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Chapter: Modern Pharmacology with Clinical Applications: Antifungal Drugs

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Ketoconazole Antifungal Drug

Absorption, Distribution, Metabolism, and Excretion, Adverse Effects, Drug Interactions, Clinical Uses

KETOCONAZOLE

 

Absorption, Distribution, Metabolism, and Excretion

 

Unlike other imidazoles, ketoconazole (Nizoral) can be absorbed orally, but it requires an acidic gastric environment; patients concurrently treated with H2 blockers or who have achlorhydria have minimal drug absorption. Serum protein binding exceeds 90%. The drug is metabolized in the liver and excreted in the bile. The initial half-life of ketoconazole is 2 hours; 8 to 12 hours after ingestion, the half-life increases to 9 hours.

 

Reductions in renal and hepatic function do not al-ter plasma drug concentrations, and ketoconazole is not removed by hemodialysis or peritoneal dialysis. Penetration into cerebrospinal fluid is negligible, so that ketoconazole is ineffective in the treatment of fungal meningitis. Since only small amounts of active drug ap-pear in the urine, ketoconazole is not effective in the treatment of Candida cystitis.

 

Clinical Uses

 

Ketoconazole remains useful in the treatment of cuta-neous and mucous membrane dermatophyte and yeast infections, but it has been replaced by the newer tria-zoles in the treatment of most serious Candida infec-tions and disseminated mycoses. Ketoconazole is usu-ally effective in the treatment of thrush, but fluconazole is superior to ketoconazole for refractory thrush. Widespread dermatophyte infections on skin surfaces can be treated easily with oral ketoconazole when the use of topical antifungal agents would be impractical. Treatment of vulvovaginal candidiasis with topical imi-dazoles is less expensive.

 

Blastomycosis, histoplasmosis, sporotrichosis, paracoc-cidioidomycosis, and chromomycosis are better treated with itraconazole than ketoconazole, although ketocona-zole remains an alternative agent. Ketoconazole is inef-fective in the treatment of cryptococcosis, aspergillosis, and mucormycosis. Candidemia is best treated with flu-conazole or amphotericin B.

 

Adverse Effects

 

Nausea, vomiting, and anorexia occur commonly with ketoconazole, especially when high doses are pre-scribed. Epigastric distress can be reduced by taking ke-toconazole with food. Pruritis and/or allergic dermatitis occurs in 10% of patients. Liver enzyme elevations dur-ing therapy are not unusual and are usually reversible. Severe ketoconazole-associated hepatitis is rare.

 

At high doses, ketoconazole causes a clinically sig-nificant reduction in testosterone synthesis and blocks the adrenal response to corticotropin. Gynecomastia, impotence, reduced sperm counts, and diminished li-bido can occur in men, and prolonged drug use can re-sult in irregular menses in women. These hormonal ef-fects have led to the use of ketoconazole as a potential adjunctive treatment for prostatic carcinoma.

 

Drug Interactions

 

Both rifampin and isoniazid lower plasma ketoconazole levels, and concomitant administration should be avoided.

Phenytoin serum levels should be monitored closely when ketoconazole is prescribed. Ketoconazole causes in-creases in serum concentrations of warfarin, cyclosporine, and sulfonylureas. Because of its ability to increase serum cyclosporine levels, ketoconazole has been given to cy-closporine-dependent cardiac transplant recipients to re-duce the dose of cyclosporine needed and as a cost-saving measure.

 

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