Ketoconazole
Overview
Ketoconazole is a synthetic antifungal drug
Antifungal drug
An antifungal medication is a medication used to treat fungal infections such as athlete's foot, ringworm, candidiasis , serious systemic infections such as cryptococcal meningitis, and others...

 used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...

 or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff
Dandruff
Dandruff is the shedding of dead skin cells from the scalp . Dandruff is sometimes caused by frequent exposure to extreme heat and cold. As it is normal for skin cells to die and flake off, a small amount of flaking is normal and common; about 487,000 cells/cm2 get released normally after...

 shampoo
Shampoo
Shampoo is a hair care product used for the removal of oils, dirt, skin particles, dandruff, environmental pollutants and other contaminant particles that gradually build up in hair...

, topical
Topical
In medicine, a topical medication is applied to body surfaces such as the skin or mucous membranes such as the vagina, anus, throat, eyes and ears.Many topical medications are epicutaneous, meaning that they are applied directly to the skin...

 cream
Cream
Cream is a dairy product that is composed of the higher-butterfat layer skimmed from the top of milk before homogenization. In un-homogenized milk, over time, the lighter fat rises to the top. In the industrial production of cream this process is accelerated by using centrifuges called "separators"...

, and oral
Oral administration
Oral administration is a route of administration where a substance is taken through the mouth.-Terminology:Per os is an adverbial phrase meaning literally from Latin "by mouth" or "by way of the mouth." The expression is used in medicine to describe a treatment that is taken orally. The...

 tablet
Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...

.

Ketoconazole is very lipophilic, which leads to accumulation in fatty tissues. The less toxic and more effective triazole
Triazole
Triazole refers to either one of a pair of isomeric chemical compounds with molecular formula C2H3N3, having a five-membered ring of two carbon atoms and three nitrogen atoms.The two isomers are:*1,2,3-Triazole 100px*1,2,4-Triazole 100px...

 compounds fluconazole
Fluconazole
Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...

 and itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...

 have largely replaced ketoconazole for internal use.
Encyclopedia
Ketoconazole is a synthetic antifungal drug
Antifungal drug
An antifungal medication is a medication used to treat fungal infections such as athlete's foot, ringworm, candidiasis , serious systemic infections such as cryptococcal meningitis, and others...

 used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...

 or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff
Dandruff
Dandruff is the shedding of dead skin cells from the scalp . Dandruff is sometimes caused by frequent exposure to extreme heat and cold. As it is normal for skin cells to die and flake off, a small amount of flaking is normal and common; about 487,000 cells/cm2 get released normally after...

 shampoo
Shampoo
Shampoo is a hair care product used for the removal of oils, dirt, skin particles, dandruff, environmental pollutants and other contaminant particles that gradually build up in hair...

, topical
Topical
In medicine, a topical medication is applied to body surfaces such as the skin or mucous membranes such as the vagina, anus, throat, eyes and ears.Many topical medications are epicutaneous, meaning that they are applied directly to the skin...

 cream
Cream
Cream is a dairy product that is composed of the higher-butterfat layer skimmed from the top of milk before homogenization. In un-homogenized milk, over time, the lighter fat rises to the top. In the industrial production of cream this process is accelerated by using centrifuges called "separators"...

, and oral
Oral administration
Oral administration is a route of administration where a substance is taken through the mouth.-Terminology:Per os is an adverbial phrase meaning literally from Latin "by mouth" or "by way of the mouth." The expression is used in medicine to describe a treatment that is taken orally. The...

 tablet
Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...

.

Ketoconazole is very lipophilic, which leads to accumulation in fatty tissues. The less toxic and more effective triazole
Triazole
Triazole refers to either one of a pair of isomeric chemical compounds with molecular formula C2H3N3, having a five-membered ring of two carbon atoms and three nitrogen atoms.The two isomers are:*1,2,3-Triazole 100px*1,2,4-Triazole 100px...

 compounds fluconazole
Fluconazole
Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...

 and itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...

 have largely replaced ketoconazole for internal use. Ketoconazole is best absorbed at highly acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...

ic levels, so antacid
Antacid
An antacid is a substance which neutralizes stomach acidity.-Mechanism of action:Antacids perform a neutralization reaction, increasing the pH to reduce acidity in the stomach. When gastric hydrochloric acid reaches the nerves in the gastrointestinal mucosa, they signal pain to the central nervous...

s or other causes of decreased stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...

 acid levels will lower the drug's absorption when taken orally. Absorption can be increased by taking it with an acidic beverage, such as cola
Cola
Cola is a carbonated beverage that was typically flavored by the kola nut as well as vanilla and other flavorings, however, some colas are now flavored artificially. It became popular worldwide after druggist John Pemberton invented Coca-Cola in 1886...

