Aldosterone inhibitors

Aldosterone inhibitors (antihormone diuretics) are agents which particularly compete with aldosterone at the specific receptor site located in the distal tubule, thereby reversing the electrolyte 

17-Hydroxy-7a-mercapto-3-oxo-17a-pregn-4-ene-21-carboxylic acid, y-lactone acetate Pregn- 

4-ene-21-carboxylic acid, 7-(acetylthio)-17-hydroxy-3-oxo-y-lactone, (7a, 17a)- 7a-Acetylthio- 

It acts both as a diuretic and as an antihypertensive drug. It is mostly employed in the treatment of refractory oedema associated with congestive heart failure, nephrotic syndrome or cirrhosis of the liver in which secretion of aldosterone plays a part. It has also been used successfully in the treatment of primary hyper aldosteronism. 

Dose Usual, initial, 100 mg per day in divided doses in hyperaldosteronism 400 mg per day. B. Metyrapone INN, BAN, USAN, 

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At Cynthia s pharmacy, patients with heart disease are usually on several medications for their heart disease a diuretic, a beta blocker, and an angiotensin-converting enzyme (ACE) inhibitor. Patients with more severe disease may also be on an aldosterone inhibitor such as spironolactone, digoxin, hydralazine nitrate, and/or an angiotensin-receptor blocker (ARB). Some patients are... 

Epoxides - The first indication of the synthetic utility of metalated carboxylic acids resulted from efforts to prepare steroidal aldosterone inhibitors from spiroepoxides.39 Model studies indicated that the reaction fails as a result of severe steric hindrance in either the epoxide or carboxylic acid and that monosubstitution occurs for the same reason.39 The reaction has been used in a key step of an elegant synthesis of vernolepin, 5. 40 Forcing conditions are required, and, in contrast to acid dianions, anions of unactivated esters fail to react with epoxides.39 41... 

Aldosterone inhibitors Eplerenone, Potassium canrenoate. Spironolactone... 

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. 

Renin-Angiotensin-Aldosterone System ACE Inhibitors Nuclear Factor-icB... 

Aminooglutethimide was the fust aromatase inhibitor to be used in patients with metastatic breast cancer, where response rates of up to 30% have been reported. Unfortunately, due to its lack of selectivity for aromatase, it induced a medical adrenelectomy that resulted in suppression of aldosterone and cortisol. With the development of more selective aromatase... 

Renin-Angiotensin-Aldosterone System Epithelial Na+ Channels ACE Inhibitors... 

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. 

ACE-I, angiotensin-converting enzyme inhibitor Aid Ant, aldosterone antagonist ARB, angiotensin receptor blocker BB, beta-blocker CCBA, calcium channel blocking agent DirVaso, direct vasodilator. 

P-Blockers and ACE inhibitors are also indicated for post-myocardial infarction for the reduction of cardiovascular morbidity and mortality, as are aldosterone antagonists, in post-myocardial infarction patients with reduced left ventricular systolic function and diabetes or signs and symptoms of heart failure.2,48... 

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... 

Develop a medication regimen to slow the progression of HF with the use of neurohormonal blockers such as vasodilators (ACE inhibitors, ARBs, or hydralazine/ isosorbide dinitrate), P-blockers, and aldosterone antagonists. Utilize digoxin if the patient remains symptomatic despite optimization of the above therapies. 

To reduce mortality, administration of an aldosterone antagonist, either eplerenone or spironolactone, should be considered within the first 2 weeks following MI in all patients who are already receiving an ACE inhibitor (or ARB) and have an EF of equal to or less than 40% and either heart failure symptoms or diagnosis of diabetes mellitus.3 Aldosterone plays an important role in heart failure and in MI because it promotes vascular and myocardial fibrosis, endothelial dysfunction, hypertension, left ventricular hypertrophy, sodium retention, potassium and magnesium loss, and arrhythmias. Aldosterone antagonists have been shown in experimental and human studies to attenuate these adverse effects.70 Spironolactone decreases all-cause mortality in patients with stable, severe heart failure.71... 

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. 

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