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.