Drug-drug Interaction fggffggggIIyr.ppt.pdf
- 1. Drug-drug Interactions Drug interaction results from the use of two or more drugs. Interaction can occur when a drug is added to or withdrawn from a previously stable therapeutic regimen resulting alteration of pharmacokinetic as well as pharmacodynamic properties of individual drug. This may lead to enhanced or diminished effect and occur at many different site. While such an interaction may be therapeutically beneficial occasionally, in many instances it may result in adverse effects. About 7% of all adverse drug reactions are estimated to be due to drug interactions, and account for approximately one third of mortality of such patients. The elderly are more prone to such reactions.
- 2. Classification of interactions • Pharmaceutical interactions • Pharmacokinetic interactions • Pharmacodynamic interactions
- 3. Pharmacokinetic interactions • This is due to the modification of the action of the body on drugs. Such interaction occur when one agent changes the plasma concentration and bio-availabity of another drug as a consequence of alteration of its absorption, distribution, metabolism and excretion. The interaction can be anticipated but their extent cannot be predicted because there are marked individual variations in there pharmacokinetic properties.
- 4. Drug Absorption Interactions • One drug may retard the rate and extent of absorption of another drug variety of ways. Alteration of rate is significant for only short plasma half life ( procainamide) and when quick action is required like analgesic , hypnotics. • Mechanisms • Intraluminal binding or chelation of drugs: • Chelation- Iron-tetracycline, Al, Mg, Ca containig antacids and Tcs • Adsorption-Kaolin, charcoal ,cholestyramine- digitalis, Sural fate-phenytoin, liquid paraffin-fat soluble vitamins.
- 5. Absorption Mechanisms • Gastrointestinal motility and transit time- Most drugs absorbed from the first part of the small intestine and the rate of gastric emptying time will influence their rate. Drugs such as opiates, anticholinergic, TCA, Anti H1, phenothiazines slows motility where as prokinetics-metoclopramide, domperidone, cholinergics increases. Such interaction is important for antibiotics and analgesics. Metoclopramide & analgesics benificial in acute attack of migraine. • Alteration in the pH of gastrointestinal fluids- Basic drugs are ionized, become less lipid soluble and are poorly absorbed in acidic medium , whereas reverse is true for acidic drugs in alkaline medium.
- 6. • Antacids with aspirin, barbiturates, warfarin. • H2 blockers and proton pump inhibitor with ketoconazole • Alterations in gut bacterial flora: Broad spectrum antibiotics , cephalosporins and erythromycin adversely affect the gut bacterial flora and may affect the action of many drugs-sulphasalazine activated, l-dopa converted to dopamine, digoxin partly metabolised, vitamine K synthesise and neutralise oral anticoagulant, enterohepatic cycling of female sex hormone product of oral contraceptive by gut flora- interaction accordingly.
- 7. Absorption mechanism • Mucosal damage: The long term use of drugs likely to induce gut mucosal damage such as neomycin, colchicine, phenformin, mefenamic acid and cytotoxic agents, can impair the absorption of other drugs, particularly those which are normally poorly absorbed like digoxin, phenytoin. Colchicine can induce pernicious anaemiaby interfering with vit B12 absorption. • Competition for active absorption: • Other Mechanisms: Corticosteroid reduce calcium, Phenobarbitone reduce griseofulvin, phenytoin and nitrofurantoin reduce folic acid absorption.
- 8. Drug Distribution Interactions • One drug may alter the distribution of another and thereby affect the concentration of the unbound active drug at the site of action. Plasma protein binding displacement: The majority of acidic drugs are transported partially bound to plasma proteins. The free drug exists in equilibrium with the bound drug and available for action. Displacement of bond drug by high afinity other drug cause toxicity. a. Anticoagulants displaced by phenylbutazone, indomethacin, phenytoin, clofibrate,. Sulphonamides. b. Oral hypoglycemics by phenylbutazone, indomethacin, anticoagulants, sulphonamides
- 9. Distribution interactions • c. Phenytoin by phenylbutazone, indomethacine. • d. Digoxin by quinidine, nifedipine,. verapamil, amiodarone. • e. Primaquine by mepacrine • f.Methotrexate by salicylates, sulphonamides salicylate also decrease renal clearance of methotrexate by competition with anion secretary carrier. • g. Displacement of bilirubin from albumin by metabolites of chloralhydrate, aspirin , sulphonamide.
- 10. Drug Metabolism Interactions • Among the major sites for drug interactions are the hepatic drug-metabolizing microsomal enzymes. One drug may interfere with the metabolism of another drug by either inducing or inhibiting these enzymes • a. Enzyme induction: Some drugs and environmental chemicals stimulate drug metabolism through induction of hepatic microsomal enzymes.They bind to the cytosolic receptors in the hepatic endoplasmic reticulum to activate the production of mono-oxygenase affecting mainly fast inactivated drugs. Enzyme induction is slow process and reversible with withdrawal inducing agents causing toxicity of stable regimen.
