From the Guidelines
Ketoconazole works as an antifungal by inhibiting the synthesis of ergosterol, an essential component of fungal cell membranes, through the inhibition of the cytochrome P450 enzyme 14-alpha-demethylase. This mechanism is supported by the fact that ketoconazole targets and inhibits the fungal cytochrome P450–dependent enzyme lanosterol 14-a-demethylase, resulting in altered cell membrane function and cell death or inhibition of cell growth and replication 1. The provided evidence does not directly describe the mechanism of action of ketoconazole as an antifungal, but it does discuss its use in treating Cushing's disease and its potential side effects, including hepatotoxicity and gastrointestinal disturbances 1. However, based on the general knowledge of antifungal medications and the information provided in the evidence, it can be inferred that ketoconazole's mechanism of action is similar to that of other azole antifungals, which inhibit ergosterol synthesis and disrupt fungal cell membrane function. Some key points to consider when using ketoconazole as an antifungal include:
- Its broad-spectrum activity against dermatophytes, yeasts, and some molds
- Its potential for liver toxicity, which has limited its use in systemic infections
- Its availability in topical formulations for treating superficial fungal infections
- The importance of monitoring liver function tests in patients taking ketoconazole, especially those with fungal infections 1. Overall, ketoconazole's mechanism of action as an antifungal is well-established, and its use should be guided by careful consideration of its potential benefits and risks.
From the FDA Drug Label
Ketoconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. The mechanism of action (MOA) of ketoconazole as an antifungal is through the inhibition of ergosterol synthesis by blocking the enzyme lanosterol 14α-demethylase, resulting in a weakening of the fungal cell membrane 2.
- The key steps involved are:
- Inhibition of cytochrome P-450 dependent enzyme
- Blockage of lanosterol to ergosterol conversion
- Accumulation of methylated sterol precursors and depletion of ergosterol
- Ultimately leading to a compromised fungal cell membrane 2
From the Research
Mechanism of Action of Ketoconazole as Antifungal
- Ketoconazole interferes with the fungal synthesis of ergosterol, a constituent of cell membranes, which is essential for the survival of fungi 3.
- The inhibition of ergosterol synthesis leads to the disruption of the fungal cell membrane, ultimately resulting in the death of the fungal cells.
- Ketoconazole has a wide spectrum of use, including effectiveness against deep fungal infections as well as superficial infections such as candidiasis, dermatophytosis, and tinea versicolor 4.
Clinical Efficacy of Ketoconazole
- Ketoconazole has been shown to be clinically effective for the treatment of Malassezia-related conditions such as seborrheic dermatitis and pityriasis versicolor, with a reported efficacy of 63-90% and 71-89%, respectively 5.
- It is also effective against dermatophyte infections, with a cure rate of 74% in patients treated with oral ketoconazole 6.
- Topical ketoconazole is effective against superficial fungal and yeast infections, and new foam and gel formulations have been developed for the treatment of seborrheic dermatitis 3.
Adverse Effects of Ketoconazole
- Oral ketoconazole has been associated with serious adverse effects, including symptomatic drug-induced hepatitis, which occurs in approximately 1 in 12,000 patients 4.
- Topical ketoconazole is generally thought to be safe, but allergic contact dermatitis may occur 5.
- Other potential adverse effects of ketoconazole include effects on testosterone and cortisol synthesis, which may limit its use to deep fungal infections and severe recalcitrant superficial infections of the skin 4.