3-4 years- 1/4×adult dose

4-7 years- 1/3×adult dose

14-12 years- 1/2×adult dose

21-60 years- 2/3×adult dose

From 60 years- Adult dose

 Drug therapy for Neonates

INTRODUCTION

 Children cannot be regarded as miniature adults in terms of drug response, due to

differences in body constitution, drug absorption and elimination, and sensitivity to
adverse reactions. Informed consent is problematic and commercial interest has been
limited by the small size of the market, so clinical trials in children have lagged behind
those in adults.
 At birth, renal and hepatic functions are less efficient than in adulthood. Drug effects
may be prolonged and accumulation may occur. These factors are exaggerated in the
premature infant.
 Traditionally, paediatricians have used drugs ‘off-label’ often gaining experience in age
groups close to those for which a product is licensed and then extending this to younger
children.
 Drug responses are thus usually qualitatively similar in children and adults, although
there are important exceptions, including some central nervous system (CNS) responses
and immunological responses to ciclosporin.
 Furthermore, some adverse effects occur only during certain stages of development, for
example, retrolental fibroplasia induced by excess oxygen in the premature neonate and
staining of teeth by tetracycline which occurs only in developing enamel.

PHARMACOKINETICS

ABSORPTION

 Gastro-intestinal absorption is slower in infancy, but absorption from intramuscular

injection is faster.
 The rate of gastric emptying is very variable during the neonatal period and may be
delayed by disease, such as respiratory distress syndrome and congenital heart disease.
 In older and less severely ill children, oral liquid preparations are commonly used,
resulting in less accurate dosing and a more rapid rate of absorption. This is important
for drugs with adverse effects that occur predictably at high plasma concentration, and
which show lack of efficacy if trough concentration is low (e.g. carbamazepine and
theophylline).
 Infant skin is thin and percutaneous absorption can cause systemic toxicity if topical
preparations (e.g. of potent corticosteroids) are applied too extensively.

DISTRIBUTION
 Body fat content is relatively low in children, whereas water content is greater, leading
to a lower volume of distribution of fat-soluble drugs (e.g. diazepam) in infants.
  Plasma protein binding of drugs is reduced in neonates due to a lower plasma albumin
concentration and altered binding properties. The risk of kernicterus caused by
displacement of bilirubin from albumin by sulphonamides is well recognized.
 The blood–brain barrier is more permeable in neonates and young children, leading to
an increased risk of CNS adverse effects.

METABOLISM
 At birth, the hepatic microsomal enzyme system is relatively immature but after the first
four weeks it matures rapidly.
 Chloramphenicol can produce ‘grey baby syndrome’ in neonates due to high plasma
levels secondary to inefficient elimination.
 Drugs administered to the mother can induce neonatal enzyme activity (e.g.
barbiturates). Phenobarbitone metabolism is faster inchildren than in adults because of
greater induction of hepaticenzyme activity.

EXCRETION
 All renal mechanisms (filtration, secretion and reabsorption) are reduced in neonates,
and renal excretion of drugs is relatively reduced in the new-born.
 Glomerular filtration rate (GFR) increases rapidly during the first four weeks of life, with
consequent changes in the rate of drug elimination.

Changes in rate of drug elimination with development

Stage of development Plasma half-life of gentamicin

Premature infant
48 hours old 18 hours
5–22 days old 6 hours
Normal infant
1–4 weeks old 3 hours
Adult 2 hours

PHARMACODYNAMICS

 Documented evidence of differences in receptor sensitivity in children is lacking, and the

apparently paradoxical effects of some drugs (e.g. hyperkinesia with phenobarbitone,
sedation of hyperactive children with amphetamine) are as yet unexplained.
 Augmented responses to warfarin in prepubertal patients occur at similar plasma
concentrations as in adults, implying a pharmacodynamic mechanism.
  Ciclosporin added in vitro to cultured monocytes has greater effects in cells isolated
from infants, providing another example of an age-related pharmacodynamics
difference.

BREAST-FEEDING

 Breast-feeding can lead to toxicity in the infant if the drug enters the milk in
pharmacological quantities.
 The milk concentration of some drugs (e.g. iodides) may exceed the maternal plasma
concentration, but the total dose delivered to the baby is usually very small.
 However, drugs in breast milk may cause hypersensitivity reactions even in very low
doses.
 Virtually all drugs that reach the maternal systemic circulation will enter breast milk,
especially lipid-soluble unionized low molecular- weight drugs.
 Milk is weakly acidic, so drugs that are weak bases are concentrated in breast milk by
trapping of the charged form of the drug.
 The infant should be monitored if β-adrenoceptor antagonists, carbimazole,
corticosteroids or lithium are prescribed to the mother.
 β-Adrenoceptor antagonists rarely cause significant bradycardia in the suckling infant.
Carbimazole should be prescribed at its lowest effective dose to reduce the risk of
hypothyroidism in the neonate/infant.
 In high doses, corticosteroids can affect the infant’s adrenal function and lithium may
cause intoxication.
 There is a theoretical risk of Reye’s syndrome if aspirin is prescribed to the breast-
feeding mother.
 Warfarin is not contraindicated during breast-feeding.
 Bromocriptine suppresses lactation and large doses of diuretics may do likewise.
Metronidazole gives milk anunpleasant taste.

