Fluconazole standard dose, mechanism of action, side effects
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fluconazole antifungal mechanism dose
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Fluconazole
Mechanism of Action
Fluconazole is a triazole antifungal that works by inhibiting fungal lanosterol 14-alpha-demethylase (CYP51), a cytochrome P450-dependent enzyme required for the conversion of lanosterol to ergosterol. Ergosterol is the principal sterol in fungal cell membranes (analogous to cholesterol in mammalian cells). Its depletion disrupts membrane integrity, increases permeability, and impairs fungal growth and replication.
Compared to other azoles, fluconazole is relatively selective for the fungal CYP450 system over mammalian enzymes, giving it a wider therapeutic index. - Katzung's Basic and Clinical Pharmacology, 16th Ed.
Standard Doses
| Indication | Dose |
|---|---|
| Vaginal candidiasis | 150 mg single oral dose |
| Oropharyngeal/esophageal candidiasis | 100-200 mg/day for 7-14 days |
| Invasive/systemic candidiasis | 400-800 mg/day (IV or oral) |
| Cryptococcal meningitis (acute) | 400-800 mg/day (after amphotericin B induction) |
| Cryptococcal meningitis (maintenance/secondary prophylaxis) | 200 mg/day |
| Prophylaxis in immunocompromised (BMT, AIDS) | 200-400 mg/day |
| Dermatophytosis / onychomycosis | 150-300 mg once weekly |
Overall dosage range: 100-800 mg/day, available in both oral and IV formulations. Oral bioavailability is exceptionally high (~90%), making IV-to-oral switch straightforward. - Katzung's Basic and Clinical Pharmacology, 16th Ed.
Side Effects
Common
- Nausea, dyspepsia, diarrhea, abdominal pain
- Headache, dizziness, myalgia
- Skin rash
Serious / Less Common
- Hepatotoxicity - elevated liver enzymes and, rarely, clinical hepatitis (class effect for all azoles)
- QT prolongation and torsade de pointes - a significant cardiac risk, especially with other QT-prolonging drugs
- Teratogenicity - associated with tetralogy of Fallot when used in pregnancy; should be avoided in the first trimester
Compared to Other Azoles
Fluconazole has the widest therapeutic index of the azoles and is the best-tolerated systemically, with fewer hepatic enzyme interactions and better GI tolerability than ketoconazole or itraconazole. - Fitzpatrick's Dermatology, 9th Ed.; Katzung's Basic and Clinical Pharmacology, 16th Ed.
Drug Interactions
Fluconazole has the least effect of all azoles on hepatic CYP450 enzymes, but interactions still occur:
-
Increases levels of: cyclosporine, tacrolimus, warfarin, phenytoin, sulfonylureas, statins, benzodiazepines
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Rifampin reduces fluconazole levels (induces its metabolism)
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Contraindicated combinations include: artemether, clopidogrel, QT-prolonging agents (dronedarone, cisapride) due to risk of fatal arrhythmias
-
Goodman & Gilman's Pharmacological Basis of Therapeutics
Key Pharmacokinetic Properties
| Property | Detail |
|---|---|
| Oral bioavailability | ~90% (not affected by food or gastric pH) |
| CNS penetration | Excellent - achieves high CSF levels (unlike ketoconazole/itraconazole) |
| Protein binding | Low (~12%) |
| Elimination | Primarily renal (dose reduction needed in renal impairment) |
| Half-life | ~30 hours (allows once-daily dosing) |
Spectrum of Activity
Fluconazole is active against most Candida species, Cryptococcus neoformans, and endemic mycoses. Key resistance patterns to remember:
-
Candida krusei - intrinsically resistant
-
Candida glabrata - ~30% are resistant
-
Candida auris - typically resistant to all azoles
-
Quick Compendium of Clinical Pathology, 5th Ed.
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