Phenytoin intoxication during concurrent diazepam therapy

Abstract

Phenytoin possesses a relatively small therapeutic index, and toxicity is by no means uncommon during therapy making monitoring of plasma levels an important adjunct to clinical management (Dawson and Jamieson, 1971). This situation is further complicated by the non-linear relationship between dose and the resulting plasma concentration (Bochner et al., 1972). The apparent half-life of the drug increases as the plasma level rises, phenytoin elimination being described as dose-dependent. This type of elimination can be described as obeying Michaelis-Menten kinetics overall (Gerber and Wagner, 1972). It follows from these kinetic properties that the relationship of plasma levels to dose is non-linear, and that at higher plasma levels a small increase in dose produces a disproportionately large increase in plasma levels. The Institute for evaluation and the dose of phenytoin increased to 9 mg/kg/day which resulted in levels of 36 ,tmol/l. Diazepam was added (for spasticity) in a dose of 0.3 mg/kg/day and increased by increments of 0.1 mg/kg/day at intervals of approximately five days to 0.6 mg/kg/day. Simultaneously the phenytoin dose was increased to 12.5 mg/kg/ day. Fourteen days after the addition of diazepam and the increased dose of phenytoin the patient experienced phenytoin toxicity characterised by 890

Pharmacokinetic Interactions with Antiepileptic Drugs

“…However, the opposite effect has also been reported (e.g. Rogers et al, 1977). At therapeutic dosages benzodiazepines seem to be devoid of enzyme-inducing effects, and it is unlikely 68 that they increase the metabolic rate of phenytoin by this mechanism.…”