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

2. Pharmacokinetic interactions or interactions due to alter- ations in the absorption, distribution, metabolism or Adverse drug interactions excretion of one drug by another. 3. Pharmacodynamic interactions or interactions due to S. K. BHATIACHARYA alterations in the pharmacological action of one drug by another, at or near the target site of action, and may involve the basic mechanism by which these drugs act.

PHARMACEUTICAL INTERACTIONS INTRODUCTION Drugs may be inactivated or precipitated from solution if The pharmacokinetics as well as the effects of a drug can mixed in syringes or added to blood or infusion fluids prior to be altered by the previous or concurrent administration of administration. Generally the manufacturer's literature anoth~~. While .such an .interacti~n may be therapeutically provides specific warnings and guidelines which should be beneficial occasionally, In many Instances it may result in checked. Important drug interactions are listed in Table I. adverse effects. The increasing tendency for polypharmacy It is advisable to avoid mixing drugs in infusion solutions is not always guided by principles of rational drug therapy. unless it is known that the mixture is safe (e.g. potassium The long term use of potent drugs and self-medication has chloride and insulin). Two infusion sites can be used if two resulted in an increase in the incidence of adverse drug drugs have to be administered simultaneously. interactions. Every time a physician prescribes an additional drug, he or she is adding to the risk of these interactions. It PHARMACOKINETIC INTERACTIONS has been estimated that patients in hospital who are receiving These interactions may take place during absorption, more than six drugs at a time, have a 6 to 7 times greater incidence of adverse effects (including those due to drug metabolism, distribution and excretion of drugs-factors interactions) than those who are receiving less than six which .~re impo~tant for the bioavailability of a drug at its drugs. Also, about 7% of all adverse drug reactions are target site of action. The interactions can be anticipated but estimated to be due to drug interactions and account for their extent cannot be predicted because there are marked approximately one-third of the mortality of such patients. individual variations in their pharmacokinetic properties. The elderly are more prone to drug interactions, not only The clinically important interactions are the following: because they receive more drugs than younger patients, but Drug absorption interactions because in them the pharmacokinetics of drugs are different. Th~ literat~re is replete with numerous examples of likely One drug may retard the rate or extent of absorption of drug mteracnons, most of the data being based on animal another drug in a variety of ways. It is important to differen- studies, single case reports or anecdotal evidence. Fortu- tiate between the two since the consequences are likely to be nately, the drug interactions of clinical importance are quite different. For instance, an alteration in the rate of relatively few and many of these can be predicted if their a~sorption ?f a drug wit~ a long plasma half-life (warfarin) pharmacodynamic effects, salient pharmacokinetic proper- Will have httle effect SInce the drug will eventually be ties and mechanisms of action are known and logically absorbed. However, when the drug has a short plasma half- applied in the clinical setting. life (procainamide) reduction in the rate of absorption means that an effective therapeutic concentration in the plasma MECHANISMS OF DRUG INTERACTIONS may never be achieved. A delay in the rate of absorption is Unfortunately, most physicians are often unaware of the also import~nt with ~rugs s~ch as analgesics and hypnotics, where a rapid effect IS required. Some important causes of pharmacological properties of the drugs they prescribe, absorption interactions are as follows: cannot recognize their unwanted reactions and are unable to . identify the likely adverse effects due to drug interaction. Intralum~nal binding or chelation of drugs: Drugs may react chemically to form unabsorbable chelates, viz. iron and To confound the issue further, the large number (approxi- tetracycline, aluminium, magnesium or calcium containing ma~ely 65.(00) of fixed-dose combination drugs available in India which are frequently irrational pharmacologically, antacids with tetracycline. Drug absorption may be reduced by adsorbents, such as kaolin or charcoal and by anion contribute to the incidence of drug interactions because the exch~ng~ .r~sins such as cholestyramine and colestipol, prescribers do not remember their constituents. e.g: Inhibition of digoxin absorption by anion exchange The important mechanisms responsible for drug inter- resms. Sucralfate reduces absorption of phenytoin and liquid actions can be classified as follows: paraffin reduces absorption of fat soluble vitamins. 1. Pharmaceutical interactions or interactions occurring out- Gastrointestinal motility and transit time: Most drugs are side the body. absorbed from the first part of the small intestine and the rate of gastric emptying will influence their rate of absorption. Institute of Medical Sciences, Banaras Hindu University, Drugs such as opiates, anticholinergics, tricyclic anti- Varanasi 221005, Uttar Pradesh, India depressants, antihistaminics and phenothiazines slow gastric S. K. BHA IT ACHARY A Department of Pharmacology emptying time, whereas metoclopramide increases it. This © The National Medical Journal of India 1993 BHAITACHARYA ; ADVERSE DRUG INTERACTIONS 81

