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DRUG DRUG ––DRUG DRUG INTERACTIONSINTERACTIONS

Dr.Abdul latif MahesarDr.Abdul latif MahesarKing Saud UniversityKing Saud University

May 2010May 2010

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DRUG – DRUG INTERACTIONDRUG – DRUG INTERACTION• When one drug is administered, a response When one drug is administered, a response

occurs, if a second drug is given and response occurs, if a second drug is given and response to other drug is altered , a drug interactions to other drug is altered , a drug interactions is said to have occurredis said to have occurred

• This effect may be This effect may be • Desired or beneficial Desired or beneficial (efficacy ↑es with out (efficacy ↑es with out

↑in toxicity)↑in toxicity) e.g.e.g. Multi drug treatment of T.B Multi drug treatment of T.B

Amoxicillin + clavulanic acidAmoxicillin + clavulanic acidL-Dopa + CarbidopaL-Dopa + CarbidopaNaloxone to treat Morphine overdoseNaloxone to treat Morphine overdose

• Undesired or harmful Undesired or harmful (toxicity is (toxicity is ↑ed with ↓in efficacy)↑ed with ↓in efficacy)

• Aspirin and WarfarinAspirin and Warfarin• Propranolol + SalbutamolPropranolol + Salbutamol• Paracetamol + AlcoholParacetamol + Alcohol• Gentamycin + loop dirueticsGentamycin + loop diruetics

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•Clinically important drug interactionsClinically important drug interactions

• 1. Drugs that have steep dose response 1. Drugs that have steep dose response curve and small therapeutic index, small curve and small therapeutic index, small change in concentration at site will lead to change in concentration at site will lead to substantial increase in effect.substantial increase in effect.e.g. Digoxin , Lithiume.g. Digoxin , Lithium

2. Drugs that are known enzyme 2. Drugs that are known enzyme inducers/inhibitorsinducers/inhibitors

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3. Drugs that exibit saturable metabolism 3. Drugs that exibit saturable metabolism e.g. Phenytoin , Theophyllinee.g. Phenytoin , Theophylline

4. Drugs used for prolong period and precise plasma 4. Drugs used for prolong period and precise plasma concentration are requiredconcentration are required

e.g. oral contraceptive , antiepileptic drugs , lithiume.g. oral contraceptive , antiepileptic drugs , lithium

5.5. Different drugs used to treat same disease Different drugs used to treat same disease e.g. Theophylline, Salbutamole.g. Theophylline, Salbutamol

6. In patients with impaired kidney and liver functions6. In patients with impaired kidney and liver functions

7. In elderly who receive several drugs at the same 7. In elderly who receive several drugs at the same timetime

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PHARMACODYNAMIC INTERACTIONSPHARMACODYNAMIC INTERACTIONS

• Both drugs act at same target site exerting synergism Both drugs act at same target site exerting synergism or antagonismor antagonism

• Drugs may act at same or different receptors or Drugs may act at same or different receptors or process.process.

• The effect may be The effect may be SynergisticSynergistic or or AntagonismAntagonism

SYNERGISTIC PHARMACODYNAMIC SYNERGISTIC PHARMACODYNAMIC DRUG INTERACTIONSDRUG INTERACTIONS  

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

DRUG INTERACTIONS MAY BE DRUG INTERACTIONS MAY BE ANTAGONISTICANTAGONISTIC

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

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PHARMACOKINETIC INTERACTIONSPHARMACOKINETIC INTERACTIONS

• Drug act remotely from target site to alter plasma concentrationDrug act remotely from target site to alter plasma concentratione.g. enzyme induction /inhibitione.g. enzyme induction /inhibition

interaction may be synergistic or antagonistic.interaction may be synergistic or antagonistic.

Drug interaction can occur atDrug interaction can occur at

1.1. out side the bodyout side the body2.2. At site of absorptionAt site of absorption3.3. During drug distributionDuring drug distribution4.4. During drug metabolismDuring drug metabolism5.5. During drug excretion.During drug excretion.6.6. On receptor or body system.On receptor or body system.

