作用于腎素血管緊張素醛固酮系統(tǒng)的藥課件

1、第 23 章 作用于腎素-血管緊張素-醛固酮系統(tǒng)的藥物華中科技大學(xué)同濟醫(yī)學(xué)院藥理學(xué)系授課教師 金滿文2015年10月本次課要求掌握的內(nèi)容2.ACE抑制藥的藥理作用、作用機理、主要的臨床應(yīng)用和不良反應(yīng)。2/743.全面比較AT1受體拮抗藥與ACE抑制藥在藥理作用、作用機理、臨床應(yīng)用和不良反應(yīng)方面的異同。4.通過本章學(xué)習(xí)，你對靶點發(fā)現(xiàn)、確認(rèn)及與藥物研發(fā)的關(guān)系有何心得？ 1.RAAS抑制藥分類及各類的主要代表藥。hypertension, myocardial hypertrophy, congestive heart failure, etc.physiologyRenin-Angiotensin

2、-Aldosterone SystemRAAS3/74Patho第一節(jié) 腎素-血管緊張素-醛固酮系統(tǒng)及其功能 簡史 History of RAAS RAAS的組成成份 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)發(fā)現(xiàn)兔腎臟的鹽水粗提物含有加壓物質(zhì)，他們將其命名為“腎素”。5/74Tigerstedt R, Bergman PG: Niere und Kreislauf 腎臟和循環(huán). Skand Arch Physiol 1898; 8:223-271.1934, Goldblatt 狹窄狗腎血管可產(chǎn)生持續(xù)的高血壓 (renal hypertension)Braun-Menendez(Argentina, 1956), Page and Helmer (USA, Eli-Lilly Lab, 1957) 分別報道縮血管物質(zhì)，前者稱其為hy

4、pertensin ，后者稱其為angiotonin. 1958年，Page and Braun-Menndez將此過程中的升壓物質(zhì)命名為血管緊張素angiotensin，7/74 血漿中的前體物質(zhì)物稱為 血管緊張素原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. 上個世紀(jì)七十年代早期，開始認(rèn)識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藥理干預(yù) Pressor effectSympatheticstimulationADH secretionConverting enzymeantagonistCaptopril enalaprilenalkirenRemikirenAliskirenRenin inhibitorAng II receptorAntagonist losartanAldosterone secretion 腎素Aldosterone secretionAng IIIAng IVAng 1-710/74一、RAAS的組成 Components of RA

7、AS 轉(zhuǎn)換酶Converting enzyme Renin血管緊張素原Cardiac remodeling Thirst受體受體。 Angiotensin (3-8)AT4Ang IVMas AT1AT2?11/74Dihexa血管緊張素受體(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 ？大多數(shù)已知的Ang II效應(yīng)Antiproliferative 抗增生Proapoptotic 促凋亡Vasodilatory 擴血管Antihypertensive 抗高血壓12/74血管緊張素受體(Angiotensin Receptors AT) Ang IV / AT4Ang(1-7) / MasR改善認(rèn)知功能抗重構(gòu) Anti-remodeling改善記憶抗炎 Anti-inflammatory改善運動障礙抗動粥 Anti-atherogenic抗增生 Anti-proliferative小分子激

9、動劑：Dihexa擴管 Vasodilatation (+EC)13/74醛固酮及其受體(aldosterone and its receptor)14/74研究進(jìn)展：（關(guān)注心血管重構(gòu)） 醛固酮可在其他組織局部生成； 醛固酮受體可在其他細(xì)胞表達(dá)； 其作用遠(yuǎn)不只調(diào)節(jié)水鹽電解質(zhì)代謝。經(jīng)典學(xué)說：Ang II 腎上腺皮質(zhì)球狀帶細(xì)胞 分泌醛固酮 遠(yuǎn)曲小管遠(yuǎn)端及集合管上皮細(xì)胞的醛固酮受體 調(diào)節(jié)相應(yīng)功能。局部或組織RAAS Local (Tissue) RAASThe traditional view of the RAAS is that of a classical endocrine system.

