The place of aldosterone receptor blockers in the treatment of chronic heart failure

The paper contains presentation of basics of clinical pharmacology of aldosterone receptor blockers specifically that of spironolactone and eplerenone, and discussion of results of 2 large randomized placebo controlled trials which showed that long term use of aldosterone receptor blockers allowed to improve prognosis of patients with severe chronic heart failure and postinfarction systolic left ventricular dysfunction, and to reduce requirements in repetitive hospitalizations.     

The role of ACE inhibitors and angiotensin receptor blockers in the treatment of hypertension and cardiovascular disease

Pharmacologic attenuation of the renin-angiotensin-aldosterone system (RAAS) either through angiotensin-converting enzyme (ACE) inhibition or angiotensin II receptor blockade now occupies a central role in the management of hypertension, diabetes, heart failure, and cardiovascular and renal disease. Although our understanding and use of these agents has expanded significantly over the past decade, the relative and differential benefits of ACE inhibitors and angiotensin receptor blockers (ARBs) are still not entirely clear. The data continue to support the first-line use of ACE inhibitors for all indications. Results for combination ACE inhibitor and ARB therapy in clinical outcome trials have been disappointing and do not support its use. New strategies for RAAS modulation bring hope for further progress in the treatment of hypertensive and cardiovascular disease.     

The promise of selective aldosterone receptor antagonists for the treatment of hypertension and congestive heart failure

Inappropriate elevations in plasma aldosterone levels have multiple actions that play an important role in the pathophysiology of hypertension and heart failure. Patients with hypertensive cardiovascular disease are at increased risk for coronary artery disease, myocardial infarction, congestive heart failure, and sudden cardiac death. Despite long-term treatment with an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, aldosterone levels usually remain high in these patients. The effectiveness of low-dose spironolactone raises the possibility that a nonselective aldosterone antagonist can block the deleterious effects of aldosterone on the cardiovascular system. However, side effects limit the use of this drug in many patients. The advent of selective aldosterone antagonists, which have a lower affinity for androgen and progesterone receptors, should minimize these side effects, leading to better compliance.     

Angiotensin receptor blockers and aldosterone antagonists in chronic heart failure.

Prognosis in congestive heart failure is directly linked to neurohormonal activation. Angiotensin II through the activation of the renin angiotensin aldosterone system has been the principal focus therapy over the last 2 decades. New agents that target selective blockade of the angiotensin II receptor have been introduced in clinical trials for the treatment of heart failure. Aldosterone has been identified as a critically important neurohormone with direct detrimental effects on the myocardium. Aldosterone antagonists have been used in clinical trials to improve mortality in patients with chronic heart failure.     

血管紧张素受体拮抗剂治疗高血压

肾素-血管紧张素-醛固酮系统（RAAS）是调节血压的主要机制,也是治疗高血压病的重要靶点。血管紧张素受体拮抗剂（ARBs）,通过阻滞特异性血管紧张素受体,干扰RAAS的活性,成为治疗高血压的一线药物。临床结果显示ARBs作为单用药或联合其他降压药物治疗高血压有其特殊的优势。在降压方面,与血管紧张素转换酶抑制剂和其他类型的降压药物相比,ARBs具有良好的耐受性而适合用于治疗更广泛的患者。最近研究结果显示在12个月期间使用ARBs治疗高血压依从性明显高于其他降压药物,而且副作用少。具备临床有效性和良好耐受性的ARBs药物,可以作为治疗高血压的主要药物。     

Calcium channel blockers in treatment of hypertension

Calcium channel blockers (CCBs) are among the most often prescribed drugs for the treatment of hypertension, but there is still uncertainty regarding the risks and benefits of their use as first-line drugs in the treatment of hypertension. Compared with placebo, dihydropyridine CCBs (long-acting nifedipine and nitrendipine) reduce the risk for cardiovascular endpoints, and in a pooled analysis of available studies on treatment of hypertension, significantly decrease the risk for strokes and cardiovascular and total mortality. This also holds true for patients with diabetes who have a clearly reduced risk when treated with CCBs as compared with placebo. However, compared with other active treatments in mixed study populations, CCBs are associated with a small risk increase for myocardial infarction and heart failure, but for cardiovascular mortality, there is only a very small and nonsignificant trend to a risk increase, and total mortality is similar. Among patients with diabetes, compared with angiotensin-converting enzyme inhibitors in particular, available data suggest that CCB use is associated with a moderate increase in cardiac endpoints. Therefore, among patients with diabetes and those with heart failure, angiotensin-converting enzyme inhibitors are preferable as first-line drugs; among the large fraction of patients without these conditions, there is no convincing evidence that long-acting dihydropyridine or nondihydropyridine CCBs are inferior to other blood pressure-lowering drugs. In these patients, the choice of blood pressure-lowering medication can be based on the expected tolerability, costs, and personal preferences.     

