DRUG INTERACTIONS

06/03/2013

Dr Rajesh Basavaraj, PG, Dept. of Pharmacology.

DRUG INTERACTIONS
Def: Modification of response to one drug by another drug when they are administered simultaneously or in quick succession It may result into beneficial effects or into adverse effects

KD Tripathi, 6th ed.

Drug interactionslikely in following situations

Self medication
Treatment by semi qualified paramedics / quacks Drugs having steep DRC with low safety of margins

Drugs having enzyme inducing/inhibiting effects

Drugs having zero order/mixed order kinetics Drugs that are used for prolonged period with precise maintenance of plasma concentration

Regular medication drugs (likely to be involved in drug interactions)

Antidiabetics
Antihypertensives Antianginal drugs Antiepileptic drugs Antiparkinsonian drugs

Oral contraceptives
Antiasthamtic drugs Corticosteroids Psychopharmacological agents Anti-TB & anti-HIV drugs

Risky drugs
o affect vital processes - Warfarin, CPZ, morphine o saturable kinetics - phenytoin theophylline salicylates o steep DRC - verapamil, L-Dopa, chlorpropamide

o demonstrate dose dependent toxicity - digoxin, Mtx, lithium aminoglycosides

o prophylactic action - OCPs, cyclosporine

o high PPB ability - NSAIDs oral anticoagulants sulfonylureas

Vulnerable patients
Elderly pts. receiving many drugs Pts. with hepatic / renal disease Pts. with unstable disease
epilepsy, diabetes mellitus, cardiac disease

Pts. dependent on drug therapy for survival

transplant recipients, Addisons disease

Pts with more than one prescribing doctor

Adverse drug-drug interactions

A. In vitro drug interactions B. In vivo drug interactions

In vitro drug-drug interactions

Drugs
Thiopentone sodium + SCh/ morphine

Mixed into
In the same syringe

Result
Precipitation / activation
Inactivation of heparin

Hydrocortisone/gentamicin In the same syringe + Heparin

Hydrocortisone + Penicillin In the same syringe

Penicillin + Gentamicin Noradrenaline In the same syringe In i.v infusion fluid NS or BT

Inactivation of penicillin
Mutual inactivation Oxidized

IN VITRO DRUG-DRUG INTERACTIONS

Aminophylline i.v soln. i.v epinephrine, erythromycin or cephalothin In i.v infusion fluid 5% dextrose Into blood / plasma, amino acid soln., mannitol soln., NaHCO3 soln., heparin i.v These drugs get decomposed at alkaline PH of aminophylline Drugs are precipitated in the acidic PH of dextrose soln. Get inactivated or precipitated

Na+ salts of phenytoin, barbiturates, heparin, penicillin & sulfonamides Almost all drugs (as a rule)

IN VIVO DRUG-DRUG INTERACTIONS

A. Pharmacokinetic interactions B. Pharmacodynamic interactions

Pharmacokinetic interactions
o Alteration of the concentration of object drug that reaches its site of action o consequently the intensity of response will be altered

Pharmacokinetic interactions
Drug absorption: Due to formation of insoluble or poorly absorbable complexes in gut
atropine and its substitutesdelay gastric emptying intestinal absorption of other drugs

prokinetic drugs- hasten gastric emptying- intestinal absorption of other drugs

milk, antacids containing Ca2+, Mg2+, Al3+ and iron absorption of tetracyclines erythromycin/ tetracyclines- bioavailability of digoxin adrenaline + LA Systemic antacids + Omeprazole

Pharmacokinetic interactions
Drug distribution: Mainly due to displacement of one drug by another from its binding site on plasma proteins
sulfonamides displace bilirubin in neonates- kernicterus

salicylates and sulfonamidestolbutamide and Mtx

displace

warfarin,

quinidine, verapamil and amiodarone- displace digoxin and also its excretion (by inhibiting P-glycoprotein) direct curtailment of drug distribution protamine sulfate heparin desferrioxamine - iron

