Interactions between drugs were first recognised over 100 years ago. A drug interaction is said to occur when the response of a patient to a drug is changed by the presence of another drug, food, drink, herb or by some environmental chemical agent. The net effect of the combination may be:

• synergism or additive effect of one or more drugs

• antagonism or reduction of the effects of one or more drugs

• alteration of effect of one or more drugs or the production of idiosyncratic effects or toxicity.

Although many recognised interactions are deliberately used with therapeutic benefit, drug interactions are an increasingly important cause of adverse drug reactions (ADRs). Contributing factors include a plethora of new therapeutic agents with complex mechanisms of action and multiple effects, and the increasing prevalence of polypharmacy. Despite rigorous attempts to ensure that the safety profile of these new medicines is as fully defined as possible when they are authorised for marketing, the potential for adverse interactions may not be evident. This was illustrated by the worldwide withdrawal of the calcium channel blocker mibefradil, within months of launch, following reports of serious drug interactions. Recent advances in the drug treatment of HIV infection is another pertinent example; the current treatment approach involves the early use of combination antiviral therapy in an attempt to reduce the plasma viral load markedly. The combinations of drugs used are chosen to have synergistic or additive activity, a good example of beneficial drug–drug interactions. However, some of the drugs used, particularly protease inhibitors, inhibit the cytochrome P450 enzyme system and consequently their potential to cause significant drug interactions is great.

The medical literature contains thousands of reports of adverse drug interactions, of which only a relatively small proportion are clinically important. The importance of drug interactions to the clinician primarily involves knowing or predicting those occasions when a potential interaction is likely to have significant consequences for the patient. When these arise, the clinician should take steps to minimize adverse effects, for example by using an alternative treatment to avoid the combination of risk, by making a dosage adjustment, or by monitoring the patient closely. In order to predict the possible consequences of the co-administration of two or more drugs it is essential that the clinician has a practical knowledge of the pharmacological mechanisms involved in drug interactions, an awareness of the drugs associated with greatest risk, and the most susceptible patient groups. Clinicians must also be alert to the possible involvement of non-prescribed medicines and other substances in drug interactions. There is an increasing tendency for patients to self-treat with medications that can be purchased without a prescription, including herbal medicines. In addition, some foodstuffs, most notably grapefruit juice, have attracted attention as a cause of drug interactions.

This chapter reviews the main mechanisms of drug interactions. It gives some clinically important examples of these, and suggests how they can be assessed and managed. It focuses on drug interactions that may have an adverse clinical outcome, rather than those that are used to therapeutic advantage. The issues of pharmaceutical incompatibility and drug interactions with food and alcohol will not be covered here.