Imidazoles

Mechanism of action: inhibit fungal ergosterol biosynthesis

selectively inhibit fungal cytochrome P₄₅₀ enzymes

Ketoconazole

(original oral ‘azole’, not as selective as newer azoles, ie. significant inhibition of mammalian P450 enzymes)

Absorption: low - improved with food and low gastric pH

used orally, but has very slow onset; poor CSF and urinary tract penetration

Uses:

mucocutaneous candidiasis

coccidioidomycosis (non-meningeal)

in shampoos for seborrheic dermatitis

(largely supplanted by more expensive itraconazole or fluconazole)

Adverse effects: (narrow therapeutic window) highly dose-dependent

- nausea and vomiting

- endocrine: interferes with adrenal and gonadal steroid synthesis*

- hepatotoxicity (rare but can prove fatal)

- drug interactions

-*action on human cytochrome P₄₅₀ (eg. warfarin; cyclosporine; and vice versa)

- decreased absorption of ketoconazole when administered with rifampin, H₂ antagonists or antacids

Miconazole and Clotrimazole

Absorption: extremely poor - both used topically: creams and, in the case

of clotrimazole, oral troches (=lozenges)

Uses: wide-spread, over-the-counter use as topical antifungals

vulvovaginal candidiasis

dermatophytic infections (eg. tineas corporis)

oropharyngeal thrush (candidiasis; alternatives to nystatin)

Category: Pharmacology Notes