Pharmacokinetic interactions
Drug metabolism: Enzyme induction: 1-2 wks to develop
Enzyme inducer Phenobarbitone Phenytoin, CBZ Glucocorticoids Pioglitazone Rifampicin Phenobarbitone Enzyme induced CYP3A4 Drugs affected Midazolam, alprozolam Barbiturates Ritonavir, CCBs Macrolides OCPs, Warfarin, Losartan Ibuprofen, Tamoxifen

CYP3A4 CYP2C9

Smoking Omeprazole
INH Chronic alcohol intake

CYP1A2
CYP2E1

Theophylline, Warfarin Imipramine, PCT

Halothane, PCT Ethanol

Effect of rifampicin on the metabolism and anticoagulant action of warfarin

Pharmacokinetic interactions
Microsomal enzymes- liver, but also in lungs CYP1A2 in smokers Clinical significance of enzyme induction: Consequences of drug metabolism plasma levels therapeutic effect of coadministered drug Inactive metabolite Active metabolite

Enzyme induction- toxicity

Therapeutic benefits

Pharmacokinetic interactions
Enzyme inhibition: Hepatic microsomal mixed function oxidase (MFDs), MAO, xanthine oxidase, aldehyde dehydrogenase
Inhibitors Cimetidine Enzyme inhibited Hepatic microsomal MFDs Drugs affected Phenytoin, warfarin Antidepressants, Diazepam Theophylline, quinidine Phenytoin, Primidone Phenobarbitone Theophylline, CBZ Warfarin, Cyclosporine Theophylline

Sodium valproate Erythromycin Fluoroquinolones except ofloxacin

Hepatic microsomal MFDs Hepatic microsomal MFDs Hepatic microsomal MFDs

Pharmacokinetic interactions
Chloramphenicol Verapamil, diltiazem Allopurinol Hepatic microsomal MFDs Terfenadine Phenytoin, warfarin Hepatic microsomal MFDs Theophylline, CBZ Cyclosporine Xanthine oxidase 6-MP, azathioprine

MAO-Is
Disulfiram Metronidazole Chlorpropamide Cefoperazone Carbidopa Ecothiophate

MAO
Aldehyde dehydrogenase

Morphine, pethidine
Alcohol, phenytoin Warfarin

Peripheral dopa decarboxylase AChE

L-Dopa Suxamethonium

Pharmacokinetic interactions
Clinical significance of enzyme inhibition: Potentially adverse consequences Cimetidine + dicumarol- enhanced bleeding MAO-Is + Morphine - severe respiratory depression Dicumarol/ chloramphenicol + Phenytoin - severe ataxia, drowsiness Chloramphenicol/ ketoconazole + Terfenadine precipitate cardiac arrhythmias

Therapeutically beneficial consequences L-Dopa + carbidopa

d-TC + neostigmine Alcohol + disulfiram

Pharmacokinetic interactions
Drug excretion

Altering protein binding, and hence filtration

Inhibiting tubular secretion Altering urine flow &/or urine pH

Inhibition renal tubular secretion:

Drug(s) causing inhibition Probenicid, Phenlybutazone Sulfonamides, Aspirin Thiazide diuretics Verapamil Quinidine Amiodarone Indomethacin Aspirin NSAIDs Drug(s) affected Penicillin Indomethacin

Digoxin Furosemide Methotrexate

Pharmacokinetic interactions
Alteration of urine flow and pH:

Alkalinization of urine by NaHCO3 excretion of acidic drugs

Acidification of urine by ammonium chloride/ ascorbic acid- excretion of basic drugs Loop and thiazide diuretics- proximal tubular reabsorption of lithium

Pharmacodynamic interactions
Modification of the pharmacological effect of a drug without altering its concentration in tissue fluid May result in Synergism

Antagonism
Abnormal response

o Abnormal response
Propranolol + Insulin / oral hypoglycemic drugsmasks symptoms of hypoglycemia predispose to hypoglycemic coma

