80

Everyday PracticeTHE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 6, NO.2

Adverse drug interactionsS. K. BHATIACHARYA

INTRODUCTIONThe pharmacokinetics as well as the effects of a drug canbe altered by the previous or concurrent administration ofanoth~~. While .such an .interacti~n may be therapeuticallybeneficial occasionally, In many Instances it may result inadverse effects. The increasing tendency for polypharmacyis not always guided by principles of rational drug therapy.The long term use of potent drugs and self-medication hasresulted in an increase in the incidence of adverse druginteractions. Every time a physician prescribes an additionaldrug, he or she is adding to the risk of these interactions. Ithas been estimated that patients in hospital who are receivingmore than six drugs at a time, have a 6 to 7 times greaterincidence of adverse effects (including those due to druginteractions) than those who are receiving less than sixdrugs. Also, about 7% of all adverse drug reactions areestimated to be due to drug interactions and account forapproximately one-third of the mortality of such patients.The elderly are more prone to drug interactions, not onlybecause they receive more drugs than younger patients, butbecause in them the pharmacokinetics of drugs are different.Th~ literat~re is replete with numerous examples of likely

drug mteracnons, most of the data being based on animalstudies, single case reports or anecdotal evidence. Fortu-nately, the drug interactions of clinical importance arerelatively few and many of these can be predicted if theirpharmacodynamic effects, salient pharmacokinetic proper-ties and mechanisms of action are known and logicallyapplied in the clinical setting.

MECHANISMS OF DRUG INTERACTIONSUnfortunately, most physicians are often unaware of thepharmacological properties of the drugs they prescribe,cannot recognize their unwanted reactions and are unable to. identify the likely adverse effects due to drug interaction.To confound the issue further, the large number (approxi-ma~ely 65.(00) of fixed-dose combination drugs available inIndia which are frequently irrational pharmacologically,contribute to the incidence of drug interactions because theprescribers do not remember their constituents.The important mechanisms responsible for drug inter-

actions can be classified as follows:

1. Pharmaceutical interactions or interactions occurring out-side the body.

Institute of Medical Sciences, Banaras Hindu University,Varanasi 221005, Uttar Pradesh, India

S. K. BHA ITACHARY A Department of Pharmacology

© The National Medical Journal of India 1993

2. Pharmacokinetic interactions or interactions due to alter-ations in the absorption, distribution, metabolism orexcretion of one drug by another.

3. Pharmacodynamic interactions or interactions due toalterations in the pharmacological action of one drug byanother, at or near the target site of action, and mayinvolve the basic mechanism by which these drugs act.

PHARMACEUTICAL INTERACTIONSDrugs may be inactivated or precipitated from solution ifmixed in syringes or added to blood or infusion fluids prior toadministration. Generally the manufacturer's literatureprovides specific warnings and guidelines which should bechecked. Important drug interactions are listed in Table I.It is advisable to avoid mixing drugs in infusion solutionsunless it is known that the mixture is safe (e.g. potassiumchloride and insulin). Two infusion sites can be used if twodrugs have to be administered simultaneously.

PHARMACOKINETIC INTERACTIONSThese interactions may take place during absorption,metabolism, distribution and excretion of drugs-factorswhich .~re impo~tant for the bioavailability of a drug at itstarget site of action. The interactions can be anticipated buttheir extent cannot be predicted because there are markedindividual variations in their pharmacokinetic properties.The clinically important interactions are the following:

