Spironolactone aldosterone hypertension

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. 

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. 

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... 

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... 

The aldosterone antagonist, spironolactone> has been successfully used for the treatment of hypertension. Its natriuretic effect is associated with potassium retention. Specificity of spironolactone in certain types of hypertension had been suggested, but subsequently denied in well controlled studies(15,16). 

Patients with CHF and a normal ejection fraction are considered to have diastolic dysfunction. The frequency of CHF with diastolic dysfunction increases with age. Such patients benefit from treatment of the underlying cause such as hypertension or ischaemia. Inotropic agents such as digoxin should be avoided. Diuretics, -blockers, ACE inhibitors can be used. Aldosterone inhibition, using spironolactone or epleronone, may be beneficial. Carvedilol improves diastolic dysfunction in diastolic CHF. However the long-term benefit of different drug therapies has not yet been defined. 

Spironolactone Block aldosterone receptor in renal collecting tubule Increase Na and decrease excretion poorly understood reduction in heart failure mortality Aldosteronism, heart failure, hypertension ... 

Spironolactone Block cytoplasmic aldosterone receptors in collecting tubules of nephron possible membrane effect Increased salt and water excretion reduces remodeling reduces mortality Chronic heart failure aldosteronism (cirrhosis, adrenal tumor) hypertension Oral duration 24-72 h (slow onset and offset) Toxicity Hyperkalemia, antiandrogen actions... 

Eplerenone, another aldosterone antagonist, is approved for the treatment of hypertension (see Chapters 11 and 15). This aldosterone receptor antagonist is somewhat more selective than spironolactone and has no reported effects on androgen receptors. The standard dosage in hypertension is 50-100 mg/d. The most common toxicity is hyperkalemia but this is usually mild. 

Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone. Its onset and duration of 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. Eplerenone, a new spironolactone analog with greater selectivity for the aldosterone receptor, has recently been approved for the treatment of hypertension. 

Spironolactone reportedly has hypotensive activity when given to hypertensive patients, by blocking the effect of aldosterone on arteriolar smooth muscle by altering the extracellular-intracellular sodium gradient. 

Spironolactone (Aldactone) is structurally similar to aldosterone and competitively inhibits its action in the distal tubule (exchange of potassium for sodium) excessive secretion of aldosterone contributes to fluid retention in hepatic cirrhosis, nephrotic syndrome and congestive cardiac failure (see specific use in chapter 24), in which conditions as well as in primary h)q)ersecretion (Conn s syndrome) spironolactone is most useful. Spironolactone is also useful in the treatment of resistant hypertension, where increased aldosterone sensitivity is increasingly recognised as a contributory factor. 

General. Noteworthy reports- and reviews pertaining to the pharma-cologicalj endocrinological > and clinical aspects of diuretics have appeared in the recent literature. The use of diuretics in the treatment of hypertension has been reviewed with especial emphasis on the hypotensive action of the aldosterone antagonist, spironolactone.° Fundamental studies on the mechanism of transport of electrolyte across the tubular epithelium have indicated that phospholipids may play a critical role. Phospholipase C and pancreatic lipase markedly reduced the rate of reabsorption of saline droplets infused into rat proximal tubules. Likewise, phospholipase C reduced the ability of extractable lipids to bind sodium and potassium ions in rat kidney homogenates whereas, phospholipase D and ribonuclease appear to enhance cation binding. ... 

Spironolactone has been used for its competitive antagonism of aldosterone in the treatment of Cushing s syndrome. Spironolactone can provide symptomatic relief of the hypertension and hypokalemia often seen in Cushing s syndrome. 

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