Some drugs to be avoided during breast-feeding

Amiodarone
Aspirin
Benzodiazepines
Chloramphenicol
Ciclosporin
Ciprofloxacin
Cocaine
Combined oral contraceptives
Cytotoxics
Ergotamine
Octreotide
Stimulant laxatives
Sulphonylureas
Thiazide diuretics
Vitamin A/retinoid analogues (e.g. etretinate)

PRACTICAL ASPECTS OF PRESCRIBING

COMPLIANCE AND ROUTE OF ADMINISTRATION

 Children under the age of five years may have difficulty in swallowing even small tablets,
and hence oral preparations which taste pleasant are often necessary to improve
compliance. Liquid preparations are given by means of a graduated syringe.
 However, chronic use of sucrosecontaining elixirs encourages tooth cavities and
gingivitis. Moreover, the dyes and colourings used may induce hypersensitivity.
 Pressurized aerosols (e.g. salbutamol inhaler, see Chapter 33) are usually only
practicable in children over the age of ten years, as co-ordinated deep inspiration is
required unless a device such as a spacer is used.
 Spacers can be combined with a face mask from early infancy.

 Intramuscular injection should only be used when absolutely necessary.

 Children find intravenous infusions uncomfortable and restrictive.
 Rectal administration (see Chapter 4) is a convenient alternative (e.g. metronidazole to
treat anaerobic infections). Rectal diazepam is particularly valuable in the treatment of
status epilepticus when intravenous access is often difficult. Rectal diazepam may also
be administered by parents. Rectal administration should also be considered if the child
is vomiting.

ADVERSE EFFECTS

 With a few notable exceptions, drugs in children generally have a similar adverse effect
profile to those in adults.
 Of particular significance is the potential of chronic corticosteroid use, including high-
dose inhaled corticosteroids, to inhibit growth.
 Aspirin is avoided in children under 16 years (except in specific indications, such as
Kawasaki syndrome) due to an association with Reye’s syndrome, a rare but often fatal
illness of unknown aetiology consisting of hepatic necrosis and encephalopathy, often in
the aftermath of a viral illness.
 Tetracyclines are deposited in growing bone and teeth, causing staining and occasionally
dental hypoplasia, and should not be given to children. Fluoroquinolone antibacterial
drugs may damage growing cartilage.
 Dystonias with metoclopramide occur more frequently in children and young adults
than in older adults.
  Valproate hepatotoxicity is increased in young children with learning difficulties
receiving multiple anticonvulsants.

TOPIC-13
Class-13 Drug therapy for geriatrics, introduction to drug therapy for pediatrics

DRUG THERAPY IN GERIATRICS

 There is a progressive functional decline in many organ systems with advancing age.
Age-associated physiologic changes may cause reductions in functional reserve capacity
(i.e., the ability to respond to physiologic challenges or stresses) and the ability to
preserve homeostasis, thus making an elder susceptible to decompensation in a
stressful situation.
 To deal with physiologic challenges or stresses, an older individual may require up to
95% of his or her remaining reserve capacity. The cardiovascular, musculoskeletal, and
central nervous systems appear to be most affected.
 Examples of impaired homeostatic mechanisms include postural or gait stability,
orthostatic blood pressure responses, thermoregulation, cognitive reserve, and bowel
and bladder function.
 An event resulting in functional impairment may involve an insult for which the body
cannot compensate, and relatively small stresses may result in major morbidity and
mortality.
 A number of age-related physiologic changes occur that potentially could affect drug
pharmacokinetics and pharmacodynamics.

Physiologic Changes with Aging

Organ System Manifestation

Body composition ↓ Total body water
↓ Lean body mass
↑ Body fat
↔ or ↓ Serum albumin
↔ or ↑ α1-Acid glycoprotein (↑ by several disease states)

Cardiovascular ↓ Myocardial sensitivity to beta-adrenergic stimulation

↓ Baroreceptor activity
↓ Cardiac output
↑ Total peripheral resistance

Central nervous system ↓ Weight and volume of the brain

Alterations in several aspects of cognition

Endocrine Thyroid gland atrophies with age

Increase in incidence of diabetes mellitus, thyroid disease
 Menopause

Gastrointestinal ↑ Gastric pH
↓ Gastrointestinal blood flow
Delayed gastric emptying
Slowed intestinal transit

Genitourinary Atrophy of the vagina due to decreased estrogen

Prostatic hypertrophy due to androgenic hormonal changes
Age-related changes may predispose to incontinence

Immune ↓ Cell-mediated immunity

Liver ↓ Liver size

↓ Liver blood flow

Oral Altered dentition

↓ Ability to taste sweetness, sourness, and bitterness

Pulmonary ↓ Respiratory muscle strength

↓ Chest wall compliance
↓ Total alveolar surface
↓ Vital capacity
↓ Maximal breathing capacity

Renal ↓ Glomerular filtration rate

↓ Renal blood flow
↑ Filtration fraction
↓ Tubular secretory function
↓ Renal mass

Sensory ↓ Accommodation of the lens of the eye, causing farsightedness

Presbycusis (loss of auditory acuity)
↓ Conduction velocity

Skeletal Loss of skeletal bone mass (osteopenia)

Skin/hair Skin/hair Skin dryness, wrinkling, and changes in pigmentation,

epithelial thinning,
loss of dermal thickness
↓ Number of hair follicles
↓ Number of melanocytes in the hair bulbs
ALTERED PHARMACOKINETICS

ABSORPTION
 Most drugs are given orally, and thus a number of the age-related changes in
gastrointestinal physiology potentially could affect the absorption of medications.
Fortunately, most drugs are absorbed via passive diffusion, and age-related physiologic
changes appear to have little influence on drug bioavailability.
 A few drugs require active transport for their absorption, and thus their bioavailability
may be reduced.
 However, there is evidence for a decreased first-pass effect on hepatic and/or gut wall
metabolism that results in increased bioavailability and higher plasma concentrations of
drugs such as propranolol and morphine. Increased drug bioavailability also may be seen
with the concurrent ingestion of grapefruit juice.
 Constituents of this product inhibit cytochrome P450 (CYP450) isoenzyme 3A4, thus
decreasing first-pass metabolism and resulting in exaggerated pharmacologic effects.