- 11. Enzyme induction interactions • Target drug Enzyme inducer Effect • O contraceptives Rifampicin conception • O anticoagulants Rifampicin, phenobarbitone, reduce • phenytoin, carbamazepine, activity, • griseofulvine etc toxicity on withdr • Phenytoin carbamazepine R. effect • L-dopa pyridoxine R. effect • O.hypoglycemic, Rifampicin. Phenobarbitone, R.effect • Corticosteroids, phenytoin • Digoxin, digitoxin • Diazepam smoking R. effect • Paracetamol Rifampicin Toxicity due to • metabolites
- 12. Metabolism interactions b. Enzyme inhibition: One drug may inhibit the metabolism of another drug leading to an increase in circulating levels of the active drug causing prolongation, exaggeration and risk of toxicity. Ketoconazole and grape juice (food)inhibit CYP3A sub family specifically (4)- enhance activity of terfenadine (ventricular tachycardia), cyclosporine, nifedipine, midazolam. CYP1A subfamily inhibited quinolines, fluvoxamine-enhance activity of theophyline, caffeine, ondansetron, paracetamol, tacrine etc. CYP2 family specifically C9 inhibited by sulphaphenazole enhance tolbutamide, phenytoin- D6 by quinidine enhance TCA, codeine, clozapine, debrisoquine, metoprolol, dextromethorphan etc
- 13. Enzyme inhibition interactions • Xanthine oxidase inhibited by allopurinol enhance mercaptopurine, azathioprine etc. • Aldehyde dehydrogenase inhibited by disulfiram, metronidazole, chlorpropamide, talbutamide, nitrofurantoin enhance accumulation of acetaldehyde from alcohol. • UDP glucoronyl transferase inhibited by naproxene, clofibrate, ketotifen enhance morphine, benzodiazepines. • Haemodynamic effects: CO reducer reduce metabolism of fast metabolizing agents.
- 14. Enzyme inhibition interactions • Target drug Enzyme inhibitor Effect • Anticoagulants Pbz, cimetidine, metroni toxicity • chloramphenicol • O. hypoglycemic Pbz, Chloram, sulpha toxicity • Phenytoin INH, pbz, chlora, cime toxicity • Diazepam, • Theophyline, • Lognocain, morphine Cimetidine toxicity • Propranolol, • Encamide Cimetidine Reduced effect • metabol are active • Azothiprine, • Mercaptopurine Allopurinol toxicity
- 15. Drug Excretion Interactions • One drug may affect the renal excretion of another by affecting urinary pH, glomerular filtration, tubular reabsorption and tubular secretion. • a. Competition for renal tubular secretion: Probenicid, sulphinpyrazone, pbz, sulphonamides, aspirin, indomethacin, thiazides reduce excretion of penicillin, azidothymidine, indomethacin • Verapamil, amiodarone, quinidine reduces digoxin • Diuretics reduces lithium. • Indomethacin reduces frusemide. • Aspirin, NSAIDs reduce methotrexate.
- 16. • b. Altering in urine pH/ flow • The excretion of acidic drugs such as warfarin, barbiturates, pbz, salicylates, sulphonamides, streptomycin enhanced by alkaline urine • The excretion of basic drugs atropine, ephidrine, amphetamine, chloroquine, mepacrine,pethidine is greater in acidic urine and reverse is true for reabsorption. • c. Change of filtration by altering protein binding. • d. Change in hepatic blood flow/ CO.
- 17. Pharmacodynamic Interactions • Interactions manifested due to modification of action of drugs on the body, as reflected in a changes caused by one drug in the sensitivity or responsiveness of the tissue to another when drug which act at the same site or on the same physiological system. • 1. Interaction at pharmacological receptor: • a. Agonist-antagonist interactions: morphine-pentazocin, naloxone; beta blocker-salbutamol;dtc-succnylcholine. • b. Drug synergism: combination of sedatives; alcohol-diazepam,H1 antagonist, phenothizines, barbiturates, clonidine, methyldopa; eps and irreversible dementia by lithium-haloperidol, alpha methyldopa
- 18. • Alpha methyldopa-haloperidol; atreoventricular conduction block by beta blocker-calcium ch. Blocker; potentiation of NMJ blocker by verapamil. • 2. Interaction between drugs acting on the same physiological system: These may result both synergism and antagonism. Aspirin potentiate warfarin; aminoglycoside potentiate NMJ blocker, frusemide potentiate ototoxicity of aminoglycosides; ethanol potentiate antihypertensive; NSAIDS inhibit antihypertensive; antibiotics, aspirin potentiate warfarin. • Sulphonamides –trimethoprim.
- 19. 3. Interactions due to changes in fluid and electrolyte balance • Induced changes in electrolytes may alter the actions of some drugs mainly acting on heart, kidney, NMJ. • Potassium depletion caused by diuretics potentiates the action of digitalis and induces toxicity; • Hypokalaemia antagonise antiarrhythmic activity of phenytoin, lignocain, quinidine, procainamide and prolong d-tubocurarine. • Hyperkalaemia induced by spiranolactone, captopril, NASAIDs, particularly impaired renal function attenuate digitalis. • Lithium toxicity with thiazide diuretics/aspirin due to re-entry of Li exchange with sodium and PG dependent inhibition of Li excretion
- 20. 4. Interactions due to alterations in cellular transport. • One drug may interfere with the uptake and transport of another drug to intracellular sites of action. • TCA, phenothiazines attenuate intracellular uptake of guanethedine, debrisoqine, clonidine and reducing effect. Uptake inhibitors also inhibit indirectly acting sympathomimetics like amphetamine, ephedrine, phenylephrine. • These indirectly acting agents also interfere guanethidine and related drugs by competing uptake process.
- 21. 5. Interactions due to other Pharmacodynamic mecha • Interfering compensatory mechanism- beta blocker potentiate oral hypoglycemics and overdose of isulin. • Corticosteroids attenuate antihypertensives (vasodilators) and oral hypoglycemics. • MAO inhibitors potentiate indirectly acting sympathomimetics and tyramine containig Cheese. • Mutual antagonism of bacteristatic and cidal agents.