Drug absorption interactionsOne drug may retard the rate or extent of absorption ofanother drug in a variety of ways. It is important to differen-tiate between the two since the consequences are likely to bequite different. For instance, an alteration in the rate ofa~sorption ?f a drug wit~ a long plasma half-life (warfarin)Will have httle effect SInce the drug will eventually beabsorbed. However, when the drug has a short plasma half-life (procainamide) reduction in the rate of absorption meansthat an effective therapeutic concentration in the plasmamay never be achieved. A delay in the rate of absorption isalso import~nt with ~rugs s~ch as analgesics and hypnotics,where a rapid effect IS required. Some important causes ofabsorption interactions are as follows:Intralum~nal binding or chelation of drugs: Drugs may

react chemically to form unabsorbable chelates, viz. iron andtetracycline, aluminium, magnesium or calcium containingantacids with tetracycline. Drug absorption may be reducedby adsorbents, such as kaolin or charcoal and by anionexch~ng~ .r~sins such as cholestyramine and colestipol,e.g: Inhibition of digoxin absorption by anion exchangeresms. Sucralfate reduces absorption of phenytoin and liquidparaffin reduces absorption of fat soluble vitamins.Gastrointestinal motility and transit time: Most drugs are

absorbed from the first part of the small intestine and the rateof gastric emptying will influence their rate of absorption.Drugs such as opiates, anticholinergics, tricyclic anti-depressants, antihistaminics and phenothiazines slow gastricemptying time, whereas metoclopramide increases it. This

BHAITACHARYA ; ADVERSE DRUG INTERACTIONS 81

TABbEI. General guidelines for prevention of pharmaceutical interactions

A void using the [allowing together in intravenous therapy1. Antibiotics and large volumes of transfusion fluids

2. Blood, plasma, sodium bicarbonate, lactate or mannitol with any drug

3. Highly acidic solutions (e.g. dextrose and laevulose) with sodium and potassium salts ofsulphonamides, barbiturates, methicillin, penicillin. ampicillin, heparin and aminophylline

4. Heparin and tetracyclines, gentamicin, noradrenaline and hydrocortisone

5. Hydrocortisone hemisuccinate with ampillicin, methicillin, carbenicillin and the tetracyclines

6. Succinylcholine with thiopentone sodium

7. Short- and long-acting insulins

TABLEII. Displacement interactions

Bound drug Displacing drug

Oral antidiabetics

Phenytoin

Digoxin

Primaquine

Analgesics, including phenylbutazone and indomethacin, phenytoin,clofibrate, sulphonamides

Phenylbutazone, indomethacin, anticoagulants, sulphonamides

Phenylbutazone, indomethacin

Quinidine, nifedipine, verapamil, amiodarone

Mepacrine

Oral anticoagulants

type of interaction is important with drugs such as antibioticsor analgesics when rapid peak plasma concentrations aredesirable. Thus, a combination of metoc\opramide withanalgesics has been used in the treatment of an acute attackof migraine.Alterations in the pH of gastrointestinal fluids: Basic drugs

are ionized, become less lipid soluble and are poorlyabsorbed in an acidic medium, whereas the reverse is true foracidic drugs in an alkaline medium. The unsupervised intakeof antacids may thus interfere with the absorption of manyacidic drugs (aspirin, barbiturates and warfarin). A markedreduction in gastric acidity by H2 blockers and omeprazoledecreases the absorption of ketoconazole.Alterations in gut bacterial flora: Broad spectrum anti-

biotics (cephalosporins and erythromycin) adversely affectthe gut bacterial flora and may affect the action of a numberof drugs. Sulphasalazine is biotransformed into an activemetabolite. by gut flora, L-dopa is converted into dopamineand digoxin is partIy metabolized by them. Thus, the effectof sulphasalazine will be reduced while the effect of the otherdrugs will be augmented if the gut flora are reduced, and maylead to toxicity. The toxicity of oral anticoagulants can beincreased following a decrease in the vitamin K availabilityfrom these bacteria. It has been reported recently that insome women broad spectrum antibiotics interfere with theantifertility action of oral contraceptive pi\ls. The mechanisminvolved is disruption of the enterohepatic cycling of thehormones by a reduction of the gut bacteria responsible forthe deconjugation and reabsorption of the active parentdrug.Mucosal damage: The long term use of drugs likely to

induce gut mucosal damage such as neomycin, colchicine,phenformin, mefenamic acid and cytotoxic agents, canimpair the absorption of other drugs, particularly thosewhich are normally poorly absorbed (digoxin or phenytoin).Colchicine can induce pernicious anaemia by interfering withvitamin B12 absorption.

