Aldosteron und Aldosteronrezeptorantagonisten in der Herzinsuffizienztherapie

In addition to the classical effects exerted by aldosterone on water and electrolyte haemostasis, recent data suggest additional roles in the pathophysiology of cardiovascular diseases. Examples are the regulation of blood pressure (by direct aldosterone effects on vessels and the CNS), myocardial hypertrophy and remodelling. Two aldosterone receptor antagonists, spironolactone and eplerenone, are currently available for the long-term therapy of chronic heart failure. Both compounds have clearly demonstrated their efficacy in heart failure treatment in end-point based clinical trials. Spironolactone, in addition to its antagonistic effects on the mineralocorticoid receptor, has anti-androgenic and gestagenic actions which can lead to endocrine side effects. Eplerenone selectively blocks aldosterone receptors and thus lacks adverse effects caused by non-specific steroid receptor blockade. The elimination half-life of eplerenone is shorter than the half-life of the active metabolites of spironolactone. Eplerenone is metabolised by CYP3A4, and pharmacokinetic interactions with inhibitors and inducers of this enzyme have to be considered. Essential for the clinical use of aldosterone antagonists in heart failure is the careful monitoring of potassium levels and renal function. The recommended doses should be followed precisely. Higher doses increase the risk of developing life-threatening hyperkalemia. Particular attention has to be paid to patients with impaired renal function. Aldosterone receptor antagonists should not be used when the glomerular filtration rate is below 50 ml/min.     

Eplerenone--a novel selective aldosterone blocker

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of eplerenone, a new selective aldosterone blocker. DATA SOURCES: Primary literature and review articles were obtained via MEDLINE search (1966-April 2002). Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles related to eplerenone, aldosterone, aldosterone antagonist, and spironolactone were reviewed. Data pertinent to this article were included. DATA SYNTHESIS: Eplerenone is a selective aldosterone blocker. Recent data have demonstrated the deleterious effects of aldosterone in several chronic disease states including hypertension and heart failure. Animal studies using eplerenone have shown a positive role for aldosterone antagonism in the treatment of hypertension, heart failure, myocardial infarction, renal disease, and atherosclerosis. In humans, eplerenone appears to be effective for the treatment of hypertension. An ongoing study will examine the effect of eplerenone for heart failure. To date, the incidence of adverse effects with eplerenone has been slightly lower than with spironolactone. CONCLUSIONS: Eplerenone appears to be a promising drug in a new class of agents called selective aldosterone blockers. The drug may be approved for treatment of hypertension in 2002. Additional studies are ongoing that may provide information on other clinical uses for this medication.     

New treatment option for heart failure patients: eplerenone

Aldosterone plays an important role in the harmful cardiac remodeling process and pathophysiology of heart failure after a myocardial infarction. Until recently, spironolactone (Aldactone) was the only pharmacologic agent available to directly block the deleterious effects of aldosterone. The use of spironolactone is complicated by its antiprogesterone and antiandrogen side effects, such as gynecomastia and menstrual irregularities. Eplerenone (Inspra), a member of a new class of drugs called selective aldosterone receptor antagonists, was recently approved for the treatment of both hypertension and post-myocardial infarction heart failure and appears to be devoid of the antiprogesterone and antiandrogen effects. In a trial in patients with heart failure following a myocardial infarction, eplerenone treatment significantly reduced mortality and morbidity compared to placebo. Eplerenone may be considered as part of the therapeutic plan in patients who have suffered a myocardial infarction and demonstrate evidence of heart failure.     