DISTRIBUTION
 The distribution of medications in the body depends on factors such as blood flow,
plasma protein binding, and body composition, each of which may be altered with age.
For example, the volume of distribution of water-soluble drugs is decreased, whereas
lipophilic drugs will exhibit an increased volume of distribution.
 Changes in the volume of distribution can have a direct impact on the amount of
medication that needs to be given as a loading dose.
 The two major plasma proteins to which medications can bind are albumin and α1-acid
glycoprotein (AAG), and concentrations of these proteins may change with concurrent
pathologies seen with increasing age.
 For acidic drugs such as naproxen, phenytoin, tolbutamide, andwarfarin, decreased
serum albumin may lead to an increase in free fraction. An increase in AAG induced by
burns, cancer, inflammatory disease, or trauma may lead to a decreased free fraction of
basic drugs such as lidocaine, propranolol, quinidine, and imipramine.

METABOLISM
 The liver is the major organ responsible for drug metabolism, including phase I
(oxidative) and phase II (conjugative) reactions.
 The most remarkable characteristic of liver function in the elderly is the increase in
inter-individual variability compared with other age groups, a feature that may obscure
true age-related changes.
 Recent data suggest that age-related declines in phase I metabolism are more likely the
result of reduced liver volume rather than reduced hepatic enzymatic activity.
Decreased phase I metabolism producing decreased drug clearance and increased
 terminal disposition half-life (t1/2) has been reported in elders for medications such as
diazepam, piroxicam, theophylline, and quinidine.
 Phase II metabolism of medications such as lorazepam and oxazepam appears to be
relatively unaffected by advancing age. Hepatic enzyme induction or inhibition does not
appear to be affected by the aging process.
 Age-related decreases in liver blood flow also can decrease significantly the metabolism
of high-hepatic-extraction-ratio drugs such as imipramine, lidocaine, morphine, and
propranolol.
 Finally, a number of potential confounding factors, including race, sex, frailty, smoking,
diet, and drug-drug interactions, may affect hepatic metabolism significantly in the
elderly.

ELIMINATION
Renal excretion is the primary route of elimination for many drugs. Although age-related
reductions in glomerular filtration are well documented, as many as one-third of “normal”
elderly subjects may have no reduction, as measured by creatinine clearance.
Medications whose excretion is primarily renal and for which there is evidence of age-related
reduction in renal and total body clearance include (but are not limited to) amantadine,
aminoglycosides, atenolol, captopril, cimetidine, digoxin, lithium, and vancomycin.

Creatinine clearance = (140 – age in years)(actual body weight in kg)

(males) 72(serum creatinine in mg/dL)

Age-Related Changes in Drug Pharmacokinetics.

Pharmacokinetic Pharmacokinetic Parameters

Phase
Gastrointestinal Unchanged passive diffusion and no change in bioavailability for
Absorption most drugs
↓ Active transport and ↓ bioavailability for some drugs
↓ First-pass extraction and ↑ bioavailability for some drugs

↓ Volume of distribution and ↑ plasma concentration of water-

Distribution soluble drugs
↑ Volume of distribution and ↑ terminal disposition half-life
(t1/2) for fat-soluble drugs
↑ or ↓ Free fraction of highly plasma protein bound drugs

Hepatic metabolism ↓ Clearance and ↑ t1/2 for some oxidatively metabolized drugs
↓ Clearance and ↑ t1/2 of drugs with high hepatic extraction
ratios
Renal excretion
 ↓ Clearance and ↑ t1/2 of renally eliminated drugs and active
metabolites

ALTERED PHARMACODYNAMICS

 There is some evidence in the elderly of altered drug response or “sensitivity.”

 Four possible mechanisms have been suggested:
 changes in receptor numbers,
 changes in receptor affinity,
 post receptor alterations, and
 Age-related impairment of homeostatic mechanisms.
 For example, muscarinic, parathyroid hormone, β-adrenergic, α1-adrenergic, and μ-
opioid receptors exhibit reduced density with increasing age.
 Evidence from epidemiologic and experimental studies suggest that, independent of
pharmacokinetic alterations, the elderly are more sensitive to the central nervous
system effects of benzodiazepines.
 The elderly also exhibit a greater analgesic responsiveness to opioids when compared
with their younger counterparts, even when pharmacokinetic parameters are similar in
the two groups.
 In addition, the elderly demonstrate an enhanced responsiveness to anticoagulants such
as warfarin and heparin, as well as thrombolytic therapy.
 In contrast, the elderly exhibit decreased responsiveness to certain drugs (e.g., β-
agonists/antagonists).

CLINICAL GERIATRICS
 Maintenance of independence and prevention of disability are primary goals in the
clinical care of persons 65 years of age or older. To achieve these goals, it is necessary
that all health care professionals understand the concept of functional status.
 One of the challenges of maintaining and improving functional status in geriatric
individuals is recognizing and managing conditions frequently seen in older adults.
Problems found more commonly in older persons sometimes are referred to as the “I’s
of geriatrics”

The I’s of Geriatrics: Common Problems in the Elderly.

