第24章 作用于肾素血管紧张素醛固酮系统的药物双语缩减版概要1

1、第 24 章 肾素-血管紧张素醛固酮系统抑制药 华中科技大学同济医学院药理学系主讲教师 金满文2021年10月Inhibitors of the renin-angiotensin-aldosterone system1/70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响。2/703.全面比较AT1受体拮抗药与ACE抑制药在药理作用、作用机理、临床应用和不良反响方面的异同。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, congestive heart failure, m

2、yocardial infarction, and diabetic nephropathy PathophysiologyRenin-Angiotensin-Aldosterone SystemRAAS3/70renin-angiotensin-aldosterone system History Components of RAAS Functions and Effects of RAAS(RAAS) 4/70In 1898, Tiegerstedt and Bergman found that crude saline extracts of the kidney contained

3、a pressor substance that they named renin. History 1898, Tiegerstedt 和 Bergman 发现肾脏的盐水粗提物含有加压物质，他们将其命名为“肾素。5/70Tigerstedt R, Bergman PG: Niere und Kreislauf 肾脏和循环. Skand Arch Physiol 1898; 8:223-271.1934, Goldblatt 证明收缩肾血管可产生持续的高血压 (renal hypertension)In 1940, Braun-Menendez(Argentina), Page and Hel

4、mer (USA) 分别报道肾素是酶，产生缩血管物质，前者称其为hypertensin ，后者称其为angiotonin. 大约20年后，将此过程中的升压物质命名为血管紧张素angiotensin，血浆中的底物称为 血管紧张素原angiotensinogen. 7/70In the mid-1950s, a decapeptide and an octape-ptide were recognized. The octapeptide was shown to be the more active form. decapeptideoctapeptideangiotensin-converti

5、ng enzyme(ACE) enzyme (Angiotensin I) (Angiotensin II) in 1957, synthesized by Schwyzer and Bumpus 8/70In 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作用。Physiological rolesPathohysiological rolesPharmacological interv

6、ention9/70Thirst Converting enzyme Pressor effectSympatheticstimulationADH secretionConverting enzymeantagonistCaptopril enalaprilenalkirenRemikirenAliskirenRenin inhibitorAng II receptorAntagonist losartanAldosterone secretion ReninComponents of RAASAldosterone secretionAng IIIAng IVAng 1-710/70。 A

7、ngiotensin (3-8)AT4Ang IVAng(1-7) receptor AT1AT2?Phe-His8 9GG 11th, 200611/70Angiotensin 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 known biological effects of angiotensin II

8、 ？Antiproliferative 抗增生Proapoptotic 促凋亡Vasodilatory 扩血管Antihypertensive 抗高血压12/70Extrinsic Local RAASLocal (Tissue) RAAS (局部或组织RAAS)Intrinsic Local RAASThe traditional view of the RAAS is that of a classical endocrine system. Renin(kidney) angiotensinogen(liver) ACEThis traditional view is an oversi

9、mplification that must be expanded to include local RAAS (tissue) . Ang IAng IIAldosterone(kidney)Biological effects13/70Extrinsic Local RAAS (take up)Circulating renin of renal origin can be taken up by the arterial wall and by other tissues. 动脉壁和其他组织从循环中摄取肾源性肾素，激活局部的RAAS。14/70许多组织脑、血管、心脏、肾脏、肾上腺表达肾

10、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. Intrinsic Local RAAS (de novo synthesis) Many tissuesincluding the brain, blood vessels, heart, kidney, and adrenal glandexpress mRNAs for renin, angiotensino-gen, and/or ACE, and various cells cultured from these tissues produce reni

11、n, angioten-sinogen, ACE, and Ang I, II, and III. 15/70Functions and Effects of the RAAS17/70. Altered Peripheral Resistance I. Direct vasoconstriction 直接收缩血管II. peripheral noradrenergic neurotransmission A.NE release 增加NE释放 B.NE reuptake 减少NE再摄取 C.vascular responsiveness 增加血管反响性III.sympathetic disc

12、harges (CNS) 增强交感中枢输出IV.release of catecholamines from adrenal MedullaRapid Pressor Response 快加压反响MechanismResult. Altered Renal Function I. Direct Na+ reabsorption in proximal tubuleII. Release of aldosterone from adrenal cortex Na+ reabsorption and K+ excretion)III. Altered renal hemodynemics: A.