螺内酯佐治慢性心力衰竭临床观察

目的观察醛固酮受体拮抗剂螺内酯佐治慢性心力衰竭（chronicheartfailure,CHF）的有效性和安全性。方法将90例CHF随机分为常规治疗组和螺内酯组,每组45例。两组均予常规抗心力衰竭治疗,螺内酯组同时予螺内酯20mg,每日2次口服。治疗时间均为6个月。观察比较两组临床疗效及治疗前后超声心动图、生化指标变化情况。结果治疗后两组心功能均较治疗前改善,但螺内酯组总有效率91．1％,与常规治疗组75．6％比较,差异有统计学意义（P〈0．05）。治疗后螺内酯组血钾水平较治疗前升高,差异有统计学意义（P〈0．05）,常规治疗组血钾水平与治疗前比较差异无统计学意义（P〉0．05）,两组治疗后血钾水平比较差异有统计学意义（P〈0．05）。螺内酯组治疗后心排出量、左室收缩末期内径、左室舒张末期内径、左室射血分数均优于常规治疗组,差异有统计学意义（P〈0．05）。结论在常规抗心力衰竭治疗基础上使用醛固酮受体拮抗剂螺内酯可改善CHF患者心功能,抑制心室重构,延缓疾病进展。     

Eplerenone in the treatment of chronic heart failure

There has been a recent revival of interest in aldosterone receptor antagonists for the treatment of chronic heart failure. This was largely triggered by fresh insights into the role of aldosterone in a number of key pathophysiological processes, including fibrosis and remodeling, inflammation, and the potentiation of catecholamine effects. The therapeutic efficacy of spironolactone (Aldactone), Pfizer) in severe chronic heart failure was established by the Randomized Aldactone Evaluation Study, but hormonal side effects (gynecomastia) associated with the drug posed a problem. More recently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study has provided firm support for the use of eplerenone (Inspra, Pfizer) in heart failure following acute myocardial infarction in addition to neurohormonal blockade with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and beta-blockers. This strategy can be expected to benefit both mortality and morbidity. Due to the fact that eplerenone is a selective aldosterone receptor antagonist, it does not cause troublesome hormonal side effects. This is an important feature of the drug that is likely to help maintain compliance.     

Eplerenone: a selective aldosterone receptor antagonist for patients with heart failure

OBJECTIVE: To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF). DATA SOURCES: English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles. STUDY SELECTION AND DATA EXTRACTION: Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated. DATA SYNTHESIS: Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence. CONCLUSIONS: The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenone's selectivity reduces sex hormone-related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.     

Spironolactone. An aldosterone agonist in the stimulation of H+ secretion by turtle urinary bladder.

In the isolated turtle bladder, spironolactone inhibits sodium transport in the presence of aldosterone or endogenous mineralocorticoid hormone. In contrast to this antagonism for the stimulation of sodium transport by aldosterone, the stimulation of hydrogen ion secretion by aldosterone is not inhibited by spironolactone. In hormone-depleted bladders, spironolactone stimulates hydrogen ion secretion. The extent of stimulation is similar to that of aldosterone. Spironolactone functions as an agonist for aldosterone for the stimulation of urinary acidification.     

Eplerenone in the treatment of chronic heart failure

There has been a recent revival of interest in aldosterone receptor antagonists for the treatment of chronic heart failure. This was largely triggered by fresh insights into the role of aldosterone in a number of key pathophysiological processes, including fibrosis and remodeling, inflammation, and the potentiation of catecholamine effects. The therapeutic efficacy of spironolactone (Aldactone^®, Pfizer) in severe chronic heart failure was established by the Randomized Aldactone Evaluation Study, but hormonal side effects (gynecomastia) associated with the drug posed a problem. More recently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study has provided firm support for the use of eplerenone (Inspra?, Pfizer) in heart failure following acute myocardial infarction in addition to neurohormonal blockade with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and β-blockers. This strategy can be expected to benefit both mortality and morbidity. Due to the fact that eplerenone is a selective aldosterone receptor antagonist, it does not cause troublesome hormonal side effects. This is an important feature of the drug that is likely to help maintain compliance.     

