23肾素血管紧张素系统相关药物

nullRAS system inhibitorsRAS system inhibitors肾素血管紧张素系统相关药物汤 勇 波 tangyb@mail.sysu.edu.cn 020-87330554Department of Pharmacology ZhongShan Medical college Sun Yat-sen UniversitynullRAS系统的组成1.Renin. 2.Angiotensinogen 3.Angiotensin-Converting Enzyme 4.Angiotensin Peptides 5. Angiotensinases. 效应（受体）ACEAng原(肝)AngⅠAng Ⅱ肾素(肾)一个核心，两个酶第一步反应第二步反应nullgranular juxtaglomerular cells afferent arterioles prorenin reninuncharacterized enzyme 肾素的作用 （第一步反应） 452 AA hepatocytes 442 AA 肾素合成与释放调节肾素合成与释放调节1.交感神经机制：通过由β受体为介导的 肾脏神经刺激分泌。交感神经张力，肾素释放； 2.肾内机制： 球旁细胞压力感受器感受肾A灌注压  致密斑感受远曲小管NaCl 3. AngII 负反馈抑制肾素释放 4. 胞内机制：cAMP↑,促进肾素分泌 Ca2+↑,抑制肾素分泌肾素 释放nullACE 由 1277 氨基酸组成 又称kininase II on the luminal face of vascular endothelial cellsAngiotensin I→Angiotensin II（第二步反应）血管紧张素受体（Angiotensin Receptors) 血管紧张素受体（Angiotensin Receptors) 受体亚型 AT1 AT2 结构 7个跨膜区段的受体 7个跨膜区段的受体 氨基酸数量 359 363 信息转导 偶联G蛋白 激活PLC，PLA2，PLD2 可能涉及蛋白酪氨 激活VDCC，抑制AC 酸磷酸酯酶 分布 成人血管、肾脏、肾上腺、 胚胎组织、脑 心脏、肝、脑 生殖系统 选择性激动剂 无 CGP42112 选择性拮抗剂 Losartan PD123319血管紧张素II的生理/药理作用（1）血管紧张素II的生理/药理作用（1）收缩血管、加压、促生长作用 血管功能：血管剧烈收缩，强于NA 40倍 血管形态：促VSMC增殖,分化; 促血管重构（remodeling) 血管顺应性 ，阻力 心脏：正性肌力和正性频率作用 促心肌细胞和间质纤维增生和肥大 促心脏重构（remodeling)null例：对血压的影响Direct Vasoconstriction Gq-PLC-IP3- Ca2+ pathway Enhancement of Peripheral Noradrenergic Neurotransmission Effects on the Central Nervous System Release of Catecholamines from the Adrenal Medulla renal blood flow Angiotensin II Increases Total Peripheral Resistance and cardiac Contractility 血管紧张素II的生理/药理作用（2）肾脏：收缩肾血管，Na+重吸收， 醛固酮分泌 ，水钠潴留; 血栓形成：妨碍血栓溶解， 参与血小板激活和聚集; 神经系统：促递质释放（e.g CA)， 中枢性加压反应。血管紧张素II的生理/药理作用（2）RAS 与心血管疾病：RAS 与心血管疾病：RAS与高血压 RAS与心力衰竭 RAS与心血管重构RAS与高血压RAS与高血压高血压病人： 血浆肾素活性，RAS活性 血管收缩 AngI，AngII  醛固酮分泌 血容量 儿茶酚胺释放 BP nullRAS与心力衰竭RAS与心血管重构心脏重构： 心肌细胞肥大与增生；左室扩大但室壁不增厚；心肌细胞间质合成增加；冠脉血管与内皮细胞增生. 血管重构: 重要的VSMC生长因子；VSMC增殖与肥大;管壁胞外间质组成改变.RAS与心血管重构nullAngiotensinogenAng IAng II Sympathetic activityACE (angiotensin-converting enzyme)Renin βreceptor in JG cellsadrenal cortex aldosteroneAT1 receptor effectsAT1 receptor antagonists ACEI ACE inhibitors Na retentionspironolactoneβ blockersnull Effects on the Cardiovascular System marked vasodilation in several vascular beds, including the heart, kidney, intestine, skeletal muscle, and liver. Effects on Endocrine & Exocrine Glands modulate the tone of salivary and pancreatic ducts and help regulate gastrointestinal motility. Kinins also influence the transepithelial transport of water, electrolytes, glucose, and amino acids, and may regulate the transport of these substances in the gastrointestinal tract and kidney. Finally, kallikreins may play a role in the physiologic activation of various prohormones, including proinsulin and prorenin. Role in Inflammation play role in the inflammatory process. Kallikreins and kinins produce redness, local heat, swelling, and pain, Effects on Sensory Nerves Kinins are potent pain-producing substances when