Ketoconazole

Ketoconazole

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Systematic (IUPAC) name
1-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)- 2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan- 4-yl]methoxy}phenyl)piperazin-1-yl]ethan-1-one
Clinical data
Pregnancy category	B3 (Au), C (U.S.)
Routes of administration	Oral, topical
Legal status
Legal status	US: OTC POM (UK, oral formulation)
Pharmacokinetic data
Bioavailability	Variable
Protein binding	84 to 99%
Metabolism	Hepatic
Biological half-life	Biphasic: Initial phase: 2 hours Terminal phase: 8 hours
Excretion	Biliary and renal
Identifiers
CAS Number	65277-42-1
ATC code	J02AB02 (WHO) D01AC08 G01AF11
PubChem	CID 47576
DrugBank	APRD00401
ChemSpider	401695
Chemical data
Formula	C26H28Cl2N4O4
Molar mass	531.431 g/mol[[]]
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Ketoconazole (pronounced /ˌkiːtɵˈkoʊnəzɒl/) 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, topical cream, and oral tablet, under the trademark name Nizoral by Johnson & Johnson in the USA, and as Sebizole by Douglas Pharmaceuticals in Australia & New Zealand.

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. Absorption can be increased by taking it with an acidic beverage, such as Coca-Cola.

History

Ketoconazole was discovered in 1976 and released in 1981. It followed griseofulvin as one of the first available oral treatments for fungal infections.

Usage

Ketoconazole is usually prescribed for topical 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 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% 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 (Perkhotal) & (Nizoral). However, 2% shampoo is sold over-the-counter in many countries as well.

Ketoconazole is also available as a topical mousse marketed under the brand name Ketomousse. In clinical studies, this preparation 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) and no adverse effects were reported, but this is not a broad enough data sample to draw any meaningful conclusions. A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.

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

Mechanism of action

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 14-alpha-demethylase (P45014DM). 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.

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 3x/day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels. Ketoconazole produces this effect through inhibition of cytochrome P450 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 as a treatment for androgen-dependent prostate cancer. Second, ketoconazole is an androgen receptor antagonist, competing with androgens such as testosterone and DHT for androgen receptor binding. This effect is thought to be quite weak, even with high oral doses of ketoconazole.

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. Multidrug-Resistance Genes (MDR) 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

File:Nizoral.jpg

Nizoral 2% shampoo (AU)

Preliminary research suggests that ketoconazole shampoo (brand name Nizoral) may be beneficial in men suffering from androgenic alopecia. Support for this comes primarily from one study in 1998 that compared ketoconazole 2% to the proven hair loss drug minoxidil 2% (brand name Rogaine) in men with androgenic alopecia. The study concluded that "Hair density and size and proportion of anagen follicles were improved almost similarly by both ketoconazole and minoxidil regimens." In other words, ketoconazole shampoo used 2-4 times weekly was nearly as effective as the proven hair loss treatment minoxidil 2%. While ketoconazole's mechanism of action in hair loss is still unclear, it has been postulated that both hormones and the immune system act synergistically to cause injury to the hair follicle. Since ketoconazole effectively treats the malassezia fungus that commonly inhabits the scalp, the researchers hypothesized that it may prevent hair loss by reducing inflammation from the fungus, in addition to having a direct anti-inflammatory effect.

The researchers were guarded about the meaning of their 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. Although no further research in humans has been undertaken, there was a study on ketoconazole in 2005 that corroborated the existence of a stimulatory effect on hair growth, this time in mice.

Anecdotal reports indicate that both the 1% and 2% dosages have hair loss benefits; however, the more potent 2% formulation may produce better results. Excessive usage of either formulation has not been shown to produce better results. The results produced in the one study in men are based on ketoconazole 2% shampoo, used once every 2-4 days, and leaving the shampoo on the scalp for 3–5 minutes before rinsing (as with the treatment of dandruff and seborrheic dermatitis). It has been stated that medications capable of maintaining the existing hair population, even in the absence of hair regrowth, should be regarded as effective treatments for androgenic alopecia. The present data suggest that ketoconazole should enter this group of drugs.

Nizoral Shampoo is only FDA approved 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.

Synthesis

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Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. (1979). "Antimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent". Journal of Medicinal Chemistry. 22 (8): 1003. doi:10.1021/jm00194a023. PMID 490531. 

See also

• Antifungal drug
• Baldness treatments
• Zinc pyrithione, an antimicrobial agent used in some medicated shampoos.
• selenium disulfide, an active ingredient used in shampoos such as Selsun Blue.

External links

• Dandruff and Ketoconazole Information
• PubPK - Ketoconazole Pharmacokinetics
• Janssen Pharmaceutica fungal infections page
• Doctor Fungus ketoconazole page
• Nizoral (manufacturer's website)
• Regenepure DR with Ketoconazole (manufacturer's website)
• Ketoconazole (patient information)
• Ketoconazole (Up to date product information)
• Piérard-Franchimont C, Goffin V, Decroix J, Piérard GE (2002). "A multicenter randomized trial of ketoconazole 2% and zinc pyrithione 1% shampoos in severe dandruff and seborrheic dermatitis". Skin Pharmacol. Appl. Skin Physiol. 15 (6): 434–41. PMID 12476017. CS1 maint: Multiple names: authors list (link) – ketoconazole (Nizoral) versus zinc pyrithione (Head & Shoulders)

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