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
6.
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
8.
9.
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
14.
15.
16.
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