Heart failure aldosterone antagonists

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. 

Antihypertensive drug name and dose is associated with compelling indications which are based on benefits from outcome studies or clinical guidelines. For example, the drug class aldosterone antagonists have eplerenone dosed at 25-50 mg per day which is indicated for heart failure patients after an Ml and supported by the EPHESUS trial. 

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... 

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... 

Potassium-sparing diuretics are useful both to avoid excessive potassium depletion and to enhance the natriuretic effects of other diuretics. Aldosterone receptor antagonists in particular also have a favorable effect on cardiac function in people with heart failure. 

Neurohumoral (extrinsic) compensation involves two major mechanisms (previously presented in Figure 6-7)—the sympathetic nervous system and the renin-angiotensin-aldosterone hormonal response—plus several others. Some of the pathologic as well as beneficial features of these compensatory responses are illustrated in Figure 13-2. The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure. As a result, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures sympathetic outflow is increased, and parasympathetic outflow is decreased. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone. Vascular tone is further increased by angiotensin II and endothelin, a potent vasoconstrictor released by vascular endothelial cells. The result is a vicious cycle that is characteristic of heart failure (Figure 13-3). Vasoconstriction increases afterload, which further reduces ejection fraction and cardiac output. Neurohumoral antagonists and vasodilators... 

Paradoxically, these agents—not positive inotropic drugs—are the first-line therapies for chronic heart failure. The drugs most commonly used are diuretics, ACE inhibitors, angiotensin receptor antagonists, aldosterone antagonists, and blockers (Table 13-1). In acute failure,... 

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. 

Khan NU, Movahed A. The role of aldosterone and aldosterone-receptor antagonists in heart failure. Rev Cardiovasc Med. 2004 5 71-81. 

Soon after the discovery of aldosterone, it became apparent that its excessive production played an important role in the physiopathology of a variety of disorders, such as Cohn s syndrome, congestive heart failure, and nephritic syndrome [3]. It therefore seemed valuable to develop compounds with aldosterone-antagonist properties. This approach had its beginning in the work of Landau et al [4],... 

The results of SPICE (The Study of Patients Intolerant of Converting Enzyme Inhibitors) and of the previously published RESOLVD led to the design of the current CHARM trial, which is investigating the effect of candesartan in 6600 patients with heart failure in three different ways versus an ACE inhibitor in patients with preserved left ventricular function versus placebo in patients intolerant of ACE inhibitors and in addition to ACE inhibitors in all other patients. While waiting for the results of this trial it is advisable to continue to use ACE inhibitors as the initial therapy for heart failure. In patients with documented intolerance of ACE inhibitors (which may represent 10-20% of patients with heart failure) angiotensin receptor antagonists may be useful as a substitute to block the renin-angiotensin-aldosterone system. 

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. 

Moore TD, Nawarskas JJ, Anderson JR. Epierenone a selective aldosterone receptor antagonist for hypertension and heart failure. Heart Dis 2003 5(5) 354-63. 

Pitt B, Roniker B. Epierenone a novel selective aldosterone receptor antagonist (SARA) dose finding study in patients with heart failure. J Am CoU Cardiol 1999 33(Suppl A) A188-9. 

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. 

Angiotensin antagonists (Angiotensin-converting enzyme inhibitors) and ACE inhibitors lower blood pressure and are used to treat heart failure by causing the excretion of sodium and water. ACE inhibitors block the release of aldosterone. Aldosterone causes the retention of sodium. Cardiac output and heart rate remain unchanged. ACE inhibitors are administered to patients with elevated serum rennin levels. ACE inhibitors can cause angioedema in which the mouth, throat, lips, eyelids, hands, and feet swell. 

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. 

Some clinicians advocate the use of aldosterone antagonists in essentially all patients with symptomatic heart failure or post-MI left ventricular dysfunction. Others believe that they should be reserved for those who remain symptomatic with NYHA class lllb or IV heart failure. 

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