The aldosterone antagonist and facultative diuretic eplerenone: a critical review

Eplerenone is a new aldosterone-receptor blocker that differs from spironolactone by virtue of higher selectivity for the aldosterone receptor. Therefore, eplerenone treatment is associated with comparative and absolute low incidences of gynecomastia, mastodynia, and abnormal vaginal bleeding. Similarly, a lower incidence of sexual impotence than that associated with spironolactone administration may be anticipated. Eplerenone and spironolactone increase natriuresis and cause renal retention of potassium when plasma aldosterone is high, i.e., both agents are facultative diuretics. Eplerenone reduces high blood pressure effectively. The results of a recent large study and an ensuing meta-analysis on antihypertensive treatment suggest that a diuretic should be the first-choice agent in most circumstances. Low-dose eplerenone combinations with a low-dose thiazide-type diuretic appear to be options worth investigating, since the overall cardiovascular benefit brought about by reducing blood pressure with the thiazide would be increased, inter alia, by the antikaliuretic action and by the blockade of extrarenal aldosterone receptors provoked by eplerenone. Eplerenone should replace spironolactone as a natriuretic and antikaliuretic in heart failure and as add-on treatment in severe systolic cardiac insufficiency, and it is indicated after an acute myocardial infarction complicated by left ventricular dysfunction and heart failure. The finding that hypertension control with diuretic-based pharmacotherapy results in better prevention of heart failure than pressure reduction with other drugs makes it pertinent to investigate whether diuretics in general, and eplerenone in particular, should constitute part of the initial pharmacotherapy for heart failure when there is no overt fluid retention and independent of the etiology. Eplerenone may cause hyperkalemia, and it might favor the development of metabolic acidosis or hyponatraemia in some circumstances.     

Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure

Aldosterone has been implicated for many years as an important substance in the pathogenesis of heart disease. Elevated aldosterone concentrations have been documented in patients with hypertension and heart failure, leading to the use of aldosterone antagonists for the treatment of these conditions. Spironolactone has been used for nearly 2 decades for the treatment of hypertension, and more recently, has become a standard agent for the treatment of systolic heart failure. Spironolactone, however, is a nonselective antagonist of the aldosterone receptor, binding also to other steroid receptors and causing a significant percentage of patients to have sex hormone-related adverse effects such as gynecomastia. Eplerenone is the first of a new class of drugs known as selective aldosterone receptor antagonists, which selectively block the aldosterone receptor with minimal effect at other steroid receptors, thereby minimizing many of the hormonal side effects seen with spironolactone. Eplerenone has been shown to be beneficial both as monotherapy and combination therapy for lowering elevated blood pressure in patients with hypertension. The antihypertensive efficacy of eplerenone is roughly similar to that of other antihypertensive agents, although in 1 study black patients responded better with eplerenone than losartan. In addition, eplerenone has demonstrated some renoprotective effects in diabetic patients with hypertension. Recently, eplerenone was shown to significantly reduce mortality and cardiovascular morbidity in post-myocardial infarction patients with systolic heart failure currently taking standard heart failure medications. Eplerenone is generally well tolerated, although hyperkalemia with this agent is of some concern. Eplerenone is metabolized by CYP3A4 and administration with potent inhibitors of this enzyme is contraindicated because of the risk of hyperkalemia. In summary, eplerenone has proven to be beneficial in treating hypertension and post-myocardial infarction heart failure. Its exact place in therapy will in large part be determined by its cost and whether or not future studies will be able to demonstrate a clinical benefit of this agent over spironolactone or other currently available treatments.     

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

Spironolacotone and eplerenone are mineralocorticoid-blocking agents used for their ability to block both the epithelial and non-epithelial actions of aldosterone. Spironolactone is a non-selective mineralocorticoid receptor antagonist with moderate affinity for both progesterone and androgen receptors. The latter property increases the likelihood of endocrine side effects with spironolactone including loss of libido, menstrual irregularities, gynecomastia and impotence. Eplerenone is a next generation aldosterone receptor antagonist selective for aldosterone receptors alone. This lesser affinity for progesterone and androgen receptors was arrived at by replacing the 17- -thioacetyl group of spironolactone with a carbomethoxy group. Eplerenone is further distinguished from spironolactone by its shorter half-life and the fact that it does not have any active metabolites. Both eplerenone and spironolactone are effective antihypertensive agents and each has been shown to improve the morbidity and mortality of heart failure. Eplerenone or spironolactone use can increase serum potassium values and occasionally results in clinically relevant hyperkalemia. This is more apt to occur with spironolactone due to the very long half-life of several of its active metabolites.     

