Mitotane

Chemotherapy using mitotane (o,o'DDD; Lysodren) is the most commonly used treatment for pituitary-dependent hyperadrenocorticism (PDH). There are two treatment protocols: the traditional approach whose goal is to control the hyperadrenal state without causing clinical signs of hypoadrenocorticism and medical adrenalectomy whose goal is to destroy the adrenal cortex and convert from a hyper- to a hypoadrenal state. We prefer the traditional approach initially and only consider medical adrenalectomy in those dogs that fail to respond to the traditional approach or who become nonresponsive to mitotane after months of maintenance therapy.

For the traditional approach, there are two phases of mitotane therapy: an initial induction phase designed to gain control of the disorder, and a lifelong maintenance phase designed to prevent recurrence of the signs of the disease. The initial induction dosage of mitotane is 40 to 50 mg/kg/day, divided bid. The dosage is reduced to 25 to 35 mg/kg/day in dogs without polydipsia or with concurrent diabetes mellitus. Mitotane is more effective when each dose is ground up, mixed with a small amount of vegetable oil, and administered with food. Concurrent administration of a low dose of prednisone (0.25 mg/kg q24h) during induction therapy is a matter of personal preference. Regardless, prednisone should always be dispensed prior to beginning induction therapy so the owner has it on hand should adverse reactions to mitotane develop.

The induction phase of mitotane treatment is done with the dog in the home environment. The induction phase of therapy is usually complete once any reduction in appetite is noted or once the daily water consumption decreases into the normal range (i.e., 80 ml/kg or less). Control is confirmed by the results of the ACTH stimulation test, which is initially performed 5 to 7 days after the start of induction therapy; earlier if clinical signs of hypocortisolism develop. The goal of therapy is to achieve an ACTH stimulation test result that is suggestive of hypoadrenocorticism (i.e., a post-ACTH plasma cortisol concentration of 55 to 140 nmol/l). Daily mitotane therapy and weekly ACTH stimulation tests should be continued until a post-ACTH plasma cortisol concentration falls within the desired range or signs of hypocortisolism develop.

The maintenance phase of mitotane therapy is initiated once a hypoadrenal response to ACTH is obtained. The typical initial weekly maintenance dosage of mitotane is 50 mg/kg PO, divided into two or three doses and administered on 2 or 3 days of each week. The maintenance dose of mitotane is decreased from 50 to 25 mg/kg if the post-ACTH plasma cortisol concentration is less than 55 nmol/l and the dog appears healthy. Subsequent dosage adjustments are based on results of ACTH stimulation tests; the first test is performed 3 to 4 weeks after the start of maintenance therapy. The goal of maintenance therapy is to maintain the post-ACTH plasma cortisol concentration between 55 and 140 nmol/l in an otherwise healthy dog. The dose and frequency of administration of mitotane are adjusted, as needed, to maintain a hypoadrenal response to ACTH administration. With time (i.e., months to years), the dose and frequency of administration of mitotane usually increase to maintain this goal. Periodic ACTH stimulation testing will identify when the post-ACTH plasma cortisol concentration increases above 140 nmol/l and an adjustment in maintenance therapy is needed.

Excessive administration of mitotane initially results in clinical signs of hypocortisolism, including weakness, lethargy, anorexia, vomiting, and diarrhea. If these signs develop, prednisone therapy is warranted. Clinical improvement is usually seen within hours of the administration of prednisone (0.25 to 0.5 mg/kg, PO). Hypoaldosteronism may also develop and should be considered if clinical signs do not respond to prednisone therapy. The finding of hyponatremia and hyperkalemia supports a diagnosis of hypoaldosteronism, and mineralocorticoid therapy is indicated in such dogs. Mitotane treatment is discontinued until the dog is healthy without prednisone treatment and the post-ACTH plasma cortisol concentration is greater than 55 nmol/l.

An alternative to the traditional mitotane treatment protocol is to intentionally cause complete destruction of the adrenal cortices by administering an excessive amount of mitotane. The protocol consists of administering mitotane at a dosage of 75 to 100 mg/kg daily for 25 consecutive days, given in three or four doses per day, with food, to minimize neurologic complications and ensure good intestinal absorption of the drug. Lifelong prednisone (0.1 to 0.5 mg/kg bid initially) and mineralocorticoid therapy is begun at the start of mitotane administration. The prednisone dose is tapered after completion of the 25-day protocol. Relapse with signs of hyperadrenocorticism is common, necessitating periodic ACTH stimulation testing similar to that done in animals treated with the traditional mode of therapy. In addition, this treatment can be considerably more expensive than long-term treatment with mitotane because of the expense of treating addisonian dogs.

