J Clin Pathol: first published as 10.1136/jcp.s3-9.1.94 on 1 January 1975. Downloaded from J. clin. Path., 28, Suppl. (Roy. Coll. Path.), 9, 94-98 The drug dilemma-benefits and hazards Drug interactions and lethal drug combinations ALAN RICHENS From the Department of Clinical Pharmacology, St Bartholomew's Hospital, London Although the development of drugs of greater example, aspirin can displace oral anticoagulants potency and efficacy confers on the physician from their plasma-protein-binding sites, and in- increasing power to treat serious diseases, it also directly acting sympathomimetics contained in cough increases the number and seriousness of potential mixtures can cause a hypertensive crisis in patients adverse effects and drug interactions which can on monoamine oxidase inhibitors. Self-medication is occur. Most hospital patients receive more than one common, and often involves drugs obtained on drug at a time, the average number often being prescription for a previous illness. greater than five (Smith, Seidl, and Cluff, 1966). The 4 When several clinics or doctors are involved in incidence of drug reactions rises with the number of the care of a patient, one doctor may not be aware of drugs prescribed simultaneously. In patients pre- what another has prescribed. scribed one to five drugs the incidence of reactions is 5 When preparations which contain more than 18-6%, while in patients prescribed six or more one ingredient are prescribed by their trade names. it rises to 814 % (Hurwitz and Wade, 1969). There are a number of ways in which drugs may The Boston Collaborative Drug Surveillance interact. These will be outlined and illustrated in the Program (1972) surveyed the incidence of drug remainder of this paper. reactions in 9900 patients admitted to nine acute disease hospitals and one chronic disease hospital. Interactions before Administration There were 83 200 drugs administered, and 3600 adverse reactions occurred of which 6-9 % were due Some drugs are chemically or physically incom- to drug interactions. The most serious interactions patible in the forms in which they are presented for included depression of the central nervous system, administration. For example, thiopentone sodium injection is strongly alkaline and will cause hydrolysis severe hypotension, gastrointestinal bleeding, psy- http://jcp.bmj.com/ chotic behaviour and superinfection. Although the of suxamethonium if both drugs are drawn up into clinical importance of drug interactions has been a syringe together for combined anaesthetic induc- exaggerated in some reports, the number which end tion and muscle relaxation. The excess of protamine in a fatal outcome is disproportionately high. In a zinc in protamine zinc insulin will combine with survey of 6199 medical inpatients in five general soluble insulin if the two preparations are mixed in hospitals and one chronic disease hospital, 744 the syringe before injection, resulting in a change in patients died in hospital, and of these deaths 27 were the rate of absorption of the latter preparation. As a considered to be due to drug treatment, of which nine general rule drug solutions should not be mixed, nor on October 1, 2021 by guest. Protected copyright. were caused by drug interactions (Shapiro, Slone, added to intravenous infusions, particularly whole Lewis, and Jick, 1971). blood, unless it is known that the components are The physician should be alert to the danger of chemically and physically compatible. drug interactions in a number of circumstances. Interactions in the Gut 1 When the pharmacological effect of a drug is harmful in excess and when the therapeutic ratio is Drugs are absorbed largely in the upper part of the low. Examples are hypoglycaemic drugs, anti- small intestine because of the enormous mucosal coagulants, digoxin, depressants of the central surface area and blood supply present there. Drugs nervous system, cytotoxic drugs. which alter the rate of gastric emptying can affect the 2 When a drug produces an altered state of delivery of the drug to this site and can thereby receptor sensitivity in the sympathetic nerve ter- influence either the rate or the extent of absorption. minals, eg, monoamine oxidase inhibitors (MA0Is), The anticholinergic properties of propantheline tricyclic antidepressants, hypotensive drugs. reduce the rate of gastric emptying and therefore 3 When interactions occur with medicines that slow down the absorption ofa drug such as paraceta- can be bought over the chemist's counter. For mol (Prescott, 1974). However, the extent of absorp- 94 J Clin Pathol: first published as 10.1136/jcp.s3-9.1.94 on 1 January 1975. Downloaded from Drug interactions and lethal drug combinations 95 tion, particularly of poorly soluble drugs like metabolism is substantially reduced by inhibition of digoxin, may be increased. As many drugs possess the metabolic enzyme. It is probable that this partly anticholinergic effects, eg, antihistamines, tricyclic accounts for the hypertensive crisis which can result antidepressants, phenothiazines and anti-Parkin- from the administration of directly acting sympa- sonian