第24章 作用于腎素血管緊張素醛固酮系統(tǒng)的藥物雙語縮減版概要1

1、第 24 章 腎素-血管緊張素醛固酮系統(tǒng)抑制藥 華中科技大學(xué)同濟(jì)醫(yī)學(xué)院藥理學(xué)系主講教師 金滿文2021年10月Inhibitors of the renin-angiotensin-aldosterone system1/70本次課要求掌握的內(nèi)容2.ACE抑制藥的藥理作用、作用機(jī)理、主要的臨床應(yīng)用和不良反響。2/703.全面比較AT1受體拮抗藥與ACE抑制藥在藥理作用、作用機(jī)理、臨床應(yīng)用和不良反響方面的異同。4.通過本章學(xué)習(xí)，你對(duì)靶點(diǎn)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, 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 發(fā)現(xiàn)腎臟的鹽水粗提物含有加壓物質(zhì)，他們將其命名為“腎素。5/70Tigerstedt R, Bergman PG: Niere und Kreislauf 腎臟和循環(huán). Skand Arch Physiol 1898; 8:223-271.1934, Goldblatt 證明收縮腎血管可產(chǎn)生持續(xù)的高血壓 (renal hypertension)In 1940, Braun-Menendez(Argentina), Page and Hel

4、mer (USA) 分別報(bào)道腎素是酶，產(chǎn)生縮血管物質(zhì)，前者稱其為hypertensin ，后者稱其為angiotonin. 大約20年后，將此過程中的升壓物質(zhì)命名為血管緊張素angiotensin，血漿中的底物稱為 血管緊張素原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. 上個(gè)世紀(jì)七十年代早期，開始認(rèn)識(shí)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 擴(kuò)血管Antihypertensive 抗高血壓12/70Extrinsic Local RAASLocal (Tissue) RAAS (局部或組織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. 動(dòng)脈壁和其他組織從循環(huán)中攝取腎源性腎素，激活局部的RAAS。14/70許多組織腦、血管、心臟、腎臟、腎上腺表達(dá)腎

10、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. 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 直接收縮血管II. peripheral noradrenergic neurotransmission A.NE release 增加NE釋放 B.NE reuptake 減少NE再攝取 C.vascular responsiveness 增加血管反響性III.sympathetic disc

12、harges (CNS) 增強(qiáng)交感中樞輸出IV.release of catecholamines from adrenal MedullaRapid Pressor Response 快加壓反響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 慢加壓反響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血管和心臟肥厚、重構(gòu)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抑制藥上市時(shí)間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補(bǔ)進(jìn)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 (頰窩毒蛇)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，是第一個(gè)用于臨床的肽類ACEI。*: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, N.J)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。一、ACE的分類和構(gòu)效關(guān)系25/70(二)ACEI與酶的結(jié)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抑制藥的適應(yīng)癥、不良反響、禁忌癥都相似。ACE inhibitors differ with regard to three properties: (1) potenc

20、y, (2) drug or prodrug, (3) pharmacokinetics (fosinopril, spirapril ).差異有3：強(qiáng)度；藥或前體藥；藥代。28/70Functions and Effects of the RAAS29/7030/70擴(kuò)管降壓，增加動(dòng)脈血管順應(yīng)性抗心血管病理性重構(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(dòng)脈粥樣硬化抗氧化作用 ACEI降低血漿脂質(zhì)過氧化物濃度，對(duì)抗自由基對(duì)心臟和血管的損傷作用。 三、作用機(jī)理機(jī)制減少Ang II的生成 因Ang II量減少，削弱Ang II對(duì)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P

21、LC和PLA2，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。31/70抑制交感神經(jīng)遞質(zhì)的釋放 減弱Ang對(duì)交感神經(jīng)沖動(dòng)傳遞的易化作用 。 Hypertension 高血壓(一線藥物)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。 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壓病人，轉(zhuǎn)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。 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 抑制藥能預(yù)防或延緩心衰的進(jìn)展，減少心梗和猝死事件，降低住院率，改善生活質(zhì)量。左室收縮功能不全(一線藥物) 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、. 大樣本、前瞻性、隨機(jī)、撫慰劑對(duì)照的臨床試驗(yàn)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。 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.只要沒有禁忌癥，無論其有否心衰病癥，所有左室收縮功能受損者，都應(yīng)使用ACE抑制藥。The more severe the ven

