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Ketoconazole for Veterinary Use
by Barbara Forney, VMD
Ketoconazole is an oral azole antifungal drug. It is used to treat a number of superficial and systemic yeast and fungal infections in dogs. Although ketoconazole has been used in cats, its use is controversial due to the risk of hepatic toxicity. There are other anti-fungal drugs that may be better options in the cat.
Ketoconazole’s mechanism of action is thought to be through a direct effect on cellular membrane permeability, and decreased cellular metabolism and growth. Azole anti-fungal drugs inhibit the fungal P-450 enzyme system and, to a lesser degree, inhibit the mammalian P-450 enzyme system. Blocking of mammalian P-450 enzymes is the mechanism behind the reduction in steroid synthesis (cortisol and testosterone). Ketoconazole has some anti-inflammatory properties and may suppress T-lymphocyte production.
Ketoconazole is generally fungistatic, although it may become fungicidal with prolonged use or at higher dosages. Susceptible fungi and yeast include: Blastomyces, Coccidioides, Cryptococcus, Histoplasma, Microsporum, Trichophyton, Malassezia, Candidia, Sporotichosis, Aspergillis.
Ketoconazole is metabolized by the liver and primarily excreted in the feces. It is well distributed through most tissues of the body, including skin and subcutaneous tissue, liver, kidneys, adrenal gland, pituitary gland, lungs, bladder, bone marrow, and myocardium. It does not adequately penetrate cerebralspinal fluid, ocular fluid, or seminal fluid. Ketoconazole is relatively poorly absorbed except in an acid environment, and there is wide inter-patient variation in absorption.
Ketoconazole is used to treat systemic coccidiomycosis, blastomycosis, histoplasmosis, aspergillosis, cryptococcosis, sporotrichosis, and fungal myocarditis. The duration of treatment for these serious systemic fungal diseases can be quite long, in some cases up to a year. In some animals, suppressive treatment may continue for life. Absorption of ketoconazole is improved by administration with food. Clinical response may not occur until after 10 -14 days of therapy. In animals that are critically ill, intravenous amphoteracin B may be used with ketoconazole as a means of increasing the efficacy and speed of response. When ketoconazole is used in combination with amphoteracin B, the dose of amphoteracin B is reduced or given at an increased interval.
When ketoconazole is used to treat dermatitis due to Malassezia pachydermatis
it is generally used with topical anti-mycotic shampoos. Two to four weeks of treatment may be necessary for chronic cases.
Ketoconazole may be used to treat adrenal hypercorticism in dogs that do not tolerate mitotane. Ketoconazole and mitotane should not be used together, as ketoconazole interferes with the mechanism of action of mitotane. Clinical response to ketoconazole is about 50% of cases.
Ketoconazole interferes with the metabolism of cyclosporine and may be used to reduce the therapeutic dose and cost of treatment with cyclosporine
- The most common side effects are gastrointestinal: nausea vomiting and loss of appetite. These may be manageable through decreasing or dividing the dose and administering the ketoconazole with a meal.
- Less common side effects include hepatotoxicity, thrombocytopenia, and transient lightening of the hair coat.
- Cats are more likely than dogs to experience side effects: particularly GI upset and hepatotoxicity.
- Liver enzymes should be monitored during therapy due to the potential for liver toxicity. A slight elevation of liver enzymes is common and would not generally cause a change in dose.
- Ketoconazole crosses the placenta and is considered teratogenic. It is generally not used in pregnant bitches except when the benefits of therapy outweigh the potential risk. Ketoconazole is found in the milk of dogs.
- Ketoconazole may cause temporary infertility in male dogs due to decreased testosterone levels.
- Ketoconazole should be used with caution in animals with liver disease or thrombocytopenia.
There are numerous potential drug interactions with ketoconazole.
- Oral antacids, proton pump inhibitors, sucralfate, and histamine H
blockers will decrease the absorption of ketoconazole. These drugs should be separated by 1-2 hours.
- Ketoconazole should be used with caution with any other drugs that may be hepatotoxic.
- Alcohol/ethanol should not be used with ketoconazole due to possible disulfram reaction.
- Ketoconazole may increase the levels of benzodiazepines, buspirone, busulfan, calcium channel blockers, cisapride, cyclosporine, digoxin, fentanyl, quinidine, sulfonylurea drugs, and vincristine.
- Ketoconazole may inhibit the metabolism of the following drugs; tricyclic antidepressants, corticosteroids, cyclophosphamide. There is an increased likelihood of adverse effects.
- Ketoconazole should not be used with ivermectin due to increased risk of neurotoxicity.
- Macrolide antibiotics may increase the concentration of ketoconazole.
- Ketoconazole interferes with the mechanism of action of mitotane. They should not be used together in the treatment of adrenal hypercorticism.
- Isoniazid may affect ketoconazole levels. They should not be used together.
- Ketoconazole levels may be decreased by phenytoin, and rifampin.
- Ketoconazole may decrease theophylline levels.
- Ketoconazole may increase prothrombin times in patients receiving warfarin or other coumarin anticoagulants.
- There is limited information on acute toxicity.
- Acute overdose should be treated with supportive measures, including gastric lavage with sodium bicarbonate.
About the Author
Dr. Barbara Forney is a veterinary practitioner in Chester County, Pennsylvania. She has a master's degree in animal science from the University of Delaware and graduated from the University of Pennsylvania School of Veterinary Medicine in 1982.
She began to develop her interest in client education and medical writing in 1997. Recent publications include portions of The Pill Book Guide to Medication for Your Dog and Cat, and most recently Understanding Equine Medications published by the Bloodhorse.
Dr. Forney is an FEI veterinarian and an active member of the AAEP, AVMA, and AMWA.
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