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Drugs Interactions.ppt
- 1. 1 DRUG –DRUG INTERACTIONS Dr.A.Prakash
- 2. 2 DRUG – DRUGINTERACTION • When one drug is administered, a response occurs, if a second drug is given and response to other drug is altered , a drug interactions is said to have occurred • This effect may be • Desired or beneficial (efficacy ↑es with out ↑in toxicity) e.g. Multi drug treatment of T.B Amoxicillin + clavulanic acid L-Dopa + Carbidopa Naloxone to treat Morphine overdose
- 3. • Undesired orharmful (toxicity is ↑ed with ↓in efficacy) • Aspirin and Warfarin • Propranolol + Salbutamol • Paracetamol + Alcohol • Gentamycin + loop diruetics 3
- 4. 4 • Clinically important druginteractions • 1. Drugs that have steep dose response curve and small therapeutic index, small change in concentration at site will lead to substantial increase in effect. e.g. Digoxin , Lithium 2. Drugs that are known enzyme inducers/inhibitors
- 5. 5 3. Drugs thatexibit saturable metabolism e.g. Phenytoin , Theophylline 4. Drugs used for prolong period and precise plasma concentration are required e.g. oral contraceptive , antiepileptic drugs , lithium 5. Different drugs used to treat same disease e.g. Theophylline, Salbutamol 6. In patients with impaired kidney and liver functions 7. In elderly who receive several drugs at the same time
- 6. 6 PHARMACODYNAMIC INTERACTIONS • Bothdrugs act at same target site exerting synergism or antagonism • Drugs may act at same or different receptors or process. • The effect may be Synergistic or Antagonism
- 7. SYNERGISTIC PHARMACODYNAMIC DRUGINTERACTIONS DRUG INTERACTS WITH RESULTS IN TUBOCURARINE AMINOGLYCOSIDES QUINIDINE PROCAINE PROLONGED PARALYSIS ORAL HYPOGLYCAEMICS SALICYLATES PROPRANOLOL EXCESSIVE HYPOGLYCAEMIA DIGITALIS PROPRANOLOL GUANETHIDINE VERAPAMIL BRADYCARDIA ANTIHYPERTENSIVES DIURETICS ENHANCED HYPOTENSION
- 8. DRUG INTERACTIONS MAYBE ANTAGONISTIC PRIMARY DRUG INTERACTS WITH RESULTING IN SALBUTAMOL -PROPRANOLOL ANTIAGONISM OF BRONCHODILATION ANTIHYPER- TENSIVES -NSAIDS ANTAGONISM OF HYPOTENSIVE EFFECT (Na+ - RETENTION) - SELECTIVE COX 2 INHIBITORS NO SIGNIFICANT EFFECTS ON Na SULPHONAMIDES -L. ANAETHETICS -(PABA) ANTAGONISM OF ANTIMICROBIAL EFFECTS WARFARIN OESTROGENS WARFARIN EFFECT ANTAGONIZED BY INCREASED CLOTTING FACTOR SYNTHESIS OPIOIDS NALOXONE ANTAGONISM
- 9. 9 PHARMACOKINETIC INTERACTIONS • Drugact remotely from target site to alter plasma concentration e.g. enzyme induction /inhibition interaction may be synergistic or antagonistic. Drug interaction can occur at 1. out side the body 2. At site of absorption 3. During drug distribution 4. During drug metabolism 5. During drug excretion. 6. On receptor or body system.
- 10. 10 Interaction out sidethe 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 insulin may bind with soluble insulin and delay its effects.
- 11. 11 AT THE SITEOF 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 emptying delay absorption of other drugs e.g anti cholinergics , antidepressants • .
- 12. PHARMACOKINETIC INTERACITONS AT THEABSORPTION LEVEL: EXAMPLES: DRUGS MECHANISM EFFECT A) TETRACYCLINE + Ca2+ , Fe2+ , AL3+ , Mg2+ SALTS CHELATION MUTUALLY REDUCED ABSORPTION A) B) ANTICOAGULANTS OR THYROXINE OR DIGOXIN OR THIAZIDES + CHOLESTYRAMINE BINDING TO RESIN REDUCED ABSORPTION
- 13. 13 • Purgatives reducetime spent in small intestine and reduce absorption. • Alteration in gut flora: antimicrobials potentiates ant coagulants by reducing bacterial synthesis of vit.K • Affect the transport as P-glycoprotein • Other than gut : Local anesthetics (xylocaine) and adrenaline.
- 14. 14 DURING DISTRIBUTION • Displacementfrom plasma proteins binding e.g. Sodium valproate displaces Phenytoin Sulphonamides displaces bilirubin ( in neonates) • Displacement from tissue binding sites e.g. Quinidine displaces Digoxin
- 15. 15 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.