Other mechanisms: Corticosteroids inhibit calciumabsorption, while phenobarbitone reduces griseofulvinabsorption, and folic acid absorption is reduced by drugs likephenytoin and nitrofurantoin leading to folic acid deficiencyand megaloblastic anaemia.

Drug distribution interactionsOne drug may alter the distribution of another and therebyaffect the concentration of the unbound active drug at thesite of action. The majority of acidic drugs are transportedpartially bound to plasma proteins. The free drug existsin equilibrium with the bound drug and only the former isavailable for pharmacological activity. Displacement (dis-placement interaction) of the bound drug by another drug,with greater affinity for plasma protein binding, willlead to release of relatively large amounts of the free drugwith an augmented action and likely toxicity. Similarly, drugsmay be displaced from tissue binding sites, viz. quinidinedisplaces digoxin from its skeletal muscle binding sites andmepacrine can displace primaquine. The importance of dis-placement interactions has been somewhat exaggerated andis likely to be of little clinical relevance unless hepaticmetabolism and renal clearance are seriously jeopardized.Normally, following displacement, the released free drugis metabolized and excreted in proportion to its degree ofdisplacement. Some examples of displacement interactionsare given in Table II.

Drug metabolism interactionsAmong the major sites for drug interactions are the hepaticdrug-metabolizing microsomal enzymes. One drug mayinterfere with the metabolism of another drug by eitherinducing or inhibiting these enzymes. In addition, extra-hepatic enzyme inhibition may also be the cause of druginteractions.Enzyme induction: Some drugs and environmental

chemicals stimulate drug metabolism through induction of

82

Target drug

TABLEIII. Drug interactions due to enzyme induction

Effect

THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 6, NO.2

Enzyme inducer

Oral contraceptivesOral anticoagulants

Phenytoin

L-dopa

Oral antidiabetics

Diazepam

Corticosteroids

Digoxin, digitoxin

Propranolol

RifampicinPhenobarbitone, phenytoin,carbamazepine, rifampicin,griseofulvinCarbamazepine

Pyridoxine

Rifampicin, phenobarbitone,phenytoinSmoking (benzpyrenes)

Phenobarbitone, phenytoin,rifampicinSame as above

Same as above

Failure of contraceptionReduced effect, toxicity on withdrawalof enzyme inducer

Reduced effect

Reduced effect

Reduced effect

Reduced effect

Reduced effect (renal transplantrejection)Reduced effect

Increased effect, biotransformed toactive metabolite

Target drug

TABLEIV. Drug interactions due to enzyme inhibition

EffectEnzyme inhibitor

Anticoagulants

Oral antidiabetics

Phenytoin

Diazepam, theophylline, .lignocaine, morphinePropranolol, encainide

Azathioprine,mercaptopurine

Phenylbutazone, cimetidine,metronidazole,chloramphenicol

Phenylbutazone,chloramphenicol,sulphonamides

Isoniazid (in slowacetylators), phenylbutazone,chloramphenicol, cimetidineCimetidine

Cimetidine

Allopurinol (inhibitsenzyme xanthine oxidase)

Increased toxicity (note thatphenylbutazone also inducesdisplacement interaction)

Increased toxicity (note thatphenylbutazone also inducesdisplacement interaction)

Increased toxicity

Increased toxicity

Reduced effect (metabolitesare clinically effective)Toxicity increased

hepatic microsomal enzymes. They bind to the cytosolicreceptors in the hepatic endoplasmic reticulum to activatethe production of mono-oxygenase and some conjugatingenzymes. The induction of enzyme activity will lead toreduced effects of the drugs which are inactivated (TableIII). However, the effects of drugs which are activated bybiotransformation, will be increased. Enzyme induction isslow in onset, since protein synthesis is involved, and theprocess is reversible with the withdrawal of the enzyme-inducing agent. The latter is of clinical relevance sincereduction in enzyme levels will result in a gradual increasein the plasma levels of the target drugs, resulting in toxicity.Thus, withdrawal of phenobarbitone, an enzyme inducer,will lead to increased toxicity of warfarin unless the dose ofthe latter is reduced.Enzyme induction and inhibition are important mechanisms

