Fluconazole
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Fluconazole
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| Systematic (IUPAC) name | |
| 2-(2,4-difluorophenyl)- 1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol |
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| Identifiers | |
| CAS number | |
| ATC code | D01 J02AC01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C13H12F2N6O |
| Mol. mass | 306.271 g/mol |
| Pharmacokinetic data | |
| Bioavailability | >90% |
| Protein binding | 11–12% |
| Metabolism | Hepatic 11% |
| Half life | 30 hours (range 20-50 hours) |
| Excretion | Renal 61–88% |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
S3/S4 (Au), POM (UK), ℞-only (U.S.) |
| Routes | Oral, IV, topical |
Fluconazole (INN) (IPA: [fluˈkɒnəzoʊl]) is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. It is commonly marketed under the trade name Diflucan (Pfizer).
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[edit] Pharmacology
[edit] Mode of action
Like other imidazole- and triazole-class antifungals, fluconazole inhibits the fungal cytochrome P450 enzyme 14α-demethylase. Mammalian demethylase activity is much less sensitive to fluconazole than fungal demethylase. This inhibition prevents the conversion of lanosterol to ergosterol, an essential component of the fungal cytoplasmic membrane, and subsequent accumulation of 14α-methyl sterols.[1] Fluconazole is primarily fungistatic, however may be fungicidal against certain organisms in a dose-dependent manner.
[edit] Microbiology
Fluconazole is active against the following microorganisms:[2]
- Blastomyces dermatitidis
- Candida spp. (except C. krusei and C. glabrata)
- Coccidioides immitis
- Cryptococcus neoformans
- Epidermophyton spp.
- Histoplasma capsulatum
- Microsporum spp.
- Trichophyton spp.
[edit] Pharmacokinetics
Following oral dosing, fluconazole is almost completely absorbed within two hours. Bioavailability is not significantly affected by concomitant intake of meals or the use of H2-antagonists (e.g. ranitidine). Concentrations measured in the urine and skin are approximately 10 times the plasma concentration, while saliva, sputum and vaginal fluid concentrations are approximately equal to the plasma concentration, following a standard dose range of between 100 mg and 400 mg per day. The elimination half-life of fluconazole follows zero order kinetics and only 10% of elimination is due to metabolism, the remainder is excreted in urine and sweat. Patients with impaired renal function will be at risk of overdose as well as patients taking drugs such as warfarin.
[edit] Clinical use
[edit] Indications
Fluconazole is indicated for the treatment and prophylaxis of fungal infections where other antifungals have failed or are not tolerated (e.g. due to adverse effects), including:[3]
- Candidiasis caused by susceptible strains of Candida
- Tinea corporis, tinea cruris or tinea pedis
- Onychomycosis
- Cryptococcal meningitis
Fluconazole can be used first-line for the following indications:[3]
- Coccidioidomycosis
- Cryptococcosis
- Histoplasmosis
- Prophylaxis of candidiasis in immunocompromised people
[edit] Dosage
Dosage varies with indication and between patient groups, ranging from: a two week course of 150 mg/day for vulvovaginal candidiasis, to 150–300 mg once weekly for resistant skin infections or some prophylactic indications. 50–600 mg/day may be used for systemic or severe infections, and in urgent infections such as meningitis caused by yeast 800 mg/day have been used. Pediatric doses are measured at 8 mg/kg max. A loading dose will be indicated when entering a daily dosage schedule, for example a loading dose of 200 mg on the first day is commonly used with 150 mg/day following that.[3]
[edit] Contraindications
Fluconazole is contraindicated in patients with:[3]
- Known hypersensitivity to fluconazole or other azole antifungals
- Concomitant use of cisapride, due to risk of serious cardiac arrhythmias
[edit] Precautions
Fluconazole therapy has been associated with QT interval prolongation, which may lead to serious cardiac arrhythmias. Thus it is used with caution in patients with risk factors for prolonged QT interval such as electrolyte imbalance or use of other drugs which may prolong the QT interval (particularly cisapride).
Fluconazole has also rarely been associated with severe or lethal hepatotoxicity and liver function tests are usually performed regularly during fluconazole therapy. Additionally, it is used with caution in patients with pre-existing liver disease.[1]
High concentrations of fluconazole have been detected in human breast milk from patients receiving fluconazole therapy, thus its use is not recommended in breastfeeding mothers.[1]
[edit] Adverse effects
Adverse drug reactions associated with fluconazole therapy include:[3]
- Common (≥1% of patients): rash, headache, dizziness, nausea, vomiting, abdominal pain, diarrhoea, and/or elevated liver enzymes
- Infrequent (0.1–1% of patients): anorexia, fatigue, constipation
- Rare (<0.1% of patients): oliguria, hypokalaemia, dizziness, paraesthesia, seizures, alopecia, Stevens-Johnson syndrome, thrombocytopenia, other blood dyscrasias, serious hepatotoxicity including hepatic failure, anaphylactic/anaphylactoid reactions
- Very rare: prolonged QT interval, torsades de pointes
[edit] Drug interactions
Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the isozymes CYP2C9 and CYP3A4. In theory, therefore, fluconazole decreases the metabolism and increases the concentration of any drug metabolised by these enzymes. Additionally, its potential effect on QT interval increases the risk of cardiac arrhythmia if used concurrently with other drugs that prolong the QT interval.
[edit] References
- ^ a b c Pfizer Australia Pty Ltd. Diflucan (Australian Approved Product Information). West Ryde (NSW): Pfizer Australia; 2004.
- ^ Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. ISBN 0-85369-550-4
- ^ a b c d e Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
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|---|---|
| Antibiotics | Griseofulvin, Hitachimycin, Natamycin, Nystatin |
| Topical Azoles | Clotrimazole, Econazole, Fluconazole, Ketoconazole, Miconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole |
| Other topicals | Ciclopirox, Ethylparaben, Flucytosine, Salicylic acid, Selenium sulfide, Terbinafine, Tolnaftate |
| For systemic use | Amphotericin B, Anidulafungin, Caspofungin, Griseofulvin, Itraconazole, Terbinafine, Voriconazole |
| Other | Posaconazole, Thiabendazole, Tea tree oil |
