Ketoconazole is the first orally active azole compound. It is a synthetic imidazole. It was first studied in the early 80's and licensed for use in 1985. It interferes with fungal biosynthesis of ergosterol like all azoles.
Dose & Delivery
Ketoconazole is only available as oral tablets or as a topical preparation such as Nizoral shampoo.
Fungi - the drug is active against
Ketoconazole is active against Candida spp, Blastomyces dermatitidis, Coccidioides spp, Histoplasma and Paracoccidioides. It is also active against skin fungi, but not to the degree of itraconazole or terbinafine. It is not active against Aspergillus spp.
Ketoconazole is used for the treatment of oral thrush in a dose of 200mg per day, or 400mg per day in patients with AIDS and resistant strains. Doses of 400mg per day have been used for blastomycosis, histoplasmosis, coccidioidomycosis and paracoccidioidomycosis (given as 200mg twice a day, but is inferior to itraconazole in these indications). The same dose is used for skin infections. As ketoconazole is not as active as itraconazole, longer courses of therapy are typically given for endemic mycoses.
Metabolism distribution and excretion
Ketoconazole is well absorbed after oral administration and there is no impact of food. Almost all the drug is metabolised in the liver and the metabolites excreted in bile.
Drug/ Drug interactions
Ketoconazole levels are slightly lower in those on anti-ulcer drugs. Rifampicin (rifampin) reduces the concentrations of ketoconazole in the blood because of accelerated metabolism.
Ketoconazole must not be given with terfenadine, astemizole or cisapride as it causes increased levels of these drugs which can cause abnormal heart rhythms (prolonged Qt interval). Ketoconazole also can prolong the action of certain sedatives such midazolam and triazolam. It increases the blood level of cyclosporin and in fact has been used in some transplant centres to reduce the cost of cyclosporin. Ketoconazole also prolongs the effect of warfarin. View drug interactions database.
Loss of appetite, feeling sick and vomiting are the most common side effects and occur in about 1 in 10 patients. The side effects are particularly a problem with high doses - above 400mg per day. Ketoconazole had caused severe liver reactions, about 1 in 20 patients get slight elevations of liver function tests on ketoconazole. If the treatment is given for longer than two weeks there is a rare side effect of severe liver disease, carrying a 1-10,000 - 15,000 risk, which is fatal if not diagnosed and ketoconazole stopped.
Ketoconazole also inhibits human adrenal and testicular steroid synthesis, particularly at high doses. This has consequences of loss of hair, breast swelling and lack of sexual function. There is a possibility that these effects may be more problematic in teenagers during puberty and ketoconazole should be avoided in this age group if possible. Ketoconazole should not be given in pregnancy. Ketoconazole is used for controlling corticosteroid excess in Cushing's disease and is quite effective, typically at 600mg daily.
The FDA has recently restricted the use of ketoconazole to last resort as other antifungals are superior and carry less risk of toxicity. (July 2013), link
Structure of ketoconazole