Azole Antifungals

Mechanism

💊 Generic and Commercial Names

Fluconazole (Diflucan), Voriconazole (Vfend), Posaconazole (Noxafil), Itraconazole (Sporanox).

🔬 Pharmacological Group

Systemic imidazole and trialic antifungals. Inhibitors of ergosterol biosynthesis.

Mechanism of Action

Its molecular target is the key enzyme of the fungal lipid cascade:

• Inhibition of the Lanosterol 14-alpha-demethylase Enzyme: They competitively bind and inhibit this fungal cytochrome P450-dependent enzyme (encoded by the ERG11 gene), responsible for the demethylation of lanosterol for the production of ergosterol (an essential lipophilic lipid component). for the fluidity and structural maintenance of the fungal membrane).
• Membrane Disruption and Instability: Blocking lanosterol 14-alpha-demethylase causes intracellular accumulation of toxic abnormal methylated sterols and ergosterol depletion, severely altering membrane permeability and arresting growth or inducing rapid fungal death.

Pharmacokinetics

Key Pharmacokinetics

Antifungal Spectrum

• Fluconazole: Excellent against yeasts such as Candida albicans, Candida parapsilosis, Candida tropicalis and Cryptococcus neoformans. It is not active against Candida krusei (innate resistance) and has variable or no coverage of Candida glabrata.
• Voriconazole: Broad spectrum. Excellent spectrum against filamentous fungi such as invasive Aspergillus spp., Scedosporium spp., Fusarium spp. and yeasts resistant to fluconazole (including C. krusei and C. glabrata).

Indicators and dose

Dosage and Adjustment

• Fluconazole: Loading dose of 400 to 800 mg orally or IV on day 1, followed by 200 to 400 mg every 24 hours in healthy adults.
• Voriconazole: Loading dose of 6 mg/kg every 12 hours IV on day 1, followed by a usual maintenance dose of 4 mg/kg every 12 hours IV (or 200 mg every 12 hours orally).
• Adjustment of Fluconazole in Renal Failure:
  • Cl_cr ≤ 50 mL/min (not on dialysis): Reduce the recommended daily maintenance dose by half (50%).

Security

Contraindications and ADRs

• Contraindications: Concomitant coadministration with potent QTe interval prolonging drugs (such as thioridazine or terfenadine); hypersensitivity to voriconazole.
• Adverse Effects (ADR):
  • Voriconazole Transient Visual Disorders: Alterations in visual perception and transient reversible photophobia ("haze or light flashes") that affect 30% of patients 30 minutes after the dose, secondary to a direct interaction of the drug with the cellular photoreceptors of the ocular retina.
  • Hepatotoxicity and Cholestasis: Elevation of transaminases and reversible alkaline phosphatase, more common with Voriconazole.
  • Visual and Auditory Hallucinations due to Voriconazole: Transient neurotoxicity associated with plasma levels greater than 5.5 mcg/mL.

Risk of Cyclodextrin Accumulation with Voriconazole IV

The intravenous formulation of Voriconazole includes the molecule sulfobutyl ether beta-cyclodextrin (SBECD) as a solubility-stabilizing excipient. In patients with pre-existing moderate to severe renal failure (Cl_cr < 50 mL/min), SBECD is not adequately filtered by the glomerulus, accumulating in the plasma with a potential risk of secondary renal tubular toxicity. Therefore, in patients with active renal failure it is recommended to avoid intravenous voriconazole and preferentially administer it orally (which does not contain SBECD) if gastric absorption is preserved.