This document discusses factors that influence individual variability in drug response and how they should guide dosing for patients. It covers differences in pharmacokinetics and pharmacodynamics based on age, organ function, genetics and other personal characteristics. Key points include how drug metabolism and excretion vary with age due to changes in liver, kidney and body composition. Dosing should be adjusted based on these patient-specific factors to ensure safety and efficacy of treatment.

1. Dr. Siddhartha Dutta
MAMC, New Delhi

2. (1) Individuals differ in pharmacokinetic handling of drugs: attain
varying plasma/target site concentration of the drug.
This is more marked for drugs disposed by metabolism (e.g.
propranolol) than for drugs excreted unchanged (e.g. atenolol).
(2) Variations in number or state of receptors, coupling proteins or other
components of response effectuation
(3) Variations in neurogenic/hormonal tone or concentrations of specific
constituents, e.g. atropine tachycardia depends on vagal tone,
propranolol bradycardia depends on sympathetic tone, captopril
hypotension depends on body Na+ status.

3. A multitude of host and external factors influence drug response
Genetic and non genetic including all environmental, circumstantial
and personal variables
Their understanding can guide the choice of appropriate drug and dose
for an individual patient
Final adjustments have to be made by observing the response in a
given patient on a given occasion

4. 1. Quantitatively --The plasma concentration and/ or the action
of the drug is increased or decreased. Most of the factors
introduce this type of change and can be dealt with by
adjustment of drug dosage
2. Qualitatively- The type of response is altered, e.g. drug
allergy or idiosyncrasy. This is less common but often
precludes further use of that drug in the affected patient.

5. 1. Body size
2. Age
3. Sex
4. Pregnancy
5. Species and race
6. Genetics

7. Influences the concentration of the drug attained at the site of action
The average adult dose refers to individuals of medium built
For exceptionally obese or lean individuals and for children dose may
be calculated on body weight (BW) basis:
Individual dose =BW (kg)/70 x average adult dose
Body surface area (BSA) provides a more accurate basis for dose
calculation, because total body water, extracellular fluid volume and
metabolic activity are better paralleled by BSA
Individual dose = BSA (m2 )/1.7 x average adult dose

10. Prescriber should know the form in
which the drug will be dispensed and
provide proper instruction to
pharmacist and parent
Many drugs prepared for children are
in the form of elixirs and suspensions
Doses should always be given after
calculating using body weight/ age of
the child.

11. Infants and children are not small adults [Physiologically different]
Newborn has low G.F.R and tubular transport is immature
Drugs excreted by glomerular filtration(gentamicin) and tubular
secretion (penicillin) is prolonged by 3 to 5 times
Hepatic drug metabolizing system is inadequate in newborns –
Chloramphenicol(gray baby syndrome)
Blood-brain barrier is more permeable-drugs attain higher concen-
tration in the CNS (accumulation of unconjugated bilirubin causes
kernicterus)

12. Lower gastric acidity and slower intestinal transit -Drug absorption is
altered in infants
Transdermal absorption however, is faster because their skin is thin
and more permeable
Solid dosage forms and aerosol inhalations are difficult to administer
to young children
After the first year of life, drug metabolism is often faster than in
adults, e.g. theophylline, phenytoin, carbamazepine t 1/2 is shorter in
children

13. Children are growing and are susceptible to special adverse effects of
drugs, e.g.
Suppression of growth can occur with corticosteroids
Androgens may promote early fusion of epiphysis(stunting)
Tetracyclines deposited in growing teeth and discolour/ deform them
Dystonic reactions to phenothiazine are more common in children
Infant doses must be learned as such and not derived

17. Age-related physiologic changes make the elderly susceptible to
adverse effects
Understanding the influence these changes have on the
pharmacokinetics and pharmacodynamics of the elderly is essential to
prevent harm
Renal function progressively declines (intact nephron loss) - 25% at 50
years and - 50% at 75 year compared to young adults
Elderly are also likely to be on multiple drug therapy for HTN, DM,
Arthritis, etc which increases many fold the chances of drug
interactions

18.  Physiologic change
 Decreased gastric acidity
 Decreased gastrointestinal blood flow
 Delayed gastric emptying
 Slowed intestinal transit time
 General clinical effect
 None on passive diffusion or bioavailability for most drugs
 Decreased active transport: Decreased bioavailability
 Decreased first-pass effect: Increased bioavailability
 Special considerations
 Antacids decrease absorption of acidic drugs: digitalis, phenytoin,
tetracycline
 Anticholinergics: Slow GI motility and absorption rate