TABbEI. General guidelines for prevention of pharmaceutical interactions

A void using the [allowing together in intravenous therapy 1. 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 of sulphonamides, 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 anticoagulants Analgesics, including phenylbutazone and indomethacin, phenytoin, clofibrate, sulphonamides Oral antidiabetics Phenylbutazone, indomethacin, anticoagulants, sulphonamides Phenytoin Phenylbutazone, indomethacin Digoxin Quinidine, nifedipine, verapamil, amiodarone Primaquine Mepacrine

type of interaction is important with drugs such as antibiotics Other mechanisms: Corticosteroids inhibit calcium or analgesics when rapid peak plasma concentrations are absorption, while phenobarbitone reduces griseofulvin desirable. Thus, a combination of metoc\opramide with absorption, and folic acid absorption is reduced by drugs like analgesics has been used in the treatment of an acute attack phenytoin and nitrofurantoin leading to folic acid deficiency of migraine. and megaloblastic anaemia. Alterations in the pH of gastrointestinal fluids: Basic drugs are ionized, become less lipid soluble and are poorly Drug distribution interactions absorbed in an acidic medium, whereas the reverse is true for One drug may alter the distribution of another and thereby acidic drugs in an alkaline medium. The unsupervised intake affect the concentration of the unbound active drug at the of antacids may thus interfere with the absorption of many site of action. The majority of acidic drugs are transported acidic drugs (aspirin, barbiturates and warfarin). A marked partially bound to plasma proteins. The free drug exists reduction in gastric acidity by H2 blockers and omeprazole in equilibrium with the bound drug and only the former is decreases the absorption of ketoconazole. available for pharmacological activity. Displacement (dis- Alterations in gut bacterial flora: Broad spectrum anti- placement interaction) of the bound drug by another drug, biotics (cephalosporins and erythromycin) adversely affect with greater affinity for plasma protein binding, will the gut bacterial flora and may affect the action of a number lead to release of relatively large amounts of the free drug of drugs. Sulphasalazine is biotransformed into an active with an augmented action and likely toxicity. Similarly, drugs metabolite. by gut flora, L-dopa is converted into dopamine may be displaced from tissue binding sites, viz. quinidine and digoxin is partIy metabolized by them. Thus, the effect displaces digoxin from its skeletal muscle binding sites and of sulphasalazine will be reduced while the effect of the other mepacrine can displace primaquine. The importance of dis- drugs will be augmented if the gut flora are reduced, and may placement interactions has been somewhat exaggerated and lead to toxicity. The toxicity of oral anticoagulants can be is likely to be of little clinical relevance unless hepatic increased following a decrease in the vitamin K availability metabolism and renal clearance are seriously jeopardized. from these bacteria. It has been reported recently that in Normally, following displacement, the released free drug some women broad spectrum antibiotics interfere with the is metabolized and excreted in proportion to its degree of antifertility action of oral contraceptive pi\ls. The mechanism displacement. Some examples of displacement interactions involved is disruption of the enterohepatic cycling of the are given in Table II. hormones by a reduction of the gut bacteria responsible for the deconjugation and reabsorption of the active parent Drug metabolism interactions drug. Among the major sites for drug interactions are the hepatic Mucosal damage: The long term use of drugs likely to drug-metabolizing microsomal enzymes. One drug may induce gut mucosal damage such as neomycin, colchicine, interfere with the metabolism of another drug by either phenformin, mefenamic acid and cytotoxic agents, can inducing or inhibiting these enzymes. In addition, extra- impair the absorption of other drugs, particularly those hepatic enzyme inhibition may also be the cause of drug which are normally poorly absorbed (digoxin or phenytoin). interactions. Colchicine can induce pernicious anaemia by interfering with Enzyme induction: Some drugs and environmental vitamin B12 absorption. chemicals stimulate drug metabolism through induction of 82 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 6, NO.2

