Eplerenone

Abstract

Abstract-Data from animal studies and clinical trials indicate that aldosterone causes cardiovascular and renal injury through mineralocorticoid receptor-dependent mechanisms. However, although aldosterone receptor antagonism reduces mortality in patients with congestive heart failure, the progestational and antiandrogenic side effects of the nonspecific aldosterone receptor antagonist, spironolactone, have limited its usefulness in the treatment of hypertension. This review provides an overview of the pharmacology, efficacy, and safety of a new, more selective aldosterone receptor antagonist, eplerenone, in the context of emerging concepts of the role of aldosterone in cardiovascular toxicity. Key Words: aldosterone Ⅲ receptors Ⅲ cardiovascular disease Ⅲ hypertension Ⅲ pharmacology T he renin-angiotensin-aldosterone system (RAAS) plays an integral role in cardiovascular homeostasis through its effects on vascular tone and volume. Activation of the RAAS is associated with an increased risk of ischemic cardiovascular events, independent of effects on blood pressure, 1 whereas interruption of the RAAS by angiotensin-converting enzyme (ACE) inhibition or angiotensin type 1 receptor (AT 1 R) blockade reduces cardiovascular mortality 2,3 and slows the progression of renal disease. 4,5 Drugs that interrupt the RAAS reduce the risk of cardiovascular events, preventing the effects of angiotensin (Ang) II on cellular growth and proliferation, 6 on vascular superoxide radical formation, 7 and on thrombotic pathways. 8 Ang II also stimulates the synthesis of the mineralocorticoid aldosterone, and emerging data indicate that aldosterone plays an independent role in vascular toxicity and fibrosis. For example, molecular studies suggest that aldosterone may be produced locally in vascular tissue. 9 Aldosterone causes myocardial and aortic fibrosis and nephrosclerosis in animal models, whereas aldosterone receptor antagonism reverses these processes. 10 -15 In humans, elevated plasma aldosterone concentrations are associated with endothelial dysfunction, myocardial infarction, left ventricular hypertrophy, and death. 16 -18 Although ACE inhibition and AT 1 receptor antagonism initially reduce aldosterone concentrations, circulating concentrations of this hormone return to baseline levels with chronic therapy. 19,20 Coadministration of the aldosterone receptor antagonist, spironolactone, enhances the beneficial effect of ACE inhibition on mortality in patients with congestive heart failure. 21 However, although administration of spironolactone reduces mortality in patients with congestive heart failure, the progestational and antiandrogenic side effects of this nonspecific aldosterone receptor antagonist have limited its usefulness in the treatment of hypertension predominantly to the treatment of patients with primary hyperaldosteronism. The Food and Drug Administration (FDA) has approved a new, more selective aldosterone receptor antagonist, eplerenone, for the treatment of hypertension. This review provides an overview of...

Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis

“…Such pharmacologic changes in the elderly can generally be inferred as being due to decreases in conventional physiologic variables such as liver volume and/or intrinsic enzyme capacity. At steady-state, the C max and AUC for eplerenone are decreased by 19 and 26%, respectively in black compared with white patients [22]. In patients with various stages of renal insufficiency, the greatest increase in C max and AUC for eplerenone was 24 and 38%, respectively.…”

“…In elderly volunteers (aged ≥ 65-yrs), receiving eplerenone 100-mg once daily, C max and the area-under-the-curve (AUC) for eplerenone are increased by 22 and 45%, respectively, compared with healthy volunteers aged 18 to 45-yrs [22,23]. Such pharmacologic changes in the elderly can generally be inferred as being due to decreases in conventional physiologic variables such as liver volume and/or intrinsic enzyme capacity.…”

The Promise of Mineralocorticoid Antagonism in Acute Kidney Injury

“…Indeed, high doses of SP increases the risk of renal side effects (hyperkalemia and renal dysfunction) and also of its anti-progesterone and anti-androgen-dependent side effects (due to lack of selectivity toward other members of the oxosteroid family) [15]. Using eplerenone, a more selective MR antagonist, may confer less side effects, but may not be as effective since it is only 50-70% as potent as SP [16]. Moreover, MR antagonists increase aldosterone levels, which may exert nongenomic effects, as well as compete with the antagonist for binding to the MR and potentially decrease their utility.…”

Pulmonary and Cardiorenal Cyclooxygenase-1 (COX-1), -2 (COX-2), and Microsomal Prostaglandin E Synthase-1 (mPGES-1) and -2 (mPGES-2) Expression in a Hypertension Model

“…The renin-angiotensin-aldosterone system (RAAS) plays an important role in the control of cardiovascular and renal homeostasis by regulating vascular tone, blood pressure (BP), and fluid volume [1, 2]. Angiotensin II (Ang II) is a physiologically active component of the RAAS, produced via an enzymatic cascade that begins with angiotensinogen (AGT) cleaving renin (REN) to form angiotensin I (Ang I), which is then cleaved by the angiotensin converting enzyme (ACE) to form Ang II [3].…”