Medical therapies for canine pituitary-dependent hyperadrenocorticism - Veterinary Medicine
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Medical therapies for canine pituitary-dependent hyperadrenocorticism
Drug administration is usually the only option for treating dogs with PDH. Mitotane is the most common choice, but some alternatives are worth considering.


Administration and monitoring

Most clinicians still follow the mitotane protocol originally proposed for treating canine PDH in 1973.10 This protocol includes an induction period followed by long-term maintenance therapy. The induction dosage of mitotane for PDH is 30 to 50 mg/kg/day for eight to 10 days or until signs suggestive of hypoadrenocorticism develop.4,6,8,10,15 When possible, the daily dose should be divided into two equal doses and administered with food to increase absorption. Concurrent glucocorticoid supplementation with prednisone or prednisolone (0.15 to 0.25 mg/kg/day orally) can be used to mitigate the possible adverse effects associated with rapid serum cortisol concentration reduction.4,5,12 However, glucocorticoid supplementation during induction makes recognition of therapeutic end points difficult. If glucocorticoids are not concurrently administered, it is imperative that clients are provided with glucocorticoids in case signs of potentially life-threatening hypoadrenocorticism develop.12

At-home monitoring is crucial, especially during the induction period. Vomiting, weakness, anorexia, depression, or ataxia may be signs of mitotane overdosage, or they may be due to stomach upset associated with drug administration.14 Owners should be educated to recognize these warning signs and instructed to discontinue mitotane, administer oral prednisone, and consult their veterinarians if these signs occur. In the absence of these adverse reactions, mitotane should be discontinued when water consumption in a previously polydipsic dog decreases, when appetite wanes, or after the initial eight to 10 days of therapy. At that time, ACTH stimulation test results and serum electrolyte concentrations should be evaluated. Glucocorticoid therapy should not be given the morning of the ACTH stimulation test to avoid cross-reaction with the cortisol assay and falsely elevated cortisol concentrations.14

The goal of mitotane induction therapy is to achieve a basal cortisol concentration of 1 to 4 g/dl with little or no increase in the cortisol concentration after ACTH stimulation.8,14 If the cortisol concentration is suppressed excessively, discontinuing mitotane for two to six weeks usually returns the serum cortisol concentration to normal.18 If the post-ACTH stimulation cortisol concentration remains elevated, induction may be continued for another five to seven days or until the previously mentioned clinical evidence of cortisol suppression is observed, whichever comes first. This course may be repeated if suppression is again inadequate. However, if suppression of cortisol has not been achieved by 21 days, the possibility of an adrenal tumor should be reconsidered.

Once pre- and post-ACTH stimulation cortisol concentrations are between 1 and 5 g/dl, initiate maintenance therapy. Maintenance therapy involves dividing the daily mitotane induction dose (25 to 50 mg/kg) over two or three days of the week (e.g. Wednesday and Saturday or Monday, Wednesday, and Friday).6 Tablets are supplied in a 500-mg size, yet most dogs with PDH require much smaller doses. Because of the potential for toxicosis, owners should not crush or break the tablets themselves; trained personnel should formulate the tablets to the appropriate size. Be sure to tell owners to wear gloves or wash their hands after handling the medication.

Repeat serum electrolyte concentration measurements and ACTH stimulation testing in three and six months and then every six months thereafter. If the ACTH stimulation test results are above the desired ranges, increase the dose of mitotane by 25% to 50%.6 If a conservative increase in the mitotane dose does not alleviate clinical signs and decrease the cortisol concentrations appropriately within two months, repeat mitotane induction.6


Table 2 Alternative Proposed Medical Therapies for Canine PDH
With greater insight into the pathophysiology of PDH, other therapies have been proposed. These therapies can be categorized based on mechanism: inhibitors of steroidogenesis (e.g. nonselective adrenocorticolysis with mitotane, ketoconazole, trilostane), central neuromodulators (e.g. L-deprenyl), and glucocorticoid-receptor antagonists (e.g. mifepristone). The following therapies may be useful in treating dogs with PDH (Table 1), but others cannot be recommended (Table 2).


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