.

Antifungal

Ketoconazole is usually prescribed for topical infections such as athlete's foot
Athlete's foot
Athlete's foot is a fungal infection of the skin that causes scaling, flaking, and itch of affected areas. It is caused by fungi in the genus Trichophyton and is typically transmitted in moist areas where people walk barefoot, such as showers or bathhouses...

, ringworm, candidiasis
Candidiasis
Thrush redirects here. For the hoof infection see Thrush .Candidiasis or thrush is a fungal infection of any of the Candida species , of which Candida albicans is the most common...

 (yeast infection or thrush), and jock itch
Jock itch
Tinea cruris, also known as crotch itch, crotch rot, Dhobie itch, eczema marginatum, gym itch, jock itch, and ringworm of the groin in American English is a dermatophyte fungal infection of the groin region in either sex, though more often seen in males...

. The over-the-counter shampoo
Shampoo
Shampoo is a hair care product used for the removal of oils, dirt, skin particles, dandruff, environmental pollutants and other contaminant particles that gradually build up in hair...

 version can also be used as a body wash for the treatment of tinea versicolor
Tinea versicolor
Tinea versicolor is a condition characterized by a rash on the trunk and proximal extremities. Recent research has shown that the majority of Tinea versicolor is caused by the Malassezia globosa fungus, although Malassezia furfur is responsible for a small number of cases...

. Ketoconazole is used to treat eumycetoma
Eumycetoma
Eumycetoma is a chronic, specific, granulomatous, fungal disease. It mainly affects the foot; and Mycetoma pedis is also known as Madura foot. This infection is endemic in Africa, India, and Central and South America.-Causes and presentation:...

, the fungal form of mycetoma
Mycetoma
Eumycetoma is a chronic, specific, granulomatous, fungal disease. It mainly affects the foot; and Mycetoma pedis is also known as Madura foot. This infection is endemic in Africa, India, and Central and South America.-Causes and presentation:...

.

The side effects of ketoconazole are sometimes used to treat non-fungal problems. The decrease in testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...

 caused by the drug makes it useful for treating prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...

 and for preventing post-operative erections following penile surgery. Another use is the suppression of glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...

 synthesis, where it is used in the treatment of Cushing's syndrome
Cushing's syndrome
Cushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...

. These side effects have also been studied for use in reducing depressive
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...

 symptoms and drug addiction; however, it has not succeeded in either of these roles.

Ketoconazole is also used in combination with other drugs such as zinc pyrithione
Zinc pyrithione
Zinc pyrithione is a coordination complex of zinc. This colourless solid is used as an antifungal and antibacterial agent. This coordination complex, which has many names, was first reported in the 1930s.- Structure of the compound :...

 in rinse-off products. 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
Animal testing
Animal testing, also known as animal experimentation, animal research, and in vivo testing, is the use of non-human animals in experiments. Worldwide it is estimated that the number of vertebrate animals—from zebrafish to non-human primates—ranges from the tens of millions to more than 100 million...

 has shown it to cause teratogenesis
Teratology
Teratology is the study of abnormalities of physiological development. It is often thought of as the study of human birth defects, but it is much broader than that, taking in other non-birth developmental stages, including puberty; and other non-human life forms, including plants.- Etymology :The...

 in high dosages. Until recently, there were two human test cases on record (both during the treatment of Cushing's syndrome
Cushing's syndrome
Cushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...

)
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.

