Horký Karel
II. interní klinika kardiologie a angiologie 1. lékarské fakulty UK a VFN Praha.
Vnitr Lek. 2010 Feb;56(2):120-6.
The role of renin-angiotensin-aldosterone system (RAAS) in regulating the volume and composition of extracellular fluid, blood pressure (BP) as well as onset and progression of cardiovascular and renal diseases has been studied for more than 150 years. The compounds that block the vital stages of the RAAS cascade, such as ACE-inhibitors (ACEI), AT1-receptor blockers (ARB) and aldosterone receptor antagonists, importantly extended our treatment options. However, the positive therapeutic effects of these compounds also have certain negative consequences. Administration of ACEIs and ARBs interrupts physiological feedback for renal renin release and leads to reactive elevation of circulating active renin and greater production of angiotensin I and angiotensin II with subsequent return of aldosterone secretion to the pre-treatment levels ('escape' phenomenon). These possible adverse effects of the intermediary products of incomplete RAAS blockade leading to organ complications have facilitated the efforts to develop compounds blocking the initial stages of renin-angiotensin cascade--i.e. direct renin blockers. After several years of unsuccessful attempts, the recent years have seen development of the first non-peptide, orally long-term effective renin inhibitor, aliskiren fumarate. In monotherapy or in combination with other antihypertensives (hydrochlorothiazide, ARB, ACEI), aliskiren reduces BP in a dose-dependent manner (75-600 mg/den). Aliskiren reduces plasma renin activity (PRA) and neutralises hydrochlorothiazide-induced RAAS activation. Once daily administration of the drug leads to longer than 24-hour activity and its prolonged blocking effects on the kidneys are the basis for its renoprotectivity. In addition to the significant antihypertensive effect, clinical studies also showed a range of organoprotective properties in patients with left ventricle hypertrophy (ALLAY study), heart failure (ALOFT study) and diabetic nephropathy (AVOID study). Similar to other AT1-blockers, aliskiren has a minimum of adverse side effects. Aliskiren for hypertension therapy was launched in clinical practice in USA in 2007 (Tekturna and combination formulation TekturnaHCl, respectively) and shortly after that in European Union as Rasilez. In the Czech Republic, aliskiren (Rasilez) was released for clinical use by diabetologists and nephrologists in patients with hypertension and concomitant diabetes, nephropathy and proteinuria in doses of 150-300 mg per day on 1. 8. 2009. It is recommended as monotherapy or in combination with other antihypertensives to treat conditions with elevated PRA, including PRA elevation following diuretic, ACEI or ARB administration. Aliskiren might be used in patients who do not tolerate ACEIs as well as in patients in whom angiotensin II participates in the pathogenesis of their diseases. Reno-protective properties leading to a reduction in proteinuria and delaying renal failure progression were observed in patients with diabetic as well as non-diabetic nephropathy. The drug is the subject to similar precautions and contraindications as ACEIs and ARBs, i.e. pregnancy and bilateral renal artery stenosis. To make meaningful conclusions about the so far positive contribution of this new treatment class and its broad applicability for the therapy of hypertension and other cardiovascular diseases, it will be imperative to assess its long-term effects on morbidity and mortality as well as to compare these agents with other RAAS blockers in long-term clinical studies; this represents a research effort for another 7-8 years.
肾素 - 血管紧张素 - 醛固酮系统(RAAS)在调节细胞外液的容量和成分、血压(BP)以及心血管和肾脏疾病的发生与发展方面的作用,已经被研究了150多年。阻断RAAS级联反应关键阶段的化合物,如血管紧张素转换酶抑制剂(ACEI)、血管紧张素Ⅱ1型受体阻滞剂(ARB)和醛固酮受体拮抗剂,显著扩展了我们的治疗选择。然而,这些化合物的积极治疗效果也有一定的负面后果。使用ACEI和ARB会中断肾脏肾素释放的生理反馈,导致循环中活性肾素反应性升高,血管紧张素I和血管紧张素II生成增加,随后醛固酮分泌恢复到治疗前水平(“逃逸”现象)。RAAS不完全阻断的中间产物的这些可能的不良反应导致器官并发症,促使人们努力开发阻断肾素 - 血管紧张素级联反应初始阶段的化合物,即直接肾素阻滞剂。经过数年的尝试失败后,近年来首个非肽类、口服长效有效的肾素抑制剂富马酸阿利吉仑得以研发。在单药治疗或与其他抗高血压药物(氢氯噻嗪、ARB、ACEI)联合使用时,阿利吉仑以剂量依赖的方式降低血压(75 - 600毫克/日)。阿利吉仑降低血浆肾素活性(PRA),并中和氢氯噻嗪诱导的RAAS激活。每日一次给药导致药物活性超过24小时,其对肾脏的长效阻断作用是其肾脏保护作用的基础。除了显著的降压作用外,临床研究还显示,在左心室肥厚患者(ALLAY研究)、心力衰竭患者(ALOFT研究)和糖尿病肾病患者(AVOID研究)中,阿利吉仑具有一系列器官保护特性。与其他AT1阻滞剂类似,阿利吉仑的副作用最少。用于高血压治疗的阿利吉仑于2007年在美国临床实践中推出(分别为Tekturna和复方制剂TekturnaHCl),此后不久在欧盟以Rasilez的名称推出。在捷克共和国,2009年8月1日起,糖尿病专家和肾病专家将阿利吉仑(Rasilez)用于高血压合并糖尿病、肾病和蛋白尿患者的临床治疗,剂量为每日150 - 300毫克。推荐将其作为单药治疗或与其他抗高血压药物联合使用,以治疗PRA升高的情况,包括利尿剂、ACEI或ARB给药后PRA升高的情况。阿利吉仑可用于不耐受ACEI的患者以及血管紧张素II参与疾病发病机制的患者。在糖尿病和非糖尿病肾病患者中均观察到了阿利吉仑的肾脏保护特性,可减少蛋白尿并延缓肾衰竭进展。该药物与ACEI和ARB有类似的注意事项和禁忌症即妊娠和双侧肾动脉狭窄。为了就这一新治疗类别迄今为止的积极贡献及其在高血压和其他心血管疾病治疗中的广泛适用性得出有意义的结论,必须评估其对发病率和死亡率的长期影响,并在长期临床研究中将这些药物与其他RAAS阻滞剂进行比较;这需要7 - 8年的研究努力。