Immobility Instability
Isolation Intellectual impairment
Incontinence Impotence
Infection Immunodeficiency
Inanition (malnutrition) Insomnia
 Impaction Iatrogenesis
Impaired senses

 Examples of diseases and syndromes that can present ascommonproblems in the elderly
include
 Parkinson’s disease, falls, hip fractures, benign prostatic hypertrophy, dementia,
glaucoma and tuberculosis.
 Another factor contributing to the challenge of clinical geriatrics is that approximately
50% of older patients present with atypical symptoms or complaints, making it difficult
to use the classic medical model for diagnosis. For example, cardiac ischemia may
present as syncope or weakness in an older person rather than the typical presentation
of chest pain.

Atypical Disease Presentation in the Elderly

Disease Presentation
Acute myocardial Only about 50% present with chest pain. In general, the elderly
infarction present with weakness, confusion, syncope, and abdominal pain;
however, electrocardiographic findings are similar to younger
patients.

Congestive heart failure Instead of dyspnea, the older patient may present with hypoxic
symptoms, lethargy, restlessness, and confusion.

Although the mortality rate is about 10%, presenting symptoms

Gastrointestinal bleed are nonspecific, ranging from mental status change to syncope
with hemodynamic collapse. Abdominal pain is often absent.

Upper respiratory Older patients typically present with lethargy, confusion,

Infection anorexia, and decompensation of a preexisting medical
condition. Fever, chills, and a productive cough may or may not
be present.

Urinary tract infection

Dysuria, fever, and flank pain may be absent. More commonly,
the elderly present with incontinence, confusion, abdominal
pain, nausea/vomiting, and azotaemia.
Multiple coexisting chronic illnesses are another common threat to independence that
distinguishes the elderly from younger patients. It is not unusual for elderly patients to have
multiple comorbidities such as osteoarthritis, heart disease, and diabetes. Although multiple
comorbidities can have a substantial impact on a patient’s functional status, the mere existence
of multiple diseases alone does not determine functional impairment.

Multiple choice questions

1. New-born infants born prior to which of the following gestational ages are considered
premature infants?
A) 37 weeks
B) 39 weeks
C) 40 weeks
D) 42 weeks

2. Kernicterus associated with sulfonamide in infants develops due to

A) Displacement of albumin by bilirubin.
B) Displacement of bilirubin from albumin by a sulfonamide.
C) Decreased metabolism of bilirubin.
D) Increased concentration of albumin.

3. Which of the following statements is false about drug absorption from an intramuscular or
percutaneous route in premature infants versus older patients?
A) Absorption of some drugs may be increased after intramuscular administration in premature
infants.
B) Absorption of certain drugs may be decreased after intramuscular administration in
premature infants.
C) Absorption of drugs from a percutaneous site is increased in premature infants.
D) Absorption of drugs from a percutaneous site is decreased in premature infants.

4. Based on extracellular fluid (ECF) volume, which of the following population is expected to
have the largest apparent volume of distribution per kilogram of body weight for a drug largely
distributed in ECF?
A) Premature infants
B) Children
C) Adolescents
D) Adults

5. Which of the following age groups generally requires the highest daily dose of theophylline
per kilogram of body weight?
A) 1monthold infant
B) 6monthold infant
C) 5yearold Child
D) 15yearold Adolescent

6. Premature infants need higher plasma concentrations of morphine for pain control than
older patients because they have
A) Decreased metabolism to the more active metabolite.
B) Lower sensitivity to pain.
C) Increased urinary excretion of morphine.
D) Decreased absorption of morphine.

7. Which of the following statements is false about adverse effects of drugs in pediatric
patients?
A) Tetracyclines are contraindicated for patients below 8 years of age.
B) Benzyl alcohol can cause severe toxicity in premature infants.
C) Fluoroquinolones are not approved but have been used safely in children with cystic fibrosis.
D) Aminoglycosides are more toxic in children than in adults.

8. The daily dosage requirement of aminoglycosides in children with cystic fibrosis (CF) versus in
those without CF is often
A) Increased.
B) Decreased.
C) Similar.
D) unknown.

9. Which of the variables of intravenous drug infusion systems influence serum concentration in
infants?
A) Flow rate
B) Injection site
C) Fluid volume of the tubing
D) All the above

10. A commercially available drug approved for adults is not available in an oral dosage form for
use in a 2yearold child. A major limitation in preparing an extemporaneous dosage form is
A) A paediatrician is not allowed to prescribe this drug.
B) A pharmacist is not allowed to prepare an extemporaneous formulation by the Food and
Drug Administration (FDA).
C) A pharmacist can prepare an extemporaneous formulation, but the stability data of the
drug in the vehicle to be used may be unknown.
D) A nurse is not allowed to administer this drug.
 DRUG THERAPY IN PEDIATRICS

 There is a progressive functional decline in many organ systems with advancing age.
Age-associated physiologic changes may cause reductions in functional reserve capacity
(i.e., the ability to respond to physiologic challenges or stresses) and the ability to
preserve homeostasis, thus making an elder susceptible to decompensation in a
stressful situation.
 To deal with physiologic challenges or stresses, an older individual may require up to
95% of his or her remaining reserve capacity. The cardiovascular, musculoskeletal, and
central nervous systems appear to be most affected.
 Examples of impaired homeostatic mechanisms include postural or gait stability,
orthostatic blood pressure responses, thermoregulation, cognitive reserve, and bowel
and bladder function.
 An event resulting in functional impairment may involve an insult for which the body
cannot compensate, and relatively small stresses may result in major morbidity and
mortality.
 A number of age-related physiologic changes occur that potentially could affect drug
pharmacokinetics and pharmacodynamics.

