Summary

Fluconazole significantly inhibits the metabolism of phenytoin, leading to increased phenytoin blood levels and potential toxicity. This interaction requires careful monitoring and possible dose adjustments when these medications are used together.

Introduction

Phenytoin is a widely used anticonvulsant medication belonging to the hydantoin class, primarily prescribed for the treatment and prevention of seizures in epilepsy and other seizure disorders. Fluconazole is a triazole antifungal agent commonly used to treat various fungal infections, including candidiasis, cryptococcal infections, and other systemic mycoses. Both medications are frequently prescribed in clinical practice, making their potential interaction clinically significant.

Mechanism of Interaction

The interaction between phenytoin and fluconazole occurs through inhibition of hepatic cytochrome P450 enzymes, particularly CYP2C9 and CYP2C19. Fluconazole is a potent inhibitor of these enzymes, which are responsible for the primary metabolic pathway of phenytoin. When fluconazole inhibits these enzymes, phenytoin clearance is significantly reduced, leading to increased plasma concentrations and prolonged half-life of phenytoin. This pharmacokinetic interaction can result in phenytoin levels rising to potentially toxic ranges.

Risks and Symptoms

The primary risk of this interaction is phenytoin toxicity, which can manifest as neurological symptoms including ataxia, diplopia, nystagmus, confusion, slurred speech, and in severe cases, altered mental status or coma. Patients may also experience nausea, vomiting, and dizziness. The interaction is considered clinically significant because phenytoin has a narrow therapeutic index, meaning small increases in blood levels can lead to toxicity. The onset of symptoms typically occurs within days to weeks of starting fluconazole therapy, and the severity depends on the doses of both medications and individual patient factors.

Management and Precautions

When concurrent use of phenytoin and fluconazole is necessary, close monitoring is essential. Baseline phenytoin levels should be obtained before starting fluconazole, followed by frequent monitoring (every 2-3 days initially, then weekly) during concurrent therapy. Consider reducing the phenytoin dose by 25-50% when initiating fluconazole, with further adjustments based on serum levels and clinical response. Monitor patients closely for signs of phenytoin toxicity, including neurological symptoms. Alternative antifungal agents with less CYP450 inhibition potential, such as terbinafine or echinocandins, should be considered when clinically appropriate. Healthcare providers should educate patients about the signs and symptoms of phenytoin toxicity and advise them to seek immediate medical attention if these occur.

Phenytoin interactions with food and lifestyle

Phenytoin has several important food and lifestyle interactions that patients should be aware of. Alcohol consumption can significantly affect phenytoin levels - chronic alcohol use may decrease phenytoin effectiveness by increasing metabolism, while acute alcohol intoxication can increase phenytoin levels and toxicity risk. Patients should discuss alcohol use with their healthcare provider. Enteral nutrition (tube feeding) can significantly reduce phenytoin absorption, requiring dosing adjustments and timing considerations. Folic acid supplementation may decrease phenytoin levels, as phenytoin can cause folate deficiency but supplementation can reduce drug effectiveness. Vitamin D supplementation may be necessary as phenytoin can cause vitamin D deficiency and bone problems. Smoking may increase phenytoin metabolism, potentially requiring dose adjustments. Patients should maintain consistent dietary habits and discuss any significant dietary changes with their healthcare provider, as phenytoin levels can be affected by nutritional status.

Fluconazole interactions with food and lifestyle

Fluconazole can be taken with or without food as food does not significantly affect its absorption. However, patients should avoid excessive alcohol consumption while taking fluconazole, as both substances can potentially affect liver function. While moderate alcohol intake is generally considered acceptable, patients with liver conditions or those taking fluconazole for extended periods should discuss alcohol use with their healthcare provider. No specific dietary restrictions are required with fluconazole therapy.