作用于肾素血管紧张素醛固酮系统的药课件

1、第 23 章 作用于肾素-血管紧张素-醛固酮系统的药物华中科技大学同济医学院药理学系授课教师 金满文2015年10月本次课要求掌握的内容2.ACE抑制药的药理作用、作用机理、主要的临床应用和不良反应。2/743.全面比较AT1受体拮抗药与ACE抑制药在药理作用、作用机理、临床应用和不良反应方面的异同。4.通过本章学习，你对靶点发现、确认及与药物研发的关系有何心得？ 1.RAAS抑制药分类及各类的主要代表药。hypertension, myocardial hypertrophy, congestive heart failure, etc.physiologyRenin-Angiotensin

2、-Aldosterone SystemRAAS3/74Patho第一节 肾素-血管紧张素-醛固酮系统及其功能 简史 History of RAAS RAAS的组成成份 Components of RAAS RAAS的功能 Functions of RAAS4/74In 1898, Tiegerstedt and Bergman found that rabbit renal tissue saline crude extracts contained a pressor substance that they named renin. History 1898, Tiegerstedt 和 B

3、ergman (The Karolinska Institute)发现兔肾脏的盐水粗提物含有加压物质，他们将其命名为“肾素”。5/74Tigerstedt R, Bergman PG: Niere und Kreislauf 肾脏和循环. Skand Arch Physiol 1898; 8:223-271.1934, Goldblatt 狭窄狗肾血管可产生持续的高血压 (renal hypertension)Braun-Menendez(Argentina, 1956), Page and Helmer (USA, Eli-Lilly Lab, 1957) 分别报道缩血管物质，前者称其为hy

4、pertensin ，后者称其为angiotonin. 1958年，Page and Braun-Menndez将此过程中的升压物质命名为血管紧张素angiotensin，7/74 血浆中的前体物质物称为 血管紧张素原angiotensinogen. In the mid-1950s, a decapeptide (10肽) and an octape-ptide (8肽) were recognized. The octapeptide was shown to be the more active form. decapeptideoctapeptideangiotensin-conver

5、ting enzyme enzyme (Angiotensin I, 10肽) (Angiotensin II，8肽) in 1957, synthesized by Schwyzer and Bumpus 8/74In the early 1970s, important physiological and pathophysiological roles for the RAAS were revealed. 上个世纪七十年代早期，开始认识RAAS的重要的生理和病理生理作用。Physiological roles 生理作用Pathohysiological roles 病理生理作用Phar

6、macological intervention9/74药理干预 Pressor effectSympatheticstimulationADH secretionConverting enzymeantagonistCaptopril enalaprilenalkirenRemikirenAliskirenRenin inhibitorAng II receptorAntagonist losartanAldosterone secretion 肾素Aldosterone secretionAng IIIAng IVAng 1-710/74一、RAAS的组成 Components of RA

7、AS 转换酶Converting enzyme Renin血管紧张素原Cardiac remodeling Thirst受体受体。 Angiotensin (3-8)AT4Ang IVMas AT1AT2?11/74Dihexa血管紧张素受体(Angiotensin Receptors AT)AT1AT2359 amino acids363 amino acidshigh affinity for losartanlow affinity for losartanlow affinity for PD 123177 high affinity for PD 123177 most of the

8、 known biological effects of angiotensin II ？大多数已知的Ang II效应Antiproliferative 抗增生Proapoptotic 促凋亡Vasodilatory 扩血管Antihypertensive 抗高血压12/74血管紧张素受体(Angiotensin Receptors AT) Ang IV / AT4Ang(1-7) / MasR改善认知功能抗重构 Anti-remodeling改善记忆抗炎 Anti-inflammatory改善运动障碍抗动粥 Anti-atherogenic抗增生 Anti-proliferative小分子激

9、动剂：Dihexa扩管 Vasodilatation (+EC)13/74醛固酮及其受体(aldosterone and its receptor)14/74研究进展：（关注心血管重构） 醛固酮可在其他组织局部生成； 醛固酮受体可在其他细胞表达； 其作用远不只调节水盐电解质代谢。经典学说：Ang II 肾上腺皮质球状带细胞 分泌醛固酮 远曲小管远端及集合管上皮细胞的醛固酮受体 调节相应功能。局部或组织RAAS Local (Tissue) RAASThe traditional view of the RAAS is that of a classical endocrine system.