of drug interaction in the clinical context, since some ofthese drugs (e.g. rifampicin, dilantin and cimetidine) arecommonly used by clinicians.Enzyme inhibition: One drug may inhibit the metabolism

of another drug leading to an increase in circulating levelsof the active drug, and result in exaggerated and prolonged

responses, with an increased risk of toxicity. As in enzymeinduction, hepatic microsomal enzymes are involved. Theenzyme inhibition, unlike induction, occurs rapidly, but isalso reversible. Such interactions are likely to be of clinicalrelevance when they co-exist with displacement interaction.Drugs may also inhibit non-microsomal enzymes and induceinteractions. The effects of those drugs, which are activatedby biotransformation, are reduced by enzyme inhibitors.Drugs which undergo substantial first-pass metabolism in theliver, following oral administration, are more vulnerable tothis type of drug interaction. In addition, the initial con-centration of the target drug, the extent of inhibition, thesusceptibility of the patient and the magnitude of the clinicalresponse, are major factors in enzyme inhibition induceddrug interaction.Though many drugs have been reported to inhibit hepatic

drug-metabolizing enzymes, only a few appear to be ofclinical relevance (Table IV).An important example of food-drug interaction involves

the inhibition of the enzyme monoamine oxidase (MAO) bya number of drugs, known as MAO inhibitors, earlier usedfor the treatment of endogenous depression. Tyramine, a

BHATTACHARYA: ADVERSE DRUG INTERACTIONS

TABLEV. Drug excretion interactions

83

Target drug Excretion inhibitor Effect

Gentamicin (and other Frusemide, bumetanideaminoglycoside antibiotics)

Digoxin Quinidine, verapamil,spironolactone

Non-steroidal anti-inflammatory agents

Phenylbutazone

Salicylates (low doses)

Probenecid

Increased toxicity

Lithium

Retention may lead to increasedtoxicity

Increased toxicity

Chlorpropamide

Sulphinpyrazone

Penicillins,cephalosporins.methotrexate,indomethacin, dapsone

Hypoglycaemia

Decreased uricosuric effect

Retention may lead to prolongedaction or increased toxicity

dietary constituent, is normally metabolized by the gut andliver MAO. However, when MAO is inhibited, tyraminepasses largely unchanged through the intestinal mucosaand liver, and can induce the release of large amounts ofnoradrenaline from the sympathetic neurones leading to ahypertensive crisis. Thus selective MAO-A inhibitors, likeclorgyline, will induce hypertensive crises with tyramine-containing foods such as cheese, meat, yeast extracts andwines.There are also some enzyme inhibition drug interactions

which are therapeutically useful. Disulfiram (and otherdrugs like metronidazole, tinidazole, chlorpropamide,tolbutamide and nitrofurantoins) inhibit the enzymealdehyde dehydrogenase so that the metabolism of ethanolis inhibited with accumulation of acetaldehyde. The un-pleasant reactions induced by the latter form the basis of'aversion therapy' for alcoholics.

Drug excretion interactionsOne drug may affect the renal excretion of another by affectingurinary pH, glomerular filtration, tubular reabsorption andtubular secretion. Competition for renal tubular secretionappears to be an important mechanism though alterations inthe filtrate pH can influence drug reabsorption. Thus theexcretion of acidic drugs such as warfarin, barbiturates,phenylbutazone, salicylates, sulphonamides and streptomycinis greater in alkaline urine because of ionization andreduced reabsorption while the excretion of basic drugssuch as atropine, ephedrine, amphetamine, chloroquine,mepacrine and pethidine, is greater in acidic urine. Thereverse is true for reabsorption. In fact, amphetamineabusers take bicarbonates to enhance reabsorption of thedrug in an alkaline urine. Modulation of excretion kineticsof one drug by another has been used for the treatment ofdiseases, e.g. using penicillin with probenicid in gonococcalinfections and alkaline diuresis in barbiturate poisoning.Some other examples of drug excretion interaction likely tobe of clinical relevance are given in Table V.

