|Trade names||Nizoral, others|
|By mouth (tablets), topical (cream, shampoo, solution)|
|Protein binding||84 to 99%|
|Metabolism||Extensive liver (predominantly oxidation, O-dealkylation)|
|Excretion||Biliary (major) and kidney|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||531.431 g/mol g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Ketoconazole is an antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candidiasis, pityriasis versicolor, dandruff, and seborrhoeic dermatitis. Taken by mouth it is a less preferred option and only recommended for severe infections when other agents cannot be used. Other uses include excessive hair growth and Cushing’s syndrome.
Common side effects when applied to the skin include redness. Common side effects when taken by mouth include nausea, headache, and liver problems. Liver problems may result in death or the need for a liver transplantation. Other severe side effect when taken by mouth include QT prolongation, adrenocortical insufficiency, and anaphylaxis. It is an imidazole and works by affecting the production of ergosterol required for the fugal cell membrane thereby slowing growth.
Ketoconazole was patented in 1977 and came into medical use in 1981. It is available as a generic medication and formulations that are applied to the skin are over the counter. A 30 gram tube in the United Kingdom costs the NHS less than 5 £ as of 2019. In the United States the wholesale cost of this amount is about 6.30 USD. In 2016 it was the 205th most prescribed medication in the United States with more than 2 million prescriptions. The formulation that is taken by mouth was discontinued in Australia in 2013 and in China in 2015.
- 1 Medical uses
- 2 Side effects
- 3 Interactions
- 4 Pharmacology
- 5 Chemistry
- 6 History
- 7 Society and culture
- 8 Veterinary use
- 9 References
- 10 External links
Topically administered ketoconazole is usually prescribed for fungal infections of the skin and mucous membranes, such as athlete's 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.
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 ketoconazole's 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.
Ketoconazole shampoo in conjunction with an oral 5α-reductase inhibitor such as finasteride or dutasteride has been used off label to treat androgenic alopecia. The antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.
The side effects of ketoconazole are sometimes harnessed in the treatment of non-fungal conditions. While ketoconazole blocks the synthesis of the sterol ergosterol in fungi, in humans, at high dosages (>800 mg/day), it potently inhibits the activity of several enzymes necessary for the conversion of cholesterol to steroid hormones such as testosterone and cortisol. Specifically, ketoconazole has been shown to inhibit cholesterol side-chain cleavage enzyme, which converts cholesterol to pregnenolone, 17α-hydroxylase and 17,20-lyase, which convert pregnenolone into androgens, and 11β-hydoxylase, which converts 11-deoxycortisol to cortisol. All of these enzymes are mitochondrial cytochrome p450 enzymes. Based on these antiandrogen and antiglucocorticoid effects, ketoconazole has been used with some success as a second-line treatment for certain forms of advanced prostate cancer and for the suppression of glucocorticoid synthesis in the treatment of Cushing's syndrome. However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to prevent adrenal insufficiency. Ketoconazole has additionally been used, in lower dosages, to treat hirsutism and, in combination with a GnRH analogue, male-limited precocious puberty. In any case, the risk of hepatotoxicity with ketoconazole limits its use in all of these indications, especially in those that are benign such as hirsutism.
On July 2013, the U.S. Food and Drug Administration (FDA) issued a warning that taking ketoconazole by mouth can cause severe liver injuries and adrenal gland problems: adrenal insufficiency and worsening of other related to the gland conditions. It recommends oral tablets should not be a first-line treatment for any fungal infection. It should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated. As contraindication it should not be used in people with acute or chronic liver disease.
The topical formulations have not been associated with liver damage, adrenal problems, or drug interactions. These formulations include creams, shampoos, foams, and gels applied to the skin, unlike the Nizoral tablets, which are taken by mouth.
Ketoconazole is likely miscategorized as pregnancy category C drug in the US. Research has shown it to cause teratogenesis when administered in high doses. Recently, the administration of systemic ketoconazole to two pregnant women for treatment of Cushing's syndrome was reported to have no adverse effects,[non-primary source needed] but this small sample precludes drawing any meaningful conclusions. A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.
- alprazolam, midazolam, triazolam;
- HMG-CoA reductase inhibitors: lovastatin, simvastatin;
- Ergot alkaloids: ergotamine, dihydroergotamine;
- others: cisapride, nisoldipine, dofetilide, pimozide;
- carbamazepine, phenytoin;
- gastric acid suppressants: antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors;
- rifampin, rifabutin, isoniazid;
Ritonavir is known for increasing activity of the ketoconazole so it is recommended to reduce dosage.
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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. As azole antifungals all act at the same point in the sterol pathway, resistant isolates are normally cross-resistant to all members of the azole family.
As an antiandrogen, ketoconazole operates through at least two mechanisms of action. First, and most notably, high oral doses of ketoconazole (e.g. 400 mg three times per day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels. It produces this effect through inhibition of 17α-hydroxylase and 17,20-lyase, which are involved in the synthesis and degradation of steroids, including the precursors of testosterone. Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer. Second, ketoconazole is an androgen receptor antagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for binding to the androgen receptor. This effect is thought to be quite weak however, even with high oral doses of ketoconazole.
Ketoconazole is a racemic mixture consisting of cis-(2S,4R)-(−) and cis-(2R,4S)-(+) enantiomers. The cis-(2S,4R) isomer was more potent in inhibiting progesterone 17α,20-lyase than its enantiomer (IC50 values of 0.05 and 2.38 μM, respectively) and in inhibiting 11β-hydroxylase (IC50 values of 0.152 and 0.608 μM, respectively). Both isomers were relatively weak inhibitors of human placental aromatase.
When administered orally, ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption. Absorption can be increased by taking it with an acidic beverage, such as cola. Ketoconazole is very lipophilic and tends to accumulate in fatty tissues.
Ketoconazole is a synthetic imidazole. It is a nonsteroidal compound. It is a racemic mixture of two enantiomers, levoketoconazole ((2S,4R)-(−)-ketoconazole) and dextroketoconazole ((2R,4S)-(+)-ketoconazole). Levoketoconazole is under development for potential clinical use as a steroidogenesis inhibitor with better tolerability and less toxicity than ketoconazole. Other steroidogenesis inhibitors besides ketoconazole and levoketoconazole include the nonsteroidal compound aminoglutethimide and the steroidal compound abiraterone acetate.
Ketoconazole was discovered in 1976 at Janssen Pharmaceutica. It was initially introduced in 1977, followed by introduction in the United States in 1981. It was introduced as the prototypical drug of the imidazole antifungals. Oral ketoconazole has been replaced with oral itraconazole for many mycoses.
Society and culture
In 2013 the European Medicines Agency's Committee on Medicinal Products for Human Use (CHMP) recommended that a ban be imposed on the use of oral ketoconazole for systemic use in humans throughout the European Union, after concluding that the risk of serious liver injury from systemic ketoconazole outweighs its benefits.
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