Spironolactone steroid

Spironolactone is the most clinically usehil steroidal aldosterone antagonist, and unlike GR antagonists, this compound is utilized much more frequendy than aldosterone agonists. Interfering with reabsorption and secretion in the late distal segment, this compound is predominantiy used with other diuretics. Canrenone, an olefinic metaboHte of spironolactone, and potassium canrenoate, in which the C-17 lactone has been hydrolyzed open, are also potent mineralocorticoid antagonists. 

The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt carbonation with CO2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cy-clized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist. ... 

ACE inhibitors do not completely block aldosterone synthesis. Since this steroid hormone is a potent inducer of fibrosis in the heart, specific antagonists, such as spironolactone and eplerenone, have recently been very successfully used in clinical trials in addition to ACE inhibitors to treat congestive heart failure [5]. Formerly, these drugs have only been applied as potassium-saving diuretics in oedematous diseases, hypertension, and hypokalemia as well as in primary hyperaldosteronism. Possible side effects of aldosterone antagonists include hyperkalemia and, in case of spironolactone, which is less specific for the mineralocorticoid receptor than eplerenone, also antiandrogenic and progestational actions. 

Aldosterone (183) is one of the key steroid hormones involved in regulation of the body s mineral and fluid balance. Excess levels of this steroid quickly lead to marked retention of sodium chloride, water and, often as a consequence, hypertension. The aldosterone antagonist spironolactone (184) has proven of great clinical value in blocking the effects... 

Endocrine effects Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Small declines in total testosterone with no commensurate elevation in LH have been noted with the use of fluvastatin. Pravastatin showed inconsistent results with regard to possible effects on basal steroid hormone levels atorvastatin, lovastatin, rosuvastatin, and simvastatin did not reduce basal plasma cortisol concentration or basal plasma testosterone concentration or impair adrenal reserve. Appropriately evaluate patients who display clinical evidence of endocrine dysfunction. Exercise caution when administering HMG-CoA reductase inhibitors with drugs that affect steroid levels or activity, such as ketoconazole, spironolactone, and cimetidine. 

Microbial and enzymic transformations of steroids have been reviewed. 5a-Pregnane-7,20-dione gave a reasonable yield of the la, 12/3-dihydroxy-derivative on incubation with Calonectria decora High yields of 10 8-hydroxy-19-nortes-tosterone were obtained by incubation of 19-nortestosterone with Rhizopus arr-hizus (Fischer 11). Oxidation of canrenone with a Penicillium species provided the 15a-hydroxy-derivative (348) which is a product of human metabolism of spironolactone.16j8-Hydroxylation of androstenolone, androst-4-ene-3,17-... 

Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone. Onset and duration of its action are determined by the kinetics of the aldosterone response in the target tissue. Substantial inactivation of spironolactone occurs in the liver. Overall, spironolactone has a rather slow onset of action, requiring several days before full therapeutic effect is achieved. 

Synthetic steroids may cause endocrine abnormalities by actions on other steroid receptors. Gynecomastia, impotence, and benign prostatic hyperplasia all have been reported with spironolactone. Such effects have not been reported with eplerenone because it is much more selective than spironolactone for the mineralocorticoid receptor, being virtually inactive on androgen or progesterone receptors. 

Protein binding of spironolactone and canrenone was determined by both ultrafiltration (room temperature) [63] and equilibrium dialysis (overnight at 37°C) [64]. Both spironolactone and canrenone were extensively (>89%) bound to plasma proteins, and their blood-to-plasma concentration ratio was about 0.5, indicating that in blood these steroids were largely confined to plasma. 

Spironolactone exhibits antiandrogenic effects in males and females. It decreases testosterone biosynthesis by inhibiting steroid 17a-monooxygenase (17a-hydroxylase) activity, possibly secondary to destruction of microsomal cytochrome P-450 in tissues with high steroid 17a-monooxygenase activity (testes, adrenals) [65],... 

Several substances have proven to be useful as inhibitors of the synthesis of adrenal steroids metyrapone [me TEER a pone], aminoglutethimide [a mee noe glu TETH i mide], ketoconazole [kee toe KON a zole], and spironolactone. Mifepristone competes with glucocorticoids for the receptor. 

In 1986, the total production of steroidal agents was about 393 tons, of which 125 tons was spironolactone [6]. Subsequently, however, the amount produced annually fell as the consequence of a reduction in the pharmaceutical application of spironolactone. 

Spironolactone (see p. 534) is a competitive aldosterone antagonist which also blocks the mineralocorticoid effect of other steroids it is used in the treatment of primary hyperaldosteronism and as a diuretic, principally when severe oedema is due to secondary hyperaldosteronism, e.g. cirrhosis, congestive cardiac failure. 

Steroid hormone receptors (for gonadal steroids and adrenocortical steroids) are complex proteins inside the target cell. The steroid penetrates, is bound and translocates into the cell nucleus, which is the principal site of action and where RNA/protein synthesis occurs. Compounds that occupy the receptor without causing translocation into the nucleus or the replenishment of receptors act as antagonists, e.g. spironolactone to aldosterone, cyproterone to androgens, clomiphene to oestrogens. 

Steimer W, Muller C, Eber B. Digoxin assays frequent, substantial, and potentially dangerous interference by spironolactone, camenone, and other steroids. Clin Chem 2002 48(3) 507-16. 

Close laboratory monitoring and judicious use of spironolactone is needed to reduce the risk of hyperkalemia. The excess of hyperkalemia in clinical practice compared with RALES can be explained largely by the use of higher doses of spironolactone and the inclusion of patients with lower glomerular filtration rates and whose aldosterone-mediated compensatory distal tubular potassium excretion is already attenuated (5). Such patients include elderly people, people with diabetes, and those taking beta-blockers, non-steroidal anti-inflammatory drugs, potassium salts, potassium-sparing diuretics, or trimethoprim. 

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