TABLEIII. Drug interactions due to enzyme induction

Target drug Enzyme inducer Effect

Oral contraceptives Rifampicin Failure of contraception Oral anticoagulants Phenobarbitone, phenytoin, Reduced effect, toxicity on withdrawal carbamazepine, rifampicin, of enzyme inducer griseofulvin Phenytoin Carbamazepine Reduced effect L-dopa Pyridoxine Reduced effect Oral antidiabetics Rifampicin, phenobarbitone, Reduced effect phenytoin Diazepam Smoking (benzpyrenes) Reduced effect Corticosteroids Phenobarbitone, phenytoin, Reduced effect (renal transplant rifampicin rejection) Digoxin, digitoxin Same as above Reduced effect Propranolol Same as above Increased effect, biotransformed to active metabolite

TABLEIV. Drug interactions due to enzyme inhibition

Target drug Enzyme inhibitor Effect

Anticoagulants Phenylbutazone, cimetidine, Increased toxicity (note that metronidazole, phenylbutazone also induces chloramphenicol displacement interaction) Oral antidiabetics Phenylbutazone, Increased toxicity (note that chloramphenicol, phenylbutazone also induces sulphonamides displacement interaction) Phenytoin Isoniazid (in slow Increased toxicity acetylators), phenylbutazone, chloramphenicol, cimetidine Diazepam, theophylline, . Cimetidine Increased toxicity lignocaine, morphine Propranolol, encainide Cimetidine Reduced effect (metabolites are clinically effective) Azathioprine, Allopurinol (inhibits Toxicity increased mercaptopurine enzyme xanthine oxidase) hepatic microsomal enzymes. They bind to the cytosolic responses, with an increased risk of toxicity. As in enzyme receptors in the hepatic endoplasmic reticulum to activate induction, hepatic microsomal enzymes are involved. The the production of mono-oxygenase and some conjugating enzyme inhibition, unlike induction, occurs rapidly, but is enzymes. The induction of enzyme activity will lead to also reversible. Such interactions are likely to be of clinical reduced effects of the drugs which are inactivated (Table relevance when they co-exist with displacement interaction. III). However, the effects of drugs which are activated by Drugs may also inhibit non-microsomal enzymes and induce biotransformation, will be increased. Enzyme induction is interactions. The effects of those drugs, which are activated slow in onset, since protein synthesis is involved, and the by biotransformation, are reduced by enzyme inhibitors. process is reversible with the withdrawal of the enzyme- Drugs which undergo substantial first-pass metabolism in the inducing agent. The latter is of clinical relevance since liver, following oral administration, are more vulnerable to reduction in enzyme levels will result in a gradual increase this type of drug interaction. In addition, the initial con- in the plasma levels of the target drugs, resulting in toxicity. centration of the target drug, the extent of inhibition, the Thus, withdrawal of phenobarbitone, an enzyme inducer, susceptibility of the patient and the magnitude of the clinical will lead to increased toxicity of warfarin unless the dose of response, are major factors in enzyme inhibition induced the latter is reduced. drug interaction. Enzyme induction and inhibition are important mechanisms Though many drugs have been reported to inhibit hepatic of drug interaction in the clinical context, since some of drug-metabolizing enzymes, only a few appear to be of these drugs (e.g. rifampicin, dilantin and cimetidine) are clinical relevance (Table IV). commonly used by clinicians. An important example of food-drug interaction involves Enzyme inhibition: One drug may inhibit the metabolism the inhibition of the enzyme monoamine oxidase (MAO) by of another drug leading to an increase in circulating levels a number of drugs, known as MAO inhibitors, earlier used of the active drug, and result in exaggerated and prolonged for the treatment of endogenous depression. Tyramine, a BHATTACHARYA: ADVERSE DRUG INTERACTIONS 83

