DR. SHABANA ALI

(Associate Professor)

FACTORS MODIFYING DRUG ACTONS

FACTORS MODIFYING DRUG ACTIONS

Individuals vary in drug effect from time to time & from other individuals

Nature of systemic effects of drugs depends on following factors:Physiological factors (age, sex, pregnancy, lactation, body wt., food)Pathological state (kidney or liver disease)Environmental factors

cont.

Psychological /emotional state

Interaction with other drugs (drug-drug interactions)

I. Physiological factors

i) Age Extreme of age show extreme drug

sensitivity Newborn babies & elderly= greater &

more prolonged effect of drugs b/c of less efficient drug metabolism & renal functions

InfantsPremature infants= poor renal & hepatic

functions more sensitive to various drugs

E.g., Chloramphenicol = Gray baby syndrome

(inadequate metabolism) Ampicillin & morphine = GIT

absorption (less acidity) Tetrycycline = staining of teeth Corticosteroids = retardation of growth in

children

ElderlyRenal & hepatic function decline

slowly after middle ageActivity of hepatic microsomal

enzymes decline with ageVd of lipid soluble drugs increasesElderly require less due to

degenerative changes in kidney, liver, brain, heart

Cont.,

E.g., Diazepam & benzodiazepines = t1/2 Digoxin = Vd

Benzodiazepines= more confusion & less sedation in elderly

Hypotensive dugs= postural hypotension in elderly

ii) Sex/GenderResponse & dose= d/f in men &

womenMetabolism of some drugs= less in

women (more adipose tissues)E.g., alcohol, diazepam Women require lesser dose than

male

iii) PregnancyAvoid drugs during pregnancy due to

teratogenic effectsReasonsLipophilic drugs cross placental barrier CO GFR & renal elimination VdMetabolism of some drugs

E.g., pregnant uterus becomes more sensitive to oxytocin

iv) LactationAvoid drugs during lactation due to harm to

babyDrugs easily appear in milk but <

therapeutic dose

E.g., tetracycline, sedatives, hypnotics, opoids

V) Body wt./surface area & sizeConc. Of drug at site of action=ratio b/w

body wt. & amount of drug

D/f quantity of drug for light & heavier persons

D/f quantity of drug for smaller & larger persons

Low amount of drug for smaller perosns

vi) foodSome drugs have interaction with food and

they alter the response of drug

E.g., toxic symptoms appear after eating of cheese, red wine & chicken liver if patient is taking MAOI (more release of NA=fatal cerebral hemorrhage)

Pathological condition modify drug action

E.g., impaired renal function = drug excretion = drug accumulation

Liver disease= metabolism of drug=accumulation

Cont.

II. Pathological state

Disease can cause pharmacokinetic or pharmacodynamic variation

a) PK variation Variation in absorption

Gastric statis –in migraineMalbsorption ---ileal or pancreatic disease

Cont.

Variation in distributionAlterd PPB of phenytoin in chronic renal

failure (binding of phenytoin to PPB

Variation in metabolismHepatic cirrhosis & portal HTN

Variation in excretionAcute and /or chronic renal failure

Pharmacodynamic alterationsVariation in receptorsIn mysthania gravis, nephrogenic

diabetes inspidus, familial hypercholesterolemia

III. Genetic factors It affects drug action due to genetic differences

among the races & certain persons in same population

Genetic variation is an important source of PK variability

Examples:

a) Genetic polymorphism= fast/slow acetylators (hydralazine, procainamide, isoniazid)

Cont.

Plasma choline estrase variant (suxamethonium)

Hydrooxylase polymorphism (extensive or poor metabolism of debrisoquine)

Ethnic differences in drug metabolism = propranolol, hemolytic anemia due to some oxidizing agents (primaquine, sulphonamides)

IV. Environmental factorsMicrosomal enzyme inducers

e.g., Hydrocarbons in tobacco smoke, charcoal broiled meat induce CYP1A

Smokers metabolize drugs more rapidly than non smokers

V) Psychological stateGeneral anesthetics required in

dose for nervous & anxious patients

Higher doses of chlorpromazine needed in schizophrenics

Placebos (inert dosage form) produce therapeutic benefits in psychomotor angina pectoris & bronchitis in asthma

VI) Interaction with other drugs

Administration of one drug (A) can alter action of another drug (B) by

PK or PD mechanismsThis is c/d drug-drug interactionMay be desired or beneficial like

multidrug treatment of tuberculosisOr undesirable or harmful