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.


VETERINARY MEDICINE



Table 1 Clinically Useful Medical Therapies for Canine PDH
HYPERADRENOCORTICISM is a common endocrinopathy in geriatric dogs. In about 85% of affected dogs, hyperadrenocorticism is secondary to excess secretion of ACTH from a benign tumor of the pituitary gland. Although people with pituitary-dependent hyperadrenocorticism (PDH) are often treated surgically, surgery remains efficacious yet impractical in dogs.1 Radiation therapy may slow the growth of pituitary tumors, but it often fails to control the hormonal effects of PDH.2,3 Thus, the mainstay of therapy in dogs with PDH is medical. The use of mitotane for selective adrenocorticolysis to treat PDH is well-described.4-8 This article discusses this use of mitotane and other medical therapies for treating PDH (Table 1).

Mitotane therapy

In the late 1940s, it was noted that dogs given the insecticide dichloro-diphenyl-dichloroethane (DDD) developed severe adrenocortical necrosis and atrophy.9 The therapeutic use of mitotane, a derivative of DDD, for hyperadrenocorticism in dogs was described in 1973, and this form of therapy has gained widespread acceptance.10 A recent survey of more than 200 veterinary internists and dermatologists revealed that 95.6% preferred mitotane to other therapies for the treatment of PDH in dogs.11

Mechanism of action


1. The enzymes involved in steroidogenesis are indicated in boxes. Specific steps in hormone synthesis blocked by the drugs mitotane ( M), trilostane (T), and ketoconazole (K) are indicated.
Mitotane exerts its cortisol-lowering effects through progressive, selective necrosis of the adrenal zona fasciculata and zona reticularis. The zona glomerulosa is relatively resistant to mitotane's cytotoxic effects, so normal aldosterone secretion is usually maintained.10 Mitotane also interferes with steroid biosynthesis, primarily by inhibiting the 11β-hydroxylase and cholesterol side-chain cleavage enzymes (Figure 1).12

Mitotane is fat-soluble, distributed to virtually all tissues, and stored primarily in adipose tissue. It is converted to its active form by mitochondrial P-450 monooxygenases.13 Although the metabolic disposition of mitotane is unknown in dogs, mitotane likely undergoes oxidative metabolism in the liver as it does in people. This pathway may be clinically important, since the induction of hepatic microsomal enzymes by drugs such as phenobarbital may increase mitotane metabolism and, concurrently, diminish the adrenocorticolytic effect.12,14

Safety

Most of mitotane's adverse effects are related to the rapid decrease in serum cortisol concentrations or to hypocortisolemia itself.15 Lethargy, ataxia, weakness, anorexia, vomiting, or diarrhea occurs in about 25% of patients.14,16 These effects are usually mild and resolve with administration of glucocorticoids. Permanent hypoadrenocorticism (Addison's disease) develops in about 2% to 5% of dogs with PDH treated with the selective adrenocorticolysis mitotane protocol.12 Despite the relative resistance of the zona glomerulosa to mitotane's effects, hypoadrenocorticism may include hypoaldosteronism with resultant hyponatremia and hyperkalemia in addition to hypocortisolemia.4,5,17 Rarely, drug-induced central nervous system (CNS) signs occur weeks to months after maintenance therapy is initiated, including wandering, circling, and head pressing. Typically, these CNS signs are transient and are abolished by giving lower doses of mitotane more frequently.18 Hepatic changes, including congestion, centrilobular atrophy, and moderate to severe fatty degeneration, have been noted.16

Efficacy

Mitotane therapy is effective in 85% to 90% of dogs with PDH.4,6,8,10,15 Despite initial efficacy, about half of dogs treated with mitotane relapse within the first year of therapy.4,8,12 Patients that relapse usually respond to reinduction and an increased maintenance dosage.12


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Source: VETERINARY MEDICINE,
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