10、Renin(kidney) angiotensinogen(liver) 轉(zhuǎn)換酶抑制劑應(yīng)用早期的臨床適應(yīng)癥：高血漿腎素活性的高血壓。但在實際用藥中發(fā)現(xiàn)，對血漿腎素活性正常、甚至偏低的病人，降壓效果依然良好！15/74何以解釋？提出假說實驗求證建立學(xué)說許多組織（腦、血管、心臟、腎臟、腎上腺等）表達(dá)腎素、血管緊張素原、轉(zhuǎn)換酶的mRNA，源于這些組織的細(xì)胞培養(yǎng)可產(chǎn)生腎素、血管緊張素原、轉(zhuǎn)換酶、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、腎素-血管緊張素-醛固酮系統(tǒng)的功能1、快速加壓效應(yīng)2、慢加壓效應(yīng)3、參與心血管重構(gòu)Functions and Effects of the RAAS18/7019/74. Altered Peripheral Resistanc

12、e I. 直接收縮血管 Direct vasoconstrictionII. peripheral noradrenergic neurotransmission A. 增加NE釋放 NE release B. 減少NE再攝取 NE reuptake C. 增加血管反應(yīng)性vascular responsivenessIII. 增強交感輸出 sympathetic discharges (CNS)IV. 增加兒茶酚胺的釋放 release of catecholamines快加壓反應(yīng) Rapid Pressor ResponseMechanismResult. Altered Renal Fun

13、ction 1. 近曲小管鈉重吸收 Direct Na+ reabsorption 2. 醛固酮分泌增加 Release of aldosterone from adrenal cortex （留鈉排鉀)3. 改變腎臟血流動力學(xué) Altered renal hemodynemics: A. 直接收縮腎血管 Direct renal vasoconstriction B. 增強腎臟去甲腎上腺素能神經(jīng)傳遞noradrenergic neurotransmission in kidney C. 腎交感張力增加 renal sympathetic tone (CNS)Slow Pressor Resp

14、onse 慢加壓反應(yīng)MechanismResult21/74. Altered Cardiovascular structure I. 非血流動學(xué)中介的效應(yīng) non-hemodynamically mediated effects: 原癌基因表達(dá) expression of proto-oncogenes 生長因子合成 production of growth factors 胞外基質(zhì)蛋白合成 extracellular matrix proteinsII.血流動學(xué)中介的效應(yīng) hemodynamically mediated effects: 心臟后負(fù)荷 afterload (cardiac)

15、 血管壁張力 wall tension (vascular)Vascular and cardiac hypertrophy & remodelling血管和心臟肥厚、重構(gòu)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抑制藥上市時間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 (頰窩毒蛇)contain factors that intensify responses to bradykinin. Erdos and coworkers established:ACE kininase IIsynthesis of Ang II血管緊張素II合成 destruction of bradykinin緩激肽降解 頰窩毒蛇的蛇毒含有增強緩激肽的物質(zhì)！繼而認(rèn)識其為激肽酶II抑制劑。26/741971年，Ondetti等*合成了tiprotide，是第一個用于臨床的肽類ACEI。*: Bristol

19、-Myers Squibb Pharmaceutical Research Institute, Princeton, N.J)1977年，Ondetti等合成卡托普利；1981年，卡托普利用于臨床。ACEI是目前主要的心血管藥物類別之一。27/74【藥理作用】Pharmacological Effects the synthesis of angiotensin II, Ang IIthe destruction of bradykinin, BK principal pharmacological and clinical effects全部ACE抑制藥的適應(yīng)癥、不良反應(yīng)、禁忌癥都相似。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. 差異：強度；藥或前體藥；藥代。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降壓：擴管、降容、增加動脈血管順應(yīng)性抑制和逆轉(zhuǎn)心血管病理性重構(gòu)保護(hù)血管內(nèi)皮細(xì)胞抗心肌缺血和保護(hù)心肌保護(hù)腎臟 抗動脈粥樣硬化【作用機制】本類藥物的作用均源于其對ACE的抑制作用。包括循環(huán)和局部組織的ACE.31/74(二)ACEI與酶的結(jié)合羧基羰基巰基清除自由基 ACEI降低血漿脂質(zhì)過氧化物濃度，對抗自由基對心臟和血管的損傷作用。 減少Ang II的生成 因Ang II量減少，削弱Ang II對心血管的直接和間接作用。減少BK的代謝 BK量增加，通過激活PLC和PLA

