Interactions During Metabolism

Enzyme induction by drugs and other substances (see p. 113) accelerates metabolism and is a cause of therapeutic failure. The following are examples:

Oral contraceptive steroids are metabolised more rapidly when an enzyme inducer, e.g. phenytoin, is added, and unplanned pregnancy has occured (doctors have been successfully sued for negligence). In this circumstance an oral contraceptive of high oestrogen content may be substituted (or an alternative contraceptive method); if breakthrough bleeding occurs, the oestrogen content is not high enough. The metabolism of progestogens is also increased by enzyme induction.

Anticoagulant control with warfarin is dependent on a steady state of elimination by metabolism. Enzyme induction leads to accelerated metabolism of warfarin, loss of anticoagulant control and danger of thrombosis. Conversely, if a patient's anticoagulant control is stable on warfarin plus an inducing agent, there is a danger of haemorrhage if the inducing agent is discontinued because warfarin will be eliminated at a slower rate.

Chronic alcohol ingestion causing enzyme induction is a likely explanation of the tolerance shown by alcoholics to hydrocarbon anaesthetics and to tolbutamide.

Cyclosporin is extensively metabolised; its concentration in blood may be reduced due to enzyme induction by rifampicin, with danger of inadequate immunosuppression hazarding an organ or marrow transplant.

Enzyme inhibition by drugs (see p. 114) potentiates other drugs that are inactivated by metabolism, causing adverse reactions. Examples appear below, and it will be noted that inhibitors of isoenzymes of microsomal cytochrome P450 figure prominently. The drugs with which they interact are also given but the list is not complete, and there should be a general awareness of the possibility of metabolic inhibition when the following drugs are used.

Cimetidine is an inhibitor of several cytochrome P450 isoenzymes and so potentiates a large number of drugs ordinarily metabolised by that system, notably, theophylline, warfarin, phenytoin and propranolol. Depending on the interacting drug, up to 50% inhibition of metabolism may occur when cimetidine 2000 mg/d is taken.

Erythromycin inhibits a cytochrome P450 isoenzyme and impairs the metabolism of theophylline, warfarin, carbamazepine and methylprednisolone. The mean reduction in drug clearance is 20-25%.

Quinolone antimicrobials inhibit specific isoenzymes of P450 responsible for the metabolism of methylxanthines; thus the clearance of theophylline is reduced by ciprofloxacin.

Monoamine oxidase inhibitors (MAOI) are not completely selective for MAO and impair the metabolism of tricyclic antidepressants, of some sympathomimetics, e.g. phenylpropanolamine, amfetamine, of opioid analgesics, especially pethidine, and of mercaptopurine.

Sodium valproate appears to be a nonspecific inhibitor and impairs the metabolism of phenytoin, phenobarbitone and primidone.

Serotonin specific reuptake inhibitors (see p. 350)

Allopurinol specifically inhibits xanthine oxidase and thus prevents metabolism of azathioprine to mercaptopurine (with potentially dangerous toxicity).

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