13、Direct renal vasoconstriction B.noradrenergic neurotransmission in kidney C.renal sympathetic tone (CNS)Slow Pressor Response 慢加压反响MechanismResult19/70. Altered Cardiovascular structure I. Non-hemodynamically mediated effects: expression of proto-oncogenes production of growth factors synthesis of e

14、xtracellular matrix proteinsII. Hemodynamically mediated effects: afterload (cardiac) wall tension (vascular)Vascular and cardiac hypertrophy & remodelling血管和心脏肥厚、重构MechanismResultThirst Converting enzyme Pressor effectSympatheticstimulationADH secretionConverting enzymeAntagonist 1981captopril enal

15、aprilAng II receptorAntagonist 1995losartan telmisartanAldosterone secretion MR antagonist spirolactone eplerenone 2002 ReninRenin inhibitorremikirenremikirenAliskiren 2007INHIBITORS OF THE RAAS20/7021/70RAAS抑制药上市时间1981, captopril(ACEI)1995, losartan(ARB)2002, eplerenone(MRA)2007, alisliren(RI) on t

16、he market上市Thirst Converting enzyme Pressor effectSympatheticstimulationADH secretionConverting enzymeantagonistCaptopril enalaprilremikirenRenin inhibitorAng II receptorAntagonist losartantelmisartanAldosterone secretion MR antagonist Spirolactone eplerenone Reninremikirenaliskiren补进展INHIBITORS OF

17、THE RAAS22/7023/70ACE Inhibitors (Angiotensin Converting Enzyme Inhibitors ) In the 1960s, Ferreira and colleagues 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 destruction of brady

18、kinin 24/701971年，Ondetti等*合成了tiprotide，是第一个用于临床的肽类ACEI。*: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, N.J)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。一、ACE的分类和构效关系25/70(二)ACEI与酶的结合27/70Pharmacological Effects the synthesis of angiotensin II, Ang IIthe destruction of bradykinin, BK prin

19、cipal pharmacological and clinical effectsAll ACE inhibitors have similar therapeutic indications, adverse-effect profiles, and contraindications. captopril may have a more favorable effect on quality of life. 全部ACE抑制药的适应症、不良反响、禁忌症都相似。ACE inhibitors differ with regard to three properties: (1) potenc

20、y, (2) drug or prodrug, (3) pharmacokinetics (fosinopril, spirapril ).差异有3：强度；药或前体药；药代。28/70Functions and Effects of the RAAS29/7030/70扩管降压，增加动脉血管顺应性抗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 抗动脉粥样硬化抗氧化作用 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。 三、作用机理机制减少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P

21、LC和PLA2，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。31/70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 。 Hypertension 高血压(一线药物)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 combina

22、tion of an ACE inhibitor and either a Calcium channel blocker, an adrenergic receptor blocker, or a diuretic. 32/70Therapeutic Uses 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。 33/70ACE inhibitors are superior to other antihyper-tensive drugs in hypertensive patients with diabetes, in whom they

23、improve endothelial function and reduce cardiovascular events. 在伴有糖尿病的高血压病人，转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。 Left Ventricular Systolic Dysfunction 34/70ACE Inhibitors prevents or delays the progression of heart failure, decreases the incidence of sudden death and myocardial infarction, decreases

24、 hospitalization, and improves quality of life. ACE 抑制药能预防或延缓心衰的进展，减少心梗和猝死事件，降低住院率，改善生活质量。左室收缩功能不全(一线药物) 35/70Several large prospective, randomized, placebo-controlled clinical studies support the useful-ness of ACE inhibitors in patients with varying degrees of left ventricular systolic dysfunction

25、. 大样本、前瞻性、随机、抚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。 36/70Unless contraindicated, 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，无论其有否心衰病症，所有左室收缩功能受损者，都应使用ACE抑制药。The more severe the ven

26、tricular dysfunction, the greater is the benefit from ACE inhibition. 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 hyperten

27、sive and diabetic patients. 37/70Acute Myocardial Infarction 急性心梗在围梗死期开始用转换酶抑制药，降低总死亡率。患有高血压和糖尿病的急性心肌梗死患者获益更甚。 38/70Unless contraindicated (e.g., cardiogenic shock or severe hypotension), ACE inhibitors should be started immediately during the acute phase of myocardial infarction.如无禁忌(心源性休克、严重的低血压)，

28、心梗的急性期应立即使用转换酶抑制药。 39/70In high-risk patients (e.g., large infarct, systolic 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。 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

29、选病人数580501556929712218观察时间1 M6 W5 yr4.2 yrMI 心肌梗死Stroke 中风cardiac deathoverall mortality：未观察40/70 ACE inhibitors tilt the fibrinolytic balance toward a profibrinolytic state in patients with coronary artery disease. 在冠心病人，ACE抑制药使纤溶系统向促纤溶方向倾斜。Patients Who Are at High Risk of Cardiovascular Events 心血管