Aldosterone and magnesium

Magnesium ion (Mg) directly inhibits aldosterone production in rat adrenal glomerulosa cells, while potassium ion directly stimulates aldosterone production. It is reported that Mg shows antihypertensive effect in patients with essential hypertension. Secondary hyperaldosteronism induced by diuretic treatment in patients with congestive heart failure accelerates potassium and magnesium ions' excretion in urine. Diuretic-induced falls in potassium and magnesium ions and aldosterone-induced cardiac fibrosis and remodelling are associated with fatal ventricular arrhythmia. Aldosterone antagonists, such as spironolactone and eplerenone, correct not only potassium deficiency but also magnesium deficiency induced by diuretics. Mg supplementation also may be useful procedure to correct potassium and magnesium deficiency, because Mg itself inhibits aldosterone release from the adrenal glands.     

Aldosterone and aldosterone antagonism in systemic hypertension

Aldosterone mediates both water and electrolyte balance by acting on the renal mineralocorticoid receptors. Recent experimental studies have also documented the presence of these receptors in other body organs, including the brain, blood vessels, and heart, suggesting that aldosterone plays a larger role in normal physiologic function and in cardiovascular diseases such as systemic hypertension and congestive heart failure (CHF). The nonspecific aldosterone inhibitor spironolactone, and the selective aldosterone inhibitor eplerenone, are both approved for clinical use in treating patients with hypertension and/or symptomatic CHF. Studies have shown that spironolactone lowers blood pressure, improves endothelial function, reduces myocardial hypertrophy and fibrosis, and lowers the incidence of fatal arrhythmias. Eplerenone, which is more specific for the mineralocorticoid receptor, appears to provide all the beneficial effects of spironolactone in hypertensive patients, with the potential to modify many of the side effects related to nonspecific steroidreceptor blockade. Hyperkalemia remains a potential problem with all aldosterone antagonists.     

The meaning of hypokalemia in heart failure

Maintenance of normal potassium (K(+)) homeostasis has become an increasingly important limiting factor in the therapy of heart failure (HF). With the application of loop diuretics and digoxin, hypokalemia has become a frequent and feared side effect of treatment. Low serum K(+) in HF may be also a marker of increased neurohormonal activity and disease progression. To gain the maximum benefit from treatment, we need to individualize drug use and carefully monitor electrolytes. Symptomatic HF patients (New York Heart Association class III-IV) should be prescribed the lowest dose of diuretic necessary to maintain euvolemia. Mild hypokalemia may be corrected by the use of aldosterone receptor antagonists such as spironolactone or eplerenone. However, a more severe hypokalemia should preferably be corrected using K(+) supplement. Serum K levels should be frequently checked and maintained between 4.0 and 5.5 mEq/l (mmol/l).     

Value of aldosterone receptor blockade in diuretic therapy of patients with chronic heart failure

