Indications
Fluconazole is indicated for the treatment of various fungal infections, including candidiasis-related conditions and cryptococcal meningitis. It is effective against vaginal yeast infections caused by Candida species, systemic Candida infections, esophageal and oropharyngeal candidiasis, and urinary tract infections due to Candida. Additionally, fluconazole is used in treating peritonitis induced by Candida. For patients undergoing bone marrow transplantation and receiving cytotoxic chemotherapy or radiation therapy, fluconazole may be administered prophylactically to prevent candidal infections. Before initiating fluconazole therapy, it is advisable to obtain specimens for fungal culture and other vital laboratory studies to identify the specific organisms responsible, although treatment can commence prior to receiving laboratory results, with subsequent adjustments based on the outcomes.
Pharmacodynamics
Fluconazole exhibits fungistatic activity primarily by inhibiting steroid synthesis in fungal cells, thereby disrupting cell wall synthesis, growth, and adhesion. It is effective against most strains of Candida species including Candida albicans, Candida glabrata, Candida parapsilosis, and Candida tropicalis, as well as Cryptococcus neoformans. In both normal and immunocompromised animal models, fluconazole has demonstrated efficacy against systemic and intracranial fungal infections caused by Cryptococcus neoformans and systemic infections by Candida albicans. Resistance has been observed in certain strains, emphasizing the importance of susceptibility testing when considering fluconazole as a therapeutic option. Concerns regarding its potential interference with human steroid production have been mitigated by studies indicating fluconazole's selective inhibitory effects on fungal cytochrome P-450 enzymes over mammalian ones.
Absorption
Fluconazole exhibits excellent oral bioavailability, exceeding 90%, comparable to its intravenous administration. It is significantly absorbed in the gastrointestinal tract; food intake does not impact its oral absorption but may extend the time to reach peak concentration. After a 50 mg/kg oral dose, Tmax is approximately 3 hours, while peak plasma concentrations are achieved between 1-2 hours in fasting conditions. Steady-state concentrations are typically reached within 5 to 10 days with daily oral doses ranging from 50 to 400 mg. Administering an initial loading dose allows near-steady-state plasma levels by the second day. The presence of lactose in fluconazole capsules necessitates caution in individuals with lactose intolerance or certain malabsorption syndromes, while the oral suspension form should be avoided in patients with specific carbohydrate intolerance issues.
Metabolism
Fluconazole undergoes minimal liver metabolism and acts as an inhibitor of the CYP2C9, CYP3A4, and CYP2C19 enzymes. In studies involving healthy volunteers administered a radiolabeled 50 mg dose of fluconazole, metabolites detected in the urine include a glucuronide conjugate and fluconazole N-oxide, albeit in small percentages. This minimal metabolic transformation differentiates fluconazole from other azole antifungals, which typically undergo extensive hepatic metabolism.
Mechanism of Action
Fluconazole exerts its antifungal effects by selectively inhibiting the fungal cytochrome P450 enzyme, lanosterol 14-α-demethylase. This enzyme is crucial for converting lanosterol into ergosterol, a key component in fungal cell wall synthesis. The azole ring of fluconazole contains a nitrogen atom that binds to the iron within the heme group of lanosterol 14-α-demethylase. This binding obstructs oxygen activation, consequently inhibiting the demethylation of lanosterol and disrupting the biosynthesis of ergosterol. As a result, methylated sterols accumulate in the fungal cell membrane, impairing the growth and structural integrity of the fungus. Resistance to fluconazole can develop through changes in the quantity or functionality of the target enzyme, altered access to the enzyme, or other mechanisms that are still under investigation.
