1 DRUG – DRUG INTERACTIONS Dr.Abdul latif Mahesar King Saud University May 2010

2 DRUG – DRUG INTERACTION 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 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 beThis effect may be Desired or beneficial (efficacy ↑es with out ↑in toxicity)Desired or beneficial (efficacy ↑es with out ↑in toxicity) e.g. Multi drug treatment of T.B e.g. Multi drug treatment of T.B Amoxicillin + clavulanic acid L-Dopa + Carbidopa Naloxone to treat Morphine overdose

Undesired or harmful (toxicity is ↑ed with ↓in efficacy) Undesired or harmful (toxicity is ↑ed with ↓in efficacy) Aspirin and Warfarin Aspirin and Warfarin Propranolol + Salbutamol Propranolol + Salbutamol Paracetamol + Alcohol Paracetamol + Alcohol Gentamycin + loop diruetics Gentamycin + loop diruetics 3

4 Clinically important drug interactionsClinically 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 increase in effect.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 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, antiepileptic drugs, lithium 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 7. In elderly who receive several drugs at the same time

6 PHARMACODYNAMIC INTERACTIONS Both drugs act at same target site exerting synergism or antagonism Both drugs act at same target site exerting synergism or antagonism Drugs may act at same or different receptors or process. Drugs may act at same or different receptors or process. The effect may be Synergistic or AntagonismThe effect may be Synergistic or Antagonism

SYNERGISTIC PHARMACODYNAMIC DRUG INTERACTIONS SYNERGISTIC PHARMACODYNAMIC DRUG INTERACTIONS

DRUG INTERACTIONS MAY BE ANTAGONISTIC

9 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 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 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 insulin may bind with soluble insulin and delay its effects. Protamine in zinc insulin may bind with soluble insulin and delay its effects.

11 AT THE SITE OF ABSORPTION Direct chemical interactionDirect 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 Gut motility: drugs which reduce gastric emptying delay absorption of other drugs e.g anti cholinergics, antidepressants e.g anti cholinergics, antidepressants.

PHARMACOKINETIC INTERACITONS AT THE ABSORPTION LEVEL: EXAMPLES:

13 Purgatives reduce time spent in small intestine and reduce absorption.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 Affect the transport as P-glycoproteinAffect the transport as P-glycoprotein Other than gut : Local anesthetics (xylocaine) and adrenaline.Other than gut : Local anesthetics (xylocaine) and adrenaline.

14 DURING DISTRIBUTION Displacement from plasma proteins bindingDisplacement 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

15 Interaction during metabolism Enzme induction: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.

EXAMPLES INCLUDE:

17 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. Eg. Cimetidine potenciates the effects of propranolol,theophylline, warfarin and othersEg. Cimetidine potenciates the effects of propranolol,theophylline, warfarin and others

INTERACTIONS OF LIVER ENZYME INHIBITORS

19 Enzyme inducers. PhenobarbitalPhenobarbital Rifampin Rifampin Grisofulvin Grisofulvin Phenytoin Phenytoin Ethanol Ethanol Carbamazepine Carbamazepine

20 Enzyme inhibitors PhenylbutazonePhenylbutazone Metronidazole Metronidazole Cimetidine Cimetidine Omperazole Omperazole

DRUG EXCRETION: MAY BE CHANGED BY DRUGS WHICH ALTER URINARY pH URINARY pH ► WEAK ACIDS LIKE (PENICILLINS, ► WEAK ACIDS LIKE (PENICILLINS, PHENOBARB, ACETAZOLAMIDE, PHENOBARB, ACETAZOLAMIDE, NITROFURANTOIN). NITROFURANTOIN). BEST ELIMINATED IN ALKALINE URINE BEST ELIMINATED IN ALKALINE URINE ► BASES LIKE (CHLOROQUINE, IMIPARMINE, ► BASES LIKE (CHLOROQUINE, IMIPARMINE, QUININE) QUININE) BEST ELIMENATED IN ACIDIC URINE B)OR DRUGS MAY COMPETE FOR RENAL TUBULAR SECRETION BEST ELIMENATED IN ACIDIC URINE B)OR DRUGS MAY COMPETE FOR RENAL TUBULAR SECRETION

DRUG EXCRETION EXAMPLES DRUG EXCRETION EXAMPLES

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

24 B- Drug may alter 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 -Displacement from tissue 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 1 st drug, so that free concentration is increased not only acutely but also chronically at new steady state, severe toxicity may occur.When one displacing drug additionally reduces elimination of the 1 st drug, so that free concentration is increased not only acutely but also chronically at new steady state, severe toxicity may occur.

26 Salicylates displace methotrexate from 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 Drugs metabolism:Drugs metabolism: Drugs can 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 Enzyme inhibitors: (inhibit cytochrome P450); more quickly than enzyme induction -Amiodarone -Androgen?? -Chloramphenicol -Cimetidine; decrease warfarin metabolism -Ciprofloxacin, clarithromycin, erythromycin -Cyclosporine, ??isoniazide,?? ketoconazole, -Delavirdine?? -Disulfiram. ؟؟