Description

Simple

A medication used to treat fungal skin infections.

Clinical

A broad spectrum antifungal used to treat seborrheic dermatitis and fungal skin infections.

Overview

Ketoconazole is an imidazole antifungal agent used in the prevention and treatment of a variety of fungal infections.[FDA Label] It functions by preventing the synthesis of ergosterol, the fungal equivalent of cholesterol, thereby increasing membrane fluidity and preventing growth of the fungus.[5,11] Ketoconazole was first approved in an oral formulation for systemic use by the FDA in 1981.[9] At this time it was considered a significant improvement over previous antifungals, [miconazole] and [clotrimazole], due to its broad spectrum and good absorption. However, it was discovered that ketoconazole produces frequent gastrointestinal side effects and dose-related hepatitis.[Read more

Ketoconazole is an imidazole antifungal agent used in the prevention and treatment of a variety of fungal infections.[FDA Label] It functions by preventing the synthesis of ergosterol, the fungal equivalent of cholesterol, thereby increasing membrane fluidity and preventing growth of the fungus.[5,11] Ketoconazole was first approved in an oral formulation for systemic use by the FDA in 1981.[9] At this time it was considered a significant improvement over previous antifungals, [miconazole] and [clotrimazole], due to its broad spectrum and good absorption. However, it was discovered that ketoconazole produces frequent gastrointestinal side effects and dose-related hepatitis.[9,10] These effects combined with waning efficacy led to its eventual replacement by triazole agents, [fluconazole], [itraconazole], [voriconazole], and [posaconazole]. Ketoconazole and its predecessor [clotrimazole] continue to be used in topical formulations. Read Less

Pharmacology

Indication

Ketoconazole is used in the treatment or prevention of fungal infections including blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis.[FDA Label] In Europe, it is also used in the treatment of endogenous Cushing's syndrome.[ Read more

Ketoconazole is used in the treatment or prevention of fungal infections including blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis.[FDA Label] In Europe, it is also used in the treatment of endogenous Cushing's syndrome.[12] Read Less

Pharmacodynamic

Ketoconazole, similarly to other azole antifungals, is a fungistatic agent which causes growth arrest in fungal cells thereby preventing growth and spread of the fungus throughout the body.[ Read more

Ketoconazole, similarly to other azole antifungals, is a fungistatic agent which causes growth arrest in fungal cells thereby preventing growth and spread of the fungus throughout the body.[11] Read Less

Mechanism of action

Ketoconazole interacts with 14-α-sterol demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol.[ Read more

Ketoconazole interacts with 14-α-sterol demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol.[5,11] This results in inhibition of ergosterol synthesis and increased fungal cellular permeability due to reduced amounts of ergosterol present in the fungal cell membrane. This metabolic inhibition also results in accumulation of 14α-methyl-3,6-diol, a toxic metabolite. The increase in membrane fluidity is also thought to produce impairment of membrane-bound enzyme systems as components become less closely packed. Read Less

Absorption

Ketoconazole requires an acidic environment to become soluble in water.[6] At pH value... Read more

Ketoconazole requires an acidic environment to become soluble in water.[6] At pH values above 3 it becomes increasingly insoluble with about 10% entering solution in 1 h. At pH less than 3 dissolution is 85% complete in 5 min and entirely complete within 30 min. A single 200 mg oral dose produces a Cmax of 2.5-3 mcg/mL with a Tmax of 1-4 h.[5,13] Administering ketoconazole with food consistently increases Cmax and delays Tmax but literature is contradictory regarding the effect on AUC, which may experience a small decrease.[5,6] A bioavailablity of 76% has been reported for ketoconazole.[5] Read Less

Protein binding

Ketoconazole is approximately 84% bound to plasma albumin with another 15% associated with blood cells for a total of 99% binding within the plasma.[ Read more

Ketoconazole is approximately 84% bound to plasma albumin with another 15% associated with blood cells for a total of 99% binding within the plasma.[5] Read Less

Volume of distribution

Ketoconazole has an estimated volume of distribution of 25.41 L or 0.36 L/kg.[ Read more

Ketoconazole has an estimated volume of distribution of 25.41 L or 0.36 L/kg.[5] It distributes widely among the tissues, reaching effective concentrations in the skin, tendons, tears, and saliva.[6] Distribution to vaginal tissue produces concentrations 2.4 times lower than plasma. Penetration into the CNS, bone, and seminal fluid are minimal. Ketoconazole has been found to enter the breast milk and cross the placenta in animal studies.[5] Read Less

Clearance

Ketoconazole has an estimated clearance of 8.66 L/h.[ Read more

Ketoconazole has an estimated clearance of 8.66 L/h.[5] Read Less

Half life

Ketoconazole experiences biphasic elimination with the first phase having a half-life of 2 hours and a terminal half life of 8 hours.[ Read more

Ketoconazole experiences biphasic elimination with the first phase having a half-life of 2 hours and a terminal half life of 8 hours.[5] Read Less

Route of elimination

Only 2-4% of the ketoconazole dose is eliminated unchanged in the urine.[ Read more

Only 2-4% of the ketoconazole dose is eliminated unchanged in the urine.[5] Over 95% is eliminated through hepatic metabolism. Read Less

Toxicity

Symptoms of overdose include acute liver injury, which may include both hepatocellular and cholestatic injury, accompanied by anorexia, fatigue, nausea, and jaundice.[14, Read more

Symptoms of overdose include acute liver injury, which may include both hepatocellular and cholestatic injury, accompanied by anorexia, fatigue, nausea, and jaundice.[14,7] In case of overdose, gastric lavage with activated charcoal may be used if within one hour of ketoconazole ingestion otherwise provide supportive care.[FDA Label,12] If the patient shows signs of adrenal insufficiency, administer 100 mg hydrocortisone once together with saline and glucose infusion and monitor the patient closely. Blood pressure and fluid and electrolyte balance should be monitored over the next few days.[12] Read Less

Adverse Effects

Contraindications