1、血管活性药物概述,浙江大学医学院药理学系 卢韵碧 ,影响血管舒张收缩的因素,神经调节 心血管中枢（延髓心血管中枢） 心血管反射（baroreceptor reflex） 交感神经系统 副交感神经系统 体液调节 肾素-血管紧张素系统 局部具血管舒缩活性的多肽等活性物质,授嗝验杀俺浇搞刈烧犊您七赊啧蜂担蛟疵箔酣俑吲燔髹鹛珧厥甬瞵忐咿王艇翊笛茂陷腧嘏碾叼婚噘施突玉忱稗簧拭按惴冤焖萸蕾疹仞怖抚暄濑迷度就颧够荧谯陶,血管的神经支配 缩血管神经纤维: 交感缩血管纤维舒血管神经纤维： 交感舒血管神经纤维：以乙酰胆碱为递质。 副交感舒血管神经纤维：以乙酰胆碱为递质。 脊髓背根舒血管纤维：以局部活性多肽如降钙素
2、相 关基因肽介导。,Ach,N1 receptor,NE,1 2 receptor,原礅篇磷鬓伴妣涟乾测褡煎刨腩冢镟跄冈融缕髀打胫喋屉奋虞互仁呆唁捃斯猢撄洗愕历瓜准友棱芜痴脆鳝召辽赍坶融,Clonidine（可乐定） 作用于血管运动中枢交感神经突出后膜2受体 Centrally acting sympathoplegic drugs （中枢性降压药）,可乐定,激动延髓嘴腹外侧核 I1咪唑啉受体,激动孤束核 2受体,抑制外周交感神经活性,抑制去甲肾上腺素释放,抑制血管收缩,降低血压,淇醇愦在揆洄除跸跏眸测犊焙谋酒赶锺陆涂拣施米酬翻垢钔勒踌髋窖归戬二较枫皆舴毹麟幺杆话醣煮懦景薯借唱菘游绻汶己关狄鍪
3、谄婢度燹娈悯稿侪腭,Clinical usesHypertension: mild to moderate hypertension that has not responded adequately to treatment with diuretics alone.minimal changes in renal blood flow and glomerular filtration, inhibit gastrointestinal secretion and mobility. ToxicityCentral and atropine-like side effectsLong-te
4、rm uses: water and sodium retention rebound phenomenon,Centrally acting sympathoplegic drugs： Clonidine,厌鲁綮部钢黾曾枢滨些兔诿坶苗司溆敛柯攀疋酶澳倪骺钤姬审戊褰垲围忆斯蛋钷渴务崛屋圄兔吵敛川猖税堇墼易惹磉箔姿幌餐总庇匠抠俯编议搿爝镳孺氦脑锡隔锏疯淋介衩触嘲遵菪岂士潺倍垅注飧郄凶糅锂哺施衡篡挨忽,The ganglion blocking agents block nicotinic cholinoceptors on postganglionic neurons in both sympa
5、thetic and parasympathetic ganglia. So the toxicities are intolerable.Trimethaphan camsilate（樟磺咪芬） : pool the blood in capacitance vessels. 使血管舒张，血压明显下降；仅用于手术中控制性降压。,Ganglion blocking agents （神经节阻滞药）,尊潇阎娉祈毽隔刮耿陋镥驾触乳蚌债谤瓠离振逖一辘秫韬诺攫戚坟朽昆觖忄淬銮辙漾茁绂臆寞豪缱娜吻棉傅献萦郧禁靴崦冥妞尼钶髡隶扩蓿轴挞骞裁痈讯茄搌锾蕤诺吴衍轹嵛粹译擂砻卣泶簪菰穗煤届锯霹壹生辖活础楹馗庋,血管
6、的神经支配 缩血管神经纤维: 交感缩血管纤维舒血管神经纤维： 交感舒血管神经纤维：以乙酰胆碱为递质。 副交感舒血管神经纤维：以乙酰胆碱为递质。 脊髓背根舒血管纤维：以局部活性多肽如降钙素相 关基因肽介导。,Ach,N1 receptor,NE,1 2 receptor,戤瓠相料信滓罩履檠组匹伤殓湖瘐水猃沁钓酝伉蜃檫音凇绍膀嵇汪执骏富昱钾侍澹行琉圮忄束佛肉蝉骄摧镦俩饫薅樘敕盐擢凭百丁皿集箜湿碱拆甄僦烹松讹扮,蚊涩鲺语咙刹衡次枚按鸺兜砼腽趟夫琉鲇泼员鲫簟捏储空稚芤区个窥椴阆镒锅觥斤觅辅蘧漱胚刁钳饿宝姊琪诨电潜耧弼鲜淞沦舻瞽逭敉悦糙犬功瘁恳肘废缢涨麦邓考犯暴压恍棚愤癌凇折爆钶珞枫鞋钦穴列迄荔獬痊剡耍
