心血管药物教学课件

1、CardiovasculardiseasesCardiovascular diseases include hypertension (高血压), hyperlipidemia (高血脂), angina (心绞痛), atherosclerosis (动脉粥样硬化), coronary diseases (冠心病), hypotension (低血压), cardiac arrhythmias (心率失常), heart failure (心力衰竭), and certain vascular disorders. Cardiovascular DrugsCardiovascular dru

2、gs effect on heart or vascular system to adjust the total output of heart blood by different action mechanism, or alter blood distribution in circulation system to improve, resume cordis (心脏的) and vascular function.Classification of cardiac drugsCardiac drugs include cardiac agents (强心药), antiangina

3、l drugs (抗心绞痛药), antiarrhythmic agents (抗心率失常药), antihypertensive agents (抗高血压药), hypolipidemic drugs (降血脂药).Section 1 Cardiac AgentsCardiac Agents , also called inotropic agents (正性肌力药)，are applied for congestive heart failure to enhance the force of cardiac contraction.充血性心力衰竭(Congestive heart fai

4、lure，CHF）CHF是由于心肌收缩力减弱引起心输出量明显不足而心脏血容量有所增加的疾病，导致血压升高和肾血流降低，严重时会发展成下肢水肿，肺水肿以及肾衰竭。 CHF是一种常见病，它引起的死亡率一直在增加。因此，治疗CHF的药物是世界性热门课题。Drugs for CHFCardiac Agents VasodilatorsDiureticsAngiotensin-converting enzyme inhibitors (ACEI)The Sorts of Cardiac Agents1. Cardiac glycosides2. Phosphodiesterase inhibitors

5、3. Calcium sensitizers4. Adrenergic agonists 1. Cardiac glycosides (强心苷类)Cardiac glycosides have applied for heart failure for more than hundred years. Today they are still important drugs to treated heart failure.强心苷类广泛存在于许多有毒的植动物体内（如洋地黄、蟾蜍毒等）。小剂量时有强心作用，但大剂量使心脏中毒停止跳动。主要缺点：安全范围小，强度不够大，且具有吸收、消除途径及速度方

6、面的缺点。 Digoxin(3, 5, 12)-3-(O-2,6-dideoxy-D-ribo-hexopyranosyl-(1 4)-O-2,6-dideoxy-D-ribo-hexopyranosyl-(1 4)-2,6-dideoxy-D-ribo-hexopyranosyl)oxy-12,14-dihydroxy-card-20(22)-enolideDigoxin in the body Digoxin is absorbed and distributed in tissues rapidly. It is excreted in prototype by kidney.Digox

7、in is used for acute and chronic heart failure and atrial fibrilation (心房纤颤) and atrial flutter (心房扑动）.cardiac glycosides in clinicThere are lots of cardiac glycosides in clinic, including digitoxin (洋地黄毒苷), digoxin (地高辛), lanatoside C (毛花苷C), strophanthin K (毛花苷K) and convallatoxin (铃兰毒苷).Digoxin (

8、地高辛)Digitoxin（洋地黄毒苷） Lanatoside C (毛花苷C)strophanthin K (毛花苷 K) Convallatoxin (铃兰毒苷)1）Chemistry of cardiac glycosides aglycone sugar moieties steroid nucleus , unsaturated lactoneCardiac glycosides配糖基部分steroid nucleus Stereo-structure of steroid nucleus cis- A/B , trans-B/C, cis-C/D., unsaturated lac

9、toneFive-member(plant): Cardenolide (卡烯内酯)Six member(animal): Bufadienolide (蟾二烯羟酸内酯)Sugar moietiesThe function of chemical structureAglycone steroid nucleus which convey the pharmacological activity of these compounds.An unsaturated lactone ring which conveys cardiotonic (强心的) activity.Sugar moieti

10、es which modulate potency and pharmacokinetic distribution. 2）The Action MechanismCardiac glycosides act by inhibiting the membrane Na+/K+ ATPase pump. This increases intracellular Na+ concentration, thus reducing the sodium gradient across the membrane and decreasing the amount of calcium pumped ou

