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.
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infections, but it has been replaced by the newer tria-zoles in the treatment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
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.
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
Both rifampin and isoniazid
lower plasma ketoconazole levels, and concomitant administration should be
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