) is a triazole antifungal drug
used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade name Diflucan
Mode of action
Like other imidazole
- and triazole
-class antifungals, fluconazole inhibits the fungal cytochrome P450
. Mammalian demethylase activity is much less sensitive to fluconazole than fungal demethylase. This inhibition prevents the conversion of lanosterol
, an essential component of the fungal cytoplasmic membrane
, and subsequent accumulation of 14α-methyl sterols. Fluconazole is primarily fungistatic
, however may be fungicidal
against certain organisms in a dose-dependent manner. Interestingly, when fluconazole was in development at Pfizer it was decided early in the process to avoid producing any chiral
centers in the drug so that subsequent synthesis and purification did not encounter difficulties with enantiomer
separation and associated variations in biological effect. A number of related compounds were found to be extremely potent teratogens
and subsequently discarded.
Fluconazole is active against the following microorganisms:
Following oral dosing, fluconazole is almost completely absorbed within two hours. Bioavailability
is not significantly affected by the absence of stomach acid. Concentrations measured in the urine, tears 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
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:
Fluconazole can be used first-line for the following indications:
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 6-12 mg/kg/d . 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.
Fluconazole is contraindicated in patients with:
- Known hypersensitivity to fluconazole or other azole antifungals
- Concomitant use of cisapride, due to risk of serious cardiac arrhythmias (relative contraindication).
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 prolonged fluconazole therapy. Additionally, it is used with caution in patients with pre-existing liver disease.
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.
Adverse drug reactions
associated with fluconazole therapy include:
- Common (≥1% of patients): rash, headache, dizziness, nausea, vomiting, abdominal pain, diarrhea, and/or elevated liver enzymes
- Infrequent (0.1–1% of patients): anorexia, fatigue, constipation
- Rare (<0.1% of patients): oliguria, hypokalaemia, 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
Fluconazole is an inhibitor of the human cytochrome P450
system, particularly the isozymes CYP2C9
. 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.