Adverse Drug Interactions: A Handbook for Prescribers

Abstract

Professor Karalliedde and his colleagues have set themselves a hard task: to provide ‘a source of easily accessible and concise information and guidance to busy prescribers . . .’ on drug–drug interactions. The possibilities of interactions are many and increasing, not least because patients are taking more medicines. If a patient is taking five different medicines, which is common enough these days, there are 10 different possible combinations of two drugs. The pharmacopoeia lists approximately 6000 medicines, giving of the order of 18 million combinations two at a time, so no practical paper-based system could possibly account for every combination. One way of reducing the number of entries is to take drugs by class, but new problems arise. The classes of medicines relevant to interactions – for example, those that affect the QT interval, or CYP 3A4 – are often not the traditional therapeutic classes. Within a therapeutic class, such as the proton pump inhibitors or the statins, there will be marked differences in the behaviour of individual members of the class. Clinicians struggle in the face of the information bombardment and urgently need red signals to warn of potential danger, and ensure that they can pick out important information from the background of irrelevant theoretical concerns. If clinicians are to take precautions to avoid harm from interactions, these need to be spelled out clearly. How does the Handbook for Prescribers manage in this complex area? The first thing to say is that it is not compact; it is nearly 800 pages long and weighs more than the British National Formulary (BNF), which itself devotes nearly 90 closely printed pages to interactions. The entries are arranged by drug class, and each appears twice, so that warfarin plus opiods (tramadol) repeats what is entered under opioids (tramadol) plus warfarin. Stockley's Drug Interactions Pocket Companion (2007), by contrast, uses a more compact system of cross-referencing. The 47 page index of drug names in the Handbook could have carried cross-references, and this would have substantially reduced its size, though at the cost of increased page-turning. The authors acknowledge that information on the best way to mitigate the potentially harmful effects of an interaction is often lacking. The precautions they describe are sometimes clear, directive, and useful; for example, for midazolam plus erythromycin, ‘reduce dose of benzodiazepine by 50%; warn patients not to perform skilled tasks such as driving for at least 10 h after the dose of benzodiazepine.’ Sometimes the suggestions are trite; for example, for opioids plus antihistamines, ‘monitor vital signs closely during co-administration.’ And sometimes they are mystifying; for example, for probenicid plus penicillins, ‘watch for increased incidence of side-effect of antibiotic.’ Leaving aside the question of collateral adverse effects of penicillins, the major reason for giving probenicid in the past was to increase serum penicillin concentrations. And while the Handbook states that the mechanism of this interaction is uncertain, it is a classical example of inhibition of an organic anion transporter (OAT-3; SLC22A8) and so of the renal excretion of its substrate, penicillin. There are some exciting revelations in the Handbook. Cannabis can reduce the blood pressure response to verapamil, apparently through an action on CYP 1A2; and zinc supplements reduce the absorption of co-administered iron salts, for example; BNF (no. 59) describes the second interaction, but is silent on the first. In summary, Adverse Drug Interactions: a Handbook for Prescribers is a brave attempt to make some sense of adverse drug interactions. It is concise, but it gives rather more information on interactions, and sometimes more insight, than the BNF. Busy prescribers may struggle to find the information they need in the time they have, but when they do, it should be helpful.