Physiologic Changes with Aging

Organ System Manifestation

Body composition ↓ Total body water
↓ Lean body mass
↑ Body fat
↔ or ↓ Serum albumin
↔ or ↑ α1-Acid glycoprotein (↑ by several disease states)

Cardiovascular ↓ Myocardial sensitivity to beta-adrenergic stimulation

↓ Baroreceptor activity
↓ Cardiac output
↑ Total peripheral resistance

Central nervous system ↓ Weight and volume of the brain

Alterations in several aspects of cognition

Endocrine Thyroid gland atrophies with age

Increase in incidence of diabetes mellitus, thyroid disease
Menopause

Gastrointestinal ↑ Gastric pH
↓ Gastrointestinal blood flow
Delayed gastric emptying
Slowed intestinal transit
Genitourinary Atrophy of the vagina due to decreased estrogen
Prostatic hypertrophy due to androgenic hormonal changes
Age-related changes may predispose to incontinence

Immune ↓ Cell-mediated immunity

Liver ↓ Liver size

↓ Liver blood flow

Oral Altered dentition

↓ Ability to taste sweetness, sourness, and bitterness

Pulmonary ↓ Respiratory muscle strength

↓ Chest wall compliance
↓ Total alveolar surface
↓ Vital capacity
↓ Maximal breathing capacity

Renal ↓ Glomerular filtration rate

↓ Renal blood flow
↑ Filtration fraction
↓ Tubular secretory function
↓ Renal mass

Sensory ↓ Accommodation of the lens of the eye, causing farsightedness

Presbycusis (loss of auditory acuity)
↓ Conduction velocity

Skeletal Loss of skeletal bone mass (osteopenia)

Skin/hair Skin/hair Skin dryness, wrinkling, and changes in pigmentation,

epithelial thinning,
loss of dermal thickness
↓ Number of hair follicles
↓ Number of melanocytes in the hair bulbs
 TOPIC-14

Class-14 Drug therapy for pediatrics continuation, drug therapy for pregnancy and lactation

ALTERED PHARMACOKINETICS

ABSORPTION
 Most drugs are given orally, and thus a number of the age-related changes in
gastrointestinal physiology potentially could affect the absorption of medications.
Fortunately, most drugs are absorbed via passive diffusion, and age-related physiologic
changes appear to have little influence on drug bioavailability.
 A few drugs require active transport for their absorption, and thus their bioavailability
may be reduced.
 However, there is evidence for a decreased first-pass effect on hepatic and/or gut wall
metabolism that results in increased bioavailability and higher plasma concentrations of
drugs such as propranolol and morphine. Increased drug bioavailability also may be seen
with the concurrent ingestion of grapefruit juice.
 Constituents of this product inhibit cytochrome P450 (CYP450) isoenzyme 3A4, thus
decreasing first-pass metabolism and resulting in exaggerated pharmacologic effects.

DISTRIBUTION
 The distribution of medications in the body depends on factors such as blood flow,
plasma protein binding, and body composition, each of which may be altered with age.
For example, the volume of distribution of water-soluble drugs is decreased, whereas
lipophilic drugs will exhibit an increased volume of distribution.
 Changes in the volume of distribution can have a direct impact on the amount of
medication that needs to be given as a loading dose.
 The two major plasma proteins to which medications can bind are albumin and α1-acid
glycoprotein (AAG), and concentrations of these proteins may change with concurrent
pathologies seen with increasing age.
 For acidic drugs such as naproxen, phenytoin, tolbutamide, andwarfarin, decreased
serum albumin may lead to an increase in free fraction. An increase in AAG induced by
burns, cancer, inflammatory disease, or trauma may lead to a decreased free fraction of
basic drugs such as lidocaine, propranolol, quinidine, and imipramine.

METABOLISM
 The liver is the major organ responsible for drug metabolism, including phase I
(oxidative) and phase II (conjugative) reactions.
 The most remarkable characteristic of liver function in the elderly is the increase in
inter-individual variability compared with other age groups, a feature that may obscure
true age-related changes.
  Recent data suggest that age-related declines in phase I metabolism are more likely the
result of reduced liver volume rather than reduced hepatic enzymatic activity.
Decreased phase I metabolism producing decreased drug clearance and increased
terminal disposition half-life (t1/2) has been reported in elders for medications such as
diazepam, piroxicam, theophylline, and quinidine.
 Phase II metabolism of medications such as lorazepam and oxazepam appears to be
relatively unaffected by advancing age. Hepatic enzyme induction or inhibition does not
appear to be affected by the aging process.
 Age-related decreases in liver blood flow also can decrease significantly the metabolism
of high-hepatic-extraction-ratio drugs such as imipramine, lidocaine, morphine, and
propranolol.
 Finally, a number of potential confounding factors, including race, sex, frailty, smoking,
diet, and drug-drug interactions, may affect hepatic metabolism significantly in the
elderly.

ELIMINATION
Renal excretion is the primary route of elimination for many drugs. Although age-related
reductions in glomerular filtration are well documented, as many as one-third of “normal”
elderly subjects may have no reduction, as measured by creatinine clearance.
Medications whose excretion is primarily renal and for which there is evidence of age-related
reduction in renal and total body clearance include (but are not limited to) amantadine,
aminoglycosides, atenolol, captopril, cimetidine, digoxin, lithium, and vancomycin.

