Summary

Diltiazem can significantly increase phenytoin blood levels by inhibiting its metabolism, potentially leading to phenytoin toxicity. This 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. Diltiazem is a calcium channel blocker from the benzothiazepine class, commonly used to treat hypertension, angina, and certain cardiac arrhythmias. Both medications are frequently prescribed, making their potential interaction clinically relevant for healthcare providers managing patients with concurrent cardiovascular and neurological conditions.

Mechanism of Interaction

The interaction between phenytoin and diltiazem occurs through inhibition of hepatic metabolism. Diltiazem is a moderate inhibitor of the cytochrome P450 enzyme CYP3A4, which is responsible for metabolizing phenytoin to its inactive metabolite. When diltiazem inhibits CYP3A4, it reduces the clearance of phenytoin, leading to increased plasma concentrations and prolonged half-life of the antiepileptic drug. This pharmacokinetic interaction can result in elevated phenytoin levels that may reach toxic concentrations, particularly in patients receiving standard phenytoin doses.

Risks and Symptoms

The primary clinical risk of this interaction is phenytoin toxicity, which can manifest as neurological symptoms including ataxia, diplopia, nystagmus, confusion, slurred speech, and in severe cases, altered mental status or coma. Patients may also experience gastrointestinal symptoms such as nausea and vomiting. 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, as it can take several days to weeks for phenytoin levels to reach steady state after diltiazem initiation or dose changes.

Management and Precautions

When concurrent use of phenytoin and diltiazem is necessary, close monitoring is essential. Baseline phenytoin levels should be obtained before starting diltiazem, followed by regular monitoring at 1-2 weeks after initiation and periodically thereafter. Patients should be educated about signs and symptoms of phenytoin toxicity and advised to report any neurological changes promptly. Consider reducing the phenytoin dose by 25-50% when initiating diltiazem, with subsequent adjustments based on serum levels and clinical response. Alternative calcium channel blockers with less CYP3A4 inhibition, such as amlodipine, may be considered if clinically appropriate. Healthcare providers should maintain therapeutic phenytoin levels between 10-20 mg/L (40-80 μmol/L) and adjust dosing accordingly.

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.

Diltiazem interactions with food and lifestyle

Grapefruit and grapefruit juice should be avoided while taking diltiazem as they can significantly increase blood levels of the medication, potentially leading to dangerous drops in blood pressure and heart rate. Alcohol consumption should be limited or avoided as it can enhance the blood pressure-lowering effects of diltiazem and increase the risk of dizziness, fainting, and falls. Patients should also be cautious when standing up quickly or engaging in activities requiring alertness, as diltiazem can cause dizziness and lightheadedness, especially when starting treatment or increasing the dose.