作用于腎素血管緊張素醛固酮系統(tǒng)的藥物雙語(yǔ)縮減PPT學(xué)習(xí)教案

1、會(huì)計(jì)學(xué)1作用于腎素血管緊張素醛固酮系統(tǒng)的藥作用于腎素血管緊張素醛固酮系統(tǒng)的藥物雙語(yǔ)縮減物雙語(yǔ)縮減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)用和不良反應(yīng)。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)用和不良反應(yīng)方面的異同。4.通過(guò)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。第1頁(yè)/共77頁(yè)Renin-Angiotensin-Aldosterone System3/70第2頁(yè)/共77頁(yè) Functions and Effects of RAAS 4/70第3頁(yè)/共77頁(yè)History

2、 5/70第4頁(yè)/共77頁(yè)第5頁(yè)/共77頁(yè)1934, Goldblatt . 7/70第6頁(yè)/共77頁(yè)In the mid-1950s, a decapeptide and an octape-ptide were recognized. The octapeptide was shown to be the more active form. decapeptideoctapeptide 8/70第7頁(yè)/共77頁(yè) 9/70第8頁(yè)/共77頁(yè)Thirst Converting enzyme Pressor effectSympatheticstimulationADH secretionConv

3、erting enzymeantagonistCaptopril enalaprilenalkirenRemikirenAliskirenRenin inhibitorAng II receptorAntagonist losartanAldosterone secretion ReninAldosterone secretionAng IIIAng IVAng 1-710/70第9頁(yè)/共77頁(yè)Angiotensin (3-8)AT4Ang IVAng(1-7) receptor AT1AT2?Phe-His8 9GG 11th, 200611/70第10頁(yè)/共77頁(yè) (AT) 12/70第1

4、1頁(yè)/共77頁(yè) 13/70第12頁(yè)/共77頁(yè)14/70第13頁(yè)/共77頁(yè) 15/70第14頁(yè)/共77頁(yè)第15頁(yè)/共77頁(yè). Altered Peripheral Resistance Rapid Pressor Response 快加壓反應(yīng)MechanismResult第16頁(yè)/共77頁(yè). Altered Renal Function Slow Pressor Response MechanismResult第17頁(yè)/共77頁(yè). Altered Cardiovascular structure I. Non-hemodynamically mediated effects: expressio

5、n of proto-oncogenes production of growth factors synthesis of extracellular 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)MechanismResult第18頁(yè)/共77頁(yè)Thirst Converting enzyme Pressor effectSympathe

6、ticstimulationADH secretionConverting enzymeAntagonist 1981captopril enalaprilAng II receptorAntagonist 1995losartan telmisartanAldosterone secretion MR antagonist spirolactone eplerenone 2002 ReninRenin inhibitorremikirenremikirenAliskiren 200720/70第19頁(yè)/共77頁(yè)RAAS抑制藥上市時(shí)間第20頁(yè)/共77頁(yè)Thirst Converting enz

7、yme Pressor effectSympatheticstimulationADH secretionConverting enzymeantagonistCaptopril enalaprilremikirenRenin inhibitorAng II receptorAntagonist losartantelmisartanAldosterone secretion MR antagonist Spirolactone eplerenone Reninremikirenaliskiren補(bǔ)進(jìn)展22/70第21頁(yè)/共77頁(yè) In the 1960s, Ferreira and coll

8、eagues found that the venoms of pit vipers (頰窩毒蛇)contain factors that intensify responses to bradykinin. 第22頁(yè)/共77頁(yè)*: 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。第23頁(yè)/共77頁(yè)25/70第24頁(yè)/共77頁(yè)第25頁(yè)/共77頁(yè) 第26頁(yè)/共77頁(yè) 28/70第27頁(yè)/共77頁(yè)29/70第28頁(yè)/共77頁(yè)第29頁(yè)/共

9、77頁(yè)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(guò)激活PLC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 。第30頁(yè)/共77頁(yè)32/70 第31頁(yè)/共77頁(yè)33/70第32頁(yè)/共77頁(yè)34/70 第33頁(yè)/共77頁(yè)35/70 第34頁(yè)/共77頁(yè)36/70 第35頁(yè)/共77頁(yè)37/70 在圍梗死期開(kāi)始用轉(zhuǎn)換酶抑制藥，降低總死亡率。患有高血壓和糖尿病的急性心肌梗死患者獲益更甚。第36頁(yè)/共77頁(yè)38