drugs, this type of interaction probably thomimetic amines, eg, tyramine, ephedrine, levo- occurs commonly. Metoclopramide increases the dopa, to patients on chronic MAOI therapy. An rate of gastric emptying, particularly in patients in interaction at the sympathetic nerve terminal is also whom it is delayed, and has been shown to shorten important in causing the crisis (see below). the time to peak plasma concentration of paraceta- The administration of dopa decarboxylase inhi- mol and aspirin (Prescott, 1974; Volans, 1974). bitors, eg, carbidopa in Sinemet, or benserazide in Some drugs may interact chemically in the gut, Madopar, probably increases the quantity of leading to impaired absorption of both drugs. levodopa which reaches the systemic circulation Calcium, magnesium and aluminium ions contained unmetabolized, as well as reducing its peripheral in antacid preparations cause the formation of a metabolism in tissues which contain the enzyme, metal-tetracycline chelate which is poorly absorbed such as sympathetic nerve terminals. In this case the (Kunin and Finland, 1961). Iron salts given simul- interaction is used to advantage because the amount taneously for anaemia will have a similar effect of levodopa which has to be administered daily to (Neuvonen and Turakka, 1974). These interactions the Parkinsonian patient can be reduced to between may result in an inadequate serum concentration of a quarter and a fifth by the addition of the enzyme the antibiotic being reached, with consequent inhibitor. failure of therapy. Chemical interaction in the gut It is likely that long-term therapy with liver- appears to account also for the failure of griseoful- enzyme-inducing drugs such as barbiturates can vin's antifungal action in patients receiving a reduce the quantity of other drugs reaching the barbiturate drug (Riegelman, Rowland, and Epstein, systemic circulation by increasing their first-pass 1970), and the reduction in plasma rifampicin metabolism, although it is not easy to distinguish concentrations by concurrent administration of this type of interaction from one involving a reduc- para-aminosalicylate (Boman, Hanngren, Malm- tion in absorption from the gut. borg, Borga, and Sjoqvist, 1971). Although barbi- turates are known to induce the hepatic metabolism Plasma-protein-binding Interactions of oral anticoagulants, it has been suggested that an interaction in the gut lumen might also contribute Many drugs are loosely bound to plasma proteins, to the lowering of the serum level of the anti- usually albumin. Only the unbound drug molecules coagulant (O'Reilly and Aggeler, 1969). are available for pharmacological action, although A deficiency of vitamin K in a patient treated with as they are removed from the circulation by distri- http://jcp.bmj.com/ oral anticoagulants will exaggerate the effect of bution or elimination they are replaced by other these latter compounds. Commensal organisms in molecules detaching themselves from protein- the gut produce vitamin K and therefore gut binding sites. A number of drugs are extensively sterilization with broad-spectrum antibiotics may bound to plasma proteins and therefore competition disturb anticoagulant control. Ingestion of liquid for binding sites can be a cause of drug interaction, paraffin may have the same effect because of the fat- although it is not easy to predict which drugs are soluble nature of the vitamin. likely to interact in this way because different types of on October 1, 2021 by guest. Protected copyright. binding sites may be used by different drugs. On the Interactions during Absorption whole, it is probable that competition for binding sites is not often a cause of a clinically important Drugs which are absorbed from the gut enter the interaction. portal venous system and are therefore exposed to Although displacement of a proportion of a drug drug-metabolizing enzymes in the hepatic cells bound to plasma proteins will increase the concen- before they enter the systemic circulation. This tration of free drug in the serum and therefore its results in a considerable loss of drugs that are pharmacological effect, the extent to which it is metabolized rapidly on first passage through the increased is dependent upon the drug's distribution liver-the so-called 'first pass effect'. Examples of volume. Centrally acting drugs, eg, phenytoin, are drugs for which this is important are isoprenaline, usually highly lipid soluble and have a large distri- ephedrine, levodopa, propranolol, aspirin and bution volume. A small quantity displaced from nortriptyline. Drug interactions may alter the extent binding sites will therefore rapidly redistribute to of first pass metabolism. This is likely to be most other tissues and will not cause an important important when a normally high rate of first pass increase in the effects of the drug. Warfarin, however, J Clin Pathol: first published as 10.1136/jcp.s3-9.1.94 on 1 January 1975. Downloaded from 96 Alan Richens is both highly bound to plasma proteins (98-99%) tion (by enzyme induction). This latter type of and has a relatively small distribution volume.