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Chapter: Modern Pharmacology with Clinical Applications: Antifungal Drugs

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Fluconazole Antifungal Drug

Absorption, Distribution, Metabolism, and Excretion, Adverse Effects

FLUCONAZOLE

 

Absorption, Distribution, Metabolism, and Excretion

 

Fluconazole (Diflucan) does not require an acidic envi-ronment, as does ketoconazole, for gastrointestinal ab-sorption. About 80 to 90% of an orally administered dose is absorbed, yielding high serum drug levels. The half-life of the drug is 27 to 37 hours, permitting once-daily dosing in patients with normal renal function. Only 11% of circulating drug is bound to plasma pro-teins. The drug penetrates widely into most body tissues, including normal and inflamed meninges. Cerebrospinal fluid levels are 60 to 80% of serum levels, permitting ef-fective treatment for fungal meningitis. About 80% of the drug is excreted unchanged in the urine, and 10% is excreted unchanged in the feces. Dosage reductions are required in the presence of renal insufficiency.

 

Clinical Uses

 

Fluconazole is very effective in the treatment of infec-tions with most Candida spp. Thrush in the end-stage AIDS patient, often refractory to nystatin, clotrimazole, and ketoconazole, can usually be suppressed with oral fluconazole. AIDS patients with esophageal candidiasis also usually respond to fluconazole. A single 150-mg dose has been shown to be effective treatment for vagi-nal candidiasis. A 3-day course of oral fluconazole is ef-fective treatment for Candida urinary tract infection and is more convenient than amphotericin B bladder ir-rigation. Preliminary findings suggest that Candida en-dophthalmitis can be successfully treated with flucona-zole. Stable nonneutropenic patients with candidemia can be adequately treated with fluconazole, but unsta-ble, immunosuppressed patients should initially receive amphotericin B. Candida krusei isolates may be resist-ant to fluconazole.

 

Fluconazole may be an acceptable alternative to amphotericin B in the initial treatment of mild crypto-coccal meningitis, and it has been shown to be superior to amphotericin B in the long-term prevention of re-lapsing meningitis (such patients require lifelong treat-ment.). Coccidioidal meningitis, previously treated with both intravenous and intrathecal amphotericin B, ap-pears to respond at least as well to prolonged oral flu-conazole therapy. Aspergillosis, mucormycosis, and pseudallescheriasis do not respond to fluconazole treat-ment. Sporotrichosis, histoplasmosis, and blastomycosis appear to be better treated with itraconazole, although fluconazole does appear to have significant activity against these dimorphic fungi.

 

A significant decrease in mortality from deep-seated mycoses was noted among bone marrow transplant re-cipients treated prophylactically with fluconazole, but similar benefits have not been seen in leukemia patients receiving prophylactic fluconazole. Fluconazole taken prophylactically by end-stage AIDS patients can reduce the incidence of cryptococcal meningitis, esophageal candidiasis, and superficial fungal infections.

Adverse Effects

 

Fluconazole is well tolerated. Nausea, vomiting, abdom-inal pain, diarrhea, and skin rash have been reported in fewer than 3% of patients. Asymptomatic liver enzyme elevation has been described, and several cases of drug-associated hepatic necrosis have been reported. Alo-pecia has been reported as a common adverse event in patients receiving prolonged high-dose therapy. Coad-ministration of fluconazole with phenytoin results in in-creased serum phenytoin levels.

 

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