If doctors were to limit their prescribing to the model list of Essential Drugs (WHO) (p. 28) and were to prescribe four drugs for any patient at any
36 The term drug-drug interaction is also used, to make the distinction from drug-food interactions, and interaction with endogenous transmitters and hormones.
one time, the number of possible combinations would be more than 64 million. There can be no doubt that the number of drug interactions that might occur in this imagined situation would be too large to commit to memory or to paper. But the observation that one drug can be shown measurably to alter the disposition or effect of another drug does not mean that the interaction is necessarily of clinical importance. In this section we highlight the circumstances in which clinically important interactions can occur; we describe their pharmacological basis and provide a schematic framework to identify potential drug interactions during clinical practice.
Clinically important adverse drug interactions become likely with the following:
• Drugs that have a steep dose-response curve and a small therapeutic index (p. 94) so that relatively small quantitative changes at the target site, e.g. receptor or enzyme, will lead to substantial changes in effect, as with digoxin or lithium
• Drugs that are known enzyme inducers or inhibitors (pp. 113,114)
• Drugs that are exhibit saturable metabolism (zero-order kinetics), when small interference with kinetics may lead to large alteration of plasma concentration, e.g. phenytoin, theophylline
• Drugs that are used long-term, where precise plasma concentrations are required, e.g. oral contraceptives, antiepilepsy drugs, cardiac antiarrhythmia drugs, lithium
• When drugs that may interact are used to treat the same disease, for this increases their chance of being given concurrently, e.g. theophylline and salbutamol given for asthma may cause cardiac arrhythmia
• In severely ill patients, for they may be receiving several drugs; signs of iatrogenic disease may be difficult to distinguish from those of existing disease and the patients' condition may be such that they cannot tolerate further adversity
• In patients with significantly impaired liver or kidney function, for these are the principal organs that terminate drug action
• In the elderly, for they tend to have multiple pathology, may receive several drugs concurrently, and are specially susceptible to adverse drug effects (p. 126).
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