Aldosterone antagonist eplerenone

The aldosterone antagonist eplerenone reduces CV morbidity and mortality in patients soon after an acute MI (within 3 to 14 days) in patients with... 

DIGOXIN POTASSIUM-SPARING DIURETICS AND ALDOSTERONE ANTAGONISTS Eplerenone and spironolactone may T plasma concentrations of digoxin Uncertain spironolactone possibly L the volume of distribution of digoxin Monitor digoxin levels watch for digoxin toxicity... 

Li JS, Flynn JT, Portman R, Davis I, Ogawa M, Shi H, Pressler ML. The efficacy and safety of the novel aldosterone antagonist eplerenone in children with hypertension a randomized, double-blind, dose-response study. J Pediatr 2010 157(2) 282-7. 

The intramolecular version of hydroesterification was used for the synthesis of steroidal 17-spirolactones such as the aldosterone antagonist eplerenone starting from 17-hydroxy-17-vinyl or 17-hydroxy-17-ethynyl derivatives [46]. 

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. 

In patients without contraindications, spironolactone is initiated at a dose of 12.5 to 25 mg daily, or occasionally on alternate days for patients with baseline renal insufficiency. Eplerenone is used at a dose of 25 mg daily, with the option to titrate up to 50 mg daily. Doses should be halved or switched to alternate-day dosing if creatinine clearance falls below 50 mL/minute. Potassium supplementation is often decreased or stopped after aldosterone antagonists are initiated, and patients should be counseled to avoid high-potassium foods. At anytime after initiation of therapy, if potassium concentrations exceed... 

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... 

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). 

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. 

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. 

KETOCONAZOLE DIURETICS-POTASSIUMSPARING DIURETICS AND ALDOSTERONE ANTAGONISTS t eplerenone levels Inhibition of metabolism Avoid co-administration... 

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. 

More recently, the EPHESUS trial evaluated the effect of an aldosterone-selective receptor antagonist eplerenone in patients with... 

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. 

Drugs such as spironolactone and eplerenone competitively inhibit the binding of aldosterone to the MR. Unlike the MR-aldosterone complex, the MR-spironolactone complex is not able to induce the synthesis of MPs. Because spironolactone and eplerenone block the biological effects of aldosterone, these agents also are referred to as aldosterone antagonists. MR antagonists are the only diuretics that do not require access to the tubular lumen to induce diuresis. 

ACE inhibitors reduce the levels of aldosterone, which results in the retention of potassium. This would be expected to be additive with the potassium-retaining effects of amiloride and triamterene and aldosterone antagonists such as spironolactone and eplerenone, leading to hyperkalaemia, but usually only if other risk factors are present (see Importance and management below). 

Eplerenone, a selective aldosterone antagonist similar to spironolactone, is metabolised by the cytochrome P450 isoenzyme CYP3A4 and is therefore affected by other drugs that are inhibitors or inducers of this enzyme. 

Chatterjee S, Moeller C, Shah N, Bolorunduro O, lichstein E, Moskovits N, et al. Eplerenone is not superior to older and less expensive aldosterone antagonists. Am J Med 2012 125(8) 817-25. 

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