TABLEV. Drug excretion interactions

Target drug Excretion inhibitor Effect

Gentamicin (and other Frusemide, bumetanide Increased toxicity aminoglycoside antibiotics) Digoxin Quinidine, verapamil, Retention may lead to increased spironolactone toxicity Lithium Non-steroidal anti- Increased toxicity inflammatory agents Chlorpropamide Phenylbutazone Hypoglycaemia Sulphinpyrazone Salicylates (low doses) Decreased uricosuric effect Penicillins, Probenecid Retention may lead to prolonged cephalosporins. action or increased toxicity methotrexate, indomethacin, dapsone dietary constituent, is normally metabolized by the gut and interactions, though they often remain unsubstantiated or liver MAO. However, when MAO is inhibited, tyramine are true only in the experimental situation. I will cite only passes largely unchanged through the intestinal mucosa those examples which are either well documented or likely to and liver, and can induce the release of large amounts of have practical implications. These interactions may be con- noradrenaline from the sympathetic neurones leading to a veniently sub-grouped according to the mechanisms involved: hypertensive crisis. Thus selective MAO-A inhibitors, like clorgyline, will induce hypertensive crises with tyramine- Interactions at pharmacological receptors containing foods such as cheese, meat, yeast extracts and One drug may have greater affinity than another for a wines. receptor. If the former drug has little or no intrinsic activity, There are also some enzyme inhibition drug interactions the actions of the latter are antagonized. The first drug is which are therapeutically useful. Disulfiram (and other called the antagonist and the second the agonist. Many such drugs like metronidazole, tinidazole, chlorpropamide, interactions can occur and are easily avoidable. Thus, the tolbutamide and nitrofurantoins) inhibit the enzyme antagonism between cholinergic drugs and anti-cholinergic aldehyde dehydrogenase so that the metabolism of ethanol agents, adrenergic drugs and adrenergenic blocking agents, is inhibited with accumulation of acetaldehyde. The un- and opiates and naloxone can be predicted. However, some- pleasant reactions induced by the latter form the basis of times the antagonism appears paradoxical, viz. antagonism 'aversion therapy' for alcoholics. of morphine by pentazocine where the latter acts as a partial agonist, blocking the action of morphine on the opiate fJ. Drug excretion interactions receptors and as an analgesic by acting on the )( receptors. One drug may affect the renal excretion of another by affecting Similarly, the mutual antagonism between the two peri- urinary pH, glomerular filtration, tubular reabsorption and pherally acting muscle relaxants, d-tubocurarine and tubular secretion. Competition for renal tubular secretion succinylcholine, is based on the difference in their appears to be an important mechanism though alterations in mechanism of action, the former acting by inhibiting the filtrate pH can influence drug reabsorption. Thus the depolarization and the latter by inducing persistent depolari- excretion of acidic drugs such as warfarin, barbiturates, zation at the neuromuscular junction. Though some of these phenylbutazone, salicylates, sulphonamides and streptomycin produce adverse reactions, this pharmacodynamic inter- is greater in alkaline urine because of ionization and action is mainly useful in the treatment of patients with reduced reabsorption while the excretion of basic drugs drug overdosage. such as atropine, ephedrine, amphetamine, chloroquine, Drug synergism, involving the action of two drugs on the mepacrine and pethidine, is greater in acidic urine. The same or different receptor sites, can also lead to adverse reverse is true for reabsorption. In fact, amphetamine drug interactions. Thus, all central depressants can induce abusers take bicarbonates to enhance reabsorption of the synergistic sedation when combined. The potentiation drug in an alkaline urine. Modulation of excretion kinetics of ethanol-induced central depression by diazepam, anti- of one drug by another has been used for the treatment of histamines, phenothiazines, barbiturates, clonidine and diseases, e.g. using penicillin with probenicid in gonococcal methyldopa are well documented. This becomes more infections and alkaline diuresis in barbiturate poisoning. important in elderly subjects, where, due to their altered Some other examples of drug excretion interaction likely to pharmacokinetics, toxic manifestations appear early and be of clinical relevance are given in Table V. may become life threatening. Serious interactions charac- terized by extrapyramidal syndromes and irreversible PHARMACODYNAMIC INTERACTIONS dementia have been reported with lithium combined with The drug interactions involving additive, synergistic or haloperidol or alpha-methyldopa, and with a combination of antagonistic effects of drugs acting on the same receptors or alpha-methyldopa and haloperidol, possibly due to their physiological systems, account for most of the clinically action on dopamine receptors. The synergistic effects of important interactions. The literature is replete with such beta-adrenergic blockers and calcium channel antagonists, 84 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 6, NO.2

