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. Isoniazid is a first-line antitubercular agent used in the treatment and prevention of tuberculosis infections. 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 hepatic enzyme inhibition. Isoniazid inhibits cytochrome P450 enzymes, particularly CYP2C9 and CYP2C19, which are responsible for phenytoin metabolism. This inhibition reduces the clearance of phenytoin, leading to increased plasma concentrations and prolonged half-life. The degree of inhibition can vary among individuals due to genetic polymorphisms in acetylator status, with slow acetylators of isoniazid showing more pronounced effects on phenytoin metabolism.

Risks and Symptoms

The primary clinical risk of this interaction is phenytoin toxicity due to elevated serum 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 may also lead to gingival hyperplasia, hirsutism, and cerebellar dysfunction. The interaction typically develops within days to weeks of initiating isoniazid therapy and can persist for several weeks after discontinuation due to the long half-life of phenytoin.

Management and Precautions

When co-administering phenytoin and isoniazid, close monitoring of phenytoin serum levels is essential. Baseline phenytoin levels should be obtained before starting isoniazid, followed by regular monitoring every 1-2 weeks initially, then monthly once stable. Phenytoin dose reduction of 25-50% may be necessary to maintain therapeutic levels (10-20 mg/L). Patients should be monitored for signs of phenytoin toxicity and educated about symptoms to report. Alternative antiepileptic drugs with fewer drug interactions, such as levetiracetam or lamotrigine, may be considered if clinically appropriate. Healthcare providers should also monitor for potential hepatotoxicity, as both drugs can cause liver dysfunction.

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.