Antifungals

Antifungals are divided into following classes:

1. Azoles: These include imidazoles like clotrimazole, ketoconazole and miconazole and triazoles like fluconazole, itraconazole, terconazole and voriconazole. They inhibit the synthesis of ergosterol which is a component of the fungal cell membrane by inhibiting cyt P450 enzyme. Adverse effects include GI upset, diarrhea, hepatotoxicity and rash. Ketoconazole may have anti-androgenic effects including gynaecomastia, decreased libido, decreased sperm count and motility. They inhibit the hepatic cyt P450 system as well. Caution should be used when drugs like cisapride, dasatinib, tamsulosin, warfarin, triazolam, alprazolam, phenytoin, sirolimus etc. are used along with azoles. Ketoconazole is used as topical agent and orally to treat dermatophytes, Candida spp, Blastomyces dermatitidis and Coccidiodes spp. Fluconazole , voriconazole and itraconazole are used to treat invasive or systemic fungal infections like Candida spp, Cryptococcus neoformans, Aspergillus spp., dematiaceous fungi and Sporothrix schenckii (last three itraconazole and voriconazole only). Posaconazole is active against zygomycetes as well.
2. Polyenes: It includes amphotericin B, nystatin and natamycin. Polyenes bind to ergosterol in the fungal cell membrane and disrupt it leading to increased cellular permeability. Liposomal and carrier forms are available to reduce adverse effects. Amphotericin B is used to treat systemic fungal infections like Candida spp, Aspergillus spp, etc. Adverse effects include nephrotoxicity, hematologic toxicity and infusion related reactions such as fever, headache and thrombophlebitis. Premedication with acetaminophen and heparin is done to prevent infusion related adverse effects. Intravenous hydration with normal saline and correction of electrolyte imbalance helps to prevent nephrotoxicity. Nystatin is given orally or topically.
3. Allylamines: It includes terbinafine, and it inhibits the enzyme squalene monooxygenase that is involved in sterol synthesis. It is used to treat onychomycosis. It may cause hepatitis, elevated liver enzymes and lymphopenia.
4. Echinocandins: It includes caspofungin, micafungin and anidulafungin. They inhibit the enzyme beta 1,3 D-glucan synthase thereby blocking the synthesis of beta 1,3 D-glucan in the cell wall. This causes cell lysis. They are used in the treatment of Candidiasis, Aspergillosis etc. Anidulafungin can be safely used in the presence of hepatic or renal failure. C.neoformans is resistant to echinocandins as their cell wall lacks beta glucan. They are well tolerated, adverse effects include GI upset, infusion reactions, hypotension and rash.
5. Flucytosine: It is converted to 5-fluorouracil by the enzyme cytosine deaminase, inside fungal cells. 5FU interrupts fungal DNA and protein synthesis. It is used as a combination therapy and is active against Candida sp, Cryptococcus sp, Aspergillus sp and dematiaceous fungi. Adverse effects include diarrhea, nausea, vomiting, myelosuppression and hepatotoxicity.