Page 731 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 39 Adrenocorticosteroids & Adrenocortical Antagonists 717

the adrenal and gonadal steroids in the gonads. A compensatory withdrawn from the market in the United States but is available
increase occurs in ACTH and aldosterone synthesis, but this can on a compassionate basis.
be prevented by concomitant administration of dexamethasone.
Abiraterone is an orally active steroid prodrug and is approved for
the treatment of refractory prostate cancer. MINERALOCORTICOID ANTAGONISTS

Mifepristone (RU-486) In addition to agents that interfere with aldosterone synthesis (see
above), there are steroids that compete with aldosterone for its
The search for a glucocorticoid receptor antagonist finally receptor and decrease its effect peripherally. Progesterone is mildly
succeeded in the early 1980s with the development of the active in this respect.
11β-aminophenyl-substituted 19-norsteroid called RU-486, later Spironolactone is a 7α-acetylthiospirolactone. Its onset of action
named mifepristone. Unlike the enzyme inhibitors previously is slow, and the effects last for 2–3 days after the drug is discontin-
discussed, mifepristone is a pharmacologic antagonist at the ued. It is used in the treatment of primary aldosteronism in dosages
steroid receptor. This compound has strong antiprogestin activity of 50–100 mg/d. This agent reverses many of the manifestations
and initially was proposed as a contraceptive-contragestive agent. of aldosteronism. It has been useful in establishing the diagnosis in
High doses of mifepristone exert antiglucocorticoid activity by some patients and in ameliorating the signs and symptoms when
blocking the glucocorticoid receptor, since mifepristone binds surgical removal of an adenoma is delayed. When used diagnosti-
to it with high affinity, causing (1) some stabilization of the hsp- cally for the detection of aldosteronism in hypokalemic patients
glucocorticoid receptor complex and inhibition of the dissocia- with hypertension, dosages of 400–500 mg/d for 4–8 days—with an
tion of the RU-486–bound glucocorticoid receptor from the hsp adequate intake of sodium and potassium—restore potassium levels
chaperone proteins; and (2) alteration of the interaction of the to or toward normal. Spironolactone is also useful in preparing these
glucocorticoid receptor with coregulators, favoring the formation patients for surgery. Dosages of 300–400 mg/d for 2 weeks are used
of a transcriptionally inactive complex in the cell nucleus. The for this purpose and may reduce the incidence of cardiac arrhythmias.
result is inhibition of glucocorticoid receptor activation.
The mean half-life of mifepristone is 20 hours. This is longer O
than that of many natural and synthetic glucocorticoid agonists O
(dexamethasone has a half-life of 4–5 hours). Less than 1% of H C
3
the daily dose is excreted in the urine, suggesting a minor role of
kidneys in the clearance of the compound. The long plasma half- H C
3
life of mifepristone results from extensive and strong binding to
plasma proteins. Less than 5% of the compound is found in the O
free form when plasma is analyzed by equilibrium dialysis. Mife- O S C CH
pristone can bind to albumin and α -acid glycoprotein, but it has 3
1
no affinity for corticosteroid-binding globulin. Spironolactone
In humans, mifepristone causes generalized glucocorticoid Spironolactone is also an androgen antagonist and as such is
resistance. Given orally to several patients with Cushing’s syn- sometimes used in the treatment of hirsutism and acne in women.
drome due to ectopic ACTH production or adrenal carcinoma, Dosages of 50–200 mg/d cause a reduction in the density, diameter,
it was able to reverse the cushingoid phenotype, eliminate car- and rate of growth of facial hair in patients with idiopathic hirsut-
bohydrate intolerance, normalize blood pressure, correct thyroid ism or hirsutism secondary to androgen excess. The effect can usu-
and gonadal hormone suppression, and to ameliorate the psycho- ally be seen in 2 months and becomes maximal in about 6 months.
logical sequelae of hypercortisolism in these patients. At present, Spironolactone as a diuretic is discussed in Chapter 15. The
this use of mifepristone can only be recommended for inoperable drug has benefits in heart failure greater than those predicted from
patients with ectopic ACTH secretion or adrenal carcinoma who its diuretic effects alone (see Chapter 13). Adverse effects reported
have failed to respond to other therapeutic manipulations. Its for spironolactone include hyperkalemia, cardiac arrhythmia,
pharmacology and use in women as a progesterone antagonist are menstrual abnormalities, gynecomastia, sedation, headache,
discussed in Chapter 40.
gastrointestinal disturbances, and skin rashes.
Eplerenone, another aldosterone antagonist, is approved for
Mitotane the treatment of hypertension and heart failure (see Chapters 11,
Mitotane (Figure 39–5), a drug related to the DDT class of insec- 13, and 15). Like spironolactone, eplerenone has also been found
ticides, has a nonselective cytotoxic action on the adrenal cortex to reduce mortality in heart failure. This aldosterone receptor
in dogs and to a lesser extent in humans. This drug is adminis- antagonist is somewhat more selective than spironolactone and
tered orally in divided doses up to 12 g daily. About one-third has no reported effects on androgen receptors. The standard dos-
of patients with adrenal carcinoma show a reduction in tumor age in hypertension is 50–100 mg/d. The most common toxicity
mass. In 80% of patients, the toxic effects are sufficiently severe is hyperkalemia, but this is usually mild.
to require dose reduction. These include diarrhea, nausea, vomit- Drospirenone, a progestin, is an oral contraceptive (see
ing, depression, somnolence, and skin rashes. The drug has been Chapter 40), and also antagonizes the effects of aldosterone.