Ketoconazole; Uses, Dosage, Side Effects, Interactions, Pregnancy

Ketoconazole
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Ketoconazole is a synthetic derivative of phenylpiperazine with broad antifungal properties and potential antineoplastic activity. Ketoconazole inhibits sterol 14-a-dimethylase, a microsomal cytochrome P450-dependent enzyme, thereby disrupting the synthesis of ergosterol, an important component of the fungal cell wall. (NCI04)

Ketoconazole is an imidazole fungicidal agent with a very broad spectrum of activity against many fungal species that is used for the treatment of superficial and systemic fungal infections. Ketoconazole is a well-documented cause of clinically apparent acute drug-induced liver injury and is no longer recommended as a first line antifungal agent.
Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Ketoconazole is sold commercially as a tablet for oral administration (although this use has been discontinued in a number of countries), and in a variety of formulations for topical administration, such as creams (used to treat tinea; cutaneous candidiasis, including candidal paronychia; and pityriasis versicolor) and shampoos (used primarily to treat dandruff—seborrhoeic dermatitis of the scalp) .

Mechanism of Action of Ketoconazole

Ketoconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability. Other mechanisms may involve the inhibition of endogenous respiration, interaction with membrane phospholipids, inhibition of yeast transformation to mycelial forms, inhibition of purine uptake, and impairment of triglyceride and/or phospholipid biosynthesis. Ketoconazole can also inhibit the synthesis of thromboxane and sterols such as aldosterone, cortisol, and testosterone.

 Indications of Ketoconazole

  • Blastomycosis
  • Candidiasis, Cutaneous
  • Candiduria
  • Chromomycosis
  • Coccidioidomycosis
  • Dandruff
  • Histoplasmosis
  • Oral candida
  • Paracoccidioidomycosis
  • Pityriasis Versicolor
  • Seborrheic dermatitis
  • Tinea corporis
  • Tinea cruris
  • Tinea pedis
  • Recalcitrant cutaneous dermatophyte infection
  • Severe cutaneous dermatophyte infection
  • Chronic mucocutaneous candidiasis
  • Dermatophytosis
  • Esophageal candidiasis
  • Onychomycosis, Fingernail
  • Onychomycosis, toenail
  • Oral thrush
  • Paracoccidioidomycosis
  • Tinea corporis
  • Tinea versicolor
  • Vaginal yeast infection

Therapeutic Indications

  • For the treatment of the following systemic fungal infections: candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis.
  • Treatment of Cushing’s syndrome
  • Treatment of granulosa cell tumors
  • Ketoconazole HRA is indicated for the treatment of endogenous Cushing’s syndrome in adults and adolescents above the age of 12 years.

Contraindications of Ketoconazole

  • Have known hypersensitivity to other azole medicines such as ketoconazole;
  • Are taking terfenadine, if 400 mg per day multidose of fluconazole is administered;
  • Concomitant administration of ketoconazole and quinidine, especially when ketoconazole is administered in high dosages;
  • Take SSRIs such as fluoxetine or sertraline.

Dosage of Ketoconazole

Strengths:

Tablets: 200 mg; Shampoo: 1% and 2%; Cream: 2%, Gel: 2%, Foam: 2%

Blastomycosis

  • Initial dose: 200 mg orally once a day
  • If clinical responsiveness insufficient within expected time: Dose may be increased to 400 mg orally once a day.
  • Duration of therapy: 6 months (usual duration for systemic infection)

Chromomycosis

  • Initial dose: 200 mg orally once a day
  • If clinical responsiveness insufficient within expected time: Dose may be increased to 400 mg orally once a day.

Coccidioidomycosis

  • Initial dose: 200 mg orally once a day
  • If clinical responsiveness insufficient within expected time: Dose may be increased to 400 mg orally once a day.
  • Duration of therapy: 6 months (usual duration for systemic infection)

Histoplasmosis

  • Initial dose: 200 mg orally once a day
  • If clinical responsiveness insufficient within expected time: Dose may be increased to 400 mg orally once a day.
  • Duration of therapy: 6 months (usual duration for systemic infection)

Blastomycosis

  • 2 years or older: 3.3 to 6.6 mg/kg orally once a day
  • Duration of therapy: 6 months (usual duration for systemic infection)

Chromomycosis

  • 2 years or older: 3.3 to 6.6 mg/kg orally once a day
  • Duration of therapy: 6 months (usual duration for systemic infection)

Coccidioidomycosis

  • 2 years or older: 3.3 to 6.6 mg/kg orally once a day
  • Duration of therapy: 6 months (usual duration for systemic infection)

Paracoccidioidomycosis

  • 2 years or older: 3.3 to 6.6 mg/kg orally once a day
  • Duration of therapy: 6 months (usual duration for systemic infection)

Side Effects of Ketoconazole

The most common 

Common

Rare

Interactions of Ketoconazole

Kitoconazole may interact with following drugs ,supplyments & may change the efficacy of drugs

Interactions that can make your drugs less effective

When ketoconazole is less effective: When ketoconazole is used with certain drugs, it may not work as well to treat your condition. This is because the amount of ketoconazole in your body may be decreased. Examples of these drugs include:

  • Ranitidine, famotidine, cimetidine, pantoprazole, omeprazole, and rabeprazole. You should take ketoconazole with an acidic beverage, such as a non-diet soda, if you take these drugs together.
  • Aluminum hydroxide. You should take this drug 1 hour before or 2 hours after taking ketoconazole.
  • Antibiotics, such as isoniazid and rifabutin
  • Anticonvulsants, such as carbamazepine and phenytoin
  • Antivirals, such as efavirenz and nevirapine
  • Carbamazepine. Your doctor may monitor your carbamazepine levels.

Pregnancy & Lactation

FDA Pregnancy category C 

Ketoconazole falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. There are no well-controlled studies that have been done in humans with ketoconazole, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Lactation

It is not known if ketoconazole crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using ketoconazole.

References

Ketoconazole

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