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Fluconazole---A bis-triazole antifungal agent

Mar 28，2022

DESCRIPTION

Fluconazole (Diflucans), 2,4-difluoro-a,a1 -bis(1H-1,2,4-triazol-1- ylmethyl) benzyl alcohol, is a bis-triazole antifungal agent with the chemical formula C13H12F2N6O and a molecular weight of 306.3. Like the other drugs in the azole class, the primary mode of action of fluconazole is inhibition of fungal cytochrome P450-dependent C14-a sterol demethylase. Inhibition of this critical demethylation step in ergosterol biosynthesis leads to accumulation of methylated ergosterol precursors in the plasma membrane and depletion of ergosterol – ultimately resulting in fungal growth arrest. Available formulations include an oral tablet, a powder for oral suspension, and an intravenous formulation. Fluconazole exhibits activity against Candida, Cryptococcus, and some dimorphic fungi. Fluconazole is currently approved by the US Food and Drug Administration (FDA) for treatment of cryptococcosis and candidiasis, including invasive, oroesophageal, urogenital, and vulvovaginal disease. In addition, fluconazole is approved for prophylaxis of candidiasis in bone marrow transplant recipients.

MECHANISM OF DRUG ACTION

Like the other drugs in the azole class, the primary mode of action of fluconazole is inhibition of fungal cytochrome P450 (CYP50)-dependent C14-a sterol demethylase. Inhibition of this critical demethylation step in ergosterol biosynthesis leads to accumulation of methylated ergosterol precursors in the plasma membrane and depletion of ergosterol. Ultimately, the plasma membrane changes result in increased membrane permeability and fungal growth arrest.

TOXICITY

Fluconazole is generally safe and well tolerated. The most common side-effects in patients receiving long-term, high-dose therapy include headache, alopecia, and anorexia. The overall rate of adverse effects in manufacturer-sponsored trials was 16% in over 4000 patients treated with the drug for longer than 7 days. The most frequently reported events were nausea (3.7%), vomiting (1.7%), diarrhea (1.5%), abdominal pain (1.7%), headache (1.9%), and skin rash (1.8%) (Grant and Clissold, 1990). There does not appear to be a dose-dependent increase in the adverse event rate over the dose range of 100–400 mg. However, there may be an increase in toxicity rates when high doses (800–2000 mg daily) are used.

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