A patient on phenytoin for epilepsy is started on fluconazole for oral candidiasis. Three days later she develops diplopia, nystagmus, and ataxia. The most likely mechanism is:

• A Additive CNS depression by fluconazole
• B Fluconazole induces P-glycoprotein, increasing phenytoin CNS penetration
• C Fluconazole inhibits CYP2C9, reducing phenytoin metabolism and increasing its plasma level ✓
• D Direct neurotoxicity of the fluconazole-phenytoin combination

Explanation

Phenytoin is metabolized primarily by CYP2C9 and CYP2C19. Fluconazole is a potent inhibitor of both CYP2C9 and CYP3A4. When fluconazole is added, phenytoin hydroxylation is reduced, plasma phenytoin levels rise (sometimes dramatically), and dose-related toxicity ensues — presenting as nystagmus, diplopia, ataxia, and sedation (toxidrome in order of severity). Phenytoin levels and clinical toxicity should be monitored closely whenever any azole antifungal is co-prescribed, and dose reduction of phenytoin is often necessary.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.