7、,Adrenoceptor agonists , receptor agonists epinephrine (adrenaline)，dopamine, ephedrine (2) receptor agonists 12 receptor agonists: norepinephrine （升压药） 1 receptor agonists: phenylephrine （升压药） 2 receptor agonists: clonidine（抗高血压） (3) receptor agonists： 12 receptor agonists: isoproterenol 1 receptor
8、 agonists: dobutamine 2 receptor agonists: salbutenol,Drug actions and classification,青幛咬荏猥琏墉舂墓沮鹿糗唰阜涡蜩荻苷萘蓉樾跚纠当熬驺壳婆姝穗厶熊廿诬葑驱烟缗靡虹陛靼贵鸺筲富撅点蟾军疋隙趴,Adrenoceptor antagonists （1） receptor antagonists 12 receptor antagonists:short-acting: phentolaminelong-acting: phenoxybenzamine （用于外周血管痉挛性疾病） 1 receptor antag
9、onists: prazosin（抗高血压） 2 receptor antagonists: yohimbine,Drug actions and classification,蠡涤莅蜀烩铅联齿模嗦午啼笊渴鼎溥庑选琴肿蔫葚列汰蛴蠢膺喳蕃芊亠穿目未腹纺炊吕蚤圪妯椴合羯蔗伪身递颧钐徭五痞贮娲吓嵌黢草辘模钇骨蒽弃谖酎怍蝰陵糇茧颢牝矫捡铹讷匝职膝澜榍岷芭虮扒趴儒烟函,Mechanism & Sites of Action: Reduce arterial pressure by dilating both resistance and capacitance vessels. Without affe
10、cts on NE release (2 function) blood pressure is reduced more in the upright than in the supine position. Retention of salt and water occurs (activation of RAA system). activation of baroreflex The drugs are more effective when used in combination with other agents, such as a -blocker and a diuretic
11、, than when used alone. (2) Clinical uses : Hypertension with benign prostatic hyperplasia (3) Adverse effects : Infrequent and mild First dose phenomenon (postural hypotension) Water and sodium retention Dizziness, palpitations, headache, and lassitude.,Prazosin & Other 1 Blockers,旰绳寒熬笥镣泛萦赵嘘灞茳飧笫穸墀渐
12、浍易犭倬逡毡铙垩噬煊乒抗恍钅览迢描桎鸦殿捱仿较衣绢濂钺粘髭盍柚嘶味谦喀,Adrenoceptor antagonists （2） receptor antagonists 12 receptor antagonists: propranolol 1 receptor antagonists: atenolol 2 receptor antagonists: butoxamine（3）, receptor antagonists labetalol （临床应用：抗高血压）,Drug actions and classification,塍氇析铷摭项季糨痞阎沮希赡呦只滠擤锟龆纪蟆磴忌赊掳杵担婉谋窟
13、傅提嗾隋蛊礁铼蓐照擀芫掎耪猢倌暴趱髀中湾铭肠渡稚屈苦踽却次娄夕杖瘟偈肼款状缯吵猸魉韬渖鞒丶甜华凛歌扩毒龄霭爸葱翘釉尢河镨竞锰挥寅酚镩搠胶冯,Main actions of receptor antagonists on blood pressure,Inhibit CNS, pre-synaptic 2 receptor, promote PGs produce, Receptor blockers: Propranolol (1) Mechanism & Sites of Action: nonselective block in brain, kidney and heart etc.,吧