PHARMACODYNAMIC INTERACTIONSThe drug interactions involving additive, synergistic orantagonistic effects of drugs acting on the same receptors orphysiological systems, account for most of the clinicallyimportant interactions. The literature is replete with such

interactions, though they often remain unsubstantiated orare true only in the experimental situation. I will cite onlythose examples which are either well documented or likely tohave practical implications. These interactions may be con-veniently sub-grouped according to the mechanisms involved:

Interactions at pharmacological receptorsOne drug may have greater affinity than another for areceptor. If the former drug has little or no intrinsic activity,the actions of the latter are antagonized. The first drug iscalled the antagonist and the second the agonist. Many suchinteractions can occur and are easily avoidable. Thus, theantagonism between cholinergic drugs and anti-cholinergicagents, adrenergic drugs and adrenergenic blocking agents,and opiates and naloxone can be predicted. However, some-times the antagonism appears paradoxical, viz. antagonismof morphine by pentazocine where the latter acts as a partialagonist, blocking the action of morphine on the opiate fJ.receptors and as an analgesic by acting on the )( receptors.Similarly, the mutual antagonism between the two peri-pherally acting muscle relaxants, d-tubocurarine andsuccinylcholine, is based on the difference in theirmechanism of action, the former acting by inhibitingdepolarization and the latter by inducing persistent depolari-zation at the neuromuscular junction. Though some of theseproduce adverse reactions, this pharmacodynamic inter-action is mainly useful in the treatment of patients withdrug overdosage.Drug synergism, involving the action of two drugs on the

same or different receptor sites, can also lead to adversedrug interactions. Thus, all central depressants can inducesynergistic sedation when combined. The potentiationof ethanol-induced central depression by diazepam, anti-histamines, phenothiazines, barbiturates, clonidine andmethyldopa are well documented. This becomes moreimportant in elderly subjects, where, due to their alteredpharmacokinetics, toxic manifestations appear early andmay become life threatening. Serious interactions charac-terized by extrapyramidal syndromes and irreversibledementia have been reported with lithium combined withhaloperidol or alpha-methyldopa, and with a combination ofalpha-methyldopa and haloperidol, possibly due to theiraction on dopamine receptors. The synergistic effects ofbeta-adrenergic blockers and calcium channel antagonists,

84 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 6, NO.2

Drugs Effect

TABLEVI. Interactions of drugs acting on the same physiological system

Carbenoxolone-spironolactoneThiazides/propranolol-aspirin

Phenytoin-reserpine

Oral hypoglycaemics-steroids/thiazides/frusemide

Abolition of ulcer healingDecreased antihypertensive effect

Decreased antiepileptic action

Decreased hypoglycaemic action

leading to atrioventricular conduction blocks, and thepotentiation of neuromuscular blocking agents by verapamilare some other examples.

Interaction between drugs acting on the samephysiological systemInteractions of this type may involve both synergism andantagonism. Thus, all aspirin-like drugs reduce plateletadhesiveness and potentiate warfarin anticoagulation.Aminoglycoside antibiotics potentiate neuromuscular block-ing agents, while frusemide potentiates the ototoxicity ofaminoglycosides. Ethanol-induced vasodilatation andhypotension can have serious synergistic consequences withanti-hypertensive agents. The synergistic gastric toxicity ofparacetamol and ibuprofen combinations may be related toinhibition of prostaglandin synthesis. Some examples of thistype of interaction are given in Table VI.