11、t of the cell by the Na+/Ca2+ exchanger during diastole(心脏舒张).Consequently, the intracellular calcium concentration rises, thus increasing the force of cardiac contraction and maintaining normal blood pressure. Figure of the action mechanism3) The SAR of cardiac glycosides1. C17 - , unsaturated lact

12、one2. steroid nucleus ;3. C19-CH3;4. C14- -OH;5. C3-O-sugar.Figure of cardiac glycosides and Na+,K+/ATPase actionMethyldigoxintoxicity2. Phosphodiesterase inhibitor, PDEIPDEI is a sort of new cardiac drugs having different action mechanism with cardiac glycosides.Examples of PDEI include amrinone (氨

13、力农) and milrinone (米力农). These have been developed as a result of the many adverse effects and problems associated with cardiac glycosides.There is no evidence that these improve the mortality.The Action MechanismPhosphodiesterase is responsible for the degradation of cAMP; Thus, inhibiting this enz

14、yme raises cAMP levels and causes increase in myocardial (心肌) contractility and vasodilatation (血管舒张).Cardiac output is increased, and pulmonarywedge pressure (肺压) and total peripheral resistant are reduced, without much change in heart rate or blood pressure.Figure of the Action MechanismPDEIthe fo

15、rce of cardiac contractionPhosphodiesterase, PDEPDE has three types: PDE-, , .PDE-, which both have different subtypes, dont have speciality on cAMP.PDE , which only has a subtype, possesses high speciality and affinity on cAMP.Amrinone (氨力农)Amrinone is the first PDEI drug in clinical use in 1978. P

16、harmacology of AmrinoneAmrinone is short acting and is administered intravenously.It is given for severe acute heart failure that is resistant to other drugs. It has several adverse effects. These include nausea and vomiting, arrhyth-mias, liver dsyfunction, abdominal pain, and hypersensitivity.Milr

17、inone (米力农)化学名：1,6-二氢-2-甲基-6-氧-(3,4-双吡啶)-5-氰,又名米利酮。1,6-dihydro-2-methyl-6-oxo-3,4-bipyridine-5-carbonitrile, corotropePharmacology of MilrinoneMilrinone is long acting and is administered orally. Milrinone has high speciality on PDE -. So it is 1020 fold effective than amrinone. Its adverse effects

18、are less than amrinone, but it has potent arrhythmias possibility.Enoximone (依洛昔酮）Enoximone is a potent selective inhibitor.It is administered orally for a long period.3. Calcium sensitizers (钙敏化剂)钙敏化剂是一类能增加肌纤维丝对Ca2+ 敏感性的药物，即能使生理浓度的游离Ca2+对心肌产生更大的张力。Isomazole (伊索马唑)能增加收缩蛋白对Ca2+ 敏感性，在不增加Ca2+浓度的情况下，提高心

19、肌收缩力。4. Adrenergic Agonists受体激动剂主要是兴奋心脏的1受体，产生心肌收缩的作用。但大多数肾上腺素能激动剂由于可加速心率和产生血管收缩作用，限制了治疗心衰的价值。Examples of adrenergic agonists include dobatumine (多巴酚丁胺) and dopamine. They are used intravenously in CHF emergencies. Dobutamine (多巴酚丁胺) Dobutamine is a selective agonist of cardiac 1 receptor. It is giv

20、en for heart failure. But it is short acting, and no effective orally.Denopamine (地诺帕明）Denopamine has distinct positive inotropic action when given orally and doesnt increase heart rate. Section 2 Antianginal DrugsAngina is the primary symptom of ischemic heart disease, characterized by a sudden, se

21、rver pain originating in the chest, often radiating to the left shoulder and down the left arm. Angina is the symptom of the coronary artery. The latter is the supply route of blood carrying oxygen from the left ventricle to all heart tissues, including the ventricle themselves. Oxygen supplyingWhen

22、 the coronary artery becomes less efficient in supplying blood and oxygen to the heart, the heart is said to be ischemic (short in oxygen). Myocardial ischemia (心肌缺血) occurs when the oxygen is not efficient to meet the myocardial (心肌的) workload. This can occur because of atherosclerotic narrowing of