TABLEVI. Interactions of drugs acting on the same physiological system

Drugs Effect

Carbenoxolone-spironolactone Abolition of ulcer healing Thiazides/propranolol-aspirin Decreased antihypertensive effect Phenytoin-reserpine Decreased antiepileptic action Oral hypoglycaemics-steroids/thiazides/frusemide Decreased hypoglycaemic action leading to atrioventricular conduction blocks, and the ing sympathetic amines, such as amphetamine, ephedrine, potentiation of neuromuscular blocking agents by verapamil pseudoephedrine and phenylephrine, which release are some other examples. endogenous noradrenaline after uptake into the adrenergic neurones. The actions of exogenously administered Interaction between drugs acting on the same noradrenaline and adrenaline are also potentiated since the physiological system amines are not taken up into the neurones and exert their Interactions of this type may involve both synergism and effects on the postsynaptic receptors. The indirectly acting antagonism. Thus, all aspirin-like drugs reduce platelet sympathetic amines can also interfere with the antihyperten- adhesiveness and potentiate warfarin anticoagulation. sive effects of guanethidine and related drugs by competing Aminoglycoside antibiotics potentiate neuromuscular block- for the uptake process. ing agents, while frusemide potentiates the ototoxicity of aminoglycosides. Ethanol-induced vasodilatation and Interactions due to other pharmacodynamic mechanisms hypotension can have serious synergistic consequences with Some drug interactions may result from interference with anti-hypertensive agents. The synergistic gastric toxicity of physiological compensatory mechanisms. Thus beta- paracetamol and ibuprofen combinations may be related to adrenergic blockers may potentiate the hypoglycaemic inhibition of prostaglandin synthesis. Some examples of this effects of oral anti diabetics or an overdose of insulin by type of interaction are given in Table VI. inhibiting glycogenolysis. The attenuation of the action of antihypertensives by inducing sodium retention, and of Interactions due to changes in fluid and electrolyte balance the hypoglycaemic effects of oral antidiabetics by cortico- Induced changes in electrolytes may alter the actions of some steroids have been well demonstrated. Mutual antagonism drugs, particularly those acting on the heart, kidney and on has been noted when bacteriostatic and bactericidal drugs neuromuscular transmission. Potassium depletion caused by are administered in combination. Thus, a bactericidal agent diuretics potentiates the action of digitalis and induces such as penicillin, which acts by interfering with bacterial cell toxicity. Similarly, hypokalaemia can antagonize the anti- wall synthesis, will become less effective when cell division is arrhythmic activity of phenytoin, lignocaine, quinidine and arrested by bacteriostatic drugs such as tetracyclines. procainamide. Hypokalaemia can also prolong the muscle relaxant action of d-tubocurarine. On the other hand, CONCLUSION hyperkalaemia can be induced by potassium-sparing diuretics The true incidence and clinical relevance of drug interactions such as spironolactone, captopril and enalapril and non- is difficult to assess and published clinical reports represent steroidal anti-inflammatory agents, particularly in the only the tip of an enormous iceberg. It is equally difficult presence of impaired renal function. These drugs may to delineate the incidence of therapeutic failures due to drug attenuate the clinical efficacy of digitalis and, when com- interactions. The exhaustive tabulations of drug interactions, bined with potassium supplements, can lead to serious or often based on animal data or unconfirmed reports, tend to even fatal hyperkalaemia. Lithium intoxication can be confuse clinicians. Adverse drug interactions can be avoided precipitated by thiazide diuretics as it is reabsorbed in the if the major drugs at risk of interaction, viz. oral anti- proximal tubule in exchange for sodium. Aspirin-like drugs, coagulants, hypoglycaemic agents, cardiac glycosides, possibly by inhibiting prostaglandin-dependent renal excre- antihypertensives, psychotropic drugs, antiepileptics, tion of lithium may also cause the same effect. Potent immunosuppressants and cytotoxic agents, are prescribed diuretics, such as frusemide and bumetanide, may increase rationally. The patients at risk of interactions are the elderly, the tubular concentration of potentially nephrotoxic agents those who are acutely ill, have compromised hepatic and (e.g. gentamicin) precipitating renal toxicity. renal function, unstable disease and others who are being treated on a long term basis. Also at risk are patients being Interactions due to alterations in cellular transport mechanisms treated by two or more physicians simultaneously and those One drug may interfere with the uptake and transport of who indulge in self-medication. While polypharmacy cannot another drug to intracellular sites of action. The adrenergic always be avoided, it should be remembered that each time a neurone appears to be particularly vulnerable since an new drug is added or deleted from an existing stable uptake mechanism exists for aromatic amines which can be therapeutic regimen, drug interaction may occur. The only blocked by tricyclic antidepressants or by phenothiazine way to recognize a drug interaction is to consider that it is antipsychotic agents in larger doses. These uptake inhibitors possible. The problem is particularly important in India can attenuate the intraneuronal uptake of drugs such as where virtually any drug can be bought over the counter guanethidine, debrisoquine and clonidine, thereby inhibiting without a valid prescription, where quacks abound and their antihypertensive actions. In addition, these amine where a variety of indigenous drugs are prescribed together pump inhibitors can also inhibit the effects of indirectly act- with modern therapeutic agents.