Table 1 Clinically Useful Medical Therapies for Canine PDH
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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.
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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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