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Phenytoin-diazepam interaction.

Andrea Murphy¹, Kerry Wilbur

¹School of Nursing, Dalhousie University, Halifax, Nova Scotia, Canada.

The Annals of Pharmacotherapy

|April 24, 2003

Summary

Concurrent use of diazepam may increase phenytoin levels, leading to toxicity. This case highlights a potential drug interaction where diazepam altered phenytoin metabolism, causing adverse neurologic effects in a patient with epilepsy.

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Area of Science:

Clinical Pharmacology
Neuropharmacology
Drug Interactions

Background:

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index.
Drug interactions can significantly alter phenytoin serum concentrations and efficacy.
The metabolism of phenytoin involves hepatic cytochrome P450 enzymes, particularly CYP2C9 and CYP2C19.

Observation:

A patient with epilepsy presented with symptoms of phenytoin toxicity, including headache, nystagmus, diplopia, and ataxia.
The patient was concurrently prescribed diazepam and amoxicillin shortly before symptom onset.
Serum phenytoin concentration was significantly elevated (37 micro g/mL) compared to a previous measurement (8 micro g/L).

Findings:

Discontinuation of both phenytoin and diazepam led to the resolution of neurologic symptoms.
The Naranjo probability scale indicated a probable relationship between the observed adverse effects and the coadministration of phenytoin and diazepam.
Diazepam, metabolized by CYP2C19, may act as an alternate substrate, potentially inhibiting phenytoin's elimination via the same isoenzyme.

Implications:

This case suggests that diazepam can potentially increase serum phenytoin concentrations, leading to toxicity.
Clinicians should be aware of this potential interaction, especially when initiating diazepam in patients on phenytoin therapy.
The mechanism may involve diazepam acting as an alternate substrate for CYP2C19, affecting phenytoin metabolism through an underrecognized pathway.

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