10、/70第37頁(yè)/共77頁(yè)39/70 第38頁(yè)/共77頁(yè)SMILE HOPEUROPA資料發(fā)表時(shí)間資料發(fā)表時(shí)間199520002003入選病種入選病種MICADCAD入選病人數(shù)入選病人數(shù)1556929712218觀察時(shí)間觀察時(shí)間6 W5 yr4.2 yrMI Stroke cardiac deathoverall mortality40/70第39頁(yè)/共77頁(yè) 41/70第40頁(yè)/共77頁(yè)42/70 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。第41頁(yè)/共77頁(yè)43/70ACE inhibitors also attenuate the progres

11、sion 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.第42頁(yè)/共77頁(yè)44/70第43頁(yè)/共77頁(yè)45/70 第44頁(yè)/共77頁(yè)46/70 第45頁(yè)/共77頁(yè)尋找新的途徑！問(wèn)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：47/70第46頁(yè)/共77頁(yè)Thirst Converting

12、 enzyme Pressor effectSympatheticstimulationADH secretionConverting enzymeantagonistCaptopril enalaprilenalkirenremikirenRenin inhibitorAng II receptorBlocker losartanAldosterone secretionAldosterone receptorantagonist Renin48/70第47頁(yè)/共77頁(yè)49/70 部分激動(dòng)劑活性(ARBs)第48頁(yè)/共77頁(yè) 50/70第49頁(yè)/共77頁(yè)杜邦公司有關(guān)于聯(lián)苯四唑降壓的專利，通過(guò)

13、計(jì)算機(jī)模擬，將咪唑衍生物與聯(lián)苯四唑接起來(lái)，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(guó)作為抗高血壓藥物上市。商品名科素亞(Cozaar)。第50頁(yè)/共77頁(yè)。40/75第51頁(yè)/共77頁(yè) (losartan，cozaar)、(valsartan，diovan) (Irbesartan，aprovel)(candesartan)(telmisartan)(tasosartan，ANA-756)(eprosartan，SK&F108566)(zolarsartan，GR117289) 53/70第52頁(yè)/共77頁(yè)ARBs bind 54/70 ARBs pot

14、ently and selectively inhibit, both in vitro and in vivo, most of the biological effects of angiotensin II.第53頁(yè)/共77頁(yè)55/70第54頁(yè)/共77頁(yè)56/70ARBs potently and selectively inhibit, both in vitro and in vivo, most of the biological effects of angiotensin II.第55頁(yè)/共77頁(yè)57/70 第56頁(yè)/共77頁(yè)Curr Mol Med. 2007 Aug;7(5

15、):463-9.第57頁(yè)/共77頁(yè)59/70 Telmisartan* 第58頁(yè)/共77頁(yè)1.病人對(duì)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(jiàn)，直立性低血壓的發(fā)生率不足1%；無(wú)激動(dòng)藥活性，治療高血壓停藥時(shí)無(wú)反跳現(xiàn)象。60/70第59頁(yè)/共77頁(yè)61/70Both and reduce mortality and morbidity in heart failure patients. 第60頁(yè)/共77頁(yè) 62/70第61頁(yè)/共77頁(yè)63/70用同卡托普利。用同卡托普利。Myocardial infarction第62頁(yè)/共77頁(yè)64/70 第63頁(yè)/共77頁(yè)Thir

16、st Converting enzyme Pressor effectSympatheticstimulationADH secretionConverting enzymeantagonistCaptopril enalaprilAng II receptorAntagonist losartanAldosterone secretionAldosterone receptorantagonist ReninRenin inhibitorremikirenaliskiren補(bǔ)進(jìn)展第64頁(yè)/共77頁(yè)用腎素抗體合成一系列肽類物質(zhì)： enalkiren remikiren，分析活性中心結(jié)構(gòu)，合成非肽類物質(zhì)：阿利吉侖(66/70第65頁(yè)/共77頁(yè)(作用強(qiáng)：IC50=0.6nM選擇性高：對(duì)其他蛋白酶、肽酶作用弱。種族特異性明顯：對(duì)非靈長(zhǎng)類腎素作用弱。抑制腎素活性的作用持續(xù)時(shí)間長(zhǎng)。全部血管緊張素成份都明顯降低。67/70第66頁(yè)/共77頁(yè)68/70第67頁(yè)/共77頁(yè) 69/70第68頁(yè)/共77頁(yè)成人口服150mg/d，其降壓作用與irbesartan口服150mg/d相似。 特點(diǎn)：口服150300mg/d ，降壓作用達(dá)平臺(tái)。連續(xù)用藥8周后，撤藥無(wú)血壓反跳。降壓時(shí)心率無(wú)變化。 降壓作用較各自單用強(qiáng)；。70/70第69頁(yè)/共77頁(yè)復(fù)習(xí)題二.ACE抑制藥的藥理作用、作用機(jī)