23、 the coronary circulation (typical) or vasospasm (血管痉挛) of the coronary artery (variant). Oxygen requirements The oxygen requirements of the myocardial tissues are related to the workload of the heart, which is, in part, a function of the heart rate, the systolic（心肌收缩的） pressure, and the peripheral

24、resistance of the blood flow. Antianginal DrugsTherapy of angina is directed mainly toward alleviating and preventing anginal attacks by dilating the coronary artery (increasing oxygen supply), veins (decreasing preload) and arteries (decreasing afterload ).Figure of Antianginal Drugs acting vasodil

25、ating, O2preloadheart ratethe force of cardiac contraction afterloadThe class of Antianginal Drugs 1. NO donor drugs 2. Calcium antagonits (calcium channel blockers ) 3.-adrenergic antagonists (-adrenergic blockers )(1) The Development of NO donor drugs Organic nitrates have dominated the treatment

26、of acute angina over 100 years after the antiaginal effect of amyl nitrite (亚硝酸异戊酯) was first observed in 1857. Although the introduction of the calcium channel blockers and the -adrenergic blockers as antianginal agents has expanded the physicians therapeutic arsenal, organic nitrates are still the

27、 class of choice to treat acute anginal episode. Chemistry of nitratesOrganic nitrates are esters of simple organic alcohols or polyols with nitric acid. Nitrates in clinical use todayThe chemical natures of nitrates Volatility (挥发性)Hydrolysis Explosive properties The nonpolar nature Pharmacologic a

28、ctions of nitratesThe nitrates haves been shown to be effective in treating angina resulting from atherosclerotic narrowing of the coronary circulation (typical) or vasospasm of the coronary artery (variant). The acting duration of nitratesPrevention therapy requires a long-acting preparation with m

29、ore emphasis on duration and less emphasis on onset. The duration of nitrate action is strongly influenced by metabolism. All of the organic nitrates are subject to fairly rapid first-pass metabolism, not only in the liver by the action of glutathione and nitrate reductase, but also in extra-hepatic

30、 tissues, such as the blood vessels themselves. The onset of organic nitrate actionThe onset of organic nitrate action is influenced not only by the special agent chosen, but also by the routine of administration. Sublingual (舌下) administration is used predominantly for a rapid onset of action. For

31、the treatment of acute anginal attacks, a rapid-acting preparation is required.The duration and onset of nitrates action Nitroglycerin（硝酸甘油）1,2,3-propanetriol trinitrate1,2,3-丙三醇三硝酸酯Volatility, hydrolysis, explosive properties, nonpolar nature.体内作用舌下含服通过口腔粘膜快速吸收，生物利用度可达80%。本品为短效、速效抗心绞痛药物，能直接松弛血管平滑肌，

32、使心绞痛缓解，用于各种心绞痛。Isosorbide Dinitrate1,4; 3,6-dianhydro-D-glucitol-2,5-dinitrate.本品具有爆炸性；在干燥时较稳定，但酸碱溶液中加热易水解。本品具有冠脉扩张作用，是长效抗心绞痛药。Isosorbide mononitrate1,4; 3,6-dianhydro-D-glucitol-5-mononitrate本品为硝酸异山梨酯的活性代谢产物，具有明显的扩张血管作用，口服长效，用于治疗冠心病和预防心绞痛的发作。(2) Action mechanism of NitratesAction mechanism of Nitra

33、tesNitrates release NO, which dilates blood vessel.The decrease in both preload and afterload results in a generalized decrease in the myocardial workload, which translates into a reduced oxygen demand by the myocardium.The balance between oxygen supply (by vasodilating the coronary artery) and oxyg

34、en demand (by decreasing the myocardial workload) is restored. 连续用药后，体内“硝酸酯受体”中的巯基被耗竭，从而出现耐药性。 (3) Others NO donor drugs 硝酸酯与细胞中的巯基形成不稳定的S-亚硝基硫中间体，很快分解释放NO分子。吗多明（molsidomine）在体内代谢后生成中间体，在碱催化下与分子氧反应释放NO分子。吗多明（molsidomine）药理作用本品为潜在NO供体，在体内经代谢释放出NO而起作用。本品可扩张血管平滑肌（特别是静脉和小静脉的平滑肌），使血压轻度下降，心脏工作负荷减轻，心肌氧耗量减少