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Interaction out side the bodyInteraction out side the body

• Drugs are added to reservoir or syringes to make Drugs are added to reservoir or syringes to make drugs soluble they are prepared in salt forms, mixing drugs soluble they are prepared in salt forms, mixing these drugs may lead to precipitation these drugs may lead to precipitation (incompatibility)(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 Protamine in zinc insulin may bind with soluble insulin and delay its effectsinsulin and delay its effects..

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AT THE SITE OF ABSORPTIONAT THE SITE OF ABSORPTION

• Direct chemical interactionDirect chemical interactione.g. Antacids + Tetracycline's ,Iron form e.g. Antacids + Tetracycline's ,Iron form insoluble complexes ,this can be insoluble complexes ,this can be prevented if drugs are administered at prevented if drugs are administered at 2hrs apart.2hrs apart.

• Gut motility: drugs which reduce gastric Gut motility: drugs which reduce gastric emptying delay absorption of other drugsemptying delay absorption of other drugs

e.g anti cholinergics , antidepressantse.g anti cholinergics , antidepressants

•..

PHARMACOKINETIC INTERACITONSPHARMACOKINETIC INTERACITONS         AT THE ABSORPTION LEVEL:AT THE ABSORPTION LEVEL: EXAMPLESEXAMPLES::

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

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• Purgatives reduce time spent in small Purgatives reduce time spent in small intestine and reduce absorption.intestine and reduce absorption.

• Alteration in gut flora: antimicrobials Alteration in gut flora: antimicrobials potentiates ant coagulants by potentiates ant coagulants by reducing bacterial synthesis of vit.Kreducing bacterial synthesis of vit.K

• Affect the transport as P-glycoproteinAffect the transport as P-glycoprotein

• Other than gut : Local anesthetics Other than gut : Local anesthetics (xylocaine) and adrenaline.(xylocaine) and adrenaline.

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DURING DISTRIBUTIONDURING DISTRIBUTION

• Displacement from plasma proteins bindingDisplacement from plasma proteins binding

e.g. Sodium valproate displaces Phenytoine.g. Sodium valproate displaces PhenytoinSulphonamides displaces bilirubin ( in Sulphonamides displaces bilirubin ( in

neonates)neonates)

• Displacement from tissue binding sitesDisplacement from tissue binding sitese.g. Quinidine displaces Digoxine.g. Quinidine displaces Digoxin

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Interaction during Interaction during metabolismmetabolism

• Enzme induction:Enzme induction:• liver micsrosomal enzymes are induced by a wide liver micsrosomal enzymes are induced by a wide

variety of drugs and these affect the metabolism of other variety of drugs and these affect the metabolism of other drugs reducing their concentration and hence effect.drugs reducing their concentration and hence effect.

• e.g oral contraceptive metabolism is enhanced if e.g oral contraceptive metabolism is enhanced if Phenytoin is co-administered ,leading to unplanned Phenytoin is co-administered ,leading to unplanned pregnancypregnancy

• eg loss of anticougulant effect of Warfarin leading to eg loss of anticougulant effect of Warfarin leading to danger of thrombosis if barbiturates are administered.danger of thrombosis if barbiturates are administered.

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

EXAMPLES INCLUDEEXAMPLES INCLUDE::

PRIMARY DRUG INDUCING 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

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Enzyme inhibitionEnzyme inhibition

• Certain drugs inhibit the liver Certain drugs inhibit the liver microsomal enzymes ,hence increase microsomal enzymes ,hence increase the activity of drugs which are to be the activity of drugs which are to be metabolized by these enzymes.metabolized by these enzymes.

• Eg. Cimetidine potenciates the Eg. Cimetidine potenciates the effects of propranolol ,theophylline, effects of propranolol ,theophylline, warfarin and otherswarfarin and others

INTERACTIONS OF LIVER ENZYME INHIBITORSINTERACTIONS OF LIVER ENZYME 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

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Enzyme inducersEnzyme inducers..

