Page 730 - Basic _ Clinical Pharmacology ( PDFDrive )

716 SECTION VII Endocrine Drugs

CI CI CI N O CH 3 N
CH C C
CI C CH 3

H
Mitotane Metyrapone

C H
2 5
NH 2

O O
N
H N
Aminoglutethimide
N CI
O CH 2
O CI

CH C N N OCH 2 O
3
H
Ketoconazole

FIGURE 39–5 Some adrenocortical blockers. Because of their toxicity, some of these compounds are no longer available in the United States.

Metyrapone In patients with Cushing’s syndrome, a normal response to
metyrapone indicates that the cortisol excess is not the result of a
Metyrapone (Figure 39–5) is a relatively selective inhibitor of cortisol-secreting adrenal carcinoma or adenoma, since secretion
steroid 11-hydroxylation, interfering with cortisol and corticoste- by such tumors produces suppression of ACTH and atrophy of
rone synthesis. In the presence of a normal pituitary gland, there normal adrenal cortex.
is a compensatory increase in pituitary ACTH release and adrenal Pituitary function may also be tested by administering metyra-
11-deoxycortisol secretion. This response is a measure of the pone, 2–3 g orally at midnight and by measuring the level of ACTH
capacity of the anterior pituitary to produce ACTH and has been or 11-deoxycortisol in blood drawn at 8 am or by comparing
adapted for clinical use as a diagnostic test. Although the toxicity the excretion of 17-hydroxycorticosteroids in the urine during the
of metyrapone is much lower than that of mitotane (see text that 24-hour periods preceding and following administration of the
follows), the drug may produce transient dizziness and gastroin- drug. In patients with suspected or known lesions of the pituitary,
testinal disturbances. This agent has not been widely used in the this procedure is a means of estimating the ability of the gland to
treatment of Cushing’s syndrome. However, in doses of 0.25 g produce ACTH. Metyrapone has been withdrawn from the market
twice daily to 1 g four times daily, metyrapone can reduce cortisol in the United States but is available on a compassionate basis.
production to normal levels in some patients with endogenous
Cushing’s syndrome. Thus, it may be useful in the management
of severe manifestations of cortisol excess while the cause of this Trilostane
condition is being determined or in conjunction with radiation Trilostane is a 3β-17 hydroxysteroid dehydrogenase inhibitor that
or surgical treatment. Metyrapone is the only adrenal-inhibiting interferes with the synthesis of adrenal and gonadal hormones and
medication that can be administered to pregnant women with is comparable to aminoglutethimide. Trilostane’s adverse effects
Cushing’s syndrome. The major adverse effects observed are salt are predominantly gastrointestinal; adverse effects occur in about
and water retention and hirsutism resulting from diversion of the 50% of patients with both trilostane and aminoglutethimide.
11-deoxycortisol precursor to DOC and androgen synthesis. There is no cross-resistance or crossover of side effects between
Metyrapone is commonly used in tests of adrenal function. these compounds. Trilostane is not available in the United States.
The blood levels of 11-deoxycortisol and the urinary excretion of
17-hydroxycorticoids are measured before and after administra- Abiraterone
tion of the compound. Normally, there is a twofold or greater
increase in the urinary 17-hydroxycorticoid excretion. A dosage of Abiraterone is the newest of the steroid synthesis inhibitors to be
300–500 mg every 4 hours for six doses is often used, and urine approved. It blocks 17α-hydroxylase (P450c17) and 17,20-lyase
collections are made on the day before and the day after treatment. (Figure 39–1), and predictably reduces synthesis of cortisol in