Ketoconazole
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Ketoconazole
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| 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 |
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| Identifiers | |
| CAS number | |
| ATC code | J02 D01AC08 G01AF11 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C26H28Cl12N4O4 |
| Mol. mass | 531.43 g/mol |
| Pharmacokinetic data | |
| Bioavailability | Variable |
| Protein binding | 84 to 99% |
| Metabolism | Hepatic |
| Half life | Biphasic:
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| Excretion | Biliary and renal |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| 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 Due to its side-effect profile, it has been superseded by newer antifungals, such as fluconazole and itraconazole.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.
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[edit] Brand Names
- Nizoral
- Xolegel
[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[1] following penile surgery. Another use is the suppression of glucocorticoid synthesis, where it is used in the treatment of Cushing's disease.[2] These side effects have also been studied for use in reducing depressive symptoms[3] and drug addiction[4]; however, it has not succeeded in either of these roles.[5],[6]
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)[7],[8] 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.[9]
[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
- ^ 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.
- ^ 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.
- ^ Wolkowitz, Owen M.; Victor I. Reus (1999). "Treatment of Depression With Antiglucocorticoid Drugs". Psychosomatic Medicine 61 (5): 698-711. PubMed.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
[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) | |
|---|---|
| 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 |