applied to a blister base or injected intradermally. They elicit pain by stimulating nociceptive afferents in the skin and viscera. ACTIONS OF KININS－－激肽系统的效应 Aliskiren Renin Inhibitors Drugs that inhibit renin have been available for many years but have been limited by low potency, bioavailability, and duration of action. However, a new class of nonpeptide, low-molecular weight, orally active inhibitors has recently been developed. Aliskiren is the most advanced of these. In healthy subjects, aliskiren produces a dose-dependent reduction in plasma renin activity and angiotensin I and II and aldosterone concentrations. In patients with essential hypertension, aliskiren suppresses plasma renin activity and causes dose-related reductions in blood pressure similar to those produced by angiotensin II receptor antagonists The safety and tolerability of aliskiren appear to be comparable to angiotensin antagonists and placebo. Renin inhibition thus has considerable promise for the treatment of hypertension and other cardiovascular and renal diseases Aliskiren Renin Inhibitors Drugs that inhibit renin have been available for many years but have been limited by low potency, bioavailability, and duration of action. However, a new class of nonpeptide, low-molecular weight, orally active inhibitors has recently been developed. Aliskiren is the most advanced of these. In healthy subjects, aliskiren produces a dose-dependent reduction in plasma renin activity and angiotensin I and II and aldosterone concentrations. In patients with essential hypertension, aliskiren suppresses plasma renin activity and causes dose-related reductions in blood pressure similar to those produced by angiotensin II receptor antagonists The safety and tolerability of aliskiren appear to be comparable to angiotensin antagonists and placebo. Renin inhibition thus has considerable promise for the treatment of hypertension and other cardiovascular and renal diseases肾素血管紧张素系统相关药物Angiotensin Converting Enzyme Inhibitors (ACEI) Angiotensin Converting Enzyme Inhibitors (ACEI) History. 1960s, Ferreira 缓激肽增强因子 →kininase II↓, Erdos and coworkers： ACE = kininase II peptide (缓激肽增强因子 ) saralasin nonapeptide teprotide→captopril RAS相关药物nullACEI的分类及常用药物一、含巯基（SH） captopril/ fentiapril/ pivalopril/ zofenopril/ alacepril 二、含羧基（COO－） Enalapril/ lisinopril/ benazepril/ quinapril/ moexipril/ ramipril/ trandolapril, spirapril/ perindopril/ pentopril/ cilazapril 三、含磷酸基（POO－） FosinoprilPharmacokinetic classification Class I : Captopril - like Captopril Class II : Pro-Drug benazepril, enalapril, fosinopril, quinapril, ramipril, spirapril Class III: Not Metabolized lisinoprilRAS相关药物nullBradykininACEI Kallikrein ReninAngiotensin IIAngiotensin IAngiotensinogenAngiotensin Converting Enzyme ACEKininogens Inactive PeptidesBK receptorsAT-1 receptorsACEACEI 的药理作用ACEI 的药理作用1.