22、2，使NO和PGI2增加舒張血管、抗血小板聚集、抗心血管細(xì)胞肥大增生。抑制交感神經(jīng)遞質(zhì)的釋放 減弱Ang對交感神經(jīng)沖動傳遞的易化作用 。33/74 在冠心病人，ACE抑制藥使纖溶系統(tǒng)向促纖溶方向傾斜。 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纖溶趨勢35/74ACEI按化學(xué)結(jié)

23、構(gòu)分類 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. 高血壓 Hypertension (一線藥物)在輕中度高血壓，單用轉(zhuǎn)換酶抑制劑可使50患者的血壓得以控制，如與其他降壓藥合用，控制率可達(dá)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壓病人，轉(zhuǎn)

25、換酶抑制藥能改善內(nèi)皮細(xì)胞功能，減少心血管事件，故優(yōu)于其他抗高血壓藥物（其實AT1拮抗劑也很好）。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 抑制藥能預(yù)防或延緩心衰的進(jìn)展，減少心梗和

26、猝死事件，降低住院率，改善生活質(zhì)量。2. 充血性心力衰竭(一線藥物) 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. 大樣本、前瞻性、隨機、安慰劑對照的臨床試驗結(jié)果支持在各種程度的左室收縮性功能不全患者使用轉(zhuǎn)換酶抑制藥。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.只要沒有禁忌癥，無論其有否心衰癥狀，所有左室收縮功能受損者，都應(yīng)使用ACE抑制藥。The more severe the ventricular dysfunction, the greater is the benefit from ACE inhibition.

28、左室功能不全越嚴(yán)重，使用ACE抑制藥的受益越大。 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在圍梗死期開始用轉(zhuǎn)換酶抑制藥，降

29、低總死亡率?；加懈哐獕汉吞悄虿〉募毙孕募」Ｋ阑颊攉@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.只要沒有禁忌癥(心源性休克、嚴(yán)重的低血壓)，心梗的急性期應(yīng)立即開始使用轉(zhuǎn)換酶抑制藥。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(大面積梗死、左室收縮功能不全)，轉(zhuǎn)換酶抑制劑應(yīng)長期應(yīng)用。43/74 Clinical Trials with ACE Inhibitors in Heart Disease 臨床試驗代碼ISIS-4SMILEHOPEUROPA資料發(fā)表時間1995199520002003入選病種MIMICADCAD入選病人數(shù)580501556929712218觀察時間1 M6 W5 yr4.2 yrMI 心肌梗死Stroke 中風(fēng)cardiac death

31、overall mortality：未觀察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.慢性腎衰 Chronic Renal Failure 糖尿病是腎臟疾病的首因，在I型糖尿病和糖尿病性腎病患者，卡托普利能預(yù)防或延緩腎病的發(fā)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.轉(zhuǎn)換酶抑制藥也可延緩各種非糖尿病性腎病患者的腎功能不全的病程，甚至在嚴(yán)重腎病患者仍可阻止GFR的降低。46/74 在ACEI用于硬皮病腎危象前，該病患者均死于幾周之內(nèi)。ACEI在很大程度上改善了此可怕預(yù)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. 硬皮病腎危象 Scleroderma Renal Crisis47/74 Adverse Effects of ACE Inhibitors 英文名中文名英文名中文名Hypotension 低血壓Angioedema 血管性水腫Cough 咳