19.  Decreased Total body water
 Decreased Volume Distribution
 Increased Plasma Conc. of water soluble drugs
 Lower doses are required: Lithium, digoxin, ethanol, etc
 Decreased Lean body mass and Increased body fat
 Increased Volume Distribution, Longer (t½) of water soluble drugs
 Accumulation into fat of lipid soluble drugs: Bzd, etc
 Decreased Serum Albumin
 Increased unbound fraction of highly protein bound drugs
 Binds acidic drugs: warfarin, phenytoin, digitalis, etc
 Decreased Alpha 1 Acid glycoprotein
 Increased unbound fraction of highly protein bound drugs
 -Binds basic drugs: lidocaine and propranolol, etc

20. Aging Effect Vd Effect Examples
 body water  Vd for hydrophilic
drugs
ethanol, lithium
 lean body mass  Vd for for drugs that
bind to muscle
digoxin
 fat stores  Vd for lipophilic drugs diazepam, trazodone
 plasma protein (albumin)  % of unbound or free
drug (active)
diazepam, valproic acid,
phenytoin, warfarin
 plasma protein
(1-acid glycoprotein)
 % of unbound or free
drug (active)
quinidine, propranolol,
erythromycin, amitriptyline

21.  Determined primarily by hepatic function and blood flow
 Capacity of the liver to metabolize drugs does not appear to decline
consistently with age for all drugs
 For drugs with extensive first-pass metabolism, bioavailability may increase
because less drug is extracted by the liver
 Decreased liver mass
 Decreased liver blood flow
 Examples: morphine, meperidine, metoprolol, propranolol, verapamil,
amitryptyline, nortriptyline

22.  Determined
 Primarily by renal function
 Declines with age and is worsened by co-morbidities
 Decline is not reflected in an equivalent rise in serum creatinine since creatinine
production is reduced due to lower muscle mass
 Physiologic change
 Decreased GFR
 Decreased renal blood flow
 Decreased renal mass
 General clinical effect
 Decreased clearance, Increased (t½) of renally eliminated drugs

23.  Renal blood flow, GFR, tubular secretion decrease with age above 55 years.
 Creatinine clearance (CrCl) is used to estimate GFR
 Serum creatinine alone not accurate in the elderly
  lean body mass  lower creatinine production
  glomerular filtration rate
 Serum creatinine stays in normal range, masking change in creatinine clearance
 Creatinine clearance = (140-age) x wt (kg)
72 x S. Cr in mg/dl
For female it should be multiplied with 0.85

24.  Pharmacodynamic changes in the elderly have been less extensively
studied
 Evidence of enhanced end-organ responsiveness or “sensitivity” to
medications with aging
 Enhanced “sensitivity” may be due
 Changes in receptor affinity
 Changes in receptor number
 Post-receptor alteration
 Age-related impairment of homeostatic mechanisms Example: decreased
baroreceptor reflexes

25.  Drugs that act on the CNS appear to produce an exaggerated response than
that expected from their plasma concentration
 Old people are more sensitive to the respiratory effect of opioid analgesic
because of age related respiratory changes
 Baroreceptor sensitivity reduced– more risk of orthostatic hypotension with
antihypertensive drugs
 Response to β adrenoreceptor agonist and antagonist reduced because of
smaller number of receptor and reduced affinity for adrenoreceptors
 Prostatism in elderly males, even mild anticholinergic activity of the drug can
accentuate bladder voiding difficulty

26.  CNS drugs
 Sedative-hypnotics: Benzodiazepines and barbiturates
 Analgesics: Opioids
 Antipsychotic, antidepressants: Haloperidol, lithium, TCAs
 Cardiovascular drugs
 Antihypertensives: Thiazides, beta-blockers
 Antiarrhythmic drugs
 Quinidine and procainamide:  clearance and  (t½)
 Antimicrobial drugs
 Beta-lactams and aminoglycosides:  clearance
 Anti-inflammatory drugs
 NSAIDs: GI bleed and irritation

27.  Positive relationship between number of drugs taken and incidence of ADR
 Overall incidence is estimated to be at least twice that in the younger
population
 Prescribing errors
 Polypharmacy
 Drug interactions with other prescriptions
 Unawareness of age related physiologic changes
 Drug usage errors
 “Hidden ingredients”: OTCs

28.  There are several practical obstacles to compliance that the prescriber must
recognize
 Forgetfulness
 Prior experience
 Physical disabilities
 Recommendations to improve compliance
 Take careful drug history
 Prescribe only for a specific and rational indication
 Define goal of drug therapy
 High index of suspicion regarding drug reactions and interactions
 Simplify drug regimen