对血管作用： AngII↓→扩血管 抗动脉肥厚作用：动脉顺应性 抗动粥作用：抑制LDL氧化作用 保护血管内皮细胞作用： 恢复内皮功能，对抗自由基损伤（－SH)null3.对肾脏的保护作用： 增加肾血流（舒张出球小动脉） 明显减轻蛋白尿，与降压作用不平行 防治肾小球硬化 防治肾衰2.对心脏的保护作用： 抑制和逆转心肌肥厚：长期用药 改善冠脉循环，增加冠脉血流nullRAS相关药物ACEI的临床应用ACEI的临床应用治疗hypertension 治疗慢性心功不全:高血压合并心衰为首选 防治动脉粥样硬化 防治心肌缺血,抗心肌梗死 其他不良反应：不良反应： 血管神经性水肿、干咳（～12%):与缓激肽蓄积有关； 首剂低血压:口服吸收快，生物利用度高的药物多见 高血钾：AngII生成 ，醛固酮生成 ，排钾； 低血糖：增强对胰岛素的敏感性； 肾功能损伤：肾动脉阻塞或肾动脉硬化的双侧肾血 管病变患者；ACEI可致氮质血症。ACEI代表药物ACEI代表药物Captopril,1977,活性药 含有－SH基，直接抑制ACE作用； 降压作用起效快（30min)；达峰快（1h）；持续时间8~12h； 口服吸收快；生物利用度75%,受食物影响； 血浆蛋白结合率30%,体内分布广（中枢、乳汁较少）；从肾脏排泄；临床应用：临床应用：1.高血压： 2.充血性心力衰竭： 3.糖尿病性肾病：FDA唯一批准之药物； 4.预防心梗再发：改善心功及降低病死率。 Enalapril,1984Enalapril,1984长效（>24h)、高效、缓效(p.o. 4-6h) 口服易吸收，不受食物影响； 在肝酯酶作用下，代谢为有活性的enalaprilat;主要经肾脏排泄； 用于高血压和CHF; 不良反应95%; 肝肾双通道排泄,可用于肾功能减退者。ACEI的缺点：ACEI的缺点：抑制缓激肽降解,产生干咳等副作用,难以耐受； AngII可通过非ACE途径生成,ACEI不能完全阻断AngII的生成； 长期应用ACEI,抑制AngII的生成,AT的敏感性增加, 醛固酮逃逸现象； 不能穿透血脑屏障。血管紧张素II受体阻断药 Angiotension Receptor Blockers(ARBs)血管紧张素II受体阻断药 Angiotension Receptor Blockers(ARBs)与ACEI 相比，作用更专一，更完全： 阻滞AngII对心血管系统的作用，具有与ACEI相似的降压、改善心功能、逆转心血管肥厚增殖的作用； 不抑制ACE,无bradykinin引起的干咳； 反馈性增加肾素分泌；Aldosterone分泌减少，钠水潴留减轻，不影响血钾；血管紧张素II受体阻断药的特点：血管紧张素II受体阻断药的特点：不能耐受ACEI的病人，可改用ARBs； 保护心脏，减轻心脏重量，逆转LVH； 保护肾脏，降低蛋白尿； 对血糖、血脂含量均无影响，改善冠脉贮备，肾血流量； 不引起咳嗽.血管神经性水肿； 缺乏ACEI的缓激肽－NO途径的心血管保护作用；也不增敏胰岛素。络沙坦（Losartan)络沙坦（Losartan)口服易吸收，约14%药物在肝脏代谢为有活性的EXP3174；降压作用可持续24h。 作用于AT1受体，均不通过血脑屏障； 能降低血尿酸，增加尿酸排泄，具有肾脏保护作用；可减轻利尿药应用后的高尿酸血症； 无ACEI的首剂低血压反应，不改变血压昼夜节律，不引起心律改变，不引起咳嗽。常用ACE Inhibitors ( … pril)常用ACE Inhibitors ( … pril)Benazepril (generic, Lotensin)Oral: 5, 10, 20, 40 mg tablets Captopril (generic, Capoten)Oral: 12.5, 25, 50, 100 mg tablets Enalapril (generic, Vasotec)Oral: 2.5, 5, 10, 20 mg tablets Parenteral (Enalaprilat): 1.25 mg/mL for injection Fosinopril (generic, Monopril)Oral: 10, 20, 40 mg tablets Lisinopril (generic, Prinivil, Zestril)Oral: 2.5, 5, 10, 20, 40 mg tablet Moexipril (generic, Univasc)Oral: 7.5, 15 mg tablets Perindopril (Aceon)Oral: 2, 4, 8 mg tablets Quinapril (Accupril) Oral: 5, 10, 20, 40 mg tablets Ramipril (Altace) Oral: 1.25, 2.5, 5, 10 mg capsules Trandolapril (Mavik) Oral: 1, 2, 4 mg tablets常用ARB（…sartan）常用ARB（…sartan） Candesartan (Atacand)   Oral: 4, 8, 16, 32 mg tablets   Eprosartan (Teveten)   Oral: 400, 600 mg tablets    Irbesartan (Avapro)   Oral; 75, 150, 300 mg tablets    Losartan (Cozaar)   Oral: 25, 50, 100 mg tablets    Olmesartan (Benicar)   Oral: 5, 20, 40 mg tablets    Telmisartan (Micardis)   Oral: 20, 40, 80 mg tablets    Valsartan (Diovan)   Oral: 40, 80, 160, 320 mg tabletnull血管紧张素转化酶抑制药及血管紧张素Ⅱ受体阻断药作用环节血管紧张素原肾素血管紧张素Ⅰ血管紧张素Ⅱ激动AT 1受体转化酶血管收缩 外周阻力增加血压升高 醛固酮保钠保水排钾激肽原缓激肽血管平滑肌松弛外周阻力下降血压下降降解产物激肽酶ⅡACEI抑制抑制ATⅡRB阻断血管紧张素ⅡACEIATⅡRB卡托普利(巯甲丙脯酸) 依那普利等 不良反应: 血管神经性水肿 顽固性咳嗽氯沙坦 缬沙坦 坎地沙坦等 平滑肌细胞增殖肥大心血管重构Other vasopeptidase inhibitors Other vasopeptidase inhibitors Aprepitant 阻断Substance P和其受体结合, nonpeptide NK1 receptor antagonists Bosentan endothelin-1 receptor blockor Icatibant 缓激肽B2 receptor antagonist