Page 729 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 39 Adrenocorticosteroids & Adrenocortical Antagonists 715

tetrahydroaldosterone. Approximately 5–15 mcg/24 h is excreted ■ ANTAGONISTS OF
free or as the 3-oxo glucuronide.
ADRENOCORTICAL AGENTS
Deoxycorticosterone (DOC) SYNTHESIS INHIBITORS &

DOC, which also serves as a precursor of aldosterone (Figure 39–1), GLUCOCORTICOID ANTAGONISTS
is normally secreted in amounts of about 200 mcg/d. Its half-life
when injected into the human circulation is about 70 minutes. Inhibitors of steroid synthesis act at several different steps and one
Preliminary estimates of its concentration in plasma are approxi- glucocorticoid antagonist acts at the receptor level.
mately 0.03 mcg/dL. The control of its secretion differs from that
of aldosterone in that the secretion of DOC is primarily under the
control of ACTH. Although the response to ACTH is enhanced Aminoglutethimide
by dietary sodium restriction, due to adaptations, a low-salt diet Aminoglutethimide (Figure 39–5) blocks the conversion of
does not increase DOC secretion. The secretion of DOC may be cholesterol to pregnenolone (see Figure 39–1) and causes a
markedly increased in abnormal conditions such as adrenocorti- reduction in the synthesis of all hormonally active steroids. It has
cal carcinoma and congenital adrenal hyperplasia with reduced been used in conjunction with dexamethasone or hydrocortisone
P450c11 or P450c17 activity. to reduce or eliminate estrogen production in patients with
carcinoma of the breast. In a dosage of 1 g/d it was well toler-
Fludrocortisone ated; however, with higher dosages, lethargy and skin rash were
common effects. The use of aminoglutethimide in breast cancer
This compound, a potent steroid with both glucocorticoid and patients has now been supplanted by tamoxifen or by another
mineralocorticoid activity, is the most widely used mineralocorti- class of drugs, the aromatase inhibitors (see Chapters 40 and 54).
coid. Oral doses of 0.1 mg two to seven times weekly have potent Aminoglutethimide can be used in conjunction with metyra-
salt-retaining activity and are used in the treatment of adrenocor- pone or ketoconazole to reduce steroid secretion in patients with
tical insufficiency associated with mineralocorticoid deficiency. Cushing’s syndrome due to adrenocortical cancer who do not
These dosages are too small to have important anti-inflammatory respond to mitotane.
or antigrowth effects. Aminoglutethimide also apparently increases the clearance of
some steroids. It has been shown to enhance the metabolism of
ADRENAL ANDROGENS dexamethasone, reducing its half-life from 4–5 hours to 2 hours.

The adrenal cortex secretes large amounts of DHEA and smaller Ketoconazole
amounts of androstenedione and testosterone. Although these Ketoconazole, an antifungal imidazole derivative (see Chapter 48),
androgens are thought to contribute to the normal maturation is a potent and rather nonselective inhibitor of adrenal and
process, they do not stimulate or support major androgen- gonadal steroid synthesis. This compound inhibits the cholesterol
dependent pubertal changes in humans. Studies suggest that side-chain cleavage, P450c17, C17,20-lyase, 3β-hydroxysteroid
DHEA and its sulfate may have other important physiologic dehydrogenase, and P450c11 enzymes required for steroid hor-
actions. If that is correct, these results are probably due to the mone synthesis. The sensitivity of the P450 enzymes to this
peripheral conversion of DHEA to more potent androgens or to compound in mammalian tissues is much lower than that needed
estrogens and interaction with androgen and estrogen receptors, to treat fungal infections, so that its inhibitory effects on steroid
respectively. Additional effects may be exerted through an inter- biosynthesis are seen only at high doses.
action with the GABA and glutamate receptors in the brain or Ketoconazole has been used in the treatment of patients
A
with a nuclear receptor in several central and peripheral sites. The with Cushing’s syndrome due to several causes. Dosages of
therapeutic use of DHEA in humans has been explored, but the 200–1200 mg/d have caused a reduction in hormone levels
substance has already been adopted with uncritical enthusiasm and clinical improvement in some patients. This drug has some
by members of the sports drug culture and the vitamin and food hepatotoxicity and should be started at 200 mg/d and slowly
supplement culture. increased by 200 mg/d every 2–3 days up to a total daily dose
The results of a placebo-controlled trial of DHEA in patients of 1000 mg.
with systemic lupus erythematosus have been reported as well as
those of a study of DHEA replacement in women with adrenal
insufficiency. In both studies a small beneficial effect was seen, Etomidate
with significant improvement of the disease in the former and Etomidate [R-1-(1-ethylphenyl)imidazole-5-ethyl ester] is used
a clearly added sense of well-being in the latter. The androgenic for induction of general anesthesia and sedation. At subhypnotic
or estrogenic actions of DHEA could explain the effects of the doses of 0.1 mg/kg per hour this drug inhibits adrenal steroido-
compound in both situations. In contrast, there is no evidence genesis at the level of 11β-hydroxylase and has been used as the
to support DHEA use to increase muscle strength or improve only parenteral medication available in the treatment of severe
memory. Cushing’s syndrome.