What is the mechanism of action of Fluconazole (an antifungal medication)?

From the Guidelines

Fluconazole works by inhibiting the fungal cytochrome P450 enzyme 14α-demethylase, which is essential for converting lanosterol to ergosterol in the fungal cell membrane, leading to increased cell membrane permeability, cellular leakage, and ultimately fungal cell death. This mechanism of action is crucial for its effectiveness against Candida species and Cryptococcus, making it a valuable treatment option for candidiasis, cryptococcal meningitis, and other fungal infections 1. The medication is available in oral and intravenous forms, with typical adult dosing ranging from 100-400 mg daily depending on the infection type and severity. Fluconazole has excellent bioavailability and penetrates well into most body tissues and fluids, including the cerebrospinal fluid, achieving concentrations of >70% of those in serum 1.

Some key points to consider when using fluconazole include:

• It has a long half-life of approximately 30 hours, allowing for once-daily dosing 1
• It has a more selective effect on fungal enzymes versus human enzymes, resulting in fewer side effects, though it can still interact with medications metabolized by human cytochrome P450 enzymes, potentially causing drug interactions that should be monitored 1
• For patients with invasive candidiasis, fluconazole should be administered with an average loading dose of 800 mg (12 mg/kg), followed by an average daily dose of 400 mg (6 mg/kg) 1
• Fluconazole elimination is almost entirely renal; thus, a dose reduction is needed in patients with creatinine clearance <50 mL/minute 1

Overall, fluconazole is a effective and widely used antifungal medication, and its mechanism of action and pharmacokinetic properties make it a valuable treatment option for a range of fungal infections.

From the FDA Drug Label

Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. The mechanism of action of fluconazole is through the inhibition of the fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase, which is involved in the conversion of lanosterol to ergosterol. This inhibition leads to the accumulation of 14-α-methyl sterols in fungi, resulting in fungistatic activity 2, 2.

• The inhibition of lanosterol 14-α-demethylase is highly selective for fungal enzymes, with mammalian cell demethylation being much less sensitive to fluconazole inhibition.
• The loss of normal sterols and the accumulation of 14-α-methyl sterols in fungi may be responsible for the fungistatic activity of fluconazole.

From the Research

Mechanism of Action of Fluconazole

• Fluconazole acts by inhibiting the synthesis of ergosterol, an essential sterol in fungal cell membranes 3
• Ergosterol is critical for defining membrane fluidity and regulating cellular processes in fungi 4
• The inhibition of ergosterol synthesis by fluconazole impairs vacuolar acidification and cell growth in fungi 5
• Fluconazole also exacerbates cytosolic Ca(2+) and H(+) surges triggered by the antimicrobial agent amiodarone, and impairs Ca(2+) sequestration in purified vacuolar vesicles 5

Effects of Fluconazole on Fungal Pathogenicity

• Fluconazole has been shown to be effective in treating various fungal infections, including candidiasis and cryptococcal meningitis 3, 6, 7
• The drug has been found to be well tolerated and infrequently associated with serious adverse effects or laboratory test abnormalities 3
• Combination therapy with fluconazole and other antifungal agents, such as flucytosine, has been shown to improve outcomes in patients with cryptococcal meningitis 6, 7

Role of Ergosterol in Fungal Pathogenicity

• Ergosterol plays a crucial role in maintaining membrane fluidity and regulating cellular processes in fungi 4
• Abnormal accumulation of ergosterol at the plasma membrane can lead to invagination of the plasma membrane, malformation of the cell wall, and mislocalization of cell surface proteins 4
• Inhibition of ergosterol synthesis by fluconazole can rescue these defects and attenuate fungal virulence 4