- 16. EXAMPLES INCLUDE: PRIMARY DRUGINDUCING DRUG EFFECT OF INTERACTION ORAL ANTICOAGULANTS e.g. WARFARIN BARBITURATES RIFAMPICIN DECREASED ANTI-COAGULATION TOLBUTAMIDE PHENYTOIN CHLORPROMAZINE DECREASED HYPOGLYCAEMIA ORAL CONTRA- CEPTIVES PHENOBARBITONE FAILURE OF CONTRCEPTION PREDNISONE DEXAMETHASONE BARBITURATES REDUCED STEROID LEVELS DOXYCYCLINE BARBITURATES REDUCED DOXYCYCLINE LEVELS QUINIDINE PHENYTOIN BARBITURATES REDUCED QUINIDINE LEVELS
- 17. 17 Enzyme inhibition • Certaindrugs 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
- 18. INTERACTIONS OF LIVERENZYME INHIBITORS PRIMARY DRUG INHIBITING DRUG INTERACTION PHENYTOIN ISONIZID AZAPROPAZONE CHLORAMPHENICOL PHENYTOIN INTOXICATION ORAL ANTICOAGULANTS e.g. WARFARIN ALLOPURINOL NORTRIPTYLINE QUINIDINE HAEMORRHAGE TOLBUTAMIDE CHLORPROPAMIDE PHENYLBUTAZONE CHLORAMPHENICOL DISCOUMAROL HYPOGLYCAEMIA 6-MERCAPTOPURINE AZATHIOPRINE ALLOPURINOL BONE MARROW SUPPRESSION ANY DRUG CIMETIDINE KETOCONAZOLE FLUOXETINE RAISED PLASMA LEVEL OF DRUG
- 19. 19 Enzyme inducers. • Phenobarbital • Rifampin •Grisofulvin • Phenytoin • Ethanol • Carbamazepine
- 20. 20 Enzyme inhibitors • Phenylbutazone •Metronidazole • Cimetidine • Omperazole
- 21. DRUG EXCRETION: MAY BECHANGED BY DRUGS WHICH ALTER URINARY pH ► WEAK ACIDS LIKE (PENICILLINS, PHENOBARB, ACETAZOLAMIDE, NITROFURANTOIN). BEST ELIMINATED IN ALKALINE URINE ► BASES LIKE (CHLOROQUINE, IMIPARMINE, QUININE) BEST ELIMENATED IN ACIDIC URINE B) OR DRUGS MAY COMPETE FOR RENAL TUBULAR SECRETION
- 22. PRIMARY DRUG COMPETINGDRUG EFFECT OF INTERACTION PENICILLIN PROBENECID INCREASED PENCILLIN LEVELS METHOTREXATE SALICYLATES SULPHONAMIDES BONE MARROW DEPRESSION LITHIUM THIAZIDES LITHIUM TOXICITY HYPERNATRAEMIA DIGOXIN SPIRONOLACTONE INCREASED PLASMA DIGOXIN LEVELS SALICYLATES INDOMETHACIN PROBENECID INDOMETHACIN OR SALICYLATES TOXICITY.
- 23. 23 Haemodynamic flow • variationin 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.
- 24. 24 B- Drug mayalter drug distribution: Mechanisms: - Competition for plasma protein binding - Displacement from tissue binding sites - Alterations in local tissue barriers (P-glyco proteins inhibition in BBB).
- 25. 25 - Displacement fromtissue binding sites would tend to transiently increase blood concentration of !displaced drug. This effect is transient because of compensatory increase in drug disposition. • When one displacing drug additionally reduces elimination of the 1st drug , so that free concentration is increased not only acutely but also chronically at new steady state, severe toxicity may occur.
- 26. 26 Salicylates displace methotrexatefrom albumin and also reduce its secretion into nephron by competition with anion secretory carrier. Quinidine, verapamil, & amiodarone displace digoxin from tissue binding sites & reduce its renal excretion leading to digoxin toxicity
- 27. 27 • Drugs metabolism: Drugscan either inhibit/ induce drug-metabolizing enzymes. Enzyme inducers (stimulation of cytochrome P450 in liver): requires some days - Barbiturates - Ethanol - Carbamazepine?? - Phenytoin - Rifampicin?? - Efavirenz?? - They also increase glucuronidation (phase II) metabolism
- 28. 28 Enzyme inhibitors: (inhibitcytochrome P450); more quickly than enzyme induction - Amiodarone - Androgen?? - Chloramphenicol - Cimetidine; decrease warfarin metabolism - Ciprofloxacin, clarithromycin, erythromycin - Cyclosporine, ??isoniazide,?? ketoconazole, - Delavirdine?? - Disulfiram.؟؟