Ketoconazole

Topical antifungal Topically administered ketoconazole is usually prescribed for fungal infections of the skin and mucous membranes, such as athlete's foot, ringworm, candidiasis (yeast infection or thrush), jock itch, and tinea versicolor. Topical ketoconazole is also used as a treatment for dandruff (seborrheic dermatitis of the scalp) and for seborrheic dermatitis on other areas of the body, perhaps acting in these conditions by suppressing levels of the fungus Malassezia furfur on the skin. Systemic antifungal Ketoconazole has activity against many kinds of fungi that may cause human disease, such as Candida, Histoplasma, Coccidioides, and Blastomyces (although it is not active against Aspergillus), chromomycosis and paracoccidioidomycosis. Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections. Off-label uses Hair loss Ketoconazole shampoo in conjunction with an oral 5α-reductase inhibitor such as finasteride or dutasteride has been used off label to treat androgenic alopecia. It was speculated that antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia. Limited clinical studies suggest ketoconazole shampoo used either alone or in combination with other treatments may be useful in reducing hair loss in some cases. However, one study found that applying a 2% Topical Ketoconazole solution on the balding scalps of women found comparable regrowth to 2% Minoxidil, albeit with a longer onset of action. Hormonal The side effects of ketoconazole are sometimes harnessed in the treatment of non-fungal conditions. While ketoconazole blocks the synthesis of the sterol ergosterol in fungi, in humans, at high dosages (>800 mg/day), it potently inhibits the activity of several enzymes necessary for the conversion of cholesterol to steroid hormones such as testosterone and cortisol. All of these enzymes are mitochondrial cytochrome p450 enzymes. Based on these antiandrogen and antiglucocorticoid effects, ketoconazole has been used with some success as a second-line treatment for certain forms of advanced prostate cancer and for the suppression of glucocorticoid synthesis in the treatment of Cushing's syndrome. However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to prevent adrenal insufficiency. ==Contraindications==

Oral ketoconazole has various contraindications, such as concomitant use with certain other drugs due to known drug interactions. Other contraindications of oral ketoconazole include liver disease, adrenal insufficiency, and known hypersensitivity to oral ketoconazole. ==Side effects==

Gastrointestinal Vomiting, diarrhea, nausea, constipation, abdominal pain, upper abdominal pain, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration may occur. Liver In July 2013, the US Food and Drug Administration (FDA) issued a warning that taking ketoconazole by mouth can cause severe liver injuries and adrenal gland problems: adrenal insufficiency and worsening of other diseases related to the gland conditions. A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole. ==Overdose==

In the event of an overdose of oral ketoconazole, treatment should be supportive and based on symptoms. Activated charcoal may be administered within the first hour following overdose of oral ketoconazole. == Interactions ==

The concomitant use of the following medications are contraindicated with ketoconazole tablets: • methadone, disopyramide, dronedarone • irinotecan, lurasidone, colchicine • alprazolam, oral midazolam, oral triazolam • felodipine, ranolazine, tolvaptan, eplerenone • HMG-CoA reductase inhibitors: lovastatin, simvastatin • ergot alkaloids: ergotamine, dihydroergotamine, ergometrine, methylergometrine • Others: cisapride, nisoldipine, dofetilide, pimozide The following medications are not recommended with ketoconazole: • carbamazepine, phenytoin • gastric acid suppressants: antacids, antimuscarinics, histamine H2 blockers, proton pump inhibitors • sucralfate • rifampin, rifabutin, isoniazid • efavirenz, nevirapine Ritonavir(an antiretrovial medication), is known for increasing the activity of ketoconazole. So it is recommended to reduce dosage. There is also a list of drugs which significantly decrease systemic exposure to the ketoconazole and drugs whose systemic exposure is increased by the ketoconazole. ==Pharmacology==

Pharmacodynamics Antifungal activity 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 14α-demethylase (CYP51A1). Antihormonal activity 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 three times per day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels. It produces this effect through inhibition of 17α-hydroxylase and 17,20-lyase, which are involved in the synthesis and degradation of steroids, including the precursors of testosterone. Second, ketoconazole is an androgen receptor antagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for binding to the androgen receptor. This effect is thought to be quite weak however, even with high oral doses of ketoconazole. Ketoconazole, along with miconazole, has been found to act as an antagonist of the glucocorticoid receptor. Ketoconazole is a racemic mixture consisting of cis-(2S,4R)-(−) and cis-(2R,4S)-(+) enantiomers. Numerous small studies have investigated the effects of oral ketoconazole on hormone levels in humans. Suppression of testosterone levels by ketoconazole is generally partial and has often been found to be transient. Studies in postmenopausal women with breast cancer have found that ketoconazole significantly decreases androstenedione levels, slightly decreases estradiol levels, and does not affect estrone levels. This indicates minimal inhibition of aromatase by ketoconazole in vivo in humans. Pharmacokinetics When administered orally, ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption. Absorption can be increased by taking it with an acidic beverage, such as cola. Ketoconazole is very lipophilic and tends to accumulate in fatty tissues. ==Chemistry==

Ketoconazole is a synthetic imidazole. It is a nonsteroidal compound. It is a racemic mixture of two enantiomers, levoketoconazole ((2S,4R)-(−)-ketoconazole) and dextroketoconazole ((2R,4S)-(+)-ketoconazole). Levoketoconazole is under development for potential clinical use as a steroidogenesis inhibitor with better tolerability and less toxicity than ketoconazole. Other steroidogenesis inhibitors besides ketoconazole and levoketoconazole include the nonsteroidal compound aminoglutethimide and the steroidal compound abiraterone acetate. ==History==

Ketoconazole was discovered in 1976 at Janssen Pharmaceuticals. It was patented in 1977, Oral ketoconazole has been replaced with oral fluconazole or itraconazole for many mycoses. In 2013, oral ketoconazole was withdrawn in the European Union and Australia, and strict restrictions were placed on the use of oral ketoconazole in the United States and Canada. ==Society and culture==

Generic names Ketoconazole is the generic name of the drug and its , , , and . Brand names Ketoconazole has been marketed under a large number of brand names. == Research ==

As of March 2019, oral levoketoconazole (developmental code name COR-003, tentative brand name Recorlev) is phase III clinical trials for the treatment of Cushing's syndrome. Oral levoketoconazole may have a lower risk of liver toxicity than oral ketoconazole. ==Veterinary use==

Ketoconazole is sometimes prescribed as an antifungal by veterinarians for use in pets, often as unflavored tablets that may need to be cut to smaller size for correct dosage. == References ==