FACTORS MODIFYING DRUG EFFECTS/DRUG VARIATIONS

1. FACTORS MODIFYING DRUG EFFECTS/DRUG VARIATIONS BY Dr. Abdul Latif Mahesar Medical pharmacology King Saud University

2. On administration of a drug ,a predicted response is obtained but some times • Individuals may vary considerably in their responsiveness • Such as: respond differently to drugs both from time to time and from other individuals. • Some would show less than the usual response , and some may show more than usual response Occasionally individuals exhibit unusual response IDIOSYNCRACY

3. Physiological factors AGE: Pregnancy Sex/gender Body weight Food Timings

4. AGE In new born there occurs • Decreases acid secretion • Decreased microsomal enzymes • Decreased plasma protein binding • Decreased G.F.R

5. There is increase in G.I.T absorption in newborns like ampicillin due to decreased acidity. • Tetracyclines produce teeth staining in children • Corticosteroids cause growth and developmental retardation • Antihistamines cause hyperactivity instead of hypoactivity. • These are all different responses than adults

6. Several enzymes are important for drug metabolism , ( hepatic microsomal oxidase, glucuronyl and acetyl transferase) have low activity in neonates • Certain drugs may lead to serious consequences e.g. chloramphenicol causing gray baby syndrome. sulphonamides causing kernicterus • Activity of hepatic microsomal enzyme also decreases with age leading prolonged half life of some drugs elderly people e.g. Benzodiazepines, theophyllines This may lead to accumulation of drug on repeated doses.

7. Drug elimination is less efficient in new born babies , and in old people so that drug produces greater and more prolonged effects at extremes of age .especially drugs which are excreted through kidneys as there is decrease in G.F.R • Tubular function is also diminished. e.g. Normal plasma half life of gentamicin is 1-4 hrs, in babies it is 10 hrs and in premature babies it may be up to 18 hrs. G.F.R declines to 25% ,in person of 50 years of age and 50% in person 75 years of age. • Gentamycin ,Digoxin ,Pencillins are contraindicated in old people.

8. Pregnancy • Causes several physiological changes that influence drug disposition. • Volume of drug distribution is increased(total body water may increase by up to 8 liters) providing large space for water soluble drugs. Maternal plasma albumin concentration is reduced,more free drugs will be available • Metabolic rate is increased, so the free drugs will be available for elimination. • Cardiac out put is increased, leading to increased renal blood flow and glomerular filtration and increased renal elimination of drugs. • Lipophilic molecules readily traverse placental barrier. Drugs that are transferred to fetus are slowly eliminated.

9. Gender Evidences show that men and women may respond differently to same drugs This may be due to body size, and amount of body fats. But there are also some less easily explained differences in gender –specific drug response Aspirin shows greater benefit in men than women in cardiovascular diseases

10. There appears to be difference in the activity of liver enzymes b/w men and women Since the activity of enzymes vary that can result in major difference in drug response This difference in liver activity may explain why women routinely wakes up from general anesthesia several minutes before a man given an equal dose. It has been observed that women with red hair and fair skin are particularly responsive to effects of the analgesic Pentazosine than man of same character.

11. Temperature Addition of mild to moderate hypothermia decreases the systemic clearance of CY450 metabolizes drugs between 7-22% per degree Celsius below 37c during cooling. The addition of hypothermia decreases the potency and efficacy of certain drugs . The therapeutic index of certain drugs is narrowed during hypothermia. Therapeutic hypothermia has shown decrease in neurologic damage in patients experiencing cardiac arrest.

12. Timings It has been observed that endogenous body clock (circadian cycle) may affect the response of the drug. e.g. In CHD(coronary heart dieseases) short acting calcium channel blockers seem to be less effective than beta blockers in reducing ischemic events during the night and early morning

13. Food Presence of fatty food in stomach delays gastric emptying,the plasma concentration of rifampicin and ampicillin may be much reduced if taken on full stomach Calcium in milk interferes with absorption of tetracyclines and iron. Substituting protein for fats and carbohydrates in diet ,increases drug oxidation rates.

14. Charcoal grilled beef, cabbage, alcohol increases metabolism Protein malnutrition affects pharmacokinetics of several drugs. Citrus flavinoids in grape fruit (but not in orange juice) significantly increases absorption of cyclosporin calcium antagonists and probably other drugs

15. PATHOLOGICAL FACTORS • DISEASEScan cause individual variations in drug response. • Pharmacokinetic variations; Absorption: • Gastric and intestinal stasis during an attack of Migraine interferes absorption of drugs • Resection of gut may lead to malabsorption of iron,folic acid and fat soluble vitamins and of vit B12 after ileal resection

16. Diarrhea increases the motility of the gut and decreases absorption. • Hypoalbuminaemia from any cause such as nephrotic syndrome, burn,malnutrition,sepsis allows higher proportion of albumin free drug in plasma which is readily available for metabolism and elimination but there can be risk with initial dose for drugs which are to be highly protein bound

17. Metabolism: • Acute and chronic diseases of liver affects the blood flow and function of hepatocytes ,leading to decreased drug clearance, and prolong half life. • Drug metabolism is increased in hyperthyrodism and diminished in hypothyroidism • Excretion In acute and chronic renal impairment ,concentration of drugs is altered. .

