Summary

Ketoconazole significantly inhibits the metabolism of hydrocortisone by blocking CYP3A4 enzymes, leading to increased corticosteroid levels and enhanced therapeutic and adverse effects. This interaction requires careful monitoring and potential dose adjustments to prevent corticosteroid toxicity.

Introduction

Hydrocortisone is a corticosteroid hormone that mimics the natural hormone cortisol, commonly used to treat inflammatory conditions, adrenal insufficiency, and allergic reactions. Ketoconazole is an antifungal medication belonging to the azole class, primarily used to treat serious fungal infections and sometimes prescribed off-label for conditions like Cushing's syndrome due to its ability to inhibit steroid synthesis.

Mechanism of Interaction

The interaction between hydrocortisone and ketoconazole occurs through ketoconazole's potent inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Hydrocortisone is primarily metabolized by CYP3A4 enzymes in the liver. When ketoconazole blocks these enzymes, it significantly reduces the clearance of hydrocortisone from the body, resulting in elevated plasma concentrations and prolonged half-life of the corticosteroid. This can lead to a 2-4 fold increase in hydrocortisone exposure.

Risks and Symptoms

The primary clinical risk of this interaction is corticosteroid toxicity due to elevated hydrocortisone levels. Patients may experience enhanced therapeutic effects but also increased risk of adverse reactions including hyperglycemia, hypertension, fluid retention, electrolyte imbalances, mood changes, and immunosuppression. Long-term exposure to elevated corticosteroid levels can lead to Cushing's syndrome-like symptoms, bone loss, muscle weakness, and increased susceptibility to infections. The interaction is considered clinically significant and requires active management.

Management and Precautions

When concurrent use is necessary, consider reducing the hydrocortisone dose by 50-75% and monitor closely for signs of corticosteroid excess. Regular monitoring should include blood glucose levels, blood pressure, electrolytes (particularly potassium), and clinical assessment for Cushingoid features. Patients should be educated about signs of corticosteroid toxicity and advised to report symptoms promptly. If possible, consider alternative antifungal agents with less CYP3A4 inhibition, such as fluconazole or terbinafine. When discontinuing ketoconazole, gradually increase hydrocortisone back to the original dose while monitoring for signs of adrenal insufficiency.

Ketoconazole interactions with food and lifestyle

Ketoconazole requires an acidic environment for optimal absorption. Take ketoconazole with food or an acidic beverage to enhance absorption. Avoid taking ketoconazole with antacids, H2 blockers, or proton pump inhibitors as these medications reduce stomach acid and significantly decrease ketoconazole absorption. If antacids must be used, take them at least 2 hours after ketoconazole. Alcohol should be avoided during ketoconazole treatment as both ketoconazole and alcohol can cause liver toxicity, and concurrent use may increase the risk of hepatotoxicity. Grapefruit juice may increase ketoconazole blood levels and should be avoided to prevent increased risk of side effects.