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

27、sive and diabetic patients. 37/70Acute Myocardial Infarction 急性心梗在圍梗死期開始用轉(zhuǎn)換酶抑制藥，降低總死亡率?；加懈哐獕汉吞悄虿〉募毙孕募」Ｋ阑颊攉@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.如無禁忌(心源性休克、嚴(yán)重的低血壓)，

28、心梗的急性期應(yīng)立即使用轉(zhuǎn)換酶抑制藥。 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。 Clinical Trials with ACE Inhibitors in Heart Disease 臨床試驗(yàn)代碼ISIS-4SMILEHOPEUROPA資料發(fā)表時(shí)間1995199520002003入選病種MIMICADCAD入

29、選病人數(shù)580501556929712218觀察時(shí)間1 M6 W5 yr4.2 yrMI 心肌梗死Stroke 中風(fēng)cardiac deathoverall mortality：未觀察40/70 ACE inhibitors tilt the fibrinolytic balance toward a profibrinolytic state in patients with coronary artery disease. 在冠心病人，ACE抑制藥使纖溶系統(tǒng)向促纖溶方向傾斜。Patients Who Are at High Risk of Cardiovascular Events 心血管

30、事件高?；颊?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 (慢性腎衰) 糖尿病是腎臟疾病的首因，在I型糖尿病

31、和糖尿病性腎病患者，卡托普利能預(yù)防或延緩腎病的開展。 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.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。 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。44/70Scleroderma Renal Crisis (硬皮病腎危象) 45/70Adverse Effects of ACE Inhibitors 英文名中文名英

33、文名中文名Hypotension 低血壓Angioedema 血管性水腫Cough 咳嗽(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(xiǎn)Skin Rash 皮疹Hepatotoxicity肝毒性Proteinuria 蛋白尿Neutropenia 中白少 46/70Other drug ACE InhibitorsAntacids(抗酸藥)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、不良反響：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

35、途徑！問題的提出 盡管ACEI在很大程度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：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.肽類ARBs不能口服，無臨床應(yīng)用價(jià)值。49/70Angiotensin II receptor blockers HistoryAll peptide ARBs expressed unaccep

37、table partial agonist activity. 肽類ARBs的局部沖動(dòng)劑活性(血管緊張素II受體拮抗劑，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年關(guān)于咪唑5乙酸衍生物競爭Ang II受體的專利。51/701982年，F(xiàn)urakawa申請(qǐng)了關(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

38、專利，通過計(jì)算機(jī)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)。40/75 非肽類AT1 受體阻滯劑：氯沙坦(losartan，科素亞，cozaar)、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

39、) 53/70ARBs bind to the AT1 receptor with high affinity ( 10,000-fold selective for the AT1 versus the AT2 ) 高度選擇性地作用于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(qiáng)3慢升壓反應(yīng)9交感張力增強(qiáng)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 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年年底在美國獲準(zhǔn)上市。在臨床研究中，替米沙坦與氨氯地平相比

42、，能更大程度地降低收縮壓和舒張壓，且作用時(shí)間更長，為此類藥物中第一個(gè)真正的“一日一次治療藥。 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 高血壓 1.病人對(duì)其耐受良好，不受劑量、年齡和種族

44、的影響。2.首劑現(xiàn)象低血壓反響少見，直立性低血壓的發(fā)生率缺乏1%；無沖動(dòng)藥活性，治療高血壓停藥時(shí)無反跳現(xiàn)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. 與卡托普利比，改善病癥作用同，降低病

45、死率更好Heart failure 心衰Both valsartan and candesartan reduce mortality and morbidity in heart failure patients. 降低心衰的發(fā)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型糖尿病有明顯

46、的腎保護(hù)作用Diabetic nephropathy 糖尿病性腎病Stroke prophylaxis 預(yù)防卒中Losartan reducing stroke in hypertensive patients with left ventricular hypertrophy. 在左室肥厚的高血壓患者，氯沙坦減少卒中。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。Myocardial infarction 心肌梗死64/70The incidence of discontinuation of ARBs owing to