Article: Ketoconazole

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Ketoconazole
Systematic (IUPAC) name
1-[4-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)- 2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy] phenyl]piperazin-1-yl]ethanone
Identifiers
CAS number	65277-42-1
ATC code	J02AB02 D01AC08 G01AF11
PubChem	47576
DrugBank	APRD00401
Chemical data
Formula	C26H28N4Cl12O4
Mol. weight	531.43 g/mol
Pharmacokinetic data
Bioavailability	Variable
Protein binding	84 to 99%
Metabolism	Hepatic
Half life	Biphasic: Initial phase: 2 hours Terminal phase: 8 hours
Excretion	Biliary and renal
Therapeutic considerations
Pregnancy cat.	B3 (Au), C (U.S.)
Legal status	POM (UK, oral formulation)
Routes	Oral, topical

Ketoconazole is a synthetic antifungal drug used to prevent and treat skin and fungal infections, especially in immunocompromised patients such as those with AIDS. Due to its side-effect profile, it has been superseded by newer antifungals, such as fluconazole and itraconazole. Ketoconazole is sold commercially as an anti-dandruff shampoo, branded Nizoral®, by Janssen Pharmaceutica.

History

Ketoconazole was discovered in 1976 and released in the early 1980s, and was one of the first available oral treatment for fungal infections (griseofulvin was available before ketoconazole).

Usage

Ketoconazole is usually prescribed for infections such as athlete's foot, ringworm, candidiasis (yeast infection or thrush), and jock itch. The over-the-counter shampoo version can also be used as a body wash for the treatment of tinea versicolor.

Ketoconazole is used to treat eumycetoma, the fungal form of mycetoma.

The side-effects of ketoconazole are sometimes used to treat non-fungal problems. The decrease in testosterone caused by the drug makes it useful for treating prostate cancer and for preventing post-operative erections^[1] following penile surgery. Another use is the suppression of glucocorticoid synthesis, where it is used in the treatment of Cushing's disease. These side effects have also been studied for use in reducing depressive symptoms and drug addiction; however, it has not succeeded in either of these roles.

Ketoconazole can be prescribed as a 200-mg pill, a 2% ointment, or 2% shampoo for the treatment of dandruff or seborrhoeic dermatitis, or as a 1% over-the-counter shampoo (Nizoral).

The anti-dandruff shampoo is designed for people who have a more serious case of dandruff where symptoms include, but are not limited to constant non-stop flaking, severe itchiness, and the formation of a cold, sticky sweat on the scalp about one millimetre thick.

Ketoconazole is very lipophilic, which leads to accumulation in fatty tissues. The less toxic and more effective triazole compounds fluconazole and itraconazole have largely replaced ketoconazole for internal use. Ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's effectiveness when taken orally.

It is a pregnancy category C drug because animal testing has shown it to cause teratogenesis in high dosages. Only two human test cases have been recorded (both during the treatment of Cushing's syndrome) and no adverse effects were reported, but this is not a broad enough data sample to draw any meaningful conclusions.

Method of action

Ketoconazole is structurally similar to imidazole, and interferes with the fungal synthesis of ergosterol, the main constituent of cell membranes, as well as certain enzymes. It is specific for fungi, as mammalian cell membranes contain no ergosterol.

As with all azole antifungal agents, ketoconazole works principally by inhibition of an enzyme, cytochrome P450 14-alpha-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Fluconazole and itraconazole have been found to have a greater affinity for fungal cell membrane than ketoconazole, and thus lower doses of these azoles are required to kill fungi.

Sensitive fungi

Ketoconazole inhibits growth of dermatophytes and yeast species such as Candida albicans. No resistance has been reported.

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