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Mitotane is an adrenal cytotoxic drug that is derived from the insecticide DDT. It is commonly used for the treatment of PDH in dogs. Mitotane causes severe, progressive, cellular necrosis of the zona fasiculata and the zona reticularis. To a much lesser degree it may also affect the zona glomerulosa. Mitotane may also inhibit adrenocortical function without causing cell death, although in this case the mechanism of action is not known. Mitotane is stored in body fat, metabolized by the liver and excreted in both bile and urine.
Cushing's disease is one of the most common endocrine disorders in dogs and within that group, 80 to 85 percent of the dogs have PDH, while the remaining 15 percent have a functional adrenal tumor. Mitotane is a commonly used treatment for PDH in dogs and approximately 80 percent of dogs with PDH will respond favorably to treatment. There are two different basic protocols for using mitotane in dogs with PDH. The traditional and more commonly used protocol has an induction period of about 7 to 10 days followed by weekly treatments. The second protocol is a medical adrenalectomy using mitotane to destroy the adrenal cortex with the commitment to lifetime supplementation.
In the traditional protocol, about 25 percent of dogs
will experience some adverse side effects during the induction phase.
These usually occur when the plasma cortisol decreases too rapidly, or
is less than 1 microgram/dl. Small dogs, particularly those weighing less
than 5kg, are more likely to experience adverse side effects. There are
different schools of thought regarding the use of exogenous prednisone
during the initial treatment. The rational for this practice is to reduce
the possibility of side effects due to the rapid decline of endogenous
steroid.
There is a great deal of individual variation in sensitivity to mitotane;
owners will need to be educated to possible signs of hypoadrenocorticism.
Dogs that are being treated for PDH will require medication and monitoring
for the rest of their life. Most dogs will require gradually increasing
doses of mitotane in order to remain in remission. The oral absorption
of mitotane is poor. It is enhanced by giving the drug with food, particularly
food with a high fat or oil content. Some clinicians recommend coating
the pill with vegetable oil before giving with a meal.
Trilostane is the drug of choice for dogs that either do not respond to or do not tolerate mitotane.
Although mitotane has been used in cats, it is rarely effective. The treatment of choice in cats is adrenalectomy and supplementation with mineralocorticoids and glucocorticoids.
• The likelihood of side effects may be decreased
by dividing the daily dose and administering at 8 to 12 hour intervals.
The most common side effects include lethargy, gastritis, anorexia, vomiting
and diarrhea. Although less common, hypoadrenalcorticism and an addisonian
crisis are also potential side effects. In rare instances, dogs may experience
central nervous system (CNS) signs, ataxia, weakness and seizures.
• Animals with diabetes mellitus may have rapidly
changing insulin requirements during the induction period. They should
be closely monitored until they are in stable remission.
• Mitotane should be used with additional caution in animals who
have decreased kidney or liver function. They may require additional monitoring.
Histologic changes to the liver have been reported in dogs given mitotane.
• Mitotane should not be given to dogs who are not eating well.
• Many clinicians dispense prednisone to the clients for use in an
emergency. Clinical improvement should be seen within hours of the administration
of prednisone.
• Hypoaldosteronism may also occur in some animals. If hyponatremia
and hyperkalemia are found, supplementation with mineralocorticoids may
be warranted.
• One might consider expanding pituitary microadenoma as a differential
diagnosis in animals that persist with CNS signs after discontinuing mitotane.
• Clients should be instructed to wash their hands and or wear gloves
when handling mitotane due to toxicity concerns.
• Mitotane will have additive effects when combined
with other CNS-depressant drugs.
• Due to the induction of hepatic microsomal enzymes, phenobarbital
metabolism is affected by mitotane and conversely mitotane metabolism
is affected by phenobarbital.
• Treatment of PDH with mitotane may change the insulin requirements
in diabetic dogs.
• Spironolactone blocks the action of mitotane.
• Mitotane has both a long half life and is toxic
to the adrenals. If recognized promptly, overdose should be treated aggressively
with gut emptying protocols, activated charcoal and a cathartic. The patient
should be followed closely and receive corticosteroids as necessary.
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 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.
You can purchase books by Dr. Forney at www.exclusivelyequine.com
To help protect veterinary staff and patients from unnecessary exposure to chemotherapy medications and waste, this handling sheet will be included with all chemotherapy prescriptions we dispense.
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