PATHOGENESIS: All forms of chronic heart failure (high-output and low-output failure) are accompanied by an "arterial underfilling" inducing the activation of various neurohumoral systems (renin-angiotensin-aldosterone system, sympathic nervous system, non-osmotic stimulation of vasopressin). Elevated levels of those neurohormones detrimentally modulate renal function. Subsequently, renal salt and volume retention occurs leading to the main symptoms of heart failure, edema formation and dyspnea. DIURETIC THERAPY: Diuretics, which have been discovered more than 40 years ago, beneficially influence renal salt- and volume retention by their effects on tubular sodium reabsorption. While thiazides are recommended in mild forms, loop diuretics are used in severe stages of congestive heart failure. The clinician has to consider the changed pharmacokinetic and -dynamic properties during the application of diuretics in patients with chronic heart failure. In addition, increased sodium reabsorption occurs immediately after cessation of diuretic action often nullifying the preceding diuresis. Thus, salt- and volume restriction should be guaranteed, and a regular application of loop diuretics during the day should be preferred due to the short-acting nature of currently available loop diuretics. Sometimes, diuresis does not longer occur during the treatment with one substance (diuretic resistance), although the therapeutic goals of water excretion have not been achieved. After ruling out factors reducing the actions of diuretics (non-compliance, hyponatremia, etc.), a sequential nephron blockade should be initiated (combination of loop diuretics and a thiazide or an aldosterone-receptor antagonist) to increase diuresis and to elevate symptoms of volume overload. SIDE EFFECTS: Loop diuretics and thiazides often induce mild hypokalemia, which has been demonstrated to be not as benign as thought before. Chronic treatment with oral potassium supplements has several drawbacks, as urine excretion of potassium is subsequently increased and supplementation is not as effective as believed. Diuretic-induced hypokalemia seems to be aldosterone dependent. As aldosterone levels increase during diuretic therapy even during chronic treatment with an angiotensin-converting enzyme (aldosterone-escape) a combined treatment including an aldosterone-receptor antagonist has been suggested. Beneficial effects of aldosterone-receptor blockade on mortality (RALES trial) appear to be mediated be extrarenal and renal mechanisms. The suggested beneficial renal mechanisms of aldosterone receptor blockade are discussed in detail in the review. CONCLUSION: In conclusion, diuretic therapy of patients with congestive heart failure is effective to relieve symptoms and, presumably, to prolong life. As renal function and pharmacokinetics and -dynamics of diuretics are changed in heart failure, diuretic treatment has to be adapted to provide optimal treatment. Increased levels of aldosterone appear to play an important role in diuretic-induced hypokalemia, and in the progression of heart and renal failure. Thus, aldosterone receptor antagonists should be used in the treatment of heart failure more frequently.     

Aldosterone-receptor antagonism and end-stage renal disease

Blockade of aldosterone effect with either spironolactone or eplerenone is an approach that is being used more frequently in the treatment of hypertension and congestive heart failure; however, sparse information exists pertaining to efficacy or side-effects of this line of treatment for patients with chronic kidney disease and/or end-stage renal disease (ESRD). Hyperkalemia is, by far, the most worrisome complication of therapy with either of these compounds and, not surprisingly, hinders their use in moderateto-advanced renal failure. However, patients with anuric ESRD should theoretically not be at risk for hyperkalemia. To this end, pilot safety studies with aldosterone-receptor antagonists in ESRD patients have begun. These studies imply that spironolactone can be safely used in carefully selected and closely monitored patients. Eplerenone has not been studied in ESRD in a therapeutic or safety capacity. Additional studies are needed with these compounds in the ESRD population before their use can be considered safe.     

Eplerenone: A Selective Aldosterone Blocker

Recent studies suggest that aldosterone may play a larger role than once appreciated in normal physiologic function and cardiovascular disease. Some of the adverse cardiovascular effects that have been described include cardiac and vascular fibrosis, vascular necrosis and inflammation, impaired endothelial function, reduced fibrinolysis, hypertension, left ventricular hypertrophy (LVH), congestive heart failure, and cardiac arrhythmias. In light of these findings, the ability to block the actions of aldosterone has gained increased therapeutic importance. Eplerenone is a selective aldosterone receptor blocker that displays little interaction with androgen and progesterone receptors. Eplerenone has already been approved for the treatment of systemic hypertension and has been evaluated in numerous hypertension subgroups, including patients with low plasma renin activity; diabetes; LVH; uncontrolled blood pressure while receiving monotherapy with angiotensin‐converting enzyme inhibitors, angiotensin‐receptor blockers, calcium channel blockers, or beta‐blockers; and in black patients. Results of these trials indicate that eplerenone lowers blood pressure and reduces end‐organ damage. Further proof of the therapeutic importance of mineralocorticoid receptor blockade comes from the eplerenone post acute myocardial infarction survival and efficacy study (EPHESUS). In this large‐scale clinical outcome trial, eplerenone was shown to reduce total mortality by 15% as well as the combined endpoint of cardiovascular mortality/cardiovascular hospitalization by 13% when administered at a mean of 7.3 days post myocardial infarction to patients with evidence of systolic left ventricular dysfunction and symptoms of heart failure. Eplerenone is well tolerated, with an adverse effect profile comparable to placebo. The advent of selective aldosterone blockers, such as eplerenone, should prove to be of great therapeutic value in hypertension control and prevention of cardiovascular disease and associated end‐organ damage.     

