Spironolactone

The process for producing spiramycin comprises inoculating an aqueous nutrient medium with a culture of the NRRL No. 2420, allowing aerobic fermentation to take place and separating from the culture medium the spiramycin thus formed. The culture medium also contains the antibiotic substance known as Congocldin which, however, does not possess the same useful properties as spiramycin and which can be isolated in crystalline form. The separation of the two antibiotic substances is readily achieved. 

and Verrier, J. U.S. Patent 2,943,023 June 28, 1960 assigned to Societe des Usines Chimiques Rhone-Poulenc 

Chemical Name 7o-(acetylthio)-17a-hydroxy-3-oxopregn-4-ene-21-carboxylic acid Common Name — 

Trade Name Manufacturer Country Year Introduced 

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Hyperaldosteronism is accompanied by elevation of blood pressure (115), and can be treated with an aldosterone antagonist, eg, spironolactone (117) which... 

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. 

Gynecomastia may be associated with the use of spironolactone and is reversible upon withdrawal of the dmg. 

Potassium-Sparing Diuretics. Potassium-sparing diuretics act on the aldosterone-sensitive portion of cortical collecting tubules, and partially in the distal convoluted tubules of the nephron. The commonly used potassium-sparing diuretics are triamterene, amiloride, and spironolactone (Table 3). Spironolactone is a competitive aldosterone receptor antagonist, whereas triamterene and amiloride are not (44,45). 

Spironolactone antagonizes the effects of aldosterone by binding at the aldosterone receptor in the cytosol of the late distal tubules and renal collecting ducts. Side effects of spironolactone are gynecomastia, decreased Hbido, and impotency. 

Potassium-sparing by diuretic agents, particularly spironolactone, enhances the effectiveness of other diuretics because the secondary hyperaldosteronism is blocked. This class of diuretics decreases magnesium excretion, eg, amiloride can decrease renal excretion of potassium up to 80%. The most important and dangerous adverse effect of all potassium-sparing diuretics is hyperkalemia, which can be potentially fatal the incidence is about 0.5% (50). Therefore, blood potassium concentrations should be monitored carehiUy. 

Ascites. Patients with cirrhosis, especially fiver cirrhosis, very often develop ascites, ie, accumulation of fluid in the peritoneal cavity. This is the final event resulting from the hemodynamic disturbances in the systemic and splanchnic circulations that lead to sodium and water retention. When therapy with a low sodium diet fails, the dmg of choice for the treatment of ascites is furosemide, a high ceiling (loop) diuretic, or spironolactone, an aldosterone receptor antagonist/potassium-sparing diuretic. 

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. ... 

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