Summary

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

Introduction

Phenytoin is a widely used antiepileptic drug (AED) belonging to the hydantoin class, primarily prescribed for the treatment of tonic-clonic seizures, partial seizures, and status epilepticus. It works by blocking voltage-gated sodium channels in neurons. Isoniazid is a first-line antitubercular medication used in the treatment and prevention of tuberculosis. It acts as a bactericidal agent by inhibiting mycolic acid synthesis in mycobacteria. Both medications are commonly prescribed and may be used concurrently in patients with epilepsy who develop tuberculosis or require tuberculosis prophylaxis.

Mechanism of Interaction

The interaction between phenytoin and isoniazid occurs through metabolic inhibition. Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme system, specifically CYP2C9 and CYP2C19. Isoniazid acts as a potent inhibitor of these cytochrome P450 enzymes, particularly affecting the hydroxylation of phenytoin to its major metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). This enzymatic inhibition results in decreased phenytoin clearance, leading to accumulation of the drug in the body and elevated serum concentrations. The inhibition is dose-dependent and can occur within days of initiating concurrent therapy.

Risks and Symptoms

The primary clinical risk of this interaction is phenytoin toxicity due to elevated serum levels. Signs and symptoms of phenytoin toxicity include nystagmus, ataxia, 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 because phenytoin has a narrow therapeutic index, meaning small increases in blood levels can lead to toxicity. Patients with slow acetylator phenotypes may be at higher risk due to higher isoniazid concentrations. The onset of toxicity typically occurs within 1-4 weeks of starting concurrent therapy, but can happen sooner in some patients.

Management and Precautions

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.

Isoniazid interactions with food and lifestyle

Alcohol: Avoid alcohol consumption while taking isoniazid as it significantly increases the risk of hepatotoxicity (liver damage). The combination can lead to severe liver injury and potentially fatal hepatitis. Food interactions: Take isoniazid on an empty stomach (1 hour before or 2 hours after meals) for optimal absorption. Foods high in tyramine (aged cheeses, cured meats, fermented foods) should be avoided as isoniazid has mild MAO inhibitor properties and may cause hypertensive reactions. Histamine-rich foods (tuna, skipjack fish) should also be avoided as isoniazid can inhibit histamine metabolism, potentially causing flushing, headache, and palpitations.