Aldosterone antagonism: An emerging strategy for effective blood pressure lowering

Aldosterone antagonists have been available for many decades for the treatment of hypertension, but their use has been mostly limited to patients with classic primary aldosteronism or to combination products with hydrochlorothiazide to minimize risk for hypokalemia. Recently, indications for aldosterone antagonists have been expanded to include congestive heart failure and first-line treatment of mild-to-moderate hypertension. In addition, we have reported that spironolactone has significant antihypertensive benefit when added to existing regimens in patients with resistant hypertension. This benefit was present in patients with and without hyperaldosteronism and was additive to chronic renin-angiotensin blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensinreceptor blockers (ARBs). Eplerenone, a selective aldosterone antagonist, avoids the androgen and progesterone receptor-related adverse events that sometimes occur with spironolactone, such as breast tenderness, gynecomastia, sexual dysfunction, and menstrual irregularities. In clinical trials, eplerenone has been shown to have antihypertensive benefit in treating mild-to-moderate hypertension similar to other widely used classes of agents. With recent demonstrations of benefit in multiple segments of the hypertensive population, aldosterone antagonists represent emerging opportunity for controlling high blood pressure.     

The risks and benefits of aldosterone antagonists

Spironolactone and eplerenone are mineralocorticoidblocking agents used for their ability to block a host of epithelial and nonepithelial actions of aldosterone. These compounds are of proven benefit in reducing blood pressure and urine protein excretion, and in conferring cardiovascular gain in diverse circumstances of heart failure. However, as enthusiasm grows for use of mineralocorticoid-blocking agents, the risks inherent to use of such drugs become more pertinent. Whereas the endocrine side effects of spironolactone are in reality little more than a cosmetic disfigurement, the potassium-sparing properties of spironolactone and eplerenone can prove life-threatening if hyperkalemia develops. However, for most patients the risk of developing hyperkalemia should not dissuade the prudent clinician from use of these compounds. Hyperkalemia should be considered as a possibility in any patient receiving these medications and as such is best addressed preemptively.     

A comparison of the aldosterone-blocking agents eplerenone and spironolactone

Improved understanding of the adverse pharmacological properties of aldosterone has prompted investigation of the clinical benefits of blocking aldosterone at the receptor level. This article reviews the pharmacology, clinical efficacy, and tolerability of the two available blocking agents, spironolactone and eplerenone. A Medline search identified clinical studies assessing spironolactone and eplerenone. Priority was given to large, well-controlled, clinical trials and comparative studies. Pharmacological differences between spironolactone and eplerenone include lower affinity of eplerenone for progesterone, androgen, and glucocorticoid receptors; more consistently demonstrated nongenomic properties for eplerenone; and the presence of long-acting metabolites for spironolactone. Both agents effectively treat hypertension and heart failure but comparisons are complicated by the deficiency of head-to-head trials and differences between patient populations. There are differences in the tolerability profiles; spironolactone is associated with dose-dependent sexual side effects. Both agents produce dose-dependent increases in potassium concentrations, although the effect with spironolactone appears to be greater when both agents are administered at recommended doses. Choice of a specific agent should be based on individual patient issues, such as the nature of heart failure and patient concerns about adverse events.     

Aldosterone and aldosterone antagonism in cardiovascular disease: focus on eplerenone (Inspra)

Aldosterone has long been known to mediate water and electrolyte balance by acting on mineralocorticoid receptors in the kidneys. However, recent studies have demonstrated the presence of these receptors in nonclassical locations, including the brain, blood vessels, and the heart. This finding suggests that aldosterone may play a larger role than once appreciated in normal physiologic function and cardiovascular disease. Some of the adverse cardiovascular effects that have been described include cardiac and vascular fibrosis, left ventricular hypertrophy, congestive heart failure, hypertension, endothelial dysfunction, reduced fibrinolysis, and cardiac arrhythmias. In light of these findings, aldosterone receptor blockers have become increasingly more important. This is especially true considering the fact that traditional therapies, such as angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers, may not be effective in maintaining long-term suppression of aldosterone. Therefore, a great deal of focus has been placed on spironolactone, which has proven to be an effective, albeit nonselective, aldosterone receptor blocker. The Randomized Aldactone Evaluation Study has shown that spironolactone results in a 30% reduction in mortality among patients with severe congestive heart failure. Other studies have shown spironolactone to lower high blood pressure, improve endothelial dysfunction, reduce left ventricular hypertrophy, and lower the incidence of fatal arrhythmias. However, spironolactone, because of its interaction with other steroid receptors, is not without its limitations, which include gynecomastia, breast tenderness, menstrual irregularities, and impotence. As a result, eplerenone (INSPRA), a selective aldosterone blocker, is currently being investigated for its efficacy and side-effect profile compared with spironolactone. Eplerenone has already been approved for the treatment of systemic hypertension, and several clinical trials are currently underway to identify other therapeutic uses for this agent in cardiovascular disease management.     

Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure

Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered.     

Balancing diuretic therapy in heart failure: loop diuretics,thiazides, and aldosterone antagonists

In heart failure, sodium is retained by the kidneys despite increases in extracellular volume. There is activation of renin secretion, which culminates in the production of angiotensin II, causing vasoconstriction and aldosterone secretion. These synergistically produce an increase in tubular reabsorption of sodium and water. Diuretics are the mainstay of symptomatic treatment to remove excess extracellular fluid in heart failure. Diuretics that affect the ascending loop of Henle are most commonly used. Thiazide diuretics promote a much greater natriuretic effect when combined with a loop diuretic in patients with refractory edema. Recently, spironolactone, an aldosterone receptor blocking agent, has been recommended to attenuate some of the neurohormonal effects of heart failure. Regardless of the diuretic, patients need to be counseled on the importance of avoiding sodium in their diet     

Aldosterone receptor antagonists: Biology and novel therapeutic applications

A dysregulation of the aldosterone system has been involved in the pathophysiology of cardiovascular diseases, including myocardial failure and, partially, essential hypertension. In humans and in rat models, aldosterone action induces heart remodeling and interstitial and perivascular myocardial fibrosis. Therefore, a rationale for using aldosterone antagonists (ARAs) of the spironolactone family, which have been available for decades for the treatment of aldosterone excess syndromes, has now emerged. The development of compounds such as eplerenone, with a greater selectivity for mineralocorticoid receptors, is promising also in terms of reduction of endocrine side effects. The use of ARAs for the treatment of myocardial failure and selected cases of hypertension, in combination with the current therapy, has been strongly supported by trials such as the Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS). Thus, the addition of ARAs to the conventional therapy appears beneficial, leading to an improved survival rate and a reduced incidence of cardiac complications.     

Eplerenone,a selective aldosterone blocker,in mild-to-moderate hypertension

BACKGROUND: Eplerenone, a selective aldosterone blocker (SAB) that is highly specific for the aldosterone receptor, has the potential to be efficacious in the treatment of hypertension. METHODS: This 8-week, multicenter, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of eplerenone in eligible patients randomized to eplerenone 50, 100, or 400 mg once daily; eplerenone 25, 50, or 200 mg twice daily; spironolactone 50 mg twice daily; or placebo. The primary efficacy variable was the adjusted mean change in baseline to final visit for seated diastolic blood pressure (DBP). RESULTS: Of 417 randomized patients, 409 were evaluated for efficacy. The adjusted mean change from baseline to final visit in seated and standing systolic blood pressure (SBP) and DBP was significantly greater (P < .05) in all eplerenone groups than in the placebo group. The adjusted mean change in 24-h ambulatory blood pressure monitoring (ABPM) measurements of SBP and DBP also documented a 24-h duration significantly greater (P < .05) than placebo in eplerenone-treated patients. For all measurements, the antihypertensive effect of eplerenone increased in a dose-response fashion. Eplerenone (100 mg) reduced BP by 75% compared with spironolactone (100 mg) and had an adverse events incidence rate similar to placebo. No antiandrogenic or progestational effects or clinically relevant safety issues were observed in eplerenone-treated patients. However, one spironolactone-treated patient reported menstrual irregularities. CONCLUSIONS: Eplerenone doses of 50 to 400 mg once daily are well tolerated and effective in reducing BP in patients with mild-to-moderate hypertension during a 24-h period.     

Evidence-based diuretic therapy for improving cardiovascular prognosis in systemic hypertension

Diuretics are among the most commonly prescribed cardiovascular (CV) medications. The strength of evidence supporting the effectiveness of diuretics in lowering blood pressure and for preventing major adverse CV events in patients with hypertension varies considerably among diuretic classes and even among agents within the same class. Unfortunately, common prescribing habits among American physicians, including specialists in CV diseases, are not in line with the existing evidence regarding diuretic therapy for improving CV prognosis. In conclusion, although hydrochlorothiazide is the standard diuretic used for hypertension, the outcomes data suggest that chlorthalidone, indapamide, and possibly even the aldosterone receptor blockers (spironolactone and eplerenone) may be superior agents.