A Comprehensive Monograph on Ketoconazole: Pharmacology, Clinical Utility, and Risk Profile

Introduction: Executive Summary

Ketoconazole (DrugBank ID: DB01026) is a first-generation synthetic imidazole antifungal agent, first synthesized in 1977 and granted approval by the U.S. Food and Drug Administration (FDA) in 1981.[1] Its introduction marked a significant milestone in infectious disease therapy, as it was the first orally active azole antifungal available for the treatment of systemic mycoses, offering a major therapeutic advance over the existing intravenous agents of the era.[1]

Despite its historical importance, the clinical narrative of ketoconazole is one of profound dichotomy. On one hand, it remains a valuable and widely used topical agent for common dermatological fungal infections. On the other, its role as a systemic therapy has been dramatically curtailed due to a complex and severe risk profile that has emerged from decades of post-marketing surveillance.[1] The central theme of this monograph is an exploration of this duality, which is rooted in the drug's fundamental pharmacology.

Ketoconazole exhibits a dual pharmacological nature. Its primary therapeutic action is as an inhibitor of fungal ergosterol synthesis, a mechanism that provides its broad-spectrum antifungal activity.[6] Concurrently, it acts as a potent inhibitor of a range of human cytochrome P450 (CYP) enzymes. This lack of selectivity is the unifying principle that explains its entire clinical story; it underpins not only its intended antifungal and off-label endocrine effects but also its most severe toxicities, including life-threatening hepatotoxicity, cardiac arrhythmias, and a vast potential for clinically significant drug-drug interactions.[1]