Spironolactone in the treatment of congestive heart failure

OBJECTIVE: To evaluate evidence supporting the use of spironolactone in managing congestive heart failure. DATA SOURCES: Literature accessed through MEDLINE (January 1966-December 1999) and cross-referencing of selected articles. Search terms included spironolactone and heart failure. DATA SYNTHESIS: Heart failure is a leading cause of morbidity and mortality. Through aldosterone antagonism, spironolactone may be an effective pharmacotherapeutic addition to patients not responding to standard drug therapy for heart failure. RESULTS: Clinical trials have demonstrated that, in patients with heart failure, spironolactone improves laboratory indices, quality of life, and morbidity. Recently, spironolactone has been demonstrated to improve the survival of patients with New York Heart Association (NYHA) III or IV heart failure. CONCLUSIONS: Spironolactone use should be considered in patients with NYHA Class III or IV heart failure.     

Antiandrogens in the treatment of acne and hirsutism.

Antiandrogens have been found to be effective in the treatment of acne and hirsutism. Cyproterone acetate has been used in Europe for many years, but in the United States it has only been approved as an orphan drug to treat severe hirsutism. Spironolactone is approved in the United States for its antialdosterone effect but not for its antiandrogenic effect, although it is widely used for the latter purpose. While cyproterone is a more effective drug than spironolactone, it is more likely to produce undesirable side effects.     

螺内酯对老年心房颤动患者血清Ⅰ型胶原代谢的影响

目的 通过测定老年心房颤动(房颤)患者使用螺内酯治疗前后血清醛固酮、Ⅰ型前胶原羧基端肽(PICP)及Ⅰ型胶原羧基端交联肽(CITP)水平的变化,探讨螺内酯减轻心房纤维化的可能机制.方法 选择房颤患者67例和条件相匹配的窦性心律患者30例,并将房颤患者随机分为常规治疗组(33例)及螺内酯(20mg/d)治疗组(34例),治疗6个月,用放射免疫法测定治疗前后血清醛固酮、PICP及CITP水平.另选对照组为30例,无房颤发作史,心电图及24小时动态心电图为窦性心律,一般资料匹配.结果 房颤组血清PICP、CITP、醛固酮浓度及左房大小均显著高于对照组(P＜0.01).房颤组血清醛固酮与左房大小呈正相关( r=0.302,P＜0.05)、血清PICP浓度与左房大小呈正相关( r=0.369,P＜0.01),螺内酯治疗组与常规治疗组治疗后血清醛固酮、PICP水平与治疗前相比均下降,但螺内酯治疗组下降更明显,治疗后两组血清醛固酮及PICP水平比较差异具有统计学意义(P＜0.01).结论 螺内酯通过降低房颤患者血清醛固酮、PICP水平,从而减轻心房纤维化,延缓房颤的发生发展.     

A new enzyme-linked chemiluminescent immunosorbent digoxin assay is virtually free from interference of spironolactone, potassium canrenoate, and their common metabolite canrenone

Spironolactone and potassium canrenoate (aldosterone antagonist diuretics) are sometimes used in conjunction with digoxin for patient management. Spironolactone, potassium canrenoate, and their common metabolite canrenone interfere with serum digoxin measurement using various immunoassays. Recently a new enzyme-linked chemiluminescent immunosorbent digoxin assay (ECLIA-Digoxin) became commercially available for application on the ADVIA IMS 800i modular system (Bayer HealthCare, Tarrytown, NY). We investigated the potential interference of spironolactone and related compounds in this assay by comparing the results with the fluorescence polarization immunoassay (FPIA), which is known to have significant cross-reactivity with these compounds as well as a turbidimetric assay for digoxin with no known cross-reactivity with spironolactone and related compounds. Aliquots of drug free serum were supplemented with therapeutic and above therapeutic concentrations of spironolactone, canrenone, and potassium canrenoate, and apparent digoxin concentrations were measured. No apparent digoxin concentration was observed using the ECLIA-Digoxin or turbidimetric assay. When serum pools prepared from patients receiving digoxin were further supplemented with these compounds, we observed no significant change in digoxin concentrations in the presence of these compounds with the ECLIA-Digoxin. We conclude that this assay is virtually free from interferences from spironolactone, potassium canrenoate and their common metabolite canrenone.     

