Azoles

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Pharmacology

Summary

Azoles are a group of drugs often used for their antifungal properties. Subcategories within the azole family include the imidazoles, with drugs such as ketoconazole, miconazole, and clotrimazole, as well as the triazoles, including itraconazole, fluconazole, and voriconazole. The antifungal activity of these drugs results from the inhibition of ergosterol synthesis from lanosterol, with ergosterol being an essential component of fungal cell membranes. Specifically, azoles halt the enzyme that turns lanosterol into ergosterol, the fungal cytochrome P450. Despite their functional significance, all azole drugs are prone to drug interactions due to their effects on mammalian cytochrome enzymes.

Different azoles are used in specific clinical cases due to their unique properties. For instance, voriconazole acts against invasive aspergillosis and Candida species, but can cause visual disturbances as an adverse reaction. Fluconazole is primarily used for mucocutaneous candidiasis, demonstrating excellent activity against candida species and serving as the primary treatment for Cryptococcal meningitis. Itraconazole treats systemic mycoses, such as histoplasmosis, blastomycosis, and coccidioidomycosis, along with onychomycosis, due to its activity against dimorphic fungi. Meanwhile, ketoconazole is mainly used as a topical agent but has notable side effects due to its inhibition of adrenal steroid production. Finally, the imidazoles, clotrimazole and miconazole, are used primarily in topical treatments for infections such as tinea and vaginal candidiasis.

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FAQs

What is the mechanism of action of azole antifungals like voriconazole, fluconazole, itraconazole, ketoconazole, etc.?

Azole antifungals inhibit the synthesis of ergosterol, which is a key component of the fungal cell membrane. Specifically, these medications inhibit the conversion of lanosterol to ergosterol and disrupt the activity of fungal cytochrome P-450, thereby disrupting the integrity of the membrane and hindering fungal growth.

What possible side effects are seen with voriconazole?

There are a few potential side effects of voriconazole including changes in vision, such as blurry vision or flashes of light. Color vision may also be affected. Other side effects include hallucinations, rash, alopecia, and periostitis.

What are the typical uses of fluconazole and voriconazole in treating fungal infections?

Fluconazole is typically used to treat various Candida infections like mucocutaneous candidiasis and esophageal candidiasis. It's also used in single oral dose to treat vaginal candidiasis, and systemically to handle esophageal candidiasis. Fluconazole is also effective against Cryptococcus infections, for example, cryptococcal meningitis, given its high levels of CNS penetration. Voriconazole is widely used for managing invasive aspergillosis caused by Aspergillus fumigatus and for treating Candida infections.

How does itraconazole act against fungal infections?

Itraconazole, like other azole antifungals, acts by inhibiting the synthesis of ergosterol, a major component of the fungal cell membrane. This action inhibits the growth of a variety of fungi, making itraconazole effective in treating systemic infections with dimorphic fungi such as histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis. Itraconazole is also used to treat onychomycosis and dermatophytosis.

How are azole antifungals like ketoconazole used in endocrine disorders?

Ketoconazole inhibits 17,20-desmolase (CYP17 alpha-hydroxylase), the first step of steroid hormone synthesis from cholesterol, thus disrupting the production of androgens and estrogens. It's helpful in controlling the overproduction of cortisol and consequently treating the symptoms associated with Cushing's disease. However, it's important to note that ketoconazole can also cause anti-androgenic side effects like gynecomastia.