Medical uses
Topical antifungal
Topically administered ketoconazole is usually prescribed for fungal infections of the skin and mucous membranes, such as athletes foot, ringworm, candidiasis (yeast infection or thrush), jock itch, and tinea versicolor. Topical ketoconazole is also used as a treatment for dandruff (seborrheic dermatitis of the scalp) and for seborrheic dermatitis on other areas of the body, perhaps acting in these conditions by suppressing levels of the fungus Malassezia furfur on the skin. Systemic antifungal
Ketoconazole has activity against many kinds of fungi that may cause human disease, such as Candida, Histoplasma, Coccidioides, and Blastomyces (although it is not active against Aspergillus), chromomycosis and paracoccidioidomycosis. First made in 1977, ketoconazole was the first orally-active azole antifungal medication. However, ketoconazole has largely been replaced as a first-line systemic antifungal medication by other azole antifungal agents, such as itraconazole, because of ketoconazoles greater toxicity, poorer absorption, and more limited spectrum of activity.Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections. Off-label uses
Hair loss
Ketoconazole shampoo in conjunction with an oral 5α-reductase inhibitor such as finasteride or dutasteride has been used off label to treat androgenic alopecia. It was speculated that antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.Limited clinical studies suggest ketoconazole shampoo used either alone or in combination with other treatments may be useful in reducing hair loss in some cases. Hormonal
The side effects of ketoconazole are sometimes harnessed in the treatment of non-fungal conditions.
Interactions
The concomitant use of the following medications is contraindicated with ketoconazole tablets:
methadone, disopyramide, dronedarone
irinotecan, lurasidone, colchicine
alprazolam, oral midazolam, oral triazolam
felodipine, ranolazine, tolvaptan, eplerenone
HMG-CoA reductase inhibitors: lovastatin, simvastatin
ergot alkaloids: ergotamine, dihydroergotamine, ergometrine, methylergometrine
Others: cisapride, nisoldipine, dofetilide, pimozideAnd is not recommended:
carbamazepine, phenytoin
gastric acid suppressants: antacids, antimuscarinics, histamine H2 blockers, proton pump inhibitors
sucralfate
rifampin, rifabutin, isoniazid
efavirenz, nevirapineRitonavir is known for increasing activity of the ketoconazole so it is recommended to reduce dosage.There is also a list of drugs which significantly decrease systemic exposure to the ketoconazole and drugs whose systemic exposure is increased by the ketoconazole. Pharmacology
Pharmacodynamics
Antifungal activity
As an antifungal, ketoconazole is structurally similar to imidazole, and interferes with the fungal synthesis of ergosterol, a constituent of fungal cell membranes, as well as certain enzymes. As with all azole antifungal agents, ketoconazole works principally by inhibiting the enzyme cytochrome P450 14α-demethylase (CYP51A1). This enzyme participates in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Lower doses of fluconazole and itraconazole are required to kill fungi compared to ketoconazole, as they have been found to have a greater affinity for fungal cell membranes. Resistance to ketoconazole has been observed in a number of clinical fungal isolates, including Candida albicans. Experimentally, resistance usually arises as a result of mutations in the sterol biosynthesis pathway. Defects in the sterol 5-6 desaturase enzyme reduce the toxic effects of azole inhibition of the 14-alpha demethylation step. Multidrug-resistance (MDR) genes can also play a role in reducing cellular levels of the drug.