2012作用于内脏系统药物

1、? reduce CHF-associated morbidity and mortality rates ? may have a more favorable effect on quality of life,第二十三章,肾素-血管紧张素系统药理（Reninangiotensin system, RAS）,肾素血管紧张素系统药理 一、 肾素血管紧张素系统及意义（了解） 二、 肾素血管紧张素系统阻断药 1、 血管紧张素转化酶抑制剂（ACEI） 共性（掌握） 常用的ACEI（熟悉） 2、 AT1-R阻断剂 作用特点及应用（掌握） 常用药（熟悉）,血管紧张素原 血管紧张素 血管紧张素 ,肾素血

2、管紧张素系统,血管紧张素转换酶 （ACE）,肾素,Components of the RAS,AngII, the most active angiotensin peptide, is derived from angiotensinogen in two proteolytic steps. renin, an enzyme released from the kidneys, cleaves the decapeptide AngI from the amino terminus of angiotensinogen (renin substrate). ACE ,removes the

3、 carboxy-terminal dipeptide of AngI to produce the octapeptide AngII. AT1 and AT2, AngII acts by binding to two heptahelical GPCRs,The understanding of the RAS has expanded in recent years.,The current view of the RAS also includes a local (tissue) RAS, alternative pathways for AngII synthesis (ACE

4、independent), formation of other biologically active angiotensin peptides (AngIII, AngIV, Ang17), additional angiotensin binding receptors (angiotensin subtypes 1, 2, and 4 AT1, AT2, AT4; Mas) that participate in cell growth differentiation, hypertrophy, inflammation, fibrosis, and apoptosis.,局部组织RA

5、S（local tissue RAS）,部位：心肌、血管、肝、肾、血管、粘膜等 AngI AngII 自分泌、旁分泌等方式发挥作用。心血管组织中的RAS在高血压、心血管重构、动脉粥样硬化等发生发展过程中起重要作用。,Formation of angiotensins I-IV from the N-terminal of the precursor protein angiotensinogen,Angiotensin Peptides,Ang I(1-10) Ang II(1-8) AT1-R and AT2-R Ang III(2-8) AT1-R/? Ang IV(3-8) AT4-R(

6、IRAP)/? Ang(1-7) Mas-R,Current view of the reninangiotensin system cascade Abbreviations: ACE, angiotensin-converting enzyme; Ang, angiotensin; AMP, aminopeptidase; AT1, Ang II type 1 receptor; AT2, Ang II type 2 receptor; Mas, Ang(17) receptor Mas; D-Amp, dipeptidyl-.,Santos R A S et al. Exp Physio

7、l 2008;93:519-527,Schematic representation of the enzymatic pathways involved in the generation of angiotensin peptides,Angiotensin Receptors,Most of the known biological effects of AngII are mediated by the AT1-R. associated with hypertension, hypertrophic cardiomyopathy, and coronary artery vasoco

8、nstriction. Functional roles for the AT2 -R are less well defined, but they may counterbalance many of the effects of the AT1-R by having antiproliferative, proapoptotic, vasodilatory, natriuretic, and antihypertensive effects . The Mas-R mediates the effects of Ang(17), which include vasodilation a

9、nd anti-proliferation. Deletion of the Masgene in transgenic mice reveals cardiac dysfunction The AT4-R(IRAP) mediates the effects of AngIV. This receptor is a single transmembrane protein (1025 amino acids) that co-localizes with the glucose transporter GLUT4. AT4 receptors are detectable in a numb

10、er of tissues, such as heart, vasculature, adrenal cortex, and brain regions processing sensory and motor functions .,Angiotensin-Converting Enzyme (ACE, Kininase II, Dipeptidyl Carboxypeptidase二肽羧肽酶 ),ACE is an ectoenzyme and glycoprotein with an apparent molecular weight of 170,000. ACE is rather

11、nonspecific and cleaves dipeptide units from substrates with diverse amino acid sequences. ACE is identical to kininase II, the enzyme that inactivates bradykinin and other potent vasodilator peptides.,Angiotensin-Converting Enzyme 2,Two groups independently discovered a novel ACE-related carboxypep

12、tidase, now termed ACE2 ACE2 cleaves one amino acid from the carboxyl terminal to convert AngI to Ang(19) and AngII to Ang(17). AngII is the preferred substrate for ACE2 with 400-fold higher affinity than AngI. ACE2 may serve as a counter-regulatory mechanism to oppose the effects of ACE. ACE2 regul

