Aldosterone receptor antagonists eplerenone

Spironolactone is poorly absorbed after oral administration and has a delayed onset of action it may take several days until a peak effect is produced. It has a somewhat slower onset of action than triamterene and amiloride (discussed later), but its natriuretic effect is modestly more pronounced, especially during long-term therapy. Spironolactone is rapidly and extensively metabolized, largely to the active metabohte canrenone. Canrenone and potassium canrenoate, its K+ salt, are available for clinical use in some countries outside the United States. Canrenone has a half-life of approximately 10 to 35 hours. The metabolites of spironolactone are excreted in both the urine and feces. New selective aldosterone receptor antagonists (SARA), such as eplerenone, have been developed but have not yet been introduced into clinical practice. Eplerenone and canrenone exhibit fewer steroidlike side effects (gynecomastia, hirsutism). 

When ascites and edema become severe, diuretic therapy can be very useful. However, cirrhotic patients are often resistant to loop diuretics because of decreased secretion of the drug into the tubular fluid and because of high aldosterone levels. In contrast, cirrhotic edema is unusually responsive to spironolactone and eplerenone. The combination of loop diuretics and an aldosterone receptor antagonist may be useful in some patients. 

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. 

Weinberger MH. Eplerenone a new selective aldosterone receptor antagonist. Drugs Today. 2004 40 481-485. 

Although troublesome, these adverse effects are reversible and dose-related. The advent of selective aldosterone receptor antagonists, such as eplerenone, should reduce these adverse effects and thereby improve patient compliance. In EPHESUS there was no increase in the incidence of gynecomastia, breast pain, or impotence in men or menstrual irregularities in women who took eplerenone. 

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

Barnes, B.J. and Howard, P.A. (2005) Eplerenone a selective aldosterone receptor antagonist for patients with heart failure. Ann Pharmacother, 39, 68-76. 

Eplerenone is a selective aldosterone receptor antagonist that binds to the mineralocorticoid receptor (MR), blocking the binding of aldosterone. It is indicated in the treatment... 

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. 

The mineralocorticoid antagonists used clinically include spironolactone (Aldactone) and eplerenone (Inspra). These drugs are competitive antagonists of the aldosterone receptor that is, they bind to the receptor but do not activate it. When bound to the... 

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. 

Angiotensin II receptor antagonists 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, triamterene, spironolactone and eplerenone, leading to hyperkalaemia, but usually only if other risk factors are present. 

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... 

Eplerenone, a selective MR modulator, was discovered decades ago and has recently received approval as a treatment for hypertension [77]. This synthetic steroid derivative has a higher specificity for MR relative to other nuclear receptors and works as a partial antagonist of aldosterone [78]. 

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