Can ketoconazole (antifungal medication) affect hydrocortisone (corticosteroid) levels and glucocorticoid activity?

From the Guidelines

Ketoconazole can significantly affect hydrocortisone levels and glucocorticoid activity in the body, and its use requires careful monitoring and potential dose adjustments of hydrocortisone to avoid overexposure and symptoms of glucocorticoid excess. Ketoconazole is a potent inhibitor of cytochrome P450 enzymes, particularly CYP3A4, which are responsible for metabolizing hydrocortisone and other glucocorticoids 1. When taken together, ketoconazole can increase hydrocortisone blood levels by reducing its clearance from the body, potentially leading to symptoms of glucocorticoid excess such as fluid retention, elevated blood pressure, increased blood glucose, and mood changes.

Mechanism of Action

The mechanism involves ketoconazole blocking the liver enzymes that normally break down hydrocortisone, resulting in prolonged and enhanced glucocorticoid effects throughout the body 1. This interaction is dose-dependent, with higher doses of ketoconazole (200-400 mg daily) causing more pronounced effects. Patients taking both medications may require hydrocortisone dose reductions of approximately 30-50% to avoid overexposure.

Clinical Implications

This interaction is particularly important for patients with adrenal insufficiency who depend on hydrocortisone replacement therapy, as well as those using hydrocortisone for inflammatory conditions 1. Patients should inform all healthcare providers about this combination and watch for signs of cortisol excess if these medications are used concurrently. The use of ketoconazole for medical management of hypercortisolism is achieved with adrenostatic agents, including ketoconazole and mitotane, and ketoconazole is most commonly used due to its easy availability and relatively tolerable toxicity profile.

Key Points

• Ketoconazole can increase hydrocortisone blood levels by reducing its clearance from the body
• The interaction is dose-dependent, with higher doses of ketoconazole causing more pronounced effects
• Patients taking both medications may require hydrocortisone dose reductions of approximately 30-50% to avoid overexposure
• This interaction is particularly important for patients with adrenal insufficiency who depend on hydrocortisone replacement therapy, as well as those using hydrocortisone for inflammatory conditions
• Patients should inform all healthcare providers about this combination and watch for signs of cortisol excess if these medications are used concurrently.

From the FDA Drug Label

Ketoconazole tablets decrease adrenal corticosteroid secretion at doses of 400 mg and higher. Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.)

Ketoconazole can affect hydrocortisone levels and glucocorticoid activity by decreasing adrenal corticosteroid secretion at doses of 400 mg and higher.

• Adrenal insufficiency is a potential risk, especially in patients with pre-existing adrenal insufficiency or borderline adrenal function.
• Patients under prolonged periods of stress should also be monitored for adrenal function. 2

From the Research

Ketoconazole's Effect on Hydrocortisone Levels and Glucocorticoid Activity

• Ketoconazole has been shown to decrease cortisol synthesis by inhibiting the 11-beta-hydroxylation step in adrenal steroidogenesis 3.
• The use of ketoconazole in Cushing's disease has been found to lower circulating cortisol levels, with 49.3% of patients achieving normal urinary free cortisol levels and 25.6% experiencing at least a 50% decrease 4.
• Ketoconazole's efficacy in reducing cortisol levels is also evident in its ability to normalize cortisol concentrations in patients with Cushing's syndrome, although it may not be as effective as other treatments such as fluconazole 5, 6.
• Combination therapy using ketoconazole and cabergoline has been found to be effective in achieving a satisfactory reduction in urinary free cortisol levels and clinical improvement in patients with Cushing's disease 7.
• The mechanism of ketoconazole's effect on glucocorticoid activity involves the inhibition of steroidogenesis, which can lead to decreased cortisol production and subsequent reduction in glucocorticoid activity 6, 3.