MINERALOCORTICOIDS ALDOSTERONE DEOXYCORTICOSTERONE FLUDROCORTISONE The most important mineralocorticoid

MINERALOCORTICOIDS: (ALDOSTERONE, DEOXYCORTICOSTERONE, FLUDROCORTISONE) • The most important mineralocorticoid in humans is aldosterone but small amounts of deoxycorticosterone (DOC) are also formed and released • Fludrocortisone, a synthetic corticosteroid, is the most commonly prescribed salt-retaining hormone

Aldosterone • Aldosterone is synthesized mainly in the zona glomerulosa of the adrenal cortex ACTH produces a moderate stimulation of its release, but this effect is not sustained for more than a few days • Although aldosterone is no less than one third as effective as cortisol in suppressing ACTH, the quantities of aldosterone produced by the adrenal cortex and its plasma concentrations are insufficient for feedback control of ACTH secretion

Aldosterone A. Physiologic and Pharmacologic Effects • Aldosterone and other steroids with mineralocorticoid properties promote the reabsorption of sodium from the distal part of the distal convoluted renal tubule and from the cortical collecting tubules • Excessive levels of aldosterone produced by tumors or overdosage with synthetic mineralocorticoids lead to hypokalemia, metabolic alkalosis, increased plasma volume, and hypertension • Mineralocorticoids act by binding to the mineralocorticoid receptor in the cytoplasm of target cells

Aldosterone B. Metabolism • Aldosterone is secreted at the rate of 100– 200 mcg/d in normal individuals with a moderate dietary salt intake • The half-life of aldosterone injected in tracer quantities is 15– 20 minutes, and it does not appear to be firmly bound to serum proteins

Deoxycorticosterone (DOC) • DOC (serves as a precursor of aldosterone) is normally secreted in amounts of about 200 mcg/d • Its secretion is primarily under the control of ACTH • Although the response to ACTH is enhanced by dietary sodium restriction, a low-salt diet does not increase DOC secretion • The secretion of DOC may be markedly increased in abnormal conditions such as adrenocortical carcinoma and congenital adrenal hyperplasia

Fludrocortisone • A potent steroid with both glucocorticoid and mineralocorticoid activity • Oral doses of 0. 1 mg two to seven times weekly have potent salt-retaining activity • Used in the treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency

ADRENAL ANDROGENS • The adrenal cortex secretes large amounts of DHEA and smaller amounts of androstenedione and testosterone • These androgens do not stimulate or support major androgen-dependent pubertal changes in humans

ANTAGONISTS OF ADRENOCORTICAL AGENTS

SYNTHESIS INHIBITORS & GLUCOCORTICOID ANTAGONISTS: Aminoglutethimide • blocks the conversion of cholesterol to pregnenolone and causes a reduction in the synthesis of all hormonally active steroids • has been used in conjunction with dexamethasone or hydrocortisone to reduce estrogen production in patients with carcinoma of the breast • dosage of 1 g/d it was well tolerated; but with higher dosages lethargy and skin rash • Its use in breast cancer patients has been supplanted by tamoxifen or by aromatase inhibitors • can be used in conjunction with metyrapone or ketoconazole to reduce steroid secretion in patients with Cushing’s syndrome due to adrenocortical cancer who do not respond to mitotane

Ketoconazole • An antifungal imidazole derivative, a potent and rather nonselective inhibitor of adrenal and gonadal steroid synthesis • inhibits P 450 c 17, C 17, 20 -lyase, 3β-hydroxysteroid dehydrogenase and P 450 c 11 enzymes required for steroid hormone synthesis • has been used in the treatment of patients with Cushing’s syndrome • dosages of 200– 1200 mg/d have produced a reduction in hormone levels and clinical improvement • has some hepatotoxicity and should be started at 200 mg/d and slowly increased by 200 mg/d every 2– 3 days up to a total daily dose of 1000 mg

Etomidate • Etomidate, unique drug used for induction of general anesthesia and sedation • At subhypnotic doses of 0. 1 mg/kg/h it inhibits adrenal steroidogenesis • Has been used as the only parenteral medication in the treatment of severe Cushing’s syndrome