18. Pharmacodynamic variations: • Asthma can be precipitated by beta blocking drugs • Raised intracrainal pressure ,severe pulmonary insufficiency cuases patient to be inttolent to opioids precipitate respiratory failure • Change in receptors (Myasthenia gravis).person becomes intolerant to quinine , quinidine and aminoglycoside • Increased sensitivity of adrenergic receptors in hyperthyroidism.

19. Genetic factors: These are known as idiosyncratic response These are rare but very harmful. • Acetylator status(important for metabolism) • Slow acetylators:( isoniazid causing peripheral neuropathy on standard dose and pyridoxine is added to T.B regime) Rapid acetylators: hepatotoxicity (hepatocellular necrosis)in fast acetylators • Defective carbon oxidation • may cause poor oxidation of some drugs leading to some adverse effects with standard doses of drugs like beta blockers. • Pseudocholine estrase deficiency Failure to rapid inactivation of Suxamethonium, leading to muscular block ,results paralysis.

20. G-6-PD deficiency:( haemolysis by primaquine) G6PD is necessary to maintain reduced glutathione in red cells and to prevent their hemolysis. • This occurs in small portion of people • Such as chloramphenicol causes aplastic anemia 1 in 50,000. • Malignant hyperthermia: caused by suxamethonium in prone person due to inherited abnormality in Ca 2+ release from sarcoplamic reticulum in striated muscles.)

21. Envoirmental and diet: Pollutants are capable of inducing P450 enzymes, such as hydrocarbons present in tobacco smoke, charcoal broiled meat induce CYP 1A. Cigarette smokers metabolize some drugs more rapidly than non smokers. Industrial workers exposed to some pesticides metabolize certain drugs more rapidly than who are non exposed Polychlorinated biphenyls used in industry, cruciferous vegetables also induce CYP 1A Grapefruit juice induce CYP3A

22. Other variations(quantitative ) More common More clinically important Patient may be Hypo reactive: Hyper-reactive: to drug to a given dose Hypersensitivity: allergic or other immunologic responsiveness to drugs e.g. Penicillins

23. Tolerance with some drugs intensity of response to given dose may change during course of therapy, usually decrease in response to continued administration of drug. e.g. Salbutamol (β-adrenergic agonist) Opium ,barbiturates , Alcohol Tachyphylaxis: when responsiveness diminishes rapidly after administration of drug e.g. ephedrine Amphetamine

24. Idiosyncrasy: Is an abnormal genetic response and is usually harmful It occurs in small portion of population. e.g. aplastic anaemia due to chlormaphenicol haemolysis by primaquine in G-6-PD defiency Hepatic porphyria by carbamazipine Malignant hyperthermia by suxamethonium

25. Anaphylaxis • It is an immediate hypersensitivity reaction on exposure to specific antigen leading to life threatening respiratory distress followed by vascular collapse

26. Change in response due to altered drug concentration This may be due to change in rate of absorption ,distribution and elimination of drug. alteration in drug concentration that reaches relevant receptor may alter clinical response . Variation in response may be due to variation in concentration of endogenous receptor ligand ,alteration in number of functional receptors, change in components distal to receptors.

27. variability in response to pharmacologic antagonist as propranolol will markedly slow the heart rate of patient whose endogenous catecholamine are elevated (in pheochromocytoma ) but will not affect the resting H.R of well trained marathon runner A partial agonist SARALACIN at angiotensin II lowers blood pressure in pts with hypertension caused by increase in angiotensin II production and raises blood pressure in patients who produces low amount of angiotensin

28. Alteration in number of receptors there occurs change in responsiveness caused by increase or decrease in number of receptor sites or alteration in efficiency of coupling of receptor to distal effectors mechanism. e.g. 1) Receptors for hormones Thyroid hormones cause increase in number of β-adrenergic receptors and hence increase in cardiac sensitivity to catecholamines ii) Agonist ligand induces a decrease in number( down regulation) or coupling efficiency of its receptors.e.g salbutamol.

29. Before starting a drug therapy clinician should be aware of age general health specially severity and pathologic mechanism of disease. Drug therapy always be most successful when it is accurately directed at pathophysiologic mechanism responsible for disease. even then there may be no benefit due to compensatory mechansim e.g. Vasodilator drug for hypertension leads to reflex tachycardia and sodium retension by kidneys.

