FACTORS MODIFYING DRUG EFFECTS BY Dr. Abdul Latif Mahesar Medical pharmacology King Saud University 2008

2 Individuals respond differently to drugs both from time to time and from other individuals. Individuals respond differently to drugs both from time to time and from other individuals. Some would show less than the usual response, most would show the unusual response Some would show less than the usual response, most would show the unusual response and some would show more than usual response and some would show more than usual responseFACTORSPhysiologicalPathologicalGeneticEnvironmental

3 PHYSIOLOGICAL FACTORS: AgeSexPregnancy Body weight PATHOLOGICAL FACTORS Diseases of liver and kidney Malnutrition GENETIC FACTORS Slow acetylators Fast acetylators G-6-phosphate dehydrogenase deficiency Deficiency of pseudocholinestrase Malignant hyperthermia ENVOIRNMENTAL FACTORS Smoking SmokingAlcohol

4 AGE In new born there is Decreases acid secretion (gastric secretion ) Decreased microsomal enzymes (glucuronyltransferase) Decreased plasma protein binding Decreased G.F.R and tubular secretions Immature blood brain barrier.

5 Due decreased gastric acidity absorption of ampicillin and amoxicillin is greater in neonates. Tetracyclines produce teeth staining in children Tetracyclines produce teeth staining in children Corticosteroids cause growth and developmental retardation Antihistamines cause hyperactivity instead of hypoactivity.

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 Certain drugs may lead to serious consequences chloramphenicol causing gray baby syndrome. chloramphenicol causing gray baby syndrome. sulphonamides causing kernicterus sulphonamides causing kernicterus Activity of hepatic microsomal enzyme also Activity of hepatic microsomal enzyme also decreases with age leading prolonged half life of decreases with age leading prolonged half life of some drugs. some drugs. Benzodiazepines, theophyllines Benzodiazepines, theophyllines This may lead to accumulation of drug on repeated doses. 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 GFR is reduced. Tubular function is also diminished. 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. 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. G.F.R declines to 25%,in person of 50 years of age and 50% in person 75 years of age. gentamycin,Digoxin,pencillin are contraindicated in old people.

8 PREGNANCY: PREGNANCY: causes several physiological changes that influence drug disposition. Volume of distribution is increased Metabolic rate is increased due to placenta. Metabolic rate is increased due to placenta. Maternal plasma albumin concentration is reduced Maternal plasma albumin concentration is reduced Cardiac out put is increased, leading to increased renal blood flow and glomerular filtration and increased renal elimination of drugs. 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. Lipophilic molecules readily traverse placental barrier. Drugs that are transferred to fetus are slowly eliminated.

9 Sex Sex Testosterone increases the rate of metabolism in males benzodiazepines decrease metabolism of some drugs in females benzodiazepines decrease metabolism of some drugs in females females are more susceptible to autonomic drugs drugs ( estrogen inhibits choline estrase) females are more susceptible to autonomic drugs drugs ( estrogen inhibits choline estrase) Body weight People with more weight and larger body surface require larger dose of the drug to produce required therapeutic effect.

10 PATHOLOGICAL FACTORS Certain diseases of kidneys,liver and other systems can cause individual variations in drug response. Certain diseases of kidneys,liver and other systems can cause individual variations in drug response. Pharmacokinetic variations; Pharmacokinetic variations; Changes in Absorption: Gastric stasis (Migraine) Malabsorption (Pancreatic insufficiency) Drug absorption is incomplete in pts with malabsorption, edema of ileal mucosa due to heart failure or nephrotic syndrome.

11 In nephrotic syndrome plasma albumin is reduced, this alters disposition and protein binding In nephrotic syndrome plasma albumin is reduced, this alters disposition and protein binding Diarrhea increases the motility of the gut and decreases absorption. Diarrhea increases the motility of the gut and decreases absorption.

12 Distribution: altered plasma protein binding ( binding of penytoin in chronic renal failure decreases Impaired blood brain barrier ( infiltration of Penicillin in to meningitis increases Impaired blood brain barrier ( infiltration of Penicillin in to meningitis increases

13 Metabolism: of drugs is decreased in Chronic liver disease,altering of drugs is decreased in Chronic liver disease,altering the drug effects the drug effects Excretion: Acute and chronic renal failure,concentration of drugs is altered. Acute and chronic renal failure,concentration of drugs is altered. Hypothermia reduces clearance of many drugs in elderly. Hypothermia reduces clearance of many drugs in elderly.

14 Pharmacodynamics variations: Change in receptors (Myasthenia gravis) Increased sensitivity of adrenergic receptors in hyperthyroidism. receptors in hyperthyroidism.