Creatinine clearance = (140 – age in years)(actual body weight in kg)

(males) 72(serum creatinine in mg/dL)

Age-Related Changes in Drug Pharmacokinetics.

Pharmacokinetic Pharmacokinetic Parameters

Phase
Gastrointestinal Unchanged passive diffusion and no change in bioavailability for
Absorption most drugs
↓ Active transport and ↓ bioavailability for some drugs
↓ First-pass extraction and ↑ bioavailability for some drugs

↓ Volume of distribution and ↑ plasma concentration of water-

Distribution soluble drugs
↑ Volume of distribution and ↑ terminal disposition half-life
(t1/2) for fat-soluble drugs
↑ or ↓ Free fraction of highly plasma protein bound drugs

Hepatic metabolism ↓ Clearance and ↑ t1/2 for some oxidatively metabolized drugs
 ↓ Clearance and ↑ t1/2 of drugs with high hepatic extraction
ratios
Renal excretion
↓ Clearance and ↑ t1/2 of renally eliminated drugs and active
metabolites

ALTERED PHARMACODYNAMICS

 There is some evidence in the elderly of altered drug response or “sensitivity.”

 Four possible mechanisms have been suggested:
 changes in receptor numbers,
 changes in receptor affinity,
 post receptor alterations, and
 Age-related impairment of homeostatic mechanisms.
 For example, muscarinic, parathyroid hormone, β-adrenergic, α1-adrenergic, and μ-
opioid receptors exhibit reduced density with increasing age.
 Evidence from epidemiologic and experimental studies suggest that, independent of
pharmacokinetic alterations, the elderly are more sensitive to the central nervous
system effects of benzodiazepines.
 The elderly also exhibit a greater analgesic responsiveness to opioids when compared
with their younger counterparts, even when pharmacokinetic parameters are similar in
the two groups.
 In addition, the elderly demonstrate an enhanced responsiveness to anticoagulants such
as warfarin and heparin, as well as thrombolytic therapy.
 In contrast, the elderly exhibit decreased responsiveness to certain drugs (e.g., β-
agonists/antagonists).

CLINICAL GERIATRICS
 Maintenance of independence and prevention of disability are primary goals in the
clinical care of persons 65 years of age or older. To achieve these goals, it is necessary
that all health care professionals understand the concept of functional status.
 One of the challenges of maintaining and improving functional status in geriatric
individuals is recognizing and managing conditions frequently seen in older adults.
Problems found more commonly in older persons sometimes are referred to as the “I’s
of geriatrics”

The I’s of Geriatrics: Common Problems in the Elderly.

Immobility Instability
Isolation Intellectual impairment
 Incontinence Impotence
Infection Immunodeficiency
Inanition (malnutrition) Insomnia
Impaction Iatrogenesis
Impaired senses

 Examples of diseases and syndromes that can present ascommonproblems in the elderly
include
 Parkinson’s disease, falls, hip fractures, benign prostatic hypertrophy, dementia,
glaucoma and tuberculosis.
 Another factor contributing to the challenge of clinical geriatrics is that approximately
50% of older patients present with atypical symptoms or complaints, making it difficult
to use the classic medical model for diagnosis. For example, cardiac ischemia may
present as syncope or weakness in an older person rather than the typical presentation
of chest pain.

Atypical Disease Presentation in the Elderly

Disease Presentation
Acute myocardial Only about 50% present with chest pain. In general, the elderly
infarction present with weakness, confusion, syncope, and abdominal pain;
however, electrocardiographic findings are similar to younger
patients.

Congestive heart failure Instead of dyspnea, the older patient may present with hypoxic
symptoms, lethargy, restlessness, and confusion.

Although the mortality rate is about 10%, presenting symptoms

Gastrointestinal bleed are nonspecific, ranging from mental status change to syncope
with hemodynamic collapse. Abdominal pain is often absent.

Upper respiratory Older patients typically present with lethargy, confusion,

Infection anorexia, and decompensation of a preexisting medical
condition. Fever, chills, and a productive cough may or may not
be present.

Urinary tract infection

Dysuria, fever, and flank pain may be absent. More commonly,
the elderly present with incontinence, confusion, abdominal
pain, nausea/vomiting, and azotaemia.
Multiple coexisting chronic illnesses are another common threat to independence that
distinguishes the elderly from younger patients. It is not unusual for elderly patients to have
multiple comorbidities such as osteoarthritis, heart disease, and diabetes. Although multiple
comorbidities can have a substantial impact on a patient’s functional status, the mere existence
of multiple diseases alone does not determine functional impairment

DRUG THERAPY DURING PREGNANCY

 The greatest concern regarding the use of medications in pregnant women is the
potential risk of abnormal development in the child. Although some drugs have the
potential to cause teratogenic effects, most medications required by pregnant women
can be used safely.
 There are many misconceptions related to the role medications play in causing birth
defects.
 The vast majority of children are born healthy.
 The overall incidence of congenital malformations is approximately 3% to 5%. Although
many people assume that medications play a large role in causing birth defects, it is
estimated that medication exposure accounts for less than 1% of all birth defects.
 Genetic causes are responsible for 15% to 25%, other environmental issues (e.g.,
maternal conditions, infection, and mechanical deformations) account for 10%, and the
remaining 65% to 75% of congenital malformations result from unknown causes.
 Despite the greater potential of harm with certain drugs, not every exposure will result
in a birth defect. Factors such as the stage of pregnancy when the exposure occurred,
the route of administration, and dose all can influence outcomes.
 In the first 2 weeks after conception, exposure to a teratogen may result in an “all or
nothing” effect, which could either destroy the embryo or cause no problems. The
period from 18 to 60 days postconception (organogenesis) is the time when organ
systems are developing, and teratogenic exposures may result in structural anomalies.
 In the remainder of the pregnancy, exposure to teratogenic agents may result in
retardation of growth, central nervous system (CNS) abnormalities, or death.
 Examples of medications associated with teratogenic effects in the period of
organogenesis include chemotherapy drugs (e.g., methotrexate, cyclophosphamide), sex
hormones (e.g., diethylstilbesterol), lithium, retinoids, thalidomide, certain antiepileptic
drugs, and coumarin derivatives.
 Medications such as angiotensin-converting enzyme inhibitors, nonsteroidal anti-
inflammatory agents, and tetracycline derivatives are more likely to exhibit effects in
the second or third trimesters.
 DRUGS NOT TO BE USED IN PREGNANCY

