Triazole antifungals
Triazole antifungals are a class of medications characterized by their five-membered rings containing three nitrogen atoms, designed to combat fungal infections. They are more potent and specific compared to older antifungal agents, such as imidazoles, due to the unique chemical structure that enhances their efficacy. Triazoles are commonly used to treat a variety of fungal infections, including candidiasis (causing conditions like oral thrush and vaginal yeast infections) and onychomycosis (fungal nail infections). They are particularly important for immunocompromised individuals, as they can effectively treat serious infections like cryptococcal meningitis.
These drugs work by disrupting the synthesis of ergosterol, a vital component of fungal cell membranes, thereby compromising fungal cell integrity. Common side effects when taken orally include gastric discomfort and potential liver toxicity. Furthermore, triazoles can interact with other medications by inhibiting liver enzymes, impacting the metabolism of various drugs. While triazole antifungals have evolved since their initial discovery in the 1940s, the emergence of resistant fungal strains has prompted ongoing research for new agents within this class. Notable examples of modern triazoles include posaconazole and voriconazole, which offer improved action against a broader spectrum of fungal pathogens.
Triazole antifungals
Definition
Triazole is a class of antifungal drugs that consists of five-membered rings with three nitrogen substitution molecules. These molecules interfere with the activity of fungal organic compounds that cause infections.
Diseases Treated
First-generation triazoles, such as itraconazole and fluconazole, provide broad-spectrum action against superficial and deep fungal infections. Extra nitrogens present on the triazole antifungal drugs result in increased specificity and potency compared with the older imidazole antifungals, such as miconazole. Candidiasis infections, which cause oral thrush and vaginal yeast infections, and onychomycosis, a fungal nail infection, are two common examples of diseases treated with triazole antifungal agents. Aspergillosis, blastomycosis, histoplasmosis, and, in particular, cryptococcus meningitis, which are also treated with triazole antifungals, are more often observed in immune-compromised persons, such as those with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). Fluconazole may be used lifelong in persons with AIDS because of the increased risk of candidiasis relapse; however, prophylaxis for initial candidiasis in persons with HIV is not recommended.
Mechanism of Action
Triazole antifungals disrupt sterols in fungal cytoplasmic membranes that are essential to fungal cell functioning. These drugs bind to cytochrome P450 (CYP450) liver metabolism enzymes in the body to increase the amount of C14-alpha-methylsterol and decrease the amount of ergosterol needed by the fungal cells. Triazole effects appear proportional to drug exposure as measured by the area under the curve, and they are often longer with triazoles than with older imidazole compounds. Triazoles, when used topically, may provide, in addition to their sterol effects, direct damage to fungal cell membranes.
Adverse Drug Effects and Interactions
The most common side effects of drugs in the triazole class, when taken by mouth, are gastric discomfort, such as nausea and vomiting, and hepatotoxicity. Suppression of the body’s sterol and hormonal levels may occur as well. The interaction of the CYP liver-enzyme system with triazoles for the drug’s effect can cause increases in other drug concentrations when the drugs are taken concomitantly with triazole antifungals. All CYP3A4 enzymes are affected by triazole antifungals to cause inhibition of other drug metabolism. Fluconazole and voriconazole, additionally, interact with CYP2C9 and CYP2C19 enzymes in the same manner. Drugs that are adversely increased by inhibited CYP metabolism include rifampin, midazolam, warfarin, and phenytoin; however, CYP drug interactions are specific to each triazole antifungal.
Impact
From their early development, which resulted from natural discovery in the 1940s, through the development of second- and third-generation agents in the early twenty-first century, triazole antifungals have expanded as a class. They now include improved action in the body and widespread administration forms, from oral to topical and nonprescription to prescription.
From the early use of itraconazole and fluconazole, however, resistant fungi, especially candidiasis, have developed because of drug efflux and increased C14-alpha-demethylase changes; this resistance has led to research and development of newer agents in the triazole class.
Posaconazole, a unique late-generation triazole, is uniquely active against molds and zygomycetes in addition to typical fungal targets. Other late-generation examples, such as isavuconazole, voriconazole, ravuconazole, and albuconazole, provide longer half-lives and improved body distribution, which improves dosing regimens also.
Bibliography
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McCreary, Erin K. et al. "Utility of Triazole Antifungal Therapeutic Drug Monitoring: Insights from the Society of Infectious Diseases Pharmacists." Pharmacotherapy, 17 July 2023, doi.org/10.1002/phar.2850. Accessed 4 Feb. 2025.
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