Pharmacodynamic interactions
Synergism
Aspirin + Warfarin
BZDs + Antihistaminics+ CPZ + Morphine+ Alcohol d-TC + Aminoglycosides

Antagonism
CNS stimulants + Depressants
Thiazides + Oral hypoglycemic drugs NSAIDs + -blockers/ ACE-Is Atropine + ACh / Anti-ChEs d-TC + Ach ACE-Is + Spironolactone L-dopa + Antipsychotics Bacteriostatic + Bactericidal (tetracycline + penicillin)

TCAs + Atropine
Metoclopramide + Phenothiazines Halothane + Adrenaline Sildenafil + Organic nitrates 2 bactericidal agents (penicillin + gentamicin) Bacteriostatic + Bactericidal (Rifampicin + Dapsone)

Interactions due to change in fluid and electrolyte balance

Hypokalaemia (Thiazide / Loop diuretics) + Digoxin/d-TC Hypokalaemia + Lignocaine, quinidine, procainamide

ACE-Is + K+ sparing diuretics

Sodium depletion lithium toxicity

Beneficial drug-drug interactions

Interactions leading to therapeutic effects

Sulfamethoxazole + Trimethoprim (Cotrimoxazole)

L-Dopa + Carbidopa Nitrates + blockers angina

Nitrates + CCBs angina

Thiazides + K+ sparing diuretics + blockers HTN Probenicid + penicillin / cephalosporins Amoxicillin + -Lactamase inhibitor ACE-Is + SGLT-2 cotransporter inhibitors

Beneficial drug-drug interactions

Interactions providing advantage in management of poisoning and drug overdose Naloxone- morphine poisoning / addiction Protamine sulfate heparin toxicity

Physostigmine- atropine poisoning

Neostigmine- reversal of muscle relaxation due to d-TC Ethanol- methanol poisoning Desferrioxamine / deferiprone- iron poisoning

Drug-laboratory test interactions

Cephalosporins- false + ve urine glucose test Cephalosporins- spurious serum creatinine levels Diuretics- serum electrolyte tests, blood sugar levels ACE-Is hypokalaemia MAO-Is- urinary VMA levels

Drug-food interactions
Tyramine containing food items + MAO-Is Cheese reaction Spinach, broccoli- rich in Vit K antagonize effects of warfarin Food- bioavailability of griseofulvin, metoprolol, propranolol, phenytoin, dicumarol Food- bioavailability didanosine of NSAIDs, tetracyclines,

Protein rich diet- acidic urine- promotes excretion of basic drugs and vice-versa

Drug-food interactions
Grape, orange, garlic inhibit CYP3A4 bioavailability of indinavir, saquinavir, nimodipine, nifedipine, simvastatin, lovastatin Acarbose - inhibits -glucosidase- taken at the start of each meal- delays carbohydrate absorption Tetracyclines complex with milk Ca2+ Milk iron absorption

Drug-herbal products interactions

Ginger, Garlic & Ginkgo biloba- risk of bleedinganticoagulants and antiplatelet drugs St. Johns wort phototoxicity when sulfonamides and PPIs used with tetracyclines,

summation effects with CNS depressants plasma concentration of digoxin, cyclosporine, warfarin and protease inhibitors

Drug-herbal products interactions

Chinese ginseng potentiates effects of caffeine, anticoagulants, antiplatelets, MAO-I and CNS stimulants effects of antihypertensives, cardiac glycoside

Aloeveras latex laxative properties, blood sugar- concurrent use of laxatives and hypoglycemics should be avoided intestinal absorption of Vit K

REFERENCES:
Essentials of medical pharmacology; KD Tripathi, 6th edition Pharmacology and pharmacotherapeutics; RS Satoskar, SD Bhandarkar, Nirmala N Rege, 21st edition

Rang and Dales pharmacology; HP Rang, MM Dale, JM Ritter, RJ Flower, 6th edition
Basic and clinical pharmacology; Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor, 11th edition Principles of pharmacology; HL Sharma, KK Sharma, 2nd edition