Article: Fluconazole

Fluconazole
Systematic (IUPAC) name
2-(2,4-difluorophenyl)- 1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol
Identifiers
CAS number	86386-73-4
ATC code	D01AC15 J02AC01
PubChem	3365
DrugBank	APRD00327
Chemical data
Formula	C13H12N6F2O
Mol. weight	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.	D (Au), C (U.S.)
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).

Pharmacology

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 cell wall, and subsequent accumulation of 14α-methyl sterols.^[1] Fluconazole is primarily fungistatic, however may be fungicidal against certain organisms in a dose-dependent manner.

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.

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 urine, saliva, sputum and vaginal secrete are approximately equal to the plasma concentration measured following a wide dose range from 100–400 mg oral as a single dose. The elimination half-life of fluconazole is increased in patients with impaired renal function.

Clinical use

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

Dosage

Dosage varies with indication and between patient groups, ranging from: a 150 mg single dose for vulvovaginal candidiasis, to 150–300 mg once weekly for resistant skin infections or some prophylactic indications, to 50–400 mg once daily for systemic or severe infections.^[3]

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

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]

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

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.