Interactions due to changes in fluid and electrolyte balanceInduced changes in electrolytes may alter the actions of somedrugs, particularly those acting on the heart, kidney and onneuromuscular transmission. Potassium depletion caused bydiuretics potentiates the action of digitalis and inducestoxicity. Similarly, hypokalaemia can antagonize the anti-arrhythmic activity of phenytoin, lignocaine, quinidine andprocainamide. Hypokalaemia can also prolong the musclerelaxant action of d-tubocurarine. On the other hand,hyperkalaemia can be induced by potassium-sparing diureticssuch as spironolactone, captopril and enalapril and non-steroidal anti-inflammatory agents, particularly in thepresence of impaired renal function. These drugs mayattenuate the clinical efficacy of digitalis and, when com-bined with potassium supplements, can lead to serious oreven fatal hyperkalaemia. Lithium intoxication can beprecipitated by thiazide diuretics as it is reabsorbed in theproximal tubule in exchange for sodium. Aspirin-like drugs,possibly by inhibiting prostaglandin-dependent renal excre-tion of lithium may also cause the same effect. Potentdiuretics, such as frusemide and bumetanide, may increasethe tubular concentration of potentially nephrotoxic agents(e.g. gentamicin) precipitating renal toxicity.

Interactions due to alterations in cellular transport mechanismsOne drug may interfere with the uptake and transport ofanother drug to intracellular sites of action. The adrenergicneurone appears to be particularly vulnerable since anuptake mechanism exists for aromatic amines which can beblocked by tricyclic antidepressants or by phenothiazineantipsychotic agents in larger doses. These uptake inhibitorscan attenuate the intraneuronal uptake of drugs such asguanethidine, debrisoquine and clonidine, thereby inhibitingtheir antihypertensive actions. In addition, these aminepump inhibitors can also inhibit the effects of indirectly act-

ing sympathetic amines, such as amphetamine, ephedrine,pseudoephedrine and phenylephrine, which releaseendogenous noradrenaline after uptake into the adrenergicneurones. The actions of exogenously administerednoradrenaline and adrenaline are also potentiated since theamines are not taken up into the neurones and exert theireffects on the postsynaptic receptors. The indirectly actingsympathetic amines can also interfere with the antihyperten-sive effects of guanethidine and related drugs by competingfor the uptake process.

Interactions due to other pharmacodynamic mechanismsSome drug interactions may result from interference withphysiological compensatory mechanisms. Thus beta-adrenergic blockers may potentiate the hypoglycaemiceffects of oral anti diabetics or an overdose of insulin byinhibiting glycogenolysis. The attenuation of the action ofantihypertensives by inducing sodium retention, and ofthe hypoglycaemic effects of oral antidiabetics by cortico-steroids have been well demonstrated. Mutual antagonismhas been noted when bacteriostatic and bactericidal drugsare administered in combination. Thus, a bactericidal agentsuch as penicillin, which acts by interfering with bacterial cellwall synthesis, will become less effective when cell division isarrested by bacteriostatic drugs such as tetracyclines.

CONCLUSIONThe true incidence and clinical relevance of drug interactionsis difficult to assess and published clinical reports representonly the tip of an enormous iceberg. It is equally difficultto delineate the incidence of therapeutic failures due to druginteractions. The exhaustive tabulations of drug interactions,often based on animal data or unconfirmed reports, tend toconfuse clinicians. Adverse drug interactions can be avoidedif the major drugs at risk of interaction, viz. oral anti-coagulants, hypoglycaemic agents, cardiac glycosides,antihypertensives, psychotropic drugs, antiepileptics,immunosuppressants and cytotoxic agents, are prescribedrationally. The patients at risk of interactions are the elderly,those who are acutely ill, have compromised hepatic andrenal function, unstable disease and others who are beingtreated on a long term basis. Also at risk are patients beingtreated by two or more physicians simultaneously and thosewho indulge in self-medication. While polypharmacy cannotalways be avoided, it should be remembered that each time anew drug is added or deleted from an existing stabletherapeutic regimen, drug interaction may occur. The onlyway to recognize a drug interaction is to consider that it ispossible. The problem is particularly important in Indiawhere virtually any drug can be bought over the counterwithout a valid prescription, where quacks abound andwhere a variety of indigenous drugs are prescribed togetherwith modern therapeutic agents.