30、事件高危患者 Profibrinolytic stateAntifibrinolytic stateACEI41/70 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.42/70 Chronic Renal Failure (慢性肾衰) 糖尿病是肾脏疾病的首因，在I型糖尿病

31、和糖尿病性肾病患者，卡托普利能预防或延缓肾病的开展。 43/70ACE inhibitors 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。 Before the use

32、 of ACE inhibitors, patients with scleroderma renal crisis generally died within several weeks. ACE inhibitors have improved considerably this otherwise grim prognosis. 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。44/70Scleroderma Renal Crisis (硬皮病肾危象) 45/70Adverse Effects of ACE Inhibitors 英文名中文名英

33、文名中文名Hypotension 低血压Angioedema 血管性水肿Cough 咳嗽(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 中白少 46/70Other drug ACE InhibitorsAntacids(抗酸药)bioavailability Capsaicin(辣椒素) cough NSAIDs antihypertensive K+-spar

34、ing diur. hyperkalemia K+ supplements hyperkalemia ACE Inhibitors Other drug plasma levels of digoxin plasma levels of lithium hypersensitivity to Allopurinol Drug Interactions1、不良反响：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

35、途径！问题的提出 尽管ACEI在很大程度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：47/70Thirst Converting enzyme Pressor effectSympatheticstimulationADH secretionConverting enzymeantagonistCaptopril enalaprilenalkirenremikirenRenin inhibitorAng II receptorBlocker losartanAldosterone secretionAldosterone receptorantagonist Renin48/

36、70Attempts 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.肽类ARBs不能口服，无临床应用价值。49/70Angiotensin II receptor blockers HistoryAll peptide ARBs expressed unaccep

37、table partial agonist activity. 肽类ARBs的局部冲动剂活性(血管紧张素II受体拮抗剂，ARBs). A breakthrough came in the early 1980s with the issuance of patents on a series of imidazole-5-acetic acid derivatives. 50/70突破源于1982年关于咪唑5乙酸衍生物竞争Ang II受体的专利。51/701982年，Furakawa申请了关于咪唑-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

38、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)。40/75 非肽类AT1 受体阻滞剂：氯沙坦(losartan，科素亚，cozaar)、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

39、) 53/70ARBs bind to the AT1 receptor with high affinity ( 10,000-fold selective for the AT1 versus the AT2 ) 高度选择性地作用于AT1 。54/70Pharmacological Effects ARBs potently and selectively inhibit, both in vitro and in vivo, most of the biological effects of angiotensin II.Functions and Effects of the RAAS

40、55/7056/701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 and 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：ARBs differ from ACE inhibitors in several important aspects: 57/70ARBsACE inhibi

41、torsactivation of AT1biosynthesis of Ang II the levels of Ang IIthe levels of of Ang IIrenin releaserenin release activation of AT2angiotensin(1-7) levelsthe levels of ACE substrate (bradykinin and Ang I ) Cough, AngioedemaTeratogenic potential Fetopathic potential 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

42、，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 receptor 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59/70Therapeutic Uses Approved therapeutic usesARBsHyp

43、ertensionall ABRsHeart failure (intolerant of ACEI) valsartan Diabetic nephropathy (type 2 diabetes mellitus ) irbesartan and losartan Telmisartan*Stroke prophylaxis losartanMyocardial infarction Valsartan All ARBs are approved for the treatment of hypertension.Hypertension 高血压 1.病人对其耐受良好，不受剂量、年龄和种族

44、的影响。2.首剂现象低血压反响少见，直立性低血压的发生率缺乏1%；无冲动药活性，治疗高血压停药时无反跳现象。60/7061/70The Evaluation of Losartan 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. 与卡托普利比，改善病症作用同，降低病

45、死率更好Heart failure 心衰Both valsartan and candesartan reduce mortality and morbidity in heart failure patients. 降低心衰的发病率和病死率。ARBs are renoprotective in type 2 diabetes mellitus. Based on these results, many experts now consider them the drugs of choice for renoprotection in diabetic patients. 在2型糖尿病有明显

46、的肾保护作用Diabetic nephropathy 糖尿病性肾病Stroke prophylaxis 预防卒中Losartan reducing stroke in hypertensive patients with left ventricular hypertrophy. 在左室肥厚的高血压患者，氯沙坦减少卒中。62/7063/70Valsartan in Acute Myocardial Infarction (VALIANT) trial demonstrated that valsartan is as effective as captopril in patients with myocardial infarction complicated by left ventricular systolic dysfunction with regard to all-cause-mortality 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。Myocardial infarction 心肌梗死64/70The incidence of discontinuation of ARBs owing to