Hydrochlorothiazide and spironolactone in hypertension.

A double-blind study of hydrochlorothiazide and spironolactone, alone and in combination, was conducted in 49 patients with mild-to-moderate essential hypertension after a 4-wk placebo washout period. In the whole group mean arterial blood pressure fell to levels of less than or equal to 107 mm Hg or declined by more than 15 mm Hg in 78% of the patients after twelve weeks of treatment. Sixty-nine percent of patients receiving hydrochlorothiazide alone developed serum potassium levels lower than 3.5 mEq/L; serum potassium levels were above 5.5 mEq/L in 2 patients (5.5%) receiving spironolactone 400 mg/day. Uric acid levels rose in all patients, more in those on hydrochlorothiazide, but clinical gout did not develop in any subject. Hydrochlorothiazide, spironolactone, and the combination of the two are effective antihypertensives. Spironolactone in doses of 200 and 400 mg/day was associated with side effects but did not induce a greater antihypertensive effect than doses of 100 mg/day. Our data suggest that when hydrochlorothiazide is associated with potassium loss, when gout or elevated uric acid levels are of concern, or when carbohydrate tolerance is abnormal, supplementation or replacement with spironolactone (up to 100 mg/day) may be useful in controlling blood pressure while reducing side effects.     

螺内酯对醛固酮刺激下大鼠肾小球系膜细胞PAI-1表达的影响

目的探讨醛固酮对体外培养大鼠肾小球系膜细胞纤溶酶原激活物抑制物－1（PAl-1）表达的影响及螺内酯的干预作用。方法体外培养大鼠肾小球系膜细胞,设正常对照组、醛固酮（10-7mol·L-1）组、不同浓度螺内酯（10-7,10-8,10-9mol·L-1）干预组,48h后收集细胞及上清液,以RT-PCR检测PM-1、醛固酮受体（MR）和保护其配体特异性的11p羟类固醇脱氢酶2（11β-HSD2）的mRNA表达,采用ELISA检测培养细胞上清中PAI-1蛋白的浓度。结果RT-PCR结果,肾小球系膜细胞表达MR和118．HSD2mRNA,醛固酮可显著上调肾小球系膜细胞PM-1mRNA表达,螺内酯可抑制醛固酮诱导的PA／-1mRNA表达,且呈剂量依赖性;ELISA结果示醛固酮组上清液中PAI-1水平明显增加,螺内酯干预组PAI-1水平明显降低并与浓度有关。结论螺内酯与醛固酮竞争结合MR,抑制醛固酮刺激的大鼠。肾小球系膜细胞中PAI-1mRNA的表达和蛋白合成。     

Digoxin-quinidine-spironolactone interaction

Digoxin kinetics are substantially altered by quinidine and by spironolactone. We evaluated the effect of the combination of quinidine and spironolactone on digoxin kinetics and compared it to the effect on digoxin of each drug alone. Six normal subjects each received a 1.0-mg intravenous dose of digoxin alone, digoxin with quinidine, digoxin with spironolactone, and digoxin with both quinidine and spironolactone. Spironolactone and quinidine, alone and in combination, reduced digoxin systemic, renal, and nonrenal clearances and prolonged digoxin elimination t 1/2. A greater alteration in digoxin kinetics was induced by quinidine than by spironolactone, and an even greater effect resulted from the combination. We did not assess clinical consequences of the interaction. We advise reduction in digoxin dose, careful clinical evaluation, and measurement of serum digoxin concentrations when digoxin is used in combination with quinidine and spironolactone.     