10、Renin(kidney) angiotensinogen(liver) 转换酶抑制剂应用早期的临床适应症：高血浆肾素活性的高血压。但在实际用药中发现，对血浆肾素活性正常、甚至偏低的病人，降压效果依然良好！15/74何以解释？提出假说实验求证建立学说许多组织（脑、血管、心脏、肾脏、肾上腺等）表达肾素、血管紧张素原、转换酶的mRNA，源于这些组织的细胞培养可产生肾素、血管紧张素原、转换酶、Ang I, II, and III. Many tissuesincluding the brain, blood vessels, heart, kidney, and adrenal glandexpre

11、ss mRNAs for renin, angiotensino-gen, and/or ACE, and various cells cultured from these tissues produce renin, angioten-sinogen, ACE, and Ang I, II, and III. 16/74Functions of the RAAS二、肾素-血管紧张素-醛固酮系统的功能1、快速加压效应2、慢加压效应3、参与心血管重构Functions and Effects of the RAAS18/7019/74. Altered Peripheral Resistanc

12、e I. 直接收缩血管 Direct vasoconstrictionII. peripheral noradrenergic neurotransmission A. 增加NE释放 NE release B. 减少NE再摄取 NE reuptake C. 增加血管反应性vascular responsivenessIII. 增强交感输出 sympathetic discharges (CNS)IV. 增加儿茶酚胺的释放 release of catecholamines快加压反应 Rapid Pressor ResponseMechanismResult. Altered Renal Fun

13、ction 1. 近曲小管钠重吸收 Direct Na+ reabsorption 2. 醛固酮分泌增加 Release of aldosterone from adrenal cortex （留钠排钾)3. 改变肾脏血流动力学 Altered renal hemodynemics: A. 直接收缩肾血管 Direct renal vasoconstriction B. 增强肾脏去甲肾上腺素能神经传递noradrenergic neurotransmission in kidney C. 肾交感张力增加 renal sympathetic tone (CNS)Slow Pressor Resp

14、onse 慢加压反应MechanismResult21/74. Altered Cardiovascular structure I. 非血流动学中介的效应 non-hemodynamically mediated effects: 原癌基因表达 expression of proto-oncogenes 生长因子合成 production of growth factors 胞外基质蛋白合成 extracellular matrix proteinsII.血流动学中介的效应 hemodynamically mediated effects: 心脏后负荷 afterload (cardiac)

15、 血管壁张力 wall tension (vascular)Vascular and cardiac hypertrophy & remodelling血管和心脏肥厚、重构MechanismResultThirst Converting enzyme Pressor effectSympatheticstimulationADH secretionAldosterone secretion ReninINHIBITORS OF THE RAAS22/70Renin inhibitorremikirenremikirenAliskiren 2007ACE Inhibirorcaptopril 1

16、981enalaprilAT1 Antagonist losartan 1995telmisartan MR antagonist spirolactone eplerenone 2002 23/74RAAS抑制药上市时间1981, captopril(ACEI)1995, losartan(ARB)2002, eplerenone(MRA)2007, alisliren(RI) on the market上市Thirst Converting enzyme Pressor effectSympatheticstimulationADH secretionAldosterone secreti

17、on ReninINHIBITORS OF THE RAAS24/74Renin inhibitorremikirenremikirenAliskiren 2007AT1 Antagonist losartan 1995telmisartan MR antagonist spirolactone eplerenone 2002 ACE Inhibirorcaptopril 1981enalapril25/74ACE Inhibitors (Angiotensin Converting Enzyme Inhibitors ) In the 1960s, Ferreira and colleagu

18、es found that the venoms of pit vipers (颊窝毒蛇)contain factors that intensify responses to bradykinin. Erdos and coworkers established:ACE kininase IIsynthesis of Ang II血管紧张素II合成 destruction of bradykinin缓激肽降解 颊窝毒蛇的蛇毒含有增强缓激肽的物质！继而认识其为激肽酶II抑制剂。26/741971年，Ondetti等*合成了tiprotide，是第一个用于临床的肽类ACEI。*: Bristol

