What is the interaction between Phenytoin and Cortisol?

From the Guidelines

Phenytoin can significantly decrease the effectiveness of cortisol by increasing its metabolism in the liver, and therefore, patients on cortisol replacement therapy may require a dose increase of approximately 50-100% when phenytoin is added to their regimen. This interaction is crucial in patients with seizure disorders who also have adrenal issues, as well as in those receiving phenytoin for other indications like cardiac arrhythmias. The mechanism behind this interaction involves phenytoin inducing cytochrome P450 enzymes in the liver, particularly CYP3A4, which accelerates the breakdown of cortisol 1. As a result, reduced cortisol levels can occur in patients taking both medications, potentially leading to inadequate cortisol effects in those who require corticosteroid therapy.

Key Considerations

• Patients with primary adrenal insufficiency should be aware of the potential interaction between phenytoin and cortisol, as outlined in the consensus statement on the diagnosis, treatment, and follow-up of patients with primary adrenal insufficiency 1.
• The dose of cortisol may need to be adjusted when phenytoin is started or stopped, and regular monitoring of clinical response to cortisol therapy is essential to maintain appropriate cortisol levels.
• The interaction between phenytoin and cortisol is not directly addressed in the guideline update on the diagnosis and management of Cushing's disease 1, but the general principles of managing corticosteroid therapy and monitoring for drug interactions are relevant.

Management

• For patients on cortisol replacement therapy, the dose of cortisol may need to be increased by approximately 50-100% when phenytoin is added to their regimen.
• Conversely, if phenytoin is discontinued, cortisol doses should be reduced to prevent symptoms of excess cortisol.
• Regular monitoring of clinical response to cortisol therapy is essential when phenytoin is started or stopped, and dose adjustments should be made accordingly to maintain appropriate cortisol levels.

From the FDA Drug Label

Drugs whose efficacy is impaired by phenytoin include: ... corticosteroids ... The FDA drug label indicates that phenytoin may impair the efficacy of corticosteroids, such as cortisol.

• This means that phenytoin may reduce the effectiveness of cortisol.
• The exact mechanism of this interaction is not specified in the label.
• As a result, patients taking phenytoin and cortisol may require closer monitoring and potentially adjusted dosages 2.

From the Research

Phenytoin and Cortisol Interaction

• Phenytoin can increase the clearance rates of cortisol and synthetic glucocorticoids through hepatic microsomal enzyme induction 3, 4, 5.
• This interaction can lead to glucocorticoid deficiency in patients with adrenal insufficiency, requiring increased doses of steroid replacement therapy 3, 4.
• The effects of phenytoin on adrenal function can be significant, and patients with adrenal insufficiency should be closely monitored when taking this medication 3, 4, 5.

Clinical Implications

• Patients with primary adrenal insufficiency may require increased doses of fludrocortisone when taking phenytoin 4.
• The use of phenytoin in patients with adrenal insufficiency should be carefully considered, and alternative treatments may be preferred 3.
• Therapeutic drug monitoring of phenytoin is necessary to ensure therapeutic and non-toxic levels, especially in critically ill patients 6.

Management of Adrenal Insufficiency

• Adrenal insufficiency is a life-threatening condition that requires life-long glucocorticoid substitution therapy and stress adaptation to prevent adrenal crises 7.
• Various glucocorticoid formulations are available, and treatment decisions should be made on a case-by-case basis, taking into account the individual patient's needs and circumstances 7.