Ketoconazole

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
ChemSpider	401695
Chemical data
Formula	C26H28Cl2N4O4
Mol. mass	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. 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 absorption when taken orally.

History

Ketoconazole was discovered in 1976 and released in the early 1980s, and was one of the first available oral treatments 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^[1][2].

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^[3] following penile surgery. Another use is the suppression of glucocorticoid synthesis, where it is used in the treatment of Cushing's disease.^[4] These side effects have also been studied for use in reducing depressive symptoms^[5] and drug addiction;^[6] however, it has not succeeded in either of these roles.^[7][8]

Ketoconazole can be prescribed as a 200-mg pill, a 2% cream, a 2% gel,a 2% foam,or 2% shampoo for the treatment of dandruff or seborrhoeic dermatitis, or as a 1% over-the-counter shampoo (Nizoral). However, 2% shampoo is sold over-the-counter in many countries as well.

Ketocanazole is also available as a topical mousse, using patented Versafoam technology, marketed under the brand name Ketomousse. In clinical studies, the Versafoam proved to be a superior mechanism of delivery to the shampoo. Currently it is only available in Europe.

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, and severe itchiness.

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)^[9][10] and no adverse effects were reported, but this is not a broad enough data sample to draw any meaningful conclusions. To remedy 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.^[11]

This medication is also sometimes prescribed by veterinarians for use on pets, often as 200mg unflavored tablets that may need to be cut to smaller size for correct dosage.^[12]

Mechanism of action

Ketoconazole is structurally similar to imidazole, and interferes with the fungal synthesis of ergosterol, a constituent of cell membranes, as well as certain enzymes. It is specific for fungi, as the equivalent mammalian pathway, leading to the biosynthesis of cholesterol, is not sensitive to ketoconazole. However, other mammalian cytochrome P450 enzymes can be sensitive to ketoconazole, and inhibition of steroid hormone synthesis is a possible side effect of ketoconazole treatment.

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. The rise in the number of HIV/AIDS immune compromised patients has led to an increase in the frequency and significance of opportunistic fungal infections. Resistance to ketoconazole has been observed in a number of clinical fungal isolates, including C. 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. MDR or multidrug resistance 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.

Hair loss benefits

A study in mice indicated that ketoconazole may have a stimulatory effect on hair growth.^[13] Nizoral shampoo has shown to be beneficial in men suffering from androgenic alopecia. One 1998 study showed that Nizoral 2% worked just as well as minoxidil 2% (brand name Rogaine) in men with androgenic alopecia. Both medicines increased hair thickness and increased the number of anagen-phase hair follicles on the scalp. Researchers were guarded about the meaning of these results, saying that more rigorous studies on larger groups of men should be done to confirm the findings, both to evaluate the ideal dosage and formulation, and to assess the desirability of routine treatment in this condition. Nizoral Shampoo only has FDA approval for the treatment of dandruff and seborrheic dermatitis of the scalp, so although Nizoral may be useful as a hair loss remedy, it cannot be endorsed or marketed as one to the general public.^[14]

Results so far indicate that both the 1% and 2% dosages have positive hair loss benefits; however the more potent 2% formulation could have better results. Optimal usage is speculated at every third day, leaving the shampoo on the scalp for 3-5 minutes before rinsing. It has been stated that medications capable of maintaining the existing hair population should be regarded as effective treatments for androgenic alopecia. The present data suggests that ketoconazole should enter this group of drugs.^[15]

References

Brand names

• Nizoral
• Xolegel

External links

• Janssen Pharmaceutica fungal infections page
• Doctor Fungus ketoconazole page
• Nizoral (manufacturer's website)
• Ketoconazole (patient information)
• Ketoconazole (Up to date product information)
• Study comparing the efficacy of ketoconazole (Nizoral) versus zinc pyrithione (Head & Shoulders)