1. DR. SHABANA ALI (Associate Professor) FACTORS MODIFYING DRUG ACTONS

2. 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.

3. Psychological /emotional state Interaction with other drugs (drug-drug interactions)

4. 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

5. Infants Premature 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

6. Elderly Renal & hepatic function decline slowly after middle age Activity of hepatic microsomal enzymes decline with age Vd of lipid soluble drugs increases Elderly require less due to degenerative changes in kidney, liver, brain, heart Cont.,

7. E.g., Diazepam & benzodiazepines = t1/2 Digoxin = Vd Benzodiazepines= more confusion & less sedation in elderly Hypotensive dugs= postural hypotension in elderly

8. ii) Sex/Gender Response & dose= d/f in men & women Metabolism of some drugs= less in women (more adipose tissues) E.g., alcohol, diazepam Women require lesser dose than male

9. iii) Pregnancy Avoid drugs during pregnancy due to teratogenic effects Reasons Lipophilic drugs cross placental barrier CO GFR & renal elimination Vd Metabolism of some drugs E.g., pregnant uterus becomes more sensitive to oxytocin

10. iv) Lactation Avoid drugs during lactation due to harm to baby Drugs easily appear in milk but < therapeutic dose E.g., tetracycline, sedatives, hypnotics, opoids

11. V) Body wt./surface area & size Conc. 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

12. vi) food Some 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)

13. Pathological condition modify drug action E.g., impaired renal function = drug excretion = drug accumulation Liver disease= metabolism of drug=accumulation Cont. II. Pathological state

14. Disease can cause pharmacokinetic or pharmacodynamic variation a) PK variation Variation in absorption Gastric statis –in migraine Malbsorption ---ileal or pancreatic disease Cont.

15. Variation in distribution Alterd PPB of phenytoin in chronic renal failure (binding of phenytoin to PPB  Variation in metabolism Hepatic cirrhosis & portal HTN Variation in excretion Acute and /or chronic renal failure

16. Pharmacodynamic alterations Variation in receptors In mysthania gravis, nephrogenic diabetes inspidus, familial hypercholesterolemia

17. 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.

18. 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)

19. IV. Environmental factors Microsomal enzyme inducers e.g., Hydrocarbons in tobacco smoke, charcoal broiled meat induce CYP1A Smokers metabolize drugs more rapidly than non smokers

20. V) Psychological state General 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

21. VI) Interaction with other drugs Administration of one drug (A) can alter action of another drug (B) by PK or PD mechanisms This is c/d drug-drug interaction May be desired or beneficial like multidrug treatment of tuberculosis Or undesirable or harmful