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 both medications are used concurrently.

Introduction

Isoniazid is a first-line antituberculosis medication belonging to the hydrazide class, primarily used for treating active tuberculosis and latent tuberculosis infection. Phenytoin is a hydantoin-class antiepileptic drug (AED) commonly prescribed for seizure disorders, including focal seizures and generalized tonic-clonic seizures. Both medications are frequently prescribed and may be used simultaneously in patients with tuberculosis who also have epilepsy or seizure disorders.

Mechanism of Interaction

The interaction between isoniazid and phenytoin occurs through hepatic enzyme inhibition. Isoniazid inhibits cytochrome P450 enzymes, particularly CYP2C9 and CYP2C19, which are responsible for phenytoin metabolism. This inhibition reduces phenytoin clearance, leading to decreased metabolism and elimination of phenytoin from the body. As a result, phenytoin plasma concentrations increase, potentially reaching toxic levels even with standard dosing regimens.

Risks and Symptoms

The primary risk of this interaction is phenytoin toxicity due to elevated plasma concentrations. Signs and symptoms of phenytoin toxicity include ataxia (loss of coordination), nystagmus (involuntary eye movements), diplopia (double vision), slurred speech, confusion, and drowsiness. In severe cases, patients may experience lethargy, coma, or cardiovascular complications. The interaction is considered clinically significant because phenytoin has a narrow therapeutic index, meaning small increases in blood levels can lead to toxicity. Additionally, the onset of toxicity may be delayed, occurring days to weeks after initiating concurrent therapy.

Management and Precautions

When isoniazid and phenytoin must be used together, close monitoring is essential. Baseline phenytoin levels should be obtained before starting isoniazid, followed by regular monitoring of phenytoin plasma concentrations, particularly during the first few weeks of concurrent therapy. Clinical monitoring for signs of phenytoin toxicity should be conducted at each patient visit. Phenytoin dose reduction may be necessary, typically by 25-50%, though individual adjustments should be based on plasma levels and clinical response. Alternative antituberculosis regimens or antiepileptic medications should be considered when possible. Patients should be educated about the signs and symptoms of phenytoin toxicity and advised to report any concerning symptoms immediately to their healthcare provider.

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.

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.