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Ketoconazole for Veterinary Use

For Veterinary Practices
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By Evan Ware, DVM

Overview

Therapeutic Class
Antifungal

Species
Dogs

May Be Prescribed by Vets for:
Susceptible fungal and yeast infections and hyperadrenocorticism in dog

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Basic Information

Ketoconazole is an antifungal medication that is effective against fungal or yeast infections. It is not effective against other types of infections caused by viruses, bacteria, or parasites. 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 can be better options for cats.

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 mammalian P-450 enzymes is the mechanism behind the reduction in steroid synthesis (cortisol and testosterone). Ketoconazole has some anti-inflammatory properties and can suppress T-lymphocyte production.

Ketoconazole is generally fungistatic, although it can become fungicidal with prolonged use or at higher dosages. Susceptible fungi and yeast include: Blastomyces, Coccidioides, Cryptococcus, Histoplasma, Microsporum, Trichophyton, Malassezia, Candidia, Sporotichosis, and Aspergillus.

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 cerebrospinal 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.

Veterinary Uses for Ketoconazole

Ketoconazole is prescribed for ringworm, fungal ear infections, or skin infections. Veterinarians also prescribe this antifungal to treat more serious infections, such as cryptococcosis, coccidioidomycosis (Valley Fever), and blastomycosis.

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 can continue for life. Absorption of ketoconazole is improved by administration with food. Clinical response may not occur until after 10 to 14 days of therapy. In animals who are critically ill, intravenous amphoteracin B can 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 can be necessary for chronic cases.

Ketoconazole can 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 occurs in about 50% of cases.

Ketoconazole interferes with the metabolism of cyclosporine and can be used to reduce the therapeutic dose and cost of treatment with cyclosporine.

In rare cases of Cushing's Disease, ketoconazole has been prescribed to help treat the excessive production of cortisone because it can suppress hormone synthesis.

Potential Side-Effects of Ketoconazole

Use of ketoconazole in feline patients generally is not recommended. Some animals can be more sensitive than others and therefore can experience certain side-effects. The most-common side effects attributed to this medication include gastrointestinal effects such as vomiting, lack of appetite, and diarrhea. These can be managed by decreasing or dividing the dose and administering the ketoconazole with a meal.

More-severe side effects include increased liver enzyme levels. If the veterinary patient experiences increased enzyme levels along with anorexia, vomiting, and diarrhea, the veterinarian should be contacted immediately.

Cats are more likely than dogs to experience side effects, particularly GI upset and hepatotoxicity.

Drug Interactions with Ketoconazole

Other drugs can interact with ketoconazole, including cimetidine, antacids, methylprednisolone, cisapride, cyclosporine, theophylline, anticonvulsants, and heart medications.

Ketoconazole should be used with caution with any other drugs that can be hepatotoxic. Alcohol/ethanol should not be used with ketoconazole due to possible disulfiram reaction.

Ketoconazole can increase the levels of benzodiazepines, buspirone, busulfan, calcium channel blockers, cisapride, cyclosporine, digoxin, fentanyl, quinidine, sulfonylurea drugs, and vincristine.

Ketoconazole can inhibit the metabolism of tricyclic antidepressants, corticosteroids, and cyclophosphamide. There is an increased likelihood of adverse effects.

Ketoconazole should not be used with ivermectin due to increased risk of neurotoxicity. Macrolide antibiotics can 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 can affect ketoconazole levels. They should not be used together. Ketoconazole levels can be decreased by phenytoin, and rifampin. Ketoconazole can decrease theophylline levels. Ketoconazole can increase prothrombin times in patients receiving warfarin or other coumarin anticoagulants.

Precautions for Using Ketoconazole

Ketoconazole should not be prescribed to animal patients that have had allergic reactions to the drug in previous situations.

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.

It also should not be prescribed to pregnant animals. Ketoconazole crosses the placenta and is considered teratogenic. It generally is not used in pregnant bitches except when the benefits of therapy outweigh the potential risk. Ketoconazole is found in the milk of dogs.

Ketoconazole can cause temporary infertility in male dogs due to decreased testosterone levels. Ketoconazole should be used with caution in animals with liver disease or thrombocytopenia.

Dosage and Administration of Ketoconazole

Ketoconazole is available under the brand name Nizoral®, as well as various generic formulations. This medication is administered either orally or via injection, the mode of which is determined by the veterinarian according to the condition being treated.

When a patient is prescribed ketoconazole, it is very important to complete the entire course of treatment. Failure to complete the treatment will increase the risk of a relapse of the fungal infection.

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. Evan Ware

Dr. Evan Ware is a veterinary practitioner in Phoenix, Arizona. He received both his undergraduate degree in microbiology and his Doctorate of Veterinary Medicine from The Ohio State University.

Dr. Ware is currently the Medical Director of University Animal Hospital (VCA) and is also the owner of two other hospitals, including Laveen Veterinary Center and Phoenix Veterinary Center. His areas of expertise include orthopedic medicine and surgery, veterinary oncology and chemotherapy, and general and advanced soft-tissue surgery.