•PhenobarbitalPhenobarbital• RifampinRifampin• GrisofulvinGrisofulvin• PhenytoinPhenytoin• Ethanol Ethanol • CarbamazepineCarbamazepine

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Enzyme inhibitorsEnzyme inhibitors

• PhenylbutazonePhenylbutazone• MetronidazoleMetronidazole• CimetidineCimetidine• OmperazoleOmperazole

DRUG EXCRETIONDRUG EXCRETION::

MAY BE CHANGED BY DRUGS WHICH ALTERMAY BE CHANGED BY DRUGS WHICH ALTER URINARY pHURINARY pH

►► WEAK ACIDSWEAK ACIDS LIKE (PENICILLINS LIKE (PENICILLINS , , PHENOBARB, ACETAZOLAMIDEPHENOBARB, ACETAZOLAMIDE , ,

NITROFURANTOINNITROFURANTOIN .) .) BEST ELIMINATED IN BEST ELIMINATED IN ALKALINE URINEALKALINE URINE

►► BASES LIKEBASES LIKE (CHLOROQUINE, (CHLOROQUINE, IMIPARMINEIMIPARMINE , ,

QUININEQUININE ) ) BEST ELIMENATED IN BEST ELIMENATED IN ACIDIC URINE ACIDIC URINE B)B)OR OR

DRUGS MAY COMPETE FOR DRUGS MAY COMPETE FOR RENAL TUBULAR RENAL TUBULAR SECRETIONSECRETION

DRUG EXCRETIONDRUG EXCRETION EXAMPLES EXAMPLES

  

PRIMARY DRUG COMPETING DRUG 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.

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Haemodynamic flowHaemodynamic flow

• variation in heaptic blood flow may variation in heaptic blood flow may influence the rate of inactivation of influence the rate of inactivation of drugs as in reduced cardiac out put.drugs as in reduced cardiac out put.

• Drugs which reduce cardiac out put Drugs which reduce cardiac out put like Propranolol may reduce the like Propranolol may reduce the metabolism of other drugs.metabolism of other drugs.

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B- Drug may alter drug B- Drug may alter drug distributiondistribution: : Mechanisms:Mechanisms:

- Competition for plasma protein bindingCompetition for plasma protein binding

- Displacement from tissue binding sitesDisplacement from tissue binding sites

- Alterations in local tissue barriers (P-Alterations in local tissue barriers (P-glyco proteins inhibition in BBB).glyco proteins inhibition in BBB).

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- Displacement from tissue binding sites Displacement from tissue binding sites would tend to transiently increase blood would tend to transiently increase blood concentration of !displaced drug. concentration of !displaced drug.

This effect is transient because of This effect is transient because of compensatory increase in drug compensatory increase in drug disposition.disposition.

• When one displacing drug additionally When one displacing drug additionally reducesreduces elimination of the 1 elimination of the 1stst drug drug , so , so that free concentration is increased not that free concentration is increased not only acutely but also chronically at new only acutely but also chronically at new steady state, severe toxicity may occur.steady state, severe toxicity may occur.

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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

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• Drugs Drugs metabolismmetabolism::Drugs can either inhibit/ induce drug-Drugs can either inhibit/ induce drug-

metabolizing enzymes.metabolizing enzymes.Enzyme inducersEnzyme inducers (stimulation of cytochrome (stimulation of cytochrome

P450 in liver): requires some daysP450 in liver): requires some days- BarbituratesBarbiturates- EthanolEthanol- Carbamazepine??Carbamazepine??- PhenytoinPhenytoin- Rifampicin??Rifampicin??- Efavirenz??Efavirenz??- They also increase glucuronidation (phase II) They also increase glucuronidation (phase II)

metabolismmetabolism

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Enzyme inhibitorsEnzyme inhibitors: (inhibit cytochrome : (inhibit cytochrome P450); more quickly than enzyme inductionP450); more quickly than enzyme induction

- AmiodaroneAmiodarone- Androgen??Androgen??- Chloramphenicol Chloramphenicol - Cimetidine; decrease warfarin metabolismCimetidine; decrease warfarin metabolism- Ciprofloxacin, clarithromycin, erythromycinCiprofloxacin, clarithromycin, erythromycin- Cyclosporine, ??isoniazide,?? ketoconazole,Cyclosporine, ??isoniazide,?? ketoconazole,- Delavirdine??Delavirdine??- Disulfiram.Disulfiram.؟؟؟؟