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	J02 AB02 D01 AC08 G01 AF11
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 Due to its side-effect profile, it has been superseded by newer antifungals, such as fluconazole and itraconazole.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.

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 efficacy when taken orally.

1 History
2 Usage
3 Method of action
4 Sensitive fungi
5 Reference
6 External links

[edit] 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).

[edit] 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<ref> Evans, K. C., A. C. Peterson, H. E. Ruiz and R. A. Costabile (August 2004). "Use of oral ketoconazole to prevent postoperative erections following penile surgery". International Journal of Impotence Research 16 (4): 346–349. DOI:10.1038/sj.ijir.3901160. PubMed.</ref> following penile surgery. Another use is the suppression of glucocorticoid synthesis, where it is used in the treatment of Cushing's disease.<ref name=Cushing>Loli, Paola, Maria Elisa Berselli and Mariantonella Tagliaferri (1986). "Use of ketoconazole in the treatment of Cushing's syndrome.". Journal of Clinical Endocrinology & Metabolism 63 (6): 1365-71. PubMed.</ref> These side effects have also been studied for use in reducing depressive symptoms<ref name=antidepressant_properties>Wolkowitz, Owen M., Victor I. Reus (1999). "Treatment of Depression With Antiglucocorticoid Drugs". Psychosomatic Medicine 61 (5): 698-711. PubMed.</ref> and drug addiction<ref name=anti-drug>Goeders, Nick E., Rachel L. Peltiera and Glenn F. Guerin (December 1998). "Ketoconazole reduces low dose cocaine self-administration in rats.". Drug and Alcohol Dependence 53 (1): 67-77. DOI:10.1016/S0376-8716(98)00108-2. PubMed.</ref>; however, it has not succeeded in either of these roles.<ref name=failed_for_depression>Malison, Robert T., Amit Anand, Gregory H. Pelton, Paul Kirwin, Linda Carpenter, Christopher J. McDougle, George R. Heninger and Lawrence H. Price (October 1999). "Limited Efficacy of Ketoconazole in Treatment-Refractory Major Depression.". Journal of Clinical Psychopharmacology 19 (5): 466-470. PubMed.</ref>^,<ref name=failed_for_cocainism>Ward, Amie S., Eric D. Collins, Margaret Haney, Richard W. Foltin and Marian W Fischman (November 1998). "Ketoconazole attenuates the cortisol response but not the subjective effects of smoked cocaine in humans.". Behavioural Pharmacology 9 (7): 577-86. PubMed.</ref>

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.

It is a pregnancy category C drug because animal testing has shown it to cause teratogenesis in high dosages. Until recently, there were two human test cases on record (both during the treatment of Cushing's syndrome)<ref name=pregnancy_1>Amado, José Antonio, Carlos Pesquera, Eva M. Gonzalez, Macarena Otero, Julio Freijanes, and Angel Alvarez (March 1990). "Successful treatment with ketoconazole of Cushing's syndrome in pregnancy.". Postgraduate Medical Journal 66 (773): 221-3. PubMed.</ref>^,<ref name=pregnancy_2>Berwaerts, Joris, Johan Verhelst, Charles Mahler and Roger Abs (June 1999). "Cushing's syndrome in pregnancy treated by ketoconazole: case report and review of the literature.". Gynecological Endocrinology 13 (3): 175-82. PubMed.</ref> and no adverse effects were reported, but this is not a broad enough data sample to draw any meaningful conclusions. To rememdy this, Drs Kazy, Puhó and Czeizel of the Foundation for the Community Control of Hereditary Diseases in Budapest, Hungary decided to go through the Hungarian Case–Control Surveillance of Congenital Abnormalities, specifically the years 1980 through 1996; that was 22,843 cases and 38,151 controls. There were six infants with congenital abnormalities and twelve infants without whose mothers received ketoconazole. No group of birth defects was preferentially associated with use of ketoconazole.<ref name=Giant_Hungarian_Human_Birth_Defects_Study>Kazy, Zoltán, Erzsébet Puhó and Andrew E. Czeizel (March 2005). "Population-based case–control study of oral ketoconazole treatment for birth outcomes". Congenital Anomalies 45 (1): 5-8. DOI:10.1111/j.1741-4520.2005.00053.x. PubMed.</ref>

[edit] 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.

[edit] Sensitive fungi

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

[edit] Reference

[edit] External links

Janssen Pharmaceutica fungal infections page
Doctor Fungus ketoconazole page
Nizoral (manufacturer's website)
Ketoconazole (patient information)
Ketoconazole (Up to date product information)

Antifungals (D01 and J02) edit
Antibiotics:	Griseofulvin, Hitachimycin, Natamycin, Nystatin
Topical Azoles:	Clotrimazole, Econazole, Fluconazole, Ketoconazole, Miconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole
Other topicals:	Ciclopirox, Ethylparaben, Flucytosine, Salicylic acid, Selenium sulfide, Terbinafine, Tolnaftate
For systemic use:	Amphotericin B, Anidulafungin, Caspofungin, Griseofulvin, Itraconazole, Terbinafine, Voriconazole
Other:	Posaconazole, Thiabendazole, Tea tree oil