Ketoconazole

Ketoconazole, with its low prevalence of toxicity, ability to reversibly inhibit adrenal steroidogenesis, and negligible effects on mineralocorticoid production, is an alternative to mitotane for the medical management of canine hyperadrenocorticism. Ketoconazole affects steroid biosynthesis by interacting with the imidazole ring and the cytochrome P-450 component of various mammalian steroidogenic enzyme systems. Dogs seem to tolerate ketoconazole better when the dose is gradually increased over time. In addition, because this drug is an enzyme blocker, twice-daily administration has been necessary for the long-term management of these animals. The initial dosage of ketoconazole is 5 mg/kg bid, given for 7 days. If no problems with appetite or icterus are noted, the dose is increased to 10 mg/kg bid, given for 14 days. An ACTH stimulation test should be performed after 10 to 14 days of therapy at the higher dose and while the dog is still receiving ketoconazole. The goals of therapy are the same as those of mitotane therapy: the lack of an adrenocortical response to ACTH and clinical improvement without illness developing. If a hypoadrenal response to ACTH (i.e., post-ACTH plasma cortisol concentration of between 55 and 140 nmol/l) is not obtained with a dosage of 10 mg/kg bid, then the dose should be increased to 15 mg/kg bid. Approximately half of the dogs that respond to ketoconazole require 15 mg of ketoconazole/kg bid to maintain control of the hyperadrenocorticism. Approximately 20% to 25% of dogs do not respond to the drug as a result of poor intestinal absorption. Adverse reactions are primarily a result of hypocortisolism. The dose should be reduced or therapy discontinued if anorexia, depression, vomiting, or diarrhea is observed. Glucocorticoid treatment may be required if an overdose is suspected. Rechecks, including an ACTH stimulation test, every 3 to 6 months are recommended.

Trilostane

Trilostane is a competitive inhibitor of 3-beta-hydroxysteroid dehydrogenase, which mediates the conversion of pregnenolone to progesterone in the adrenal gland; the net effect is inhibition of cortisol production. Preliminary studies suggest that trilostane is effective in controlling clinical signs of hyperadrenocorticism in dogs for prolonged periods of time (greater than 1 year) and may be a viable option for treatment of PDH in dogs, especially in those dogs where mitotane is ineffective or in dogs which can not tolerate mitotane due to drug sensitivity. Trilostane is currently available as 60 and 120 mg capsules. The recommended dosage is 60 mg, 120 mg and 240 mg of trilostane PO once a day for dogs weighing 5 to 20 kg, 20 to 40 kg, and 40 to 60 kg, respectively. An ACTH stimulation test should be performed 10 to 14 days after initiating treatment and 4 to 6 hours after trilostane administration. The goals of therapy are the same as those of mitotane therapy: the lack of an adrenocortical response to ACTH and clinical improvement without illness developing. If a hypoadrenal response to ACTH (i.e., post-ACTH plasma cortisol concentration of between 55 and 140 nmol/l) is not obtained, the dosage should be increased by 60 mg increments, as necessary, until the goals of therapy are attained. If a hypoadrenal response is obtained but the dog still has clinical signs, twice a day therapy should be considered. An ACTH stimulation test should be done every 3 to 4 months, once control of the hyperadrenal state is attained. Adverse effects are uncommon and include lethargy, vomiting, and electrolyte shifts compatible with hypoadrenocorticism. A serum biochemistry panel and electrolytes should be monitored at the same time as the ACTH stimulation test.

l-Deprenyl

l-Deprenyl (selegiline HCl) has been used to treat PDH with variable but usually poor results. It is hypothesized by those who believe in this drug's effectiveness that the pituitary ACTH concentration is controlled in part by a negative feedback mechanism mediated by dopamine and that PDH may be caused by a loss of this negative suppression of ACTH, leading to the excess synthesis and secretion of the hormone. l-Deprenyl inhibits dopamine metabolism and increases hypothalamic and pituitary concentrations of dopamine, which in turn inhibits CRH and ACTH secretion and controls hypercortisolism and the associated clinical signs. l-deprenyl appears to be effective in approximately 20 to 30% of dogs with PDH. Interestingly, PDH originates from the pars intermedia and pars distalis in approximately 20% and 80% of affected dogs, respectively. Corticotrophs in the pars intermedia are under neurotransmitter control (dopamine) while corticotrophs in the pars distalis are controlled by CRH from the hypothalamus. Concentrations of an endogenous amphetamine, phenylethylamine, increase in the brain in dogs treated with l-Deprenyl, which may improve the dog's level of activity and its interactions with family members independent of any improvement in the hyperadrenal state. Current dosage recommendation for l-Deprenyl is 1 mg/kg once daily initially, with an increase to 2 mg/kg once daily if there is no response after 2 months. An alternative treatment should be considered if the dog fails to respond after 3 months of therapy; earlier if clinical signs worsen or the physical condition of the dog deteriorates.