Everything about Ketoconazole totally explained
| PubChem=47576
| DrugBank=APRD00401
| C = 26 |H = 28 |Cl = 2 |N = 4 |O = 4
| molecular_weight = 531.43
g/
mol
| bioavailability= Variable
| protein_bound = 84 to 99%
| metabolism =
Hepatic
| elimination_half-life= Biphasic:
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.
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's 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 hasn't 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 (
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's 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 isn't 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.
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.
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, isn't 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
Candida 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
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.
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.
Further Information
Get more info on 'Ketoconazole'.
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