Imidazole antifungals
Imidazole antifungals are a subgroup of the azole family of antifungal medications, characterized by their unique five-membered ring structure containing two nitrogen atoms. Primarily used to treat common yeast infections like oral thrush and vaginal candidiasis, imidazoles have demonstrated effectiveness comparable to polyene antifungals for oral thrush and superior effectiveness for vaginal candidiasis. They work by inhibiting an enzyme vital for the production of ergosterol, a key component of fungal cell membranes, leading to altered membrane permeability and ultimately cell death.
Ketoconazole is the most notable imidazole antifungal, available for both topical and systemic use, though its oral absorption is unpredictable and can be affected by stomach acidity. Other commonly used imidazoles include clotrimazole and miconazole, which are primarily topical agents effective against various yeast and fungal infections. Vaginal creams and oral suspensions are typically employed for treating specific conditions, while over-the-counter options are easily accessible, benefiting those with recurrent infections. Given that a significant portion of women experience vaginal candidiasis in their lifetime, imidazole antifungals remain a critical treatment choice, especially in the context of rising antibiotic usage that can predispose individuals to such infections.
Imidazole antifungals
Definition
Imidazole antifungals belong to the azole family, which also includes triazole and thiazole. An imidazole functional group, which is a five-membered ring containing two nitrogens, differentiates these drugs from other members of the azole family. Thiazole groups are similar rings with one nitrogen and one sulfur, while triazoles contain three nitrogens.
Imidazoles are used primarily to treat two types of yeast infections: oral thrush and vaginal candidiasis. They are as effective as polyene antifungals such as nystatin for oral thrush and somewhat more effective for vaginal candidiasis.
Mechanism of Action
Imidazole antifungals act similarly to triazole and thiazole antifungals. They work by inhibiting cytochrome P450 demethylase, an enzyme responsible for converting lanosterol to ergosterol. Because ergosterol is a major component of fungal cell membranes, blocking this conversion leads to the buildup of lanosterol. Lanosterol contains a 14 alpha-methyl group not present in ergosterol. Because of the different shape and physical properties of this sterol, the fungal cell membrane exhibits permeability changes and becomes leaky. Key cellular components can leak, and cell death results.
Drugs in This Class
Ketoconazole is the only drug in this category that is approved for topical and systemic use. Oral absorption is erratic and dependent on an acidic pH. Ketoconazole effectiveness will be dramatically lowered if taken with antacids or other drugs that lower gastric pH. It also is less effective if taken with drugs that are inducers of the CYP3A4 pathway and can lead to an increase in blood levels of other drugs metabolized by this pathway. Ketoconazole is now used mainly as a topical drug because of these drug interactions and the availability of more effective agents. Ketoconazole is available as a cream, lotion, suppository, and shampoo.
Other drugs in this class are topical agents used to treat superficial fungal and yeast infections. In some cases, the drugs are too toxic for systemic use. In others, they are so extensively and quickly degraded by first-pass metabolism in the liver that an insufficient amount of the drug would remain in the bloodstream to treat systemic infections.
Clotrimazole (Lotrimin, Gyne-Lotrimin, Mycelex) and miconazole (Monistat, Desenex) are the most commonly used of these agents and are effective against Candida, some other yeasts, and some gram-positive bacteria. Powders, creams, and topical sprays may be used to treat ringworm and athlete’s foot. Vaginal infections are best treated with vaginal creams (to be inserted internally) and suppositories. Oral thrush is treated with oral suspensions and troches. Rash is among the more common adverse effects associated with these products.
Impact
Approximately 75 percent of women experience at least one instance of vaginal candidiasis in their lifetime, and antifungal drugs represent a necessary treatment option for many. Antibiotic use is one of the primary predisposing factors for Candida infections; it is likely that the need for drugs to treat these infections will continue to remain high based on antibiotic prescription frequency. Over-the-counter imidazole products are available and are best used by persons with recurring infections who can accurately diagnose symptoms. Initial infections should be diagnosed by a healthcare professional.
Bibliography
Griffith, R. K. “Antifungal Drugs.” In Foye’s Principles of Medicinal Chemistry, edited by Thomas L. Lemke and William O. Foye. 6th ed. Philadelphia: Wolters Kluwer, 2008.
Gullo, Antonio. “Invasive Fungal Infections.” Drugs 69 (2009): 65-73.
Murray, Patrick R., Ken S. Rosenthal, and Michael A. Pfaller. Medical Microbiology. 6th ed. Philadelphia: Mosby/Elsevier, 2009.
Ryan, Kenneth J. “Pathogenesis of Fungal Infection.” In Sherris Medical Microbiology, edited by Kenneth J. Ryan and C. George Ray. 5th ed. New York: McGraw-Hill, 2010.
"Vaginal Yeast Infection." Harvard, 21 Sept. 2023, www.health.harvard.edu/a‗to‗z/vaginal-yeast-infection-a-to-z#. Accessed 3 Feb. 2025.