13、ates the levels of AngII and limits its effects by converting it to Ang(17), which binds to Mas receptors and elicits vasodilator and anti-proliferative responses . ACE2 is not inhibited by the standard ACEI and has no effect on bradykinin.,The juxtaglomerular apparatus,Renin release,交感神经（球旁细胞1）,肾内压

14、力感受器（85mmHg）,致密斑（尿Na+）,扩血管药物与ACEI等,肾素释放的影响因素,Figure 22.4 Control of renin release and formation, and action of angiotensin II. Sites of action of drugs that inhibit the cascade are shown. ACE, angiotensin-converting enzyme; AT1, angiotensin II receptor subtype 1.,Inhibitors of the RAS. ACE-I, angiot

15、ensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; DRI, direct renin inhibitor.,Clinical interest focuses on developing inhibitors of the RAS.,Three types of inhibitors are utilized therapeutically ACE inhibitors (ACEIs) Angiotensin receptor blockers (ARBs) Direct renin inhibitors

16、 (DRIs),第二节 血管紧张素转化酶抑制剂(angiotensin converting enzyme inhibitor，ACEI),History,Bothrops Jararaca,巴西洞蛇,蝮蛇 captopril ,1981,血管紧张素转化酶抑制剂(ACEI),上市的ACEI至少有17种，是治疗HBP、CHF等心血管疾病的重要药物。 卡托普利（Captopril）是人类研制成功的第一个ACEI，施贵宝制药公司生产，1981年正式应用于临床，在心血管疾病的预防和治疗中发挥了显著的作用。 依那普利（enalapril)口服易吸收，在体内需转化，起效慢（4-6h达峰值）， 维持时间长（

17、24h），作用强（ACE抑制作用是卡托普利10倍)。毒性小，对血糖和脂质代谢影响小。,血管紧张素转化酶抑制药 (angiotensin converting enzyme inhibitor,ACEI),卡托普利 第一个 1981年 已批准上市 至少有17种 治疗高血压、CHF等心血管疾病的重要药物。,(1)含巯基类：卡托普利 (2)含羧基类：依那普利 (3)含磷酸基类：福辛普利,ACEI 的分类,ACE卡托普利,ACEI 与 ACE 结合,ACEI的药理作用,1. 减少Ang生成 改善血液动力学：减低总外周阻力，对心率无影响。 减少醛固酮释放，减少水钠潴留 逆转高血压的心血管重构，改善心血管

18、顺应性 2. 保存缓激肽（BK）活性 血管舒张、降血压、抗血小板聚集、抗心血管增生和重构,3. 保护血管内皮细胞：BK NO 逆转高血压、心衰和高血脂引起的内皮损伤。 4. 抗心肌缺血与心肌保护：-SH 5. 对代谢影响：BK 增敏INS受体（与AngII无关）、降低甘油三酯,ACEI的药理作用,ACEI的临床应用,1.高血压 2.CHF与心肌梗塞 3.糖尿病肾病和其他肾病（多囊肾无效） 4.其他：心肌缺血、动脉粥样硬化等,ACEI治疗高血压,降压特点: 肾素活性高者，降压明显； 长期应用不引起电解质和脂质代谢紊乱； 改善心、脑、肾血流量，逆转心血管重构； 对伴有心衰或糖尿病肾病的高血压首选；

19、 改善生活质量优于其它抗高血压药； 长期用药无耐受性，停药无反跳现象。,ACEI治疗高血压,各型高血压：对慢性高血压，疗效大致相同。 对急性高血压：首选卡托普利 逆转左室肥厚：褔辛普利、雷米普利 肝肾功能不全和老年性高血压：褔辛和苯那普利 伴有慢性心功能不全：卡托、依钠、培朵，长期改善心室重构作用 伴稳定型心绞痛：西拉普利较为安全，具有较好的抑制平滑肌增殖及内皮保护作用, 输出量 后负荷 前负荷 肾血流 全身阻力 + 钠潴留 肾素释放 收缩血管 醛固酮 AO Ang Ang- 缓激肽 失活肽,加 重,心力衰竭,NA释放,血压,ACE,心肌 重构,CHF时神经内分泌激活和心肌重构,减 轻,血压,ACEI治疗心衰和心梗,改善血液动力学 阻断神经内分泌的激活 降低病死率 保护肾脏，可选用褔辛普利 ACEI+受体阻滞剂联合疗效最佳,ACEI治疗糖尿病肾病,1.改善肾脏血流动力学 2.抑制肾小球硬化 3.减轻蛋白尿 4.改善内环境和循环功能,ACEI不良反应,与Ang有关的反应： 首剂低血压、高血钾、急性肾功能损害（心衰过度利尿、双肾动脉阻塞或硬化） 与BK有关的反应： 低血