Summary

Itraconazole significantly increases prednisolone blood levels by inhibiting the CYP3A4 enzyme responsible for prednisolone metabolism. This interaction can lead to enhanced corticosteroid effects and increased risk of adverse reactions including Cushing's syndrome, adrenal suppression, and other steroid-related complications.

Introduction

Itraconazole is a triazole antifungal medication commonly used to treat systemic fungal infections, including aspergillosis, candidiasis, and dermatophyte infections. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase. Prednisolone is a synthetic corticosteroid with potent anti-inflammatory and immunosuppressive properties, frequently prescribed for conditions such as asthma, rheumatoid arthritis, inflammatory bowel disease, and allergic reactions. Both medications are metabolized through the hepatic cytochrome P450 system, which creates the potential for significant drug interactions.

Mechanism of Interaction

The interaction between itraconazole and prednisolone occurs through competitive inhibition of the CYP3A4 enzyme system. Itraconazole is a potent CYP3A4 inhibitor that significantly reduces the hepatic metabolism of prednisolone. Prednisolone is primarily metabolized by CYP3A4 to inactive metabolites, and when this pathway is blocked by itraconazole, prednisolone clearance decreases substantially. This results in increased plasma concentrations and prolonged half-life of prednisolone, leading to enhanced pharmacological effects. The inhibition can increase prednisolone exposure by 2-4 fold, depending on the dose and duration of itraconazole therapy.

Risks and Symptoms

The primary clinical risks include enhanced corticosteroid effects and toxicity. Patients may experience increased susceptibility to infections due to greater immunosuppression, elevated blood glucose levels, fluid retention, hypertension, and electrolyte imbalances. Long-term exposure to elevated prednisolone levels can lead to Cushing's syndrome, characterized by weight gain, moon face, buffalo hump, and purple striae. Other significant risks include adrenal suppression, osteoporosis, muscle weakness, mood changes, and delayed wound healing. The interaction is particularly concerning in elderly patients and those with diabetes, cardiovascular disease, or existing bone density issues.

Management and Precautions

When concurrent use is necessary, prednisolone dose reduction of 50-75% should be considered, with careful monitoring for both therapeutic efficacy and adverse effects. Regular monitoring should include blood glucose levels, blood pressure, electrolytes (particularly potassium), and signs of infection. Patients should be assessed for Cushingoid features and mood changes. Consider alternative antifungal agents with less CYP3A4 inhibition if clinically appropriate. If long-term concurrent therapy is required, bone density monitoring and prophylactic measures for osteoporosis may be warranted. Gradual tapering of prednisolone is essential when discontinuing to prevent adrenal insufficiency. Healthcare providers should educate patients about signs of corticosteroid excess and the importance of infection prevention measures.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.

Prednisolone interactions with food and lifestyle

Prednisolone should be taken with food or milk to reduce stomach irritation and gastrointestinal side effects. Alcohol consumption should be limited or avoided while taking prednisolone, as both can increase the risk of stomach ulcers and gastrointestinal bleeding. Patients should also limit sodium intake and increase potassium-rich foods in their diet, as prednisolone can cause sodium retention and potassium loss. Grapefruit juice may increase prednisolone levels in the blood and should be consumed with caution. Patients should maintain adequate calcium and vitamin D intake, as long-term prednisolone use can lead to bone loss and osteoporosis.