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,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相 关基因肽介导。,Ach,N1 receptor,NE,1 2 receptor,Clonidine（可乐定） 作用于血管运动中枢交感神经突
2、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,Clinical usesHypertension: mild to moderate hypertension that has not responded adequately to treatment with diuretics alone.minimal changes in renal blood flow and glomerular filt
3、ration, inhibit gastrointestinal secretion and mobility. ToxicityCentral and atropine-like side effectsLong-term uses: water and sodium retention rebound phenomenon,Centrally acting sympathoplegic drugs： Clonidine,The ganglion blocking agents block nicotinic cholinoceptors on postganglionic neurons
4、in both sympathetic 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）,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
5、活性多肽如降钙素相 关基因肽介导。,Ach,N1 receptor,NE,1 2 receptor,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 agonist
6、s： 12 receptor agonists: isoproterenol 1 receptor agonists: dobutamine 2 receptor agonists: salbutenol,Drug actions and classification,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 antagonist
7、s: prazosin（抗高血压） 2 receptor antagonists: yohimbine,Drug actions and classification,Mechanism & Sites of Action: Reduce arterial pressure by dilating both resistance and capacitance vessels. Without affects on NE release (2 function) blood pressure is reduced more in the upright than in the supine p
8、osition. 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, than when used alone. (2) Clinical uses : Hypertension with benign prostatic hyperplasia (3) Ad
9、verse effects : Infrequent and mild First dose phenomenon (postural hypotension) Water and sodium retention Dizziness, palpitations, headache, and lassitude.,Prazosin & Other 1 Blockers,Adrenoceptor antagonists （2） receptor antagonists 12 receptor antagonists: propranolol 1 receptor antagonists: ate
10、nolol 2 receptor antagonists: butoxamine（3）, receptor antagonists labetalol （临床应用：抗高血压）,Drug actions and classification,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: no
11、nselective block in brain, kidney and heart etc.,(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 insufficiency Diabetes Withdrawal syndrom
12、e after prolonged regular use: nervousness, tachycardia, increased intensity of angina (even myocardial infarction), or increase of blood pressure;, Receptor blockers: Propranolol,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物质,Agents that block
13、 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-血管紧张素系统 ：血管紧张素II（AT）收缩血管,the Adverse effects of ACE inhibitors: Severe hypotension (esp. hypovolemic due to diuretics, salt restriction, or gastrointestinal fluid los
14、s). Acute renal failure (particularly in patients with renal artery stenosis肾动脉狭窄) Hyperkalemia 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 d
15、eath. Captopril may cause neutropenia(中性粒细胞减少) or proteinuria（蛋白尿）. Minor toxic effects like altered sense of taste, allergic skin rashes, and drug fever,NO,Autocoids Histamine 5-Hydroxytryptamine (serotonin, 5-HT) Lipid-derived autocoidsProstaglandins (PGs) Leukotrienes (LTs)Platelet activating fac
16、tor (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,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，PGI
17、2， 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,Venous NitratesMixed Calcium Antagonists a-adrenergic Blockers ACEI NitroprussideArterial Minoxidil Hydralazine,Venous Vasodilator,Arterial Vasodilator,Classification of Vasodilators,Nitrates este
18、rs (硝酸酯类)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,Sodium Nitroprusside (硝普钠)Powerful parenterally (肠道外给药) administered vasodilatorDilates both arterial and venous vessels, resulting in reduced peripheral vascul
19、ar 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.,Vasodilators,Hydralazine (肼屈嗪)Dilates arterioles but not veins. Disadvantage
20、: tachyphylaxis to hypertensive effects developed rapidly.Combination therapy are now suggested. Especially in severe hypertension. Adverse effectsCommon: headache, nausea, anorexia, palpitations, sweating, and flushing.In patients with ischemic heart disease, reflex tachycardia and sympathetic stim
21、ulation may provoke angina or ischemic arrhythmias.High dose or in patients with slow acetylate: arthralgia(关节痛), myalgia(肌痛), skin rashes, and fever that resembles lupus erythematosus.Infrequency but severe: Peripheral neuropathy and drug fever,Vasodilators,Minoxidil (米诺地尔), a potassium channel ope
22、ner Dilates arterioles but not veins.Can be used in patients with renal failure 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 h
23、irsutism, which is particularly bothersome in women,Vasodilators,Diazoxide (二氮嗪),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 a
24、gents are more selective 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,Calcium Channel BlockersChannel state,Vasodilators,1) Pharmacological roles(1) Diurectic act
25、ion: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 muscle 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）,Thanks!,