Type Example Problem

1. Antianxiety drug Diazepam When the drug is taken in late pregnancy,

depression irritability, shaking,
exaggerated refluxes in the Newborn

2. Anti biotics Chloramphenicol Grey baby syndrome in women or foetus

with G6-Pd deficiency the breaking down
of RBC

Fluroquinolones, such Posibility of joint abnormalities

as ciprofloxacin,
ofloxacin levofloxacin,
Norfloxacin

Kanamycin Damage to the foetus ear result in

deafness
Streptomycin

Sulfasalazine, When the drugs are used late in

Trimethoprim pregnancy cause jaundice, brain damage
Sulfamethoxazole in new born.
 Tetracyclines Slowered bone growth premature falling
of teeth increased susceptibility to
cavities

3. Anticoagulanls Heparin When the drug is taken for longtime

osteoporosis and decrease in number of
platelets in the pregnant women.

Warfarin Birth defects, bleeding problem in the

foetus and the pregnant women

4. Anticonvulsants Carbamazepine Some risk of birth defects bleeding

problems in new born

Trimethadone Increased risk of miscarriage in women

Valproate Risk of birth defects, cleft palate and

defects of the heart, face, skull, spine

5. Anti-hypertensives ACE inhibitors When the drugs given in late pregnancy,

renal dysfunction & oligohydraminus

Thiazide diuretics Decrease in the level of oxygen, Na+ and

K+ in foetus blood, slow growth.

6. Chemotherapy Actinomycin, Possibility of birth defects

Vinblastine, Vincristine

Busulfan Birth defects such as under development

of the lower jaw, ear defects
Clorambucil

Cyclophosphamide
 Methotrexate

7. Mood stabilizing Lithium Birth defects, lethergy, reduced muscle

drugs tone, under activity of thyroid.

8. Nonsteroidal anti Aspirin and other When the drugs are taken late in
inflammatony drugs salicylates Ibuprofen pregnancy, a reduction in amount of fluid
(NSAIDS) Naproxen around the developing foetus

9. Oral Chlorpropamide When the drug is taken early in

antihyperglycemic pregnancy by a woman with type-2
drugs diabetes, possibility of increased risk of
birth defect.

Tolbutamide Very low level of sugar in blood of new

born, inadequate control of diabetes in
pregnant woman.

10. Sex hormones Danazol When this drug is taken very early in
pregnancy, masculinization of female
Synthetic progestins
fetus genitals, sometimes requiring
surgery to correct.

Diethylstilbestrol Abnormalities of uterus, menstrual

problems and increased risk of vaginal
cancer and complications during
pregnancy in daughter, abnormality of
penis in sons.

11. Skin treatments Etretinate Birth defects such as heart defects, small
ears and hydrocephalus.

Isotretinoin Mental retardation Risk of miscarriage.

12. Thyroid drugs Methimazole. Enlarged or underactive thyroid gland in
the foetus. Scalp defects in newborn.

Propyl thiouracil Enlarged or underactive thyroid gland in

the foetus

Radioactive iodine Destruction of thyroid gland in fetus,

when the drug is given near the end of 1st
trimester, very over active and enlarged
thyroid gland in foetus

Triiodothyronine Overactive and enlarged thyroid gland in

foetus

13. vaccines (live Vaccine for German Potential infection of placenta in

virus) measles (rubella) and developing foetus.
chicken pox (varicella)

Vaccines for measles, Potential but unknown risks.

mumps, polio or yellow
fever

14. Social drugs Alcohol Foetal alcohol syndrome, deformed ribs

and sternum, small head, kidney and
urinary defects, poor body, head and
finger co-ordination, CNS problems,
genital malformations, heart defects,
premature birth if 7 or more drinks per
week are taken.

Caffine Increase Baby’s heart rate, affects

nutrition, decreased iron and calcium
intake, miscarriage (if 80 more cups
 taken)

Smoking Damages reproductive system delayed

anomalies affecting the sex of child,
decrease the semen count in males
resulting in impotency hereditary
problems difficulties in conceiving.

15. Illicit drugs Amphetamine Increase in congenital / heart defects, low

birth weight, Premature birth and
placental problems, club foot in females,
cleft lip & palate is exposed.

Heroin Premature birth and still birth increase in

sudden infants death syndrome (SIDS)

Cocaine Preterm labor, increased risk of

miscarriage, cerebral plasy, small head
and brain. Increased risk of learning
disabilities.

MCQs

1. During pregnancy, the maximum maternal serum concentration of most drugs is essentially
unchanged because

A) serum albumin output is increased.

B) hormones occupy fewer albumin binding sites.

C) more free drug is available in the plasma.