Hair loss

Some preliminary research suggests that ketoconazole shampoo may be beneficial in men suffering from androgenic alopecia. Support for this comes primarily from a single study in 1998 that compared ketoconazole to the proven hair loss drug minoxidil
Minoxidil
Minoxidil is an antihypertensive vasodilator medication which also slows or stops hair loss and promotes hair regrowth. Now off-patent, it is available over-the-counter for the treatment of androgenic alopecia. Minoxidil must be used indefinitely for continued support of existing hair follicles and...

 in men with androgenic alopecia. The FDA do not accept that there is enough evidence to market it for hair loss.

Veterinary

This medication is also sometimes prescribed by veterinarian
Veterinarian
A veterinary physician, colloquially called a vet, shortened from veterinarian or veterinary surgeon , is a professional who treats disease, disorder and injury in animals....

s for use on pets, often as 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
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...

 and interferes with the fungal synthesis of ergosterol
Ergosterol
Ergosterol is a sterol found in fungi, and named for ergot, a common name for the members of the fungal genus Claviceps from which ergosterol was first isolated. Ergosterol does not occur in plant or animal cells...

, a constituent of fungal cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

s, as well as certain enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s. As with all azole antifungal agents, ketoconazole works principally by inhibiting the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 cytochrome P450 14-alpha-demethylase (P45014DM). This enzyme participates in the sterol
Sterol
Sterols, also known as steroid alcohols, are a subgroup of the steroids and an important class of organic molecules. They occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol...

 biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...

 pathway that leads from lanosterol
Lanosterol
Lanosterol is a tetracyclic triterpenoid, which is the compound from which all steroids are derived.-Role in creation of steroids:Elaboration of lanosterol under enzyme catalysis leads to the core structure of steroids. 14-Demethylation of lanosterol by CYP51 eventually yields...

 to ergosterol
Ergosterol
Ergosterol is a sterol found in fungi, and named for ergot, a common name for the members of the fungal genus Claviceps from which ergosterol was first isolated. Ergosterol does not occur in plant or animal cells...

. Lower doses of fluconazole
Fluconazole
Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...

 and itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...

 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
Antiandrogen
Antiandrogens, or androgen antagonists, first discovered in the 1960s, prevent androgens from expressing their biological effects on responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell's surface, or affecting...

, 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
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...

 antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...

, 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.

Susceptible fungi

Ketoconazole inhibits growth of dermatophyte
Dermatophyte
Dermatophytes are a common label for a group of three types of fungus that commonly causes skin disease in animals and humans. These anamorphic genera are: Microsporum, Epidermophyton and Trichophyton. There are about 40 species in these three genera...

s and yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...

 species such as Candida albicans
Candida albicans
Candida albicans is a diploid fungus that grows both as yeast and filamentous cells and a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections including those by C...

. 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
Candida albicans
Candida albicans is a diploid fungus that grows both as yeast and filamentous cells and a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections including those by C...

. 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.

Synthesis

The chemical synthesis of ketoconazole begins with dichloroacetophenone:

History

Ketoconazole was discovered in 1976 and released in 1981. It followed griseofulvin
Griseofulvin
Griseofulvin is an antifungal drug that is administered orally. It is used both in animals and in humans, to treat fungal infections of the skin and nails...

 as one of the first available oral treatments for fungal infections.

Brand names

It is marketed under the trademark name Nizoral by Ortho-McNeil Pharmaceutical
Ortho-McNeil Pharmaceutical
The company was formed from the merger of Ortho Pharmaceutical and McNeil Pharmaceutical in 1993. Both of these pharmaceutical companies are pioneers and leaders in areas such as pain management, acid reflux disease, and infectious diseases...

 in the United States, Australia and Canada, as Sebizole by Douglas Pharmaceuticals in Australia and New Zealand and as Ketomed in Latin America
Latin America
Latin America is a region of the Americas where Romance languages  – particularly Spanish and Portuguese, and variably French – are primarily spoken. Latin America has an area of approximately 21,069,500 km² , almost 3.9% of the Earth's surface or 14.1% of its land surface area...

. In Spain, products with ketoconazole as main agent include Ketoisdin gel (gel) and Fungarest (cream). In India, ketoconazole is sold as keton (tablets,soap & cream) by Green Apple Lifesciences Limited.

External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
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