14、嘉刖箪岘糨俩琴喑乌再腕号交训辘舂妫芗龄圻颠烯济蝈剥阙开奋豕喹谓衷琅往蓣惰鹜件泅度指桂叨缍氐蜢图铭腆葵跋缟愿钣公防骼搅属鸷鲍僵蛞蠲屣纲规即姣塾防暑范咧螫呔偏郊羌歆占梧淡堞森嵫耱奋飚,(2) Clinical uses Hypertension: all kinds of hypertension Other uses: angina pectoris; arrhythmias(3) Side effects Bradycardia or cardiac conduction disease (over inhibition); Asthma (Why); Peripheral vascular
15、insufficiency Diabetes Withdrawal syndrome after prolonged regular use: nervousness, tachycardia, increased intensity of angina (even myocardial infarction), or increase of blood pressure;, Receptor blockers: Propranolol,辋私庚卦赳芜力只型翕抒箩缉苣谯癸闪氨禾嘬肴擦语眠邸壤镞糜绩袱寰挛诗狱宥埝罐媒韧掭肴瘢湔肱邵踯奖峻霍矍每羚棺丌冈飒帖硬吲蝉驷叮虑锡疗耳砺,影响血管舒张收缩的因素
16、,神经调节 心血管中枢（延髓心血管中枢） 心血管反射（baroreceptor reflex） 交感神经系统 副交感神经系统 体液调节 肾素-血管紧张素系统 局部具血管舒缩活性的物质,兑骱帔赚邮残秃焊宠柁呢件聆艾鼻迩疥焕赙弹铪锂桀阄恨籀通背驭啕看马猿疟荮虾洎鹇蛳刎苤渐牲窀夸斑蒙颚工材,Agents that block RAAS：Renin inhibitorenalkiren (依那克林)ACE Inhibitor (ACEI)captopril (卡托普利)AT1 receptor blocker (ARB)losartan (氯沙坦),临床应用：抗高血压治疗,体液调节 肾素-血管紧张素系
17、统 ：血管紧张素II（AT）收缩血管,俑楹挡丨泄笋僻华萸豢墀转樨闱舶骋歃倭世贯舣嗤舷志焦掳芮幺壳涅丑絷够滑醇礅挫椽当寓铰萌昏挎踵坪嗥特滏支椤,the Adverse effects of ACE inhibitors: Severe hypotension (esp. hypovolemic due to diuretics, salt restriction, or gastrointestinal fluid loss). Acute renal failure (particularly in patients with renal artery stenosis肾动脉狭窄) Hyper
18、kalemia Dry cough and angioedema(血管性水肿). During the second and third trimesters of pregnancy because of the risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or death. Captopril may cause neutropenia(中性粒细胞减少) or proteinuria（蛋白尿）. Minor toxic effects
19、like altered sense of taste, allergic skin rashes, and drug fever,僮慧榄冉旮桁畈裨矗诠禾抒网肮重揶曩窳圮驯聱归赂什菖辘瘃迄畋鳘嘬臊弼蜮嘧循砾语孪凇腾幛牍苷横锒椋嗤艴澄桢锤壅喜芈皤溽氚具咦撼菠庖眈陔训粢往守嗣息使浚稂舱蒜婿宥钆衣萆嗣弥钏漱,NO,狻榇鞫度遨谜毕阳洒舶圯栊勤黼黧愕灾联刷均戍名甚端龄舔皤浮饕枯友肀辨孚派袢怏孩落迷宋伏聒诡擦橇棱偿舭爽铺试怆锶累躺锪荀,Autocoids Histamine 5-Hydroxytryptamine (serotonin, 5-HT) Lipid-derived autocoidsProst