D) most of the increase in totalbody water is distributed to fetal compartments.

2. Drug elimination during pregnancy may be affected by each of the following except

A) increased renal blood flow.

B) decreased biliary clearance.

C) enhanced hepatic metabolism.

D) decreased glomerular filtration rate.

3. The most practical and reliable study design for determining the safety of a drug used during
pregnancy is

A)doubleblind, placebocontrolled trial.

B)animal studies.

C)casecontrolled studies.

D)prospective cohort studies.

4. The preferred regimen for folic acid supplementation for a 16yearold female is

A)folic acid supplement of 400 μg daily.

B)consumption of foods naturally containing folic acid.

C)folic acid supplement of 4000 μg (4 mg) daily.

D)No supplementation is necessary.

5. Antiemetic options for a 26yearold pregnant woman who is 8 weeks postfertilization include
all the following except

A)metoclopramide.
B)doxylamine.

C)prochlorperazine.

D)dicyclomine.

6. Regarding the treatment of hypertension in pregnancy, all the following medications could
be considered except

A)hydralazine.

B)enalapril.

C)labetolol.

D)methyldopa.

7. All the following therapies would be appropriate for the acute treatment of migraine in a
pregnant woman except

A)sumatriptan.

B)codeine.

C)acetaminophen.

D)propranolol.

8. The preferred antibiotic for treatment of an acute cystitis in a pregnant woman in the third
trimester is

A)doxycycline.

B)norfloxacin.

C)nitrofurantoin.

D)trimethoprimsulfamethoxazole.
9. The preferred treatment for a pregnant woman with a positive second trimester screen for
bacterial vaginosis is

A)metronidazole gel intravaginally.

B)clindamycin orally.

C)clindamycin gel intravaginally.

D)metronidazole orally.

10. A firstline treatment option for a pregnant woman at 6 weeks of gestation who has seasonal
allergic rhinitis and no history of drug allergies or adverse drug reactions is

A)loratadine.

B)chlorpheniramine.

C)nasal beclomethasone.

D)oral prednisone.

E)all of the above.

11. Guidelines for drug therapy for epilepsy during pregnancy include

A)supplementation of 100 μg folic acid daily.

B)substitution of phenobarbital for other drugs.

C)use of AED monotherapy if possible.

D)AED withdrawal 1 month prior to attempted conception.

12. The preferred treatment option for a pregnant woman at 35 weeks of gestation presenting
in labor and with a fever of 102ºF is

A)intravenous penicillin.

B)intravenous erythromycin.
C)intravenous clindamycin.

D)intravenous ampicillin.

13. The following antenatal therapy has best evidence for improvement in neonatal outcome of
preterm delivery:

A)magnesium sulfate.

B)terbutaline.

C)beclomethasone.

D)ampicillin.

14. Minimization of a breastfed infant's exposure to maternal medications can be accomplished

by

A)termination of nursing prior to hindmilk ingestion.

B)using shortacting drug dosage forms.

C)ingestion of a medication dose immediately before nursing.

D)all of the above.

15. The following medication would be preferred in a 31yearold mother who is 3 weeks
postpartum and is experiencing postpartum major depression:

A)lithium.

B)trazodone.

C)bupropion.

D)fluoxetine
 CARE TO BE TAKEN BY LACTATING MOTHER IN DRUG USE

 Moderate amount of caffeine (1 cup a day) do not cause any affect but care should be taken
while taking excess of caffine because it may cause sleeping and agitation in baby.

 Alcohol should be avoided while breast feeding because it interferes with milk ejection
reflux. Not more than two ounces of alcohol may be safe.

 Smoking should be stopped. Nicotine and other chemicals from cigarette are found in milk
which will increase number of infections in baby.

 injectables are more preferred than oral drugs as they are not absorbed from stomach
or intestine.
 Topical applications are also safe during lactation and also local anesthetics.
 Carbonated drinks with caffine are avoided.
 Cannabis / marijuana reduce the local prolactin levels reducing the milk supply.
 Paracetamol and ibuprofen are safe.
 Use of Naproxen (NSAIDS) long term use must be avoided.
 Stronger pain medications like codeine, morphine, are used but higher dose should be
avoided
 HIV positive mother can feed baby up to 1 year and can give complementary food.

Drugs that can be used in lactation under

Medical Supervision:

Some drugs require a doctor’s supervision during their use. Taking them safely while
breast feeding may require. Adjusting the dose or limiting the length of time drug is use.
1. Antianxiety drug Diazepam Cause lethargy, drowsiness,
weight loss in breast feed
bodies

2. Anticonvulsants Phenobarbital Causes excessive drowsiness

Drugs that are contraindicated while breast feeding

1. Amphetamine, chemotherapy Should not be taken by mother who are

chloramphenicol, ergotamine, lithium, breast feeding
radioactive drugs, illicit drugs such as
cocaine, heroine and phencyclidine

2. Bromocriptine , estrogen, oral May suppress milk production.

contraceptives progestin and levodopa

3. Smoking Reduces milk production and interferes with

4. Alcohol normal weight gain in the baby drowsy and
the baby may gain excess weight

Drugs that can be safely used during lactation

1. Some drugs do not pass into breast milk Epinephrine, Heparin, Insulin
and thus are safe to take

2. Some drugs pass into breast milk but the Gentamycin, Kanamycin streptomycin
baby absorbs so little of them that they do tetracycline
not affect the baby

3. Drugs that are applied to skin eyes or

nose that are inhaled are usually safe

4. most of anti hypertensives do not cause

significant problems in breast feed babies