34、嗽(干咳)Hyperkalemia 高血鉀Dysgeusia 味覺障礙Acute Renal Failure 急性腎衰Fetopathic Potential胎兒病潛在危險Skin Rash 皮疹Hepatotoxicity肝毒性Proteinuria 蛋白尿Neutropenia 中性白C減少48/74 Other drugACE InhibitorsAntacids(抗酸藥)bioavailability Capsaicin(辣椒素) cough NSAIDs 非甾體抗炎藥 antihypertensive K+-sparing diur. 留鉀利尿藥 hyperkalemia K+ su

35、pplements 補鉀 hyperkalemia Other drug ACE Inhibitors plasma levels of digoxin plasma levels of lithium hypersensitivity to Allopurinol Drug Interactions49/741.不良反應(yīng)：干咳、血管性水腫等。2.ACE不是Ang II生成的唯一途徑，甚至不是主要途徑。如糜酶(chymase)的作用,其他如胰蛋白酶、組織蛋白酶G、激肽釋放酶等也可將Ang I轉(zhuǎn)化成Ang II。3.AT2受體中介的某些作用被減弱。尋找新的途徑！問題的提出 盡管ACEI在很大程度

36、上改善了高血壓和充血性心力衰竭的治療，但仍有許多不盡人意之處：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肽類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肽類ARBs均具部分激動劑活性 All

38、 peptide ARBs expressed unacceptable partial agonist activity. (血管緊張素II受體拮抗劑，ARBs)結(jié)論：無臨床應(yīng)用價值早期制備Ang II類似物，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年關(guān)于咪唑5乙酸衍生物競爭Ang II受體的專利。53/741982年，F(xiàn)urakawa申請了

39、關(guān)于咪唑-5-乙酸衍生物能與Ang 競爭受體的專利，美國杜邦公司從中受到啟發(fā)。杜邦公司有關(guān)于聯(lián)苯四唑降壓的專利，通過計算機模擬，將咪唑衍生物與聯(lián)苯四唑接起來，合成了大量的化合物，經(jīng)不斷改構(gòu)，篩選出氯沙坦(losartan),1995年在美國作為抗高血壓藥物上市。商品名科素亞(Cozaar)。54/74Arieh WarshelMichael LevittMartin Karplus2013年化學(xué)諾貝爾獎得主的主要貢獻(xiàn)： 將實驗帶入信息時代，時至今日，化學(xué)領(lǐng)域所取得的大部分重要進(jìn)展都離不開先進(jìn)計算機模型的幫助。40/75 非肽類AT1 受體阻滯劑：氯沙坦(losartan，科素亞，cozaar)

40、纈沙坦(valsartan，代文，diovan) 厄貝沙坦(Irbesartan，安博維，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 )對AT1選擇性高親和地作用。Pharmacological

41、 Effects ARBs potently and selectively inhibit, both in vitro and in vivo, most of the biological effects of angiotensin II. 無論是體外和體內(nèi)，ARBs能強效、選擇性地抑制大多數(shù)Ang II的生物效應(yīng)。58/74Functions and Effects of the RAAS59/741血管平滑肌收縮7腎上腺兒茶酚胺釋放2快升壓反應(yīng)8NA能神經(jīng)傳遞加強3慢升壓反應(yīng)9交感張力增強4渴10腎臟功能改變5加壓素分泌11細(xì)胞肥大、增生6醛固酮釋放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與 ACEI的重要差別 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年年底在美國獲準(zhǔn)上市。在臨床研究中，替米沙坦與氨氯地平相比，能更大程度地降低收縮壓和舒張壓，且作用時間更長，為此類藥物中第一個真正的“一日一次”治療藥。 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.高血壓 （一線藥物） 1.病人對其耐受良好，不受劑量、年齡和種族的影響。.2.首劑現(xiàn)象（低血壓反應(yīng)）少見，直立性低血壓的發(fā)生率不足1%；無激動藥活性，治療高血壓停藥時無反跳現(xiàn)象。64/74與卡托普利比，氯沙坦改善癥狀作用同，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在伴有左室收縮功能不全的心?；颊?，纈沙坦降低全因死亡率的作用同卡托普利。Valsartan in Acute Myocardial Infarction (VALIANT) tr