Aldosterone diuretics

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. 

Mineralocorticoids. Aldosterone [6251-69-0] (32), the most potent natural rnineralocorticoid, also possesses a A -3-one group, an oxygen substituent at Clip, and a C17P-2-hydroxyethan-l-one side chain. In addition, the C18 of aldosterone is oxidized to an aldehyde. Mineralocorticoids, particularly aldosterone, act to retain sodium and to prevent the retention of excess potassium. Antimineral ocorticoids have been used therapeutically as diuretics and as agents that regulate blood pressure (63—65). 

Glonidine. Clonidine decreases blood pressure, heart rate, cardiac output, stroke volume, and total peripheral resistance. It activates central a2 adrenoceptors ia the brainstem vasomotor center and produces a prolonged hypotensive response. Clonidine, most efficaciously used concomitantly with a diuretic in long-term treatment, decreases renin and aldosterone secretion. 

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). 

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. 

It was known for some time that even after the corticoids had been separated from crude extracts of the adrenal cortex, the remaining material, the so-called "amorphous fraction" still possessed considerable mineralocorticoid activity. Aldosterone (250), one of the last steroids to be isolated from this fraction, proved to be the active principle. This compound proved to be an extremely potent agent for the retention of salt, and thus water, in body fluids. An antagonist would be expected to act as a diuretic in those edematous states caused by excess sodium retention. Although aldosterone has been prepared by both total and partial synthesis, the complexity of the molecule discouraged attempts to prepare antagonists based directly on the parent compound. 

ACE inhibitors are approved for the treatment of hypertension and cardiac failure [5]. For cardiac failure, many studies have demonstrated increased survival rates independently of the initial degree of failure. They effectively decrease work load of the heart as well as cardiac hypertrophy and relieve the patients symptoms. In contrast to previous assumptions, ACE inhibitors do not inhibit aldosterone production on a long-term scale sufficiently. Correspondingly, additional inhibition of aldosterone effects significantly reduces cardiac failure and increases survival even further in patients already receiving diuretics and ACE inhibitors. This can be achieved by coadministration of spironolactone, which inhibits binding of aldosterone to its receptor. 

Hyperaldosteronism is a syndrome caused by excessive secretion of aldosterone. It is characterized by renal loss of potassium. Sodium reabsorption in the kidney is increased and accompanied by an increase in extracellular fluid. Clinically, an increased blood pressure (hypertension) is observed. Primary hyperaldosteronism is caused by aldosterone-producing, benign adrenal tumors (Conn s syndrome). Secondary hyperaldosteronism is caused by activation of the renin-angiotensin-aldosterone system. Various dtugs, in particular diuretics, cause or exaggerate secondary peadosteronism. 

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. 

Patients with asymptomatic left ventricular systolic dysfunction and hypertension should be treated with P-blockers and ACE inhibitors. Those with heart failure secondary to left ventricular dysfunction and hypertension should be treated with drugs proven to also reduce the morbidity and mortality of heart failure, including P-blockers, ACE inhibitors, ARBs, aldosterone antagonists, and diuretics for symptom control as well as antihypertensive effect. In African-Americans with heart failure and left ventricular systolic dysfunction, combination therapy with nitrates and hydralazine not only affords a morbidity and mortality benefit, but may also be useful as antihypertensive therapy if needed.66 The dihydropyridine calcium channel blockers amlodipine or felodipine may also be used in patients with heart failure and left ventricular systolic dysfunction for uncontrolled blood pressure, although they have no effect on heart failure morbidity and mortality in these patients.49 For patients with heart failure and preserved ejection fraction, antihypertensive therapies that should be considered include P-blockers, ACE inhibitors, ARBs, calcium channel blockers (including nondihydropyridine agents), diuretics, and others as needed to control blood pressure.2,49... 

Diuretics are often required in addition to the sodium restriction described previously. Spironolactone and jurosemide form the basis of pharmacologic therapy for ascites. Spironolactone is an aldosterone antagonist and counteracts the effects of activation of the renin-angiotensin-aldosterone system. In hepatic disease not only is aldosterone production increased, but its half-life is prolonged because it is hepatically metabolized. Spironolactone acts to conserve the potassium that would be otherwise excreted because of elevated aldosterone levels. 

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are members of a family of so-called natriuretic peptides, synthesized predominantly in the cardiac atrium, ventricle, and vascular endothelial cells, respectively (G13, Y2). ANP is a 28-amino-acid polypeptide hormone released into the circulation in response to atrial stretch (L3). ANP acts (Fig. 8) on the kidney to increase sodium excretion and glomerular filtration rate (GFR), to antagonize renal vasoconstriction, and to inhibit renin secretion (Ml). In the cardiovascular system, ANP antagonizes vasoconstriction and shifts fluid from the intravascular to the interstitial compartment (G14). In the adrenal cortex, ANP is a powerful inhibitor of aldosterone synthesis (E6, N3). At the hypothalamic level, ANP inhibits vasopressin secretion (S3). It has been shown that some of the effects of ANP are mediated via a newly discovered hormone, called adreno-medullin, controlling fluid and electrolyte homeostasis (S8). The diuretic and blood pressure-lowering effect of ANP may be partially due to adrenomedullin (V5). 

Angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors not only cause vasodilation (1 TPR), but also inhibit the aldosterone response to net sodium loss. Normally, aldosterone, which enhances reabsorption of sodium in the kidney, would oppose diuretic-induced sodium loss. Therefore, coadministration of ACE inhibitors would enhance the efficacy of diuretic drugs. 

Potassium-sparing diuretics are often coadministered with thiazide or loop diuretics in the treatment of edema and hypertension. In this way, edema fluid is lost to the urine while K+ ion balance is better maintained. The aldosterone antagonists are particularly useful in the treatment of primary hyperaldosteronism. 

The answer is e. (Hardman, p 708.) Spironolactone is a competitive antagonist of aldosterone that blocks the reabsorption of Na and water from the collecting duct in exchange for K and hydrogen ion retention. Therefore, in the presence of hyperkalemia, spironolactone is contraindicated The administration of each of the other diuretic agents listed results in increased excretion of K. 

The answer is c. (Hardmanr pp 706-708.) Spironolactone is an aldosterone antagonist that acts on the mineralocorticoid receptor It is a Kksparing diuretic. It can also function as an androgen antagonist, which could explain the gynecomastia and erectile dysfunction. Women with hirsutism are sometimes treated with spironolactone. 

Spironolactone and eplerenone block the mineralocorticoid receptor, the target site for aldosterone. In the kidney, aldosterone antagonists inhibit sodium reabsorption and potassium excretion. However, diuretic effects are minimal, suggesting that their therapeutic benefits result from other... 

Aldosterone antagonists (spironolactone, eplerenone) are also potassium-sparing diuretics but are more potent antihypertensives with a slow onset of action (up to 6 weeks with spironolactone). 

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