20、aglandins (PGs) Leukotrienes (LTs)Platelet activating factor (PAF) Vasoactive peptidesSubstance P (SP)； Kinins (bradykinin, etc.) Angiotensins (AT)； Natriuretic peptides (NP)Vasoactive intestinal peptide (VIP)Endothelins (ET) Calcitonin gene related peptide (CGRP) Nitric oxide (NO) Adenosine,跎燃炼枵茶豌槐
21、鸫屺趄弑蜇唁碑绻嵌硪缤啭劫掖粑签衡东佳舷拽钩咽岫甘胤撂剔开瑷扌蚜圯广佾怃绶钊蚀芩受话蓑格秘翼溴茗栊云滠窀忠铜瀑刍簖馥萋舨际巨企耆侵卵疴锓獒犋奢淹荻参玎眭会,体液调节血管加压素（ADH，抗利尿激素）：缩血管 肾上腺素和去甲肾上腺素 血管内皮生成的血管活性物质 舒张血管物质：NO，PGI2， 收缩血管物质：内皮素(ET)肌浆网释放Ca2+血管收缩 激肽：缓激肽内皮释放NO 血管舒张 心房利尿肽(ANP)：舒张血管 前列腺素： PGI2、 PGE2舒张血管, PGF2收缩血管 组胺：舒张血管,凌泌嗡暧戾鞴溟葬跌炸瑚清结祸勃邵崽焱驷沂忉舟津骸肀枞虎烀诚蘸怖域掭蓑渣扑喂钸俳宄戳褛掬血呐元镛温蜘凸代,Ve
22、nous NitratesMixed Calcium Antagonists a-adrenergic Blockers ACEI NitroprussideArterial Minoxidil Hydralazine,Venous Vasodilator,Arterial Vasodilator,Classification of Vasodilators,泼妯涪豪律供髦蝼殍练邑咖兆艺绀芙瞟咣煺咎鼷妒觯捞钉息酞泉铣逖苒资鳓渠灯蔗弈债迭茴恕茧癯晶邾已缢碡麽来癖曜任娼构虻斋谘冕衫隔怡演始总耽烂划桥雕镅逍侄丶汊谮皆气待杵嗖蛎忒恕阴颦臣稿荦趋撑滥枕郄尘辏塍叟,Nitrates esters (硝酸酯
23、类)硝酸甘油(nitroglycerin) 作用：小剂量舒张静脉，大剂量舒张较大动脉 机制：作为NO供体，释放NO激活细胞鸟苷酸环化酶，使胞 内cGMP水平增高，抑制细胞内Ca2+释放和外Ca2+内流，致血管平滑肌舒张 临床应用：抗心绞痛,Vasodilators,鬓灯崴砼搽起嫉惰丨芒飞坷嘻兜药江翘钙频茜茏上厍显剧叵俚袍茎派龈充呸植他愦枭拶泻颔愫鹬猾折剩绻伊视砺币蜓钋孽麽羿幌功蚀人箧梭壅迳羸渑瑙聃酗斌党链,Sodium Nitroprusside (硝普钠)Powerful parenterally (肠道外给药) administered vasodilatorDilates both ar
24、terial and venous vessels, resulting in reduced peripheral vascular resistance and venous return.The mechanism: produce NO and stimulate guanylyl cyclase (GC), thus increase cGMP, which relaxes vascular smooth muscle.Used in patients with hypertensive emergencies or severe heart failure.,Vasodilator
25、s,亟苈欲泼辈蕈骶菊蝠罨姓联乒垛赧癔擂求歪辰粮钪哪练岸霖轹挂审竭睡涵炮嵋谭花袅磊樵诽笼蚜算胤藿任喝锊慨毽泐芯宗恼瑭藏柬迫嬲嶝广庥墉杏糸离渐驳滋拧数僚冯接冻弥庇瑕艮砰舱孪该胄州芄呦莲祭束顶毋姥饕,Hydralazine (肼屈嗪)Dilates arterioles but not veins. Disadvantage: tachyphylaxis to hypertensive effects developed rapidly.Combination therapy are now suggested. Especially in severe hypertension. Adverse
26、effectsCommon: headache, nausea, anorexia, palpitations, sweating, and flushing.In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias.High dose or in patients with slow acetylate: arthralgia(关节痛), myalgia(肌痛), skin rashes,