The role of calcium channel blockers in the treatment of essential hypertension

Calcium channel blockers, originally developed for the treatment of angina and supraventricular arrhythmias, have been shown to lower elevated blood pressure effectively in hypertensive patients. Verapamil, nifedipine, and diltiazem represent prototype compounds for unique chemical classes with differing pharmacologic properties. These drugs lower elevated blood pressure with efficacy comparable with other commonly used antihypertensives. Combination therapy with other agents usually results in an additive response. Side effects are usually mild and reversible and usually are an extension of the drug's pharmacologic effects. Moreover, adverse metabolic effects on lipid, glucose, or potassium levels are not common. Because of the excellent antihypertensive effects of calcium channel blockers and their potential importance in a variety of other disease states, these agents should be routinely considered for use as a first-line antihypertensive agent in appropriately selected patients with hypertension of any severity as part of a comprehensive plan to minimize cardiovascular risk.     

Efficacy of add-on aldosterone receptor blocker in uncontrolled hypertension

BACKGROUND: Uncontrolled hypertension (UH) may be caused by hyperaldosteronism, and some experts recommend the routine use of aldosterone antagonists in this condition. The purpose of this study was to evaluate the efficacy of this approach and to characterize those who respond effectively to an add-on aldosterone antagonist. METHODS: We retrospectively analyzed the effectiveness of spironolactone, an aldosterone antagonist, used as add-on therapy, compared with a standard add-on treatment, in patients referred to a hypertension clinic with UH despite the use of two or more antihypertensive drugs. RESULTS: A total of 340 patients (186 male) with an average age of 63 +/- 14 years were followed for at least 3 months. Of the patients, 42 received add-on spironolactone and 298 received an additional antihypertensive drug other than spironolactone. Baseline characteristics were similar in both groups. Blood pressure (BP) decreased significantly in both groups. In patients who received spironolactone, BP decreased by 23.2/12.5 mm Hg from 165 +/- 27/94 +/- 15 to 142 +/- 25/81 +/- 9 mm Hg, whereas in patients who received other add-on therapy BP decreased by 7.6/5.8 mm Hg from 160 +/- 24/91 +/- 12 to 152 +/- 20/85 +/- 11 mm Hg (P < .05). Patients who received spironolactone had lower serum potassium levels than those who did not receive spironolactone 3.8 +/- 0.4 v 4.5 +/- 0.5 mmol/L respectively (P < .001). Potassium levels <4 mmol/L were associated with a greater reduction in BP. CONCLUSIONS: Add-on spironolactone is a highly effective add-on treatment in UH, mainly in patients with low serum potassium levels. Further studies assessing serum potassium as a marker for treatment approach are needed to establish the role of aldosterone antagonists in the management of UH.     

Geriatric hypertension: the growing use of calcium-channel blockers

The recognition of essential hypertension as a heterogeneous entity mandates that therapy be individualized according to the subset of hypertension that characterizes each patient. Choosing the most appropriate therapeutic regimen in elderly hypertensives is complicated by a greater susceptibility to side effects from medications, and by concomitant diseases. Calcium-channel blockers address the pathophysiologic mechanisms of generic hypertension, thus providing clinicians with more specific pharmacologic tools for treating elderly hypertensives. In addition, these agents will avoid many of the side effects of other antihypertensive agents and can ameliorate certain concomitant diseases.     

Optimal use and interpretation of the aldosterone renin ratio to detect aldosterone excess in hypertension

With the introduction of the aldosterone/renin ratio as a screening test, the detection rate of primary aldosteronism has increased considerably. Nevertheless, no consensus has so far been reached regarding the cutoff points, operating characteristics or indeed even the reference values for reporting the aldosterone/renin ratio using plasma active renin (ng/l or mU/l) measured by immunoradiometric assay. We review the characteristics of this ratio in normal individuals, essential hypertension and primary hyperaldosteronism in an attempt to reach an agreement regarding its optimum use and interpretation - both using the renin activity or concentration. It seems that the optimal cutoff for patients with primary aldosteronism is above 30 ng/dl per mug/l/h or 800 pmol/l per mug/l/h or 130 pmol/ng or 80 pmol/mU. We explore enhancing measures such as captopril loading or use with a plasma aldosterone cutoff as well as pitfalls with the test such as confounding medications or the need for confirmatory testing. For the latter, demonstration of autonomous aldosterone production via salt loading is widely used, but may not be most advantageous and may even be contraindicated in patients with severe hypertension. The renin stimulation test may be an alternative being safe, well tolerated, and cost effective.     

