Spironolactone aldosterone heart failure

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

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... 

Diuretics are the mainstay of heart failure management and are discussed in detail in Chapter 15. They have no direct effect on cardiac contractility their major mechanism of action in heart failure is to reduce venous pressure and ventricular preload. This results in reduction of salt and water retention and edema and its symptoms. The reduction of cardiac size, which leads to improved pump efficiency, is of major importance in systolic failure. Spironolactone and eplerenone, the aldosterone antagonist diuretics (see Chapter 15), have the additional benefit of decreasing morbidity and mortality in patients with severe heart failure who are also receiving ACE inhibitors and other standard therapy. One possible mechanism for this benefit lies in accumulating evidence that aldosterone may also cause myocardial and vascular fibrosis and baroreceptor dysfunction in addition to its renal effects. 

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... 

It has also been suggested that certain diuretics such as spironolactone (Aldactone) might be especially helpful in heart failure.14,42 Spironolactone blocks aldosterone receptors in the kidneys and other tissues, thereby producing a diuretic effect as well as preventing adverse cardiovascular changes associated with excess aldosterone production. Future studies will help clarify whether spironolactone should be used preferentially in heart failure because of its ability to reduce fluid volume and protect against aldosterone-induced damage.53... 

Spironolactone. Plasma aldosterone is elevated in heart failure. Spironolactone acts as a diuretic by competitively blocking the aldosterone-receptor, but in addition it has a powerful effect on outcome in cardiac failure (see below). 

Several mechanisms have been postulated to underlie the benefits of aldosterone receptor antagonists in heart failure (30). Aldosterone-induced cardiac fibrosis may reduce systolic function, impair diastolic function, and promote intracardiac conduction defects, with the potential for serious dysrhythmias. Aldosterone may also increase vulnerability to serious dysrhythmias by other mechanisms. The diuretic and hemodynamic effects of spironolactone in RALES and EPHESUS were subtle, and there were no significant changes in body weight, sodium retention, or systemic blood pressure. 

Although spironolactone has been available for more than 30 years, its efficacy and safety in patients with heart failure have only recently been recognized in the Randomized Aldosterone Evaluation Study (RALES), in which it reduced mortahty (1). Based on this and numerous smaller trials, the use of spironolactone, in conjunction with ACE inhibitors, other diuretics, and possibly beta-blockers or digoxin, represents a promising strategy for patients with severe heart failure. Its main adverse effects are hyperkalemia and antiadrenergic complications (SED-14, 675). 

ALDOSTERONE ANTAGONISTS (e.g. potassium canrenoate and spironolactone) work by blocking the action of the hormone aldosterone (a MINERALOCORTICOId), and this makes them suitable for treating oedema associated with aldosteronism, liver failure and certain heart conditions. 

The addition of aldosterone antagonists can rednce morbidity and mortality in systolic heart failure. Spironolactone has been studied in severe heart failure and has shown benefit in addition to diuretic and ACE inhibitor therapy. Eplerenone, the newest aldosterone antagonist, has been smdied in patients with symptomatic systolic heart failure within 3 to 14 days after an acute myocardial infarction in addition to a standard three-drug regimen. Collectively, both these agents should be considered in the specific heart failure population smdied but only in addition to diuretics, ACE/ARBs, and /8-blockers. 

Aldosterone antagonism with low-dose spironolactone has been shown to reduce mortality in patients with New York Heart Association (NYHA) class III and IV heartfailure and thus should be strongly considered in these patients. Given its low cost and safety profile at the doses studied, it may be reasonable to consider in other patients with symptomatic heart failure, especially those taking potassium supplementation, in whom the aldosterone antagonist might allow dose reduction or discontinuation of the potassium supplement, and should be considered strongly in patients with severe heart failure. 

The benefits of aldosterone antagonists in heart failure appear to be due largely to their neurohormonal inhibition, namely, inhibition of aldosterone s actions in the heart. Specifically, the benefits are believed to be due to the ability of these agents to inhibit aldosterone-mediated cardiac fibrosis and thus ventricular remodeling. And while spironolactone historically has been viewed as a diuretic, this is believed to contribute little to its benefits in heart failure in part because the doses used have minimal diuretic effect. Thus, as with ACE inhibitors and /S-blockers, the data on aldosterone antagonists also support the neurohormonal model of heart failure. 

Apart from the valuable benefit of aldosterone antagonism in hypertension, MR blockade has been shown to substantially reduce both morbidity and mortality among patients with severe chronic heart failure (CHF) and post-myocardial infarction (MI) in clinical trials [17, 18]. The Randomized Aldactone Evaluation Study (RALES) has shown that 26 mg spironolactone on average per day on top of existing standard therapy [i.e. an angiotensin-converting enzyme (ACE) inhibitor, aspirin and a loop diuretic] given to patients with severe heart failure (New York Heart Association class III or IV, left ventricular ejection fraction <35%) results in 30%... 

Overall, clinical trials have impressively demonstrated that aldosterone is a major contributor to cardiovascular morbidity and mortality in patients with arterial hypertension and heart failure. However, the currently available MR antagonists suffer from two substantial drawbacks that limit their benefit in clinical practice, i.e. lack of selectivity (in the case of spironolactone) and limited efficacy (in the case of eplerenone). Consequently a second race for new aldosterone antagonists has started, in search of a compound which ideally should combine the potency and efficacy of spironolactone with the selectivity of eplerenone. 

As with other K+-sparing diuretics, spironolactone often is coadministered with thiazide or loop diuretics in the treatment of edema and hypertension. Such combinations result in increased mobilization of edema fluid while causing lesser perturbations of K+ homeostasis. Spironolactone is particularly useful in the treatment of primary hyperaldosteronism (adrenal adenomas or bilateral adrenal hyperplasia) and of refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, and severe ascites). Spironolactone is considered the diuretic of choice in patients with hepatic cirrhosis. Added to standard therapy, spironolactone substantially reduces morbidity and mortality and ventricular arrhythmias in patients with heart failure. 

M i neralocorticoid receptor MR NR3C2 Aldosterone deoxycorticosterone Spironolactone (Aldactone), eplerenone (Inspra) Hypertension, heart failure... 

Studies also have shown direct effects of aldosterone on the heart and vascular lining aldosterone induces hypertension and interstitial cardiac fibrosis in animal models. The increased cardiac fibrosis is proposed to result from direct mineralocorticoid actions in the heart rather than from the effect of hypertension, because treatment with spironolactone, a MR antagonist, blocks the fibrosis without altering blood pressure. Similar effects of mineralocorticoids on cardiac fibrosis in human beings may explain, at least in part, the beneficial effects of spironolactone in patients with congestive heart failure (see Chapter 33). 

Spironolactone is an antagonist to aldosterone —the latter when elaborated in the body in excessive amounts gives rise to a syndrome called aldosteronism. Spironolactone, a synthetically produced steroid does not have a natural counterpart in the body, is diuretic when mercurial or thiazide diuretics are ineffective it prevents sodium retention and potassium excretion— effects opposite to aldosterone. Hence spironolactone is used in aldosteronism, against edema, in the treatment of congestive heart failure and in other conditions in which an accumulation of water, and water-retaining salt, is to be corrected. 

Aldosteronism (eg, the elevated serum aldosterone levels that occur in cirrhosis) is an important indication for spironolactone. Aldosteronism is also a feature of heart failure, and spironolactone has been shown to have significant long-term benefits in this condition (Chapter 13). Some of this effect may occur in the heart, an action that is not yet understood. 

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