19、-Myers Squibb Pharmaceutical Research Institute, Princeton, N.J)1977年，Ondetti等合成卡托普利；1981年，卡托普利用于临床。ACEI是目前主要的心血管药物类别之一。27/74【药理作用】Pharmacological Effects the synthesis of angiotensin II, Ang IIthe destruction of bradykinin, BK principal pharmacological and clinical effects全部ACE抑制药的适应症、不良反应、禁忌症都相似。A

20、ll ACE inhibitors have similar therapeutic indications, adverse-effect profiles, and contraindications. captopril may have a more favorable effect on quality of life. 差异：强度；药或前体药；药代。ACE inhibitors differ with regard to three properties: (1) potency, (2) drug or prodrug, (3) pharmacokinetics (fosinop

21、ril, spirapril ).28/74Functions and Effects of the RAAS29/7430/74降压：扩管、降容、增加动脉血管顺应性抑制和逆转心血管病理性重构保护血管内皮细胞抗心肌缺血和保护心肌保护肾脏 抗动脉粥样硬化【作用机制】本类药物的作用均源于其对ACE的抑制作用。包括循环和局部组织的ACE.31/74(二)ACEI与酶的结合羧基羰基巯基清除自由基 ACEI降低血浆脂质过氧化物浓度，对抗自由基对心脏和血管的损伤作用。 减少Ang II的生成 因Ang II量减少，削弱Ang II对心血管的直接和间接作用。减少BK的代谢 BK量增加，通过激活PLC和PLA

22、2，使NO和PGI2增加舒张血管、抗血小板聚集、抗心血管细胞肥大增生。抑制交感神经递质的释放 减弱Ang对交感神经冲动传递的易化作用 。33/74 在冠心病人，ACE抑制药使纤溶系统向促纤溶方向倾斜。 ACE inhibitors tilt the fibrinolytic balance toward a profibrinolytic state in patients with coronary artery disease. Profibrinolytic stateAntifibrinolytic stateACEI34/74在心血管事件高危患者有促纤溶趋势35/74ACEI按化学结

23、构分类 ACE inhibitors alone normalize blood pressure in approximately 50% of patients with mild to moderate hypertension. 90 of patients with mild to moderate hypertension will be controlled by the combination of an ACE inhibitor and either a Calcium channel blocker, an adrenergic receptor blocker, or

24、a diuretic. 35/70Therapeutic Uses 1. 高血压 Hypertension (一线药物)在轻中度高血压，单用转换酶抑制剂可使50患者的血压得以控制，如与其他降压药合用，控制率可达90。 ACE inhibitors are superior to other antihyper-tensive drugs in hypertensive patients with diabetes, in whom they improve endothelial function and reduce cardiovascular events. 在伴有糖尿病的高血压病人，转

25、换酶抑制药能改善内皮细胞功能，减少心血管事件，故优于其他抗高血压药物（其实AT1拮抗剂也很好）。37/74 Congestive heart failure 38/70ACE Inhibitors prevents or delays the progression of heart failure, decreases the incidence of sudden death and myocardial infarction, decreases hospitalization, and improves quality of life. ACE 抑制药能预防或延缓心衰的进展，减少心梗和

26、猝死事件，降低住院率，改善生活质量。2. 充血性心力衰竭(一线药物) Several large prospective, randomized, placebo-controlled clinical studies support the useful-ness of ACE inhibitors in patients with varying degrees of left ventricular systolic dysfunction. 大样本、前瞻性、随机、安慰剂对照的临床试验结果支持在各种程度的左室收缩性功能不全患者使用转换酶抑制药。39/74 36/70Unless cont

27、raindicated, ACE inhibitors should be given to all patients with impaired left ventricular systolic function whether or not they have symptoms of overt heart failure.只要没有禁忌症，无论其有否心衰症状，所有左室收缩功能受损者，都应使用ACE抑制药。The more severe the ventricular dysfunction, the greater is the benefit from ACE inhibition.