螺内酯对碱烧伤诱导大鼠角膜新生血管形成的影响及其机制研究

背景:螺内酯为醛固酮受体拮抗剂,近来有实验证实螺内酯在体内外能够有效地抑制新生血管的形成.目的:验证螺内酯对碱烧伤诱导大鼠角膜新生血管的抑制作用.方法:取SD大鼠36只,采用碱烧伤方法制各大鼠角膜新生血管模型,造模后以数字表法随机分成实验组和对照组.实验组术后灌胃给予螺内酯100 mg/kg,1次/d,对照组灌胃给予等量生理盐水.另取大鼠6只不作任何处理作为正常对照组.于造模后4,7,14 d运用裂隙灯观察各组大鼠角膜新生血管并计算面积,并每组随机处死6只大鼠,运用免疫组化染色方法和计算机图像分析系统检测观察血管内皮细胞生长因子及基质金属蛋白酶2的表达.结果与结论:正常角膜组织未见炎症细胞与新生血管,角膜上皮及基质层仅见微弱血管内皮细胞生长因子表达,未见基质金属蛋白酶2表达.与对照组比较,实验组各个时期新生血管面积减小,血管内皮细胞生长因子和基质金属蛋白酶2表达降低(P<0.05).提示螺内酯可能通过参与下调血管内皮生长因子和基质金属蛋白酶2表达,从而有效地抑制角膜新生血管的形成.     

Interactions between digoxin and potassium-sparing diuretics

A kinetic and hemodynamic study of digoxin was performed in six healthy subjects and similar studies were performed during digoxin with spironolactone and with triamterene. Spironolactone reduced renal tubular secretion of digoxin and attenuated its positive inotropic effect (evaluated by systolic time intervals and echocardiography) and triamterene reduced the extrarenal elimination of digoxin, but induced no changes in digoxin-elicited inotrophy. It is suggested that the renal handling of digoxin is influenced by the intracellular potassium concentration in the renal tubular cell. The results indicate a drug-receptor interaction between spironolactone metabolites and digoxin at the hypothetical inotropic digitalis receptor. Amiloride has been reported to suppress digoxin inotropism, whereas spironolactone induces minor inhibition and triamterene does not affect digoxin inotropism.     

Prevalence of primary hyperaldosteronism assessed by aldosterone/renin ratio and spironolactone testing

Recent studies have suggested that primary hyperaldosteronism may be present in more than 10% of patients with hypertension. We aimed to estimate the prevalence in unselected patients in primary care, and investigate the influence of current drug treatment upon the aldosterone/renin ratio (ARR) and its prediction of blood pressure response to spironolactone. We measured blood pressure, plasma electrolytes, renin activity and aldosterone in 846 patients with hypertension. Spironolactone 50 mg was prescribed for one month to patients with blood pressure > or = 130/85 mmHg and ARR > or = 400. The primary outcome measure was to discover the proportion of patients with plasma aldosterone > or = 400 pmol/l and ARR > or = 800 and either an adrenal adenoma on computed tomography scan or a systolic blood pressure response to spironolactone > or = 20 mmHg. Only one patient had an adenoma, and only 16 (1.8%) had both a plasma aldosterone > or = 400 pmol/l and ARR > or = 800. By contrast, 119 patients (14.1%) had an elevated ARR but normal plasma aldosterone. In 69 patients out of the 119 who received spironolactone, blood pressure fell by 26/11 mmHg. These patients were normokalaemic but had uncontrolled hypertension despite multiple drugs. The response to spironolactone was best predicted by a low plasma renin, < or = 0.5 pmol/ml/h (<10 mU/l), despite treatment with an ACE inhibitor. We concluded that adrenal adenomas are an uncommon cause of hypertension. In the absence of hypokalaemia, a low plasma renin is a sufficient and simple way of detecting spironolactone-responders among patients with resistant hypertension. Only patients with both hypokalaemia and low plasma renin, measured while the patient is off beta blockade, require measurement of aldosterone. A plasma aldosterone >400 pmol/l together with renin activity < or = 0.5 pmol/ml/h should trigger further investigations for an adrenal adenoma.