Summary

Fluconazole significantly inhibits the metabolism of phenytoin through CYP2C9 enzyme inhibition, leading to increased phenytoin levels and potential toxicity. This interaction requires careful monitoring and possible dose adjustments when these medications are used concurrently.

Introduction

Fluconazole is a triazole antifungal medication commonly prescribed for treating various fungal infections, including candidiasis and cryptococcal infections. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase. Phenytoin is a hydantoin anticonvulsant medication primarily used to treat and prevent seizures, including tonic-clonic and focal seizures. It works by blocking voltage-gated sodium channels in neuronal membranes, stabilizing the neuronal membrane and preventing abnormal electrical activity.

Mechanism of Interaction

The interaction between fluconazole and phenytoin occurs through competitive inhibition of the cytochrome P450 enzyme system, specifically CYP2C9. Fluconazole is a potent inhibitor of CYP2C9, which is the primary enzyme responsible for phenytoin metabolism. When fluconazole inhibits CYP2C9, it significantly reduces the clearance of phenytoin, leading to increased plasma concentrations and prolonged half-life of phenytoin. This mechanism-based inhibition can result in phenytoin levels increasing by 75-100% or more, depending on the fluconazole dose and individual patient factors.

Risks and Symptoms

The primary clinical risk of this interaction is phenytoin toxicity due to elevated plasma concentrations. Signs and symptoms of phenytoin toxicity include ataxia, nystagmus, diplopia, slurred speech, confusion, drowsiness, and in severe cases, coma. Chronic elevation of phenytoin levels can lead to cerebellar dysfunction, peripheral neuropathy, and gingival hyperplasia. The interaction is considered clinically significant and can occur within days of initiating concurrent therapy. Patients with pre-existing high-normal phenytoin levels are at particularly high risk for developing toxicity. The severity of the interaction is dose-dependent, with higher fluconazole doses (≥200mg daily) posing greater risk.

Management and Precautions

When concurrent use of fluconazole and phenytoin is necessary, several management strategies should be implemented. First, consider reducing the phenytoin dose by 25-50% when initiating fluconazole therapy, particularly with doses ≥200mg daily. Monitor phenytoin serum levels closely, with baseline levels obtained before starting fluconazole and follow-up levels within 3-7 days of concurrent therapy initiation. Continue monitoring throughout the treatment course and for several days after fluconazole discontinuation. Watch for clinical signs of phenytoin toxicity and adjust doses accordingly. If possible, consider alternative antifungal agents with less CYP2C9 inhibition potential, such as terbinafine or echinocandins, depending on the indication. When fluconazole is discontinued, phenytoin doses may need to be increased back to previous levels, with continued monitoring to prevent subtherapeutic levels and breakthrough seizures.

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.

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.