28、左室功能不全越严重，使用ACE抑制药的受益越大。 ACE inhibitors reduce overall mortality when treatment is begun during the peri-infarction period. The beneficial effects of ACE inhibitors in acute myocardial infarction are particularly large in hypertensive and diabetic patients. 心肌梗死 Myocardial Infarction在围梗死期开始用转换酶抑制药，降

29、低总死亡率。患有高血压和糖尿病的急性心肌梗死患者获益更甚。41/74 Unless contraindicated (e.g., cardiogenic shock or severe hypotension), ACE inhibitors should be started immediately during the acute phase of myocardial infarction.只要没有禁忌症(心源性休克、严重的低血压)，心梗的急性期应立即开始使用转换酶抑制药。42/74 In high-risk patients (e.g., large infarct, systolic

30、 ventricular dysfunction), ACE inhibition should be continued long term. 在高危病人(大面积梗死、左室收缩功能不全)，转换酶抑制剂应长期应用。43/74 Clinical Trials with ACE Inhibitors in Heart Disease 临床试验代码ISIS-4SMILEHOPEUROPA资料发表时间1995199520002003入选病种MIMICADCAD入选病人数580501556929712218观察时间1 M6 W5 yr4.2 yrMI 心肌梗死Stroke 中风cardiac death

31、overall mortality：未观察44/74 Diabetes mellitus is the leading cause of renal disease. In patients with type 1 diabetes mellitus and diabetic nephropathy, captopril prevents or delays the progression of renal disease.慢性肾衰 Chronic Renal Failure 糖尿病是肾脏疾病的首因，在I型糖尿病和糖尿病性肾病患者，卡托普利能预防或延缓肾病的发展。45/74 ACE inhib

32、itors also attenuate the progression of renal insufficiency in patients with a variety of nondiabetic nephropathies and may arrest the decline in GFR even in patients with severe renal disease.转换酶抑制药也可延缓各种非糖尿病性肾病患者的肾功能不全的病程，甚至在严重肾病患者仍可阻止GFR的降低。46/74 在ACEI用于硬皮病肾危象前，该病患者均死于几周之内。ACEI在很大程度上改善了此可怕预后。Befo

33、re the use of ACE inhibitors, patients with scleroderma renal crisis generally died within several weeks. ACE inhibitors have improved considerably this otherwise grim prognosis. 硬皮病肾危象 Scleroderma Renal Crisis47/74 Adverse Effects of ACE Inhibitors 英文名中文名英文名中文名Hypotension 低血压Angioedema 血管性水肿Cough 咳

34、嗽(干咳)Hyperkalemia 高血钾Dysgeusia 味觉障碍Acute Renal Failure 急性肾衰Fetopathic Potential胎儿病潜在危险Skin Rash 皮疹Hepatotoxicity肝毒性Proteinuria 蛋白尿Neutropenia 中性白C减少48/74 Other drugACE InhibitorsAntacids(抗酸药)bioavailability Capsaicin(辣椒素) cough NSAIDs 非甾体抗炎药 antihypertensive K+-sparing diur. 留钾利尿药 hyperkalemia K+ su

35、pplements 补钾 hyperkalemia Other drug ACE Inhibitors plasma levels of digoxin plasma levels of lithium hypersensitivity to Allopurinol Drug Interactions49/741.不良反应：干咳、血管性水肿等。2.ACE不是Ang II生成的唯一途径，甚至不是主要途径。如糜酶(chymase)的作用,其他如胰蛋白酶、组织蛋白酶G、激肽释放酶等也可将Ang I转化成Ang II。3.AT2受体中介的某些作用被减弱。寻找新的途径！问题的提出 尽管ACEI在很大程度

36、上改善了高血压和充血性心力衰竭的治疗，但仍有许多不尽人意之处：50/74Thirst Converting enzyme Pressor effectSympatheticstimulationADH secretionAldosterone secretion ReninINHIBITORS OF THE RAAS51/74Renin inhibitorremikirenremikirenAliskiren 2007AT1 Antagonist losartan 1995telmisartan MR antagonist spirolactone eplerenone 2002 ACE In

37、hibirorcaptopril 1981enalapril肽类ARBs不能口服 Attempts to develop therapeutically useful ARBs date to the early 1970s. Saralasin was potent angiotensin II receptor antagonists but were of no clinical value because of lack of oral bioavailability.Angiotensin II receptor blockers History肽类ARBs均具部分激动剂活性 All