30. Drug resistance When drug looses the effectiveness. usually this happens with the improper use of antibacterial drugs

31. Synergism: when two drugs are administered at the same time , the effect increases. Summation: the effect of two drugs having same action are added have aditie effect. e.g. beta blocker + diuretic have additive antihypertensive effect Potenciation: when one drug increases the effect of other drug e.g. levodopa +cabidopa

32. DRUG – DRUG INTERACTION • when one drug is administered, a response occurs, if a second drug is given and response to 1st drug is altered ,a drug interaction is said to have occurred • This may be • Desired or beneficial e.g. Multi drug treatment of T.B Naloxone to treat Morphine overdose • Undesired or hamful

33. Clinically important drug interactions • 1. Drugs that have steep dose response curve and small therapeutic index, small change in concentration at site will lead to substantial changes in effect. e.g. Digoxin , Lithium 2. Drugs that are known enzyme inducers/inhibitors

34. Distribution: altered plasma protein binding ( binding of penytoin in chronic renal failure decreases Impaired blood brain barrier ( infilitration of Penicillin in meningitis increases

35. 3. Drugs that exibit saturable metabolism e.g. Phenytoin , Theophylline 4. Drugs used for prolong period and precise plasma concentration are required e.g. oral contraceptive ,lithium, antiepileptic drugs • Different durgs used to treat same disease e.g. Theophylline, Salbutamol 6. In patients with impaired kidney and liver function 7. In elderly who receive several drugs at the same time

36. PHARMACODYNAMIC INTERACTIONS • Both drugs act at same target site exerting synergism or antagonism • Drugs may act at same or different receptors or process. • eg alcohal + benzpdiazepines (sedation) • Morphine + Naloxone ( to reverse opoid overdose) • Rifampicin + INH ( effective anti TB combination.)

37. PHARMACOKINETIC INTERACTIONS • Drug act remotely from target site to alter plasma concentration e.g. enzyme induction /inhibition interaction may be synergistic or antagonistic. Drug interaction can occur at • out side the body • At site of absorption • During drug distribution • During drug metabolism • During drug excretion. • On receptor or body system.

38. Interaction out side the body • Drugs are added to reservoir or syringes to make drugs soluble they are prepared in salt forms, mixing these drugs may lead to precipitation (incompatibility) • Dilution in reservoir may also lead to loss of stability. • Protamine in zinc may bind with soluble insulin and delay its effects.

39. AT THE SITE OF ABSORPTION • Direct chemical interaction e.g. Antacids + Tetracycline's ,Iron form insoluble complexes ,this can be prevented if drugs are administered at 2hrs apart. • Gut motility: drugs which reduce gastric emtying delay absorption of other drugs e.g anti cholinergics , antidepressants • . • Other than gut : Local anesthetics and adrenaline.

40. Purgatives reduce time spent in small intestine and reduce absorption. • Alteration in gut flora: antimicrobials potentiates ant coagulants by reducing bacterial synthesis of vit.K • Other than gut : Local anesthetics and adrenaline.

41. DURING DISTRIBUTION • Displacement from plasma proteins binding e.g. Sodium valproate displaces Phenytoin Sulphonamides displaces bilirubin ( in neonates) • Displacement from tissue binding sites e.g. Quinidine displaces Digoxin.

42. Interaction during metabolism • Enzme induction: • liver micsrosomal enzymes are induced by a wide variety of drugs and these affect the metabolism of other drugs reducing their concentration and hence effect. • e.g oral contraceptive metabolism is enhanced if Phenytoin is co-administered ,leading to unplanned pregnancy • eg loss of anticougulant effect of Warfarin leading to danger of thrombosis if barbiturates are administered. • chronic use of alcohal shows tolerance to general anesthetics.

43. Enzyme inhibition • Certain drugs inhibit the liver microsomal enzymes ,hence increase the activity of drugs which are to be metabolized by these enzymes. • Eg. Cimetidine potenciates the effects of propranolol ,theophylline, warfarin and others

44. Enzyme inducers. • Phenobarbital • Rifampin • Grisofulvin • Phenytoin • Ethanol • Carbamazepine

45. Enzyme inhibitors • Phenylbutazone • Metronidazole • Cimetidine • Omperazole

46. Interaction during excretion • this occurs in kidney • by latering binding and hence filtration • by inhibitin tubular secretion • eg probenecid and pencillins • by latering urine flow and or urine PH.

47. Haemodynamic flow • variation in heaptic blood flow may influence the rate of inactivation of drugs as in reduced cardiac out put. • drugs which reduce cardiac out put like Propranolol may reduce the metabolism of other drugs.