Mitotane

Mitotane was once the mainstay of medical management of canine hyperadrenocorticism in many countries and is reviewed in detail elsewhere (Kintzer and Peterson, 1991). It is a cytotoxic agent that principally causes necrosis of the zona fasciculata and zona reticularis of the adrenal glands. It is slightly more efficacious than trilostane (see next section) but is reported to have a higher incidence of side effects (Kintzer and Peterson, 1991). Because it can be absorbed through the skin and is cytotoxic to humans, it should be handled carefully with gloves. Splitting tablets should be avoided when possible.

Mitotane is given initially as an induction course (50 mg/kg PO) administered once daily or divided twice daily, as required. Since it is a drug that has a narrow therapeutic index, stabilization in a hospital should be considered in some cases (e.g., dogs with concurrent diabetes) during the induction phase. The drug should be administered either in or immediately following a meal because this enhances its absorption. The induction course is monitored by carefully measuring the dog’s water intake and observing its feeding behavior. Concomitant prednisone or prednisolone administration is generally not recommended. Mitotane can also be used at higher doses in a protocol designed to permanently destroy the adrenal gland. This protocol is no longer in widespread use, and interested readers are advised to consult relevant texts for further details.

Treatment is stopped when water consumption or the appetite starts to decrease. Once these end points are reached, if the animal is unusually listless, begins vomiting, or has diarrhea or 7 days of treatment have elapsed, an ACTH stimulation test is performed. A response signifying mild adrenal cortex suppression indicates satisfactory control. For most laboratories this means a post-ACTH cortisol less than 120 nmol/L (<4.3 µg/dl).

Most induction courses last 5 to 10 days. Almost all dogs with pituitary-dependent hyperadrenocorticism respond by day 14. Maintenance therapy (25 to 50 mg/kg PO every 7 days or divided into 2 or 3 smaller doses over the course of a week) is then given and checked by ACTH stimulation tests, initially every month and then every 3 months.

Many dogs relapse at some point and require adjustments to the dose of mitotane. If responses to ACTH stimulation tests suggest a failure of adrenal suppression (post-ACTH cortisol greater than 250 nmol/L [>9 µg/dl]) and clinical signs of hyperadrenocorticism, the dog should be treated with a 3-day reinduction course and the effects of this monitored with further ACTH stimulation tests at the end of the reinduction course. The maintenance dose should then be increased (usually best done by increases in frequency [e.g., from once every 7 days to once every 5 days]) and the ACTH stimulation test repeated in 1 month. When the clinical signs are minimal but the post-ACTH cortisol is greater than 250 nmol/L (>9 µg/dl), the dose frequency may be increased without a reinduction course.

Dogs that are treated with mitotane, particularly those that have been treated for several months, may develop acute signs of hypoadrenocorticism (e.g., severe depression, anorexia, vomiting, diarrhea). Intravenous fluids, glucocorticoids, and rest are usually effective. Mitotane administration should be discontinued until adrenal gland function has recovered, demonstrated by a post-ACTH cortisol concentration greater than 250 nmol/L (>9 µg/dl). The dose should then be decreased from the previous amount and/or frequency.

Occasionally there may be evidence of hyperkalemia and hyponatremia. If these occur, an ACTH stimulation test should be performed; post-ACTH cortisol would be expected to be less than 20 nmol/L (<0.7 µg/dl). Mineralocorticoids should be given if hyperkalemia has been documented and will likely be needed for the rest of the animal’s life (see Chapter 53). Pancreatitis and hemorrhagic gastroenteritis are potential complications of the acute iatrogenic hypoadrenocorticism. Oral prednisolone (0.2 to 0.4 mg/kg PO every 24 hours) is given once the vomiting has subsided. Some dogs require this for life, but others may revert to their original state of hyperadrenocorticism.

Routine monitoring with ACTH stimulation tests is recommended; the frequency of monitoring largely depends on the clinical progression of the case. Some dogs receiving long-term prednisolone as a result of mitotane-induced hypoadrenocorticism only require ACTH stimulation tests annually.

Some animals become intolerant of mitotane and show signs of gastrointestinal upset without a reduction in post-ACTH cortisol concentrations. These dogs should be treated by other means.

Trilostane

Trilostane is a synthetic steroid that competitively inhibits steroid synthesis by blocking 3β-hydroxysteroid dehydrogenase. The adrenal glands and in particular the synthesis of glucocorticoids are more susceptible to its action than are other steroid-producing tissues. The reasons for this are not known. Trilostane is now authorized in most European countries and in the United States for the treatment of pituitary-dependent and adrenal-dependent hyperadrenocorticism in dogs.

Trilostane has proven to be well tolerated by almost all dogs with pituitary-dependent hyperadrenocorticism in several published trials (totaling more than 120 dogs) summarized elsewhere (Ramsey, 2010). Few dogs develop signs of hypoadrenocorticism when treated with trilostane, although mild asymptomatic hyperkalemia is common. When hypoadrenocorticism does occur, dogs usually rapidly recover with appropriate therapy. The low prevalence of side effects compares favorably with those reported with mitotane.

Trilostane is safer for owners to handle when compared with mitotane. However, pregnant women are advised to wear gloves when handling the drug because it has been shown to cause abortion in monkeys given large doses.

Although few pharmacokinetic studies have been performed, trilostane is known to be short acting. The recommended starting dose is 2 to 5 mg/kg orally once daily, using the lower dosage range in small dogs. (Figure 51-1 is an algorithm of trilostane therapy.) Trilostane is better absorbed if given with food. It is effective in resolving the signs of pituitary-dependent hyperadrenocorticism in about 75% of cases (Neiger et al, 2002; Ruckstuhl, Nett, and Reusch, 2002). Polyuria, polydipsia, and polyphagia should dissipate within 4 weeks after starting trilostane. Skin changes should resolve within 4 months of starting treatment. All these improvements should be maintained as long as the dogs remain on adequate doses of trilostane.