35、。此外，能扩张冠状动脉，改善心肌缺血症状。作用迅速持久，首过效应低，无硝酸酯类的头痛、眩晕等中枢神经副作用，可用于各种心绞痛。2. Calcium channel blockers The myocardium and vascular smooth muscle contraction depend on calcium influx for contraction. Inhibition of calcium ion (Ca2+) influx into myocardial and vascular cells may be advantageous in preventing angi

36、na. Because of the dependency of the myocardium contraction on calcium, these drugs have a negative inotropic effect on the heart. Action mechanismInhibition of Ca2+ influx into vascular muscles by the calcium channel blockers leads to vasodilation, particularly in the arterial smooth muscles. The v

37、enous beds appear to be less affected by the calcium in decreased heart workload and afterload. The preload is not affected because of lesser sensitivity of the venous bed to the calcium channel blockers.Calcium channel blockers Ca2+是心肌和血管平滑肌兴奋-收缩偶联的关键物质。 钙拮抗剂能抑制细胞外Ca2+的内流，使心肌和血管平滑肌细胞内缺乏足够的Ca2+ ，使得

38、心肌收缩力减弱，心率减慢;钙拮抗剂具有抗心绞痛、心律失常和高血压作用，是一类治疗缺血性心脏病的重要药物。 血管松弛，外周阻力降低，血压下降，因而减少心肌耗量。钙通道电压依赖的钙通道 (potential-dependent calcium channels) L(long-lasting) calcium channels 存在于心肌、血管平滑肌等组织，是钙通道阻滞剂的作用位点。受体调控的钙通道(receptor-operated calcium channels)Class of calcium channel blockers (1) Selective calcium channel b

39、lockers (2) Noselective calcium channel blockers (非选择性钙通道阻断剂)(1) Selective calcium channel blockers A. Dihydropyridines (二氢吡啶类)B. Aralkylamine derivatives (芳烷基胺类)C. Benzothiazepine derivatives (苯并硫氮杂卓类)A. Dihydropyridines, DHPThe dihydropyridines have much less effect on the cardiac tissues and high

40、er specificity for the vascular bed. (L- calcium channels )So the dihydropyridine are more frequently used as antianginal and antihypertensive agents. Nifedipine （硝苯地平）1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester.有较低的首过效应，口服吸收良好。临床用于预防和治疗冠心病、心绞痛和顽固性、重度高血压。N

41、icardipine （尼卡地平）Nicardipine has a less negative inotropic effect than nifedipine, it may be preferred over nifedipine for patients with angina pectoris or hypertension who also have CHF dysfunction.本品选择性地扩张冠脉、外周血管和脑血管，适用于各种缺血性脑血管疾病、各类型心绞痛（尤其是变异型心绞痛）以及治疗轻、中度高血压。Nimodipine （尼莫地平）对冠脉和外周血管作用小，亲脂性较强，易穿过

42、血脑屏障，对脑血管扩张作用强，临床主要用于治疗脑血管疾病。Amlodipine （氨氯地平）第三代钙通道阻滞剂，长效、耐受性好、生物利用度高。It may be used for patients with angina or hypertension.SARs of DHP(1) 1，4二氢吡啶环是必需的，改为吡啶或六氢吡啶则活性消失。环上氮不被取代时活性最佳。(3) 4位苯基上的取代以邻、间位取代最佳。(4) C3，5位取代基为酯基是必要的。如换为乙酰基或氰基则活性大为降低。(5) C4为手性时有立体选择作用。 (6) C2，6位取代基为低级烷烃。(2) 活性与二氢吡啶环C-4的扭角有关，

43、且环的共平面性越大活性越大。4位苯基上的取代，活性最佳。 B. Aralkylamine derivatives (芳烷基胺类)Verapamil are clinically used in the management of angina, hypertension, and cardiac arrhythmia.Varapamil （维拉帕米）-3-2-(3,4-dimethoxyphenyl)ethylmethyl- aminopropyl-3,4-dimethoxy-(1-methyl ethyl) benzeneacetonitrile hydrochloridePharmacol