Metyrapone • relatively selective inhibitor of steroid 11 -hydroxylation, interfering with cortisol and corticosterone synthesis • Although the toxicity of metyrapone is much lower than that of mitotane, the drug may produce transient dizziness and gastrointestinal disturbances • Only adrenal-inhibiting medication that can be administered to pregnant women with Cushing’s syndrome • The major adverse effects are salt and water retention and hirsutism resulting from diversion of the 11 -deoxycortisol precursor to DOC androgen synthesis

Metyrapone • commonly used in tests of adrenal function, blood levels of 11 deoxycortisol and the urinary excretion of 17 - hydroxycorticoids are measured before and after administration • In Cushing’s syndrome, a normal response to metyrapone indicates that the cortisol excess is not the result of a cortisolsecreting adrenal carcinoma or adenoma, given that secretion by such tumors produces suppression of ACTH and atrophy of normal adrenal cortex

Metyrapone • Pituitary function may also be tested by administering metyrapone, 2– 3 g orally at midnight and by measuring the level of ACTH or 11 -deoxycortisol in blood drawn at 8 AM or by comparing the excretion of 17 -hydroxycorticosteroids in the urine during the 24 -hour periods

Trilostane • a 3β-17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones • predominantly gastrointestinal adverse effects

Abiraterone • the newest of the steroid synthesis inhibitors to be approved • blocks 17α-hydroxylase (P 450 c 17) and 17, 20 -lyase and predictably reduces synthesis of cortisol in the adrenal and gonadal steroids in the gonads • orally active steroid prodrug and is approved for the treatment of refractory prostate cancer

Mifepristone (RU-486) • a pharmacologic antagonist at the steroid receptor • has strong antiprogestin activity and initially was proposed as a contraceptive-contragestive agent • high doses of mifepristone exert antiglucocorticoid activity by blocking the glucocorticoid receptor

Mifepristone (RU-486) • The mean half-life is 20 hours, longer than that of many natural and synthetic glucocorticoid agonists • Mifepristone can bind to albumin and α 1 -acid glycoprotein, but it has no affinity for corticosteroid-binding globulin

Mifepristone (RU-486) • causes generalized glucocorticoid resistance • orally use of mifepristone can only be recommended for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to otherapeutic manipulations.

Mitotane • a drug related to the DDT class of insecticides, has a nonselective cytotoxic action on the adrenal cortex in dogs and to a lesser extent in humans • administered orally in divided doses up to 12 g daily. • reduction in tumor mass in patients with adrenal carcinoma • dose reduction may be needed due to the toxic effects (diarrhea, nausea, vomiting, depression, somnolence, and skin rashes)

MINERALOCORTICOID ANTAGONISTS • Compete with aldosterone for its receptor and decrease its effect peripherally • Spironolactone is a 7α-acetylthiospironolactone, its onset of action is slow, and the effects last for 2– 3 days, used in the treatment of primary aldosteronism in dosages of 50– 100 mg/d • useful in the diagnosis in some patients and in ameliorating the signs and symptoms when surgical removal of an adenoma is delayed

MINERALOCORTICOID ANTAGONISTS • Spironolactone is also an androgen antagonist, sometimes used in the treatment of hirsutism in women • dosages of 50– 200 mg/d cause a reduction in the density, diameter, and rate of growth of facial hair in patients with idiopathic hirsutism or hirsutism secondary to androgen excess • has benefits in heart failure as a diuretic • adverse effects such as hyperkalemia, cardiac arrhythmia, menstrualabnormalities, gynecomastia, sedation, headache, gastrointestinal disturbances, and skin rashes

MINERALOCORTICOID ANTAGONISTS • Eplerenone, aldosterone antagonist, approved for the treatment of hypertension • reduce mortality in heart failure • more selective than spironolactone and has no reported effects on androgen receptors • dosage in hypertension is 50– 100 mg/d, the most common toxicity is hyperkalemia (mild) • Drospirenone, a progestin, in an oral contraceptive also antagonizes the effects of aldosterone