38、 peptide ARBs expressed unacceptable partial agonist activity. (血管紧张素II受体拮抗剂，ARBs)结论：无临床应用价值早期制备Ang II类似物，如 Saralasin。52/74. A breakthrough came in the early 1980s with the issuance of patents on a series of imidazole-5-acetic acid derivatives. 突破始于1982年关于咪唑5乙酸衍生物竞争Ang II受体的专利。53/741982年，Furakawa申请了

39、关于咪唑-5-乙酸衍生物能与Ang 竞争受体的专利，美国杜邦公司从中受到启发。杜邦公司有关于联苯四唑降压的专利，通过计算机模拟，将咪唑衍生物与联苯四唑接起来，合成了大量的化合物，经不断改构，筛选出氯沙坦(losartan),1995年在美国作为抗高血压药物上市。商品名科素亚(Cozaar)。54/74Arieh WarshelMichael LevittMartin Karplus2013年化学诺贝尔奖得主的主要贡献： 将实验带入信息时代，时至今日，化学领域所取得的大部分重要进展都离不开先进计算机模型的帮助。40/75 非肽类AT1 受体阻滞剂：氯沙坦(losartan，科素亚，cozaar)

40、缬沙坦(valsartan，代文，diovan) 厄贝沙坦(Irbesartan，安博维，aprovel)坎地沙坦(candesartan)替米沙坦(telmisartan)他索沙坦(tasosartan，ANA-756)依普沙坦(eprosartan，SK&F108566)佐拉沙坦(zolarsartan，GR117289) 57/74ARBs bind to the AT1 receptor with high affinity ( 10,000-fold selective for the AT1 versus the AT2 )对AT1选择性高亲和地作用。Pharmacological

41、 Effects ARBs potently and selectively inhibit, both in vitro and in vivo, most of the biological effects of angiotensin II. 无论是体外和体内，ARBs能强效、选择性地抑制大多数Ang II的生物效应。58/74Functions and Effects of the RAAS59/741血管平滑肌收缩7肾上腺儿茶酚胺释放2快升压反应8NA能神经传递加强3慢升压反应9交感张力增强4渴10肾脏功能改变5加压素分泌11细胞肥大、增生6醛固酮释放ARBs potently an

42、d selectively inhibit, both in vitro and in vivo, most of the biological effects of angiotensin II.被拮抗的Ang II的作用包括：60/74ARB与 ACEI的重要差别 ARBs differ from ACE inhibitors in several important aspects: ARBsACE inhibitorsactivation of AT1biosynthesis of Ang II the levels of Ang IIthe levels of of Ang IIre

43、nin releaserenin release activation of AT2angiotensin(1-7) levelsthe levels of ACE substrate Cough, AngioedemaTeratogenic potential Fetopathic potential 61/74于1998年年底在美国获准上市。在临床研究中，替米沙坦与氨氯地平相比，能更大程度地降低收缩压和舒张压，且作用时间更长，为此类药物中第一个真正的“一日一次”治疗药。 Potential utility of telmisartan, an angiotensin II type 1 r

44、eceptor blocker with PPAR-gamma-modulating activity for the treatment of cardiometabolic disorders. Curr Mol Med. 2007 Aug;7(5):463-9. 替米沙坦Therapeutic Uses Approved therapeutic usesARBsHypertensionall ABRsHeart failure (intolerant of ACEI) valsartan Diabetic nephropathy (type 2 diabetes mellitus ) i

45、rbesartan and losartan Telmisartan*Stroke prophylaxis losartanMyocardial infarction Valsartan 63/74All ARBs are approved for the treatment of hypertension.高血压 （一线药物） 1.病人对其耐受良好，不受剂量、年龄和种族的影响。.2.首剂现象（低血压反应）少见，直立性低血压的发生率不足1%；无激动药活性，治疗高血压停药时无反跳现象。64/74与卡托普利比，氯沙坦改善症状作用同，降低病死率更好。 The Evaluation of Losart

46、an in the Elderly (ELITE) study reported that in elderly patients with heart failure, losartan was as effective as captopril in improving symptoms and reduced mortality more than did captopril. 心衰 Heart failureBoth valsartan and candesartan reduce mortality and morbidity in heart failure patients. 65/74在伴有左室收缩功能不全的心梗患者，缬沙坦降低全因死亡率的作用同卡托普利。Valsartan in Acute Myocardial Infarction (VALIANT) tr