15 Genetic factors: Acetylator status ( to isoniazid causing peripheral neuropathy) Acetylator status ( to isoniazid causing peripheral neuropathy) hepatotoxicity in fast acetylators hepatotoxicity in fast acetylators Defective carbon oxidation Defective carbon oxidation Pseudocholine estrase defeciency Failure to rapid inactivation of Suxamethonim, leading to muscular block,results paralysis. G6PD deficiency: ( haemolysis by primaquine) G6PD is necessary to maintain reduced glutathione in red cells and to prevent their hemolysis. G6PD deficiency: ( haemolysis by primaquine) G6PD is necessary to maintain reduced glutathione in red cells and to prevent their hemolysis.

16 Hepatic porphyria Hepatic porphyria Polymorphism Polymorphism Malignant hyperthermia: (by suxamethonium due to inherited abnormality in Ca 2+ release from sarcoplamic reticulum in striated muscles.) Malignant hyperthermia: (by suxamethonium due to inherited abnormality in Ca 2+ release from sarcoplamic reticulum in striated muscles.)

17 Envoirmental and diet: Envoirmental and diet: Pollutants are capable of inducing P450 enzymes, such as hydrocarbons present in tobacco smoke, charcoal broiled meat induce CYP 1A. Polychlorinated biphenyls used in industry, cuciferous vegetables also induce CYP 1A Polychlorinated biphenyls used in industry, cuciferous vegetables also induce CYP 1A grapefruit juice induceCYP3A grapefruit juice induceCYP3A Cigrate smokers metabolise some drugs more rapidly than non smokers. Cigrate smokers metabolise some drugs more rapidly than non smokers. Industrial workers exposed to some pesticides metabolisze certain drugs more rapidly than who are non exposed. Industrial workers exposed to some pesticides metabolisze certain drugs more rapidly than who are non exposed.

18 DRUG – DRUG INTERACTION when one drug is administered, a response occurs, if a second drug is given and response to 1 st drug is altered,a drug interaction is said to have occurred when one drug is administered, a response occurs, if a second drug is given and response to 1 st 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 e.g. Multi drug treatment of T.B Naloxone to treat Morphine overdose Naloxone to treat Morphine overdose Undesired or harmful Undesired or harmful

19 Clinically important drug interactions 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

20 3. Drugs that exibit saturable metabolism e.g. Phenytoin, Theophylline e.g. Phenytoin, Theophylline 4. Drugs used for prolong period and precise plasma concentration are required e.g. oral contraceptive,lithium, antiepileptic drugs e.g. oral contraceptive,lithium, antiepileptic drugs 5. 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 7. In elderly who receive several drugs at the same time

21 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) eg alcohal + benzpdiazepines (sedation) Morphine + Naloxone ( to reverse opoid overdose) Rifampicin + INH ( effective anti TB combination.)

22 PHARMACOKINETIC INTERACTIONS Drug act remotely from target site to alter plasma concentration Drug act remotely from target site to alter plasma concentration e.g. enzyme induction /inhibition interaction may be synergistic or antagonistic. interaction may be synergistic or antagonistic. Drug interaction can occur at 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. On receptor or body system.

23 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) 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. Dilution in reservoir may also lead to loss of stability. Protamine in zinc may bind with soluble insulin and delay its effects. Protamine in zinc may bind with soluble insulin and delay its effects.

24 AT THE SITE OF ABSORPTION Direct chemical interaction 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 Gut motility: drugs which reduce gastric emtying delay absorption of other drugs e.g anti cholinergics, antidepressants e.g anti cholinergics, antidepressants.Other than gut : Local anesthetics and adrenaline.

25 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 Alteration in gut flora: antimicrobials potentiates ant coagulants by reducing bacterial synthesis of vit.K Other than gut : Local anesthetics and adrenaline.

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

27 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. 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 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. 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. chronic use of alcohal shows tolerance to general anesthetics.

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

29 Enzyme inducers. Phenobarbital Phenobarbital Rifampin Rifampin Grisofulvin Grisofulvin Phenytoin Phenytoin Ethanol Ethanol Carbamazepine Carbamazepine

30 Enzyme inhibitors Phenylbutazone Phenylbutazone Metronidazole Metronidazole Cimetidine Cimetidine Omperazole Omperazole

31 Interaction during excretion this occurs in kidney this occurs in kidney by binding at glomeruli and hence by pass filtration by binding at glomeruli and hence by pass filtration by inhibitin tubular secretion by inhibitin tubular secretion eg probenecid and pencillins eg probenecid and pencillins by changing urine PH. by changing urine PH.

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