Newer beta blockers and the treatment of hypertension

Beta-adrenoceptor blocking agents are established as one of the principal classes of antihypertensive agents. Despite progressive refinements over the years, they still possess some unwanted effects, which limit their considerable value. In recent years a wide range of variations upon the beta-blocker theme has been developed. The full clinical advantages of the newer agents remain to be defined.     

Aldosterone receptor blockers in the treatment of heart failure

Opinion statement Heart failure is associated with neurohormonal activation, including activation of the renin-angiotensin-aldosterone system. Plasma aldosterone levels are elevated in patients with heart failure in spite of the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers because of angiotensin-independent stimuli for aldosterone production. In addition to its long recognized role in sodium retention, aldosterone has a number of other deleterious effects, including the increase in myocardial and vascular fibrosis and myocardial remodeling in patients with heart failure. Based on strong clinical trial data, low-dose aldosterone receptor blockers are recommended to improve morbidity and mortality in patients with severe chronic heart failure due to left ventricular systolic dysfunction and in patients with heart failure associated with left ventricular systolic dysfunction after acute myocardial infarction, and in patients already on standard therapy including ACE inhibitors (or angiotensin receptor blockers) and β blockers. In view of the potential for serious hyperkalemia with the use of aldosterone receptor blockers, it is essential to monitor serum potassium closely and to adjust the dose of aldosterone antagonists based on serum potassium levels. Close adherence to the dosing regimens used in the clinical trials (RALES [Randomized Aldactone Evaluation Study] and EPHESUS [Eplerenone Post-AMI Heart Failure Efficacy and Survival Study]) is recommended. These agents should not be initiated in patients with severe renal insufficiency and closer monitoring is warranted in those with mild to moderate renal insufficiency or diabetes.     

The role of aldosterone blockers in the management of chronic heart failure

The neurohormonal model of congestive heart failure (CHF) has replaced the previously accepted hemodynamic model. A shift in this paradigm has allowed alterations in therapy of CHF such that agents that target the neurohormonal axis and specifically the renin-angiotensin-aldosterone system, with drugs such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, are utilized. Employment of these drugs markedly improves survival in patients with CHF. Recent animal and human data demonstrate that aldosterone is directly pathogenic in this disease process and is insufficiently suppressed by these agents. Furthermore, when aldosterone is directly antagonized, vascular and myocardial damage is greatly ameliorated in both experimental animals and humans. Significant mortality benefits of aldosterone antagonists in patients with CHF from systolic dysfunction have been subsequently witnessed. Herein, the pathophysiology of CHF, the beneficial role of aldosterone antagonists in this disease process, and potential adverse consequences of these agents are reviewed.     

Pulmonary hypertension and right ventricular failure. Part XI. Endothelin receptor blockers in the treatment of primary pulmonary arterial hypertension

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary arterial hypertension (PAH), its current classification; peculiarities of its pathogenesis and treatment in various diseases and conditions. In the eleventh communication the authors discuss literature data related to the role of endothelin system in pathogenesis of primary (idiopathic) PAH, as well as PAH associated with diffuse diseases of connective tissue and congenital heart disease. This communication also contains presentation of clinical pharmacology of three available endothelin receptor blockers - bosentan, sitaxsentan, ambrisentan, and analysis of results of randomized controlled trials of efficacy and safety of these agents in patients with idiopathic PAH and PAH associated with diffuse diseases of connective tissue and congenital heart disease.     

Evolving role of aldosterone blockers alone and in combination with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in hypertension management: a review of mechanistic and clinical data

The renin-angiotensin-aldosterone system (RAAS) plays an integral role in blood pressure regulation and has long been a target of pharmacologic approaches to controlling blood pressure. Traditionally, clinical interventions involving the RAAS have focused mainly on inhibiting the action of angiotensin II with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and limited attention has been devoted to direct inhibition of the action of aldosterone. Recent advances in understanding the role of aldosterone in cardiovascular injury have elevated the importance of direct inhibition of the action of this hormone in the long-term control of blood pressure and have led to the development of the selective aldosterone blocker eplerenone. This article reviews the role of the RAAS in the development of hypertension and discusses the rationale for the use of eplerenone with other medications affecting the RAAS to control blood pressure.