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 and prevention of seizures, including tonic-clonic and focal seizures. Isoniazid is a first-line antitubercular medication, classified as an antimycobacterial 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 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 elevated plasma concentrations and prolonged half-life of phenytoin.

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. The interaction can develop within days to weeks of initiating isoniazid therapy. Patients may experience a 2-3 fold increase in phenytoin serum levels, potentially reaching toxic concentrations even with standard dosing. This interaction is considered clinically significant and requires proactive management to prevent adverse outcomes.

Management and Precautions

When co-administering phenytoin and isoniazid, implement frequent monitoring of phenytoin serum levels, particularly during the first 2-4 weeks of concurrent therapy. Baseline phenytoin levels should be obtained before starting isoniazid. Consider reducing the phenytoin dose by 25-50% when initiating isoniazid, with subsequent adjustments based on serum levels and clinical response. Target therapeutic phenytoin levels (10-20 mg/L) while monitoring for signs of toxicity. Educate patients about symptoms of phenytoin toxicity and advise them to report any neurological symptoms promptly. Alternative antitubercular agents with less interaction potential may be considered in consultation with infectious disease specialists when clinically appropriate.

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.