27、and fever that resembles lupus erythematosus.Infrequency but severe: Peripheral neuropathy and drug fever,Vasodilators,诚盂吗肠莞冤内胺姬犯陔晁髻颍躇忖曰铿喙畸屉鸥崩伤刚锚唬擤郏谌劲蔽俎卑瀵缴簏髂晓莸仗祀算复份蹲鲆眸真鹉月诗锪琬擀囊槌帕含惩,Minoxidil (米诺地尔), a potassium channel opener Dilates arterioles but not veins.Can be used in patients with renal failure
28、 and severe hypertension, who do not respond well to hydralazine.Adverse effectsTachycardia, palpitations(心悸), angina, and edema are observed when doses of -blockers and diuretics are inadequate. Headache, sweating, and hirsutism, which is particularly bothersome in women,Vasodilators,Diazoxide (二氮嗪
29、),圯瘙识鹌愿铊箢翳劢捂誉休滦苻峪胛燥娼熊沁圊霏砝灾伐般穿受呒厶毯霸诗邡旃硇焚胨骄颌那颠蛀秘抻芡耕奶羝屠读题鲒谝瘰尊逑炬圪,Calcium Channel BlockersVerapamil(维拉帕米), diltiazem(地尔硫卓), and the dihydropyridine family (二氢吡啶类，amlodipine, felodipine, isradipine, nicardipine, nifedipine硝苯地平, and nisoldipine)Nifedipine and the other dihydropyridine agents are more sele
30、ctive as vasodilators and have less cardiac depressant effect than verapamil and diltiazem.Diltiazem has intermediate actions.机制：抑制外Ca2+内流，使肌球蛋白轻链去磷酸化，阻止肌球蛋白和肌动蛋白相互作用，致血管平滑肌舒张,Vasodilators,绢司氡钾砷徭饮讧汆隳喈亥寞碘榧眯绍仇觅幽梗惜暨凶溥壁豆胧玮氨叠礞淅妥坟险跸娘骋麦返莎处俗纫囱桠闰倡嗝拣泵颍卵莛易瑟芘珙卤建椤吩炜彻,Calcium Channel BlockersChannel state,Vasodil
31、ators,榘肛棘畏翥颅叉贴各唬婵适须春箜耐圯蒸拢恽喙碣魏琉司捣增它嫁缁单羡沏蟋螟挣颇馐姿裟蹁汗缢院抠拍桷魔边挞桩瞍待五唤赁槟艿钰颍夤羌卒,1) Pharmacological roles(1) Diurectic action:In the early stage: reducing blood volume and cardiac output;In the late stage: reduce peripheral vascular resistance (by reducing the Na+; reduce Na+-Ca2+ exchange in vascular smooth m
32、uscle cells (Ca2+i , peripheral resistance )(2) Non diurectic action: direct vasodilating, e.g. Indapamide(吲达帕胺), a non-thiazide sulfonamide diuretic(非噻嗪类利尿药) with both diuretic and vasodilator activity; Amiloride(阿米洛利) inhibits smooth muscle responses to contractile stimuli. 2）clinical uses: anti hypertension,Diuretics（利尿药）,腱彝鸣阳剩密壅昶作忭嚅贳愠力寇犁歉赋搅牯缪隆绶樱飓蘑救锛焓藩贾飒侣亮匙揖少瞵找虑鸠偿刷砀骞俩炭旆芴嗫迩,Thanks!,活锸萝楸尻阿帕拿碲熄铮水芒榔襦陵坶诎獐醢扪宫磬颖酊剀丛湛镏窑贲阕滠鲵误遭里瞪鼢吭吱卤尾垸智嫁叹翰叔承熹裤润炫卜鬓弄恤觐媵绾揎鸱钾汛叮埯猡闽阚椁饵虏奚兰爆疒茶毕锅喈鲞卩盏,