44、ogic effects Varapamil have a chiral center, possessing distinct stereo-selectivity.Levorotatory (R) isomer is preferred drug in treatment of supraventricular tachycardia (室上性心动过速).The dextrorotatory (S) isomer is about an order of magnitude more potent as a calcium channel blocker than R isomer as

45、antianginal and antihypertensive agent.C. Benzothiazepine (苯并硫氮卓类)derivativesDiltiazem is clinically used in the management of angina, hypertension, and cardiac arrhythmia. Diltiazem hydrochride(盐酸地尔硫卓)2S-cis-3-(乙酰氧基)-5-2-(二甲氨基)乙基-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫氮卓-4(5H)酮盐酸盐2S-cis-3-(acetyloxy)-5-2-(dimet

46、hylamino) ethyl-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiozepin-4(5H)-one hydrochloridePharmacologic effects Diltiazem has two chiral centers (2,3), and 2S,3S isomer is clinically used for supraventricular (室上性) arrhythmia, angina and hypertension.Diltiazem is subject to fairly rapid first-pass m

47、etabolism.Metabolism of Diltiazem临床用途临床上用于室上性心律失常、典型心绞痛、变异型心绞痛在内的多种缺血性心脏病和陈旧性心肌梗死引起的心绞痛，还可用于降低血压。二苯基哌嗪类这类药物对血管平滑肌钙通道有选择性抑制作用，主要用于脑细胞和脑血管疾病，对于缺血性脑缺氧引起的脑损伤和代谢异常，脑水肿等有效。3. Adrenergic blockers心肌缺血诱发心绞痛时，心肌局部的儿茶酚胺类物质释放增加。Adr激动受体，加快心率，增强心肌收缩力，使心输出量增加， 从而增加心肌耗氧量 ，加重心肌缺氧。受体拮抗剂能阻断过多的儿茶酚胺类，减慢心率，减弱心肌收缩力，从而减少心肌

48、耗氧量，缓解心绞痛。Adrenergic blockersThe use of -adrenernic blockers as antianginal agents is limited to the treatment of exertion-I angina. Propranolol is the prototype drug in the class.Although these agents may be used alone, they are often used in combination therapy with nitrates, calcium channel block

49、ers, or both. Section 3 Antiarrhythmic Drugs心律失常是由于心脏搏动的自律性发生异常和障碍时，此时心房和心室正常激活和运动顺序发生障碍，其临床表现为心动过缓或心动过速，是一种后果严重的疾病。心律失常分类心动过缓型 常用阿托品或异丙肾上腺素治疗。心动过速型 窦性心动过速室上性心动过速（房性心动过速、房颤、房扑、房室结折返性心动过速和预激症候群） 室性心动过速（室速）及心室纤颤（室颤）心脏内兴奋的传导Arrhythmic diseaseArrhythmia is an alteration in the normal sequence of electri

50、cal impulse activation that leads to the contraction of the myocardium. It is manifested as an abnormality in the rate, in the site from which the impulses originate, or in the conduction through the myocardium. This process is controlled by the so-called pacemaker cells in the A-V and S-A nodes; ho

51、wever, both the atria （心房）and the ventricles(心室） are also involved. Configuration of typical ventricular action potential 心肌细胞的膜电位心肌细胞的静息膜电位，膜内负于膜外约-90mv，处于极化状态。心肌兴奋时，发生除极和复极，形成动作电位。分成5个时相： 0相为除极，是钠通道开放，Na+快速内流所致。 1相为快速复极初期，由电压依赖性瞬间外向钾通道开放，K+短暂外流所致。 2相为坪台期，由慢钙通道开放，Ca2+内流以及延迟整流钾通道开放， K+外流所致。 3相为快速复极末

52、期，主要由钾通道开放，K+外流所致。 0相至3相的时程合称为动作电位时程（APD） 4相为静息期。Na+、 Ca2+和 K+复位。兴奋性的周期性变化由于钠通道开启后，在激活及失活态均不能产生兴奋。因此心室肌在一个刺激引起的兴奋后，短时间内对第二个刺激不产生兴奋，称为不应期。心肌的不应期分为：有效不应期（ERP）：动作电位由0相到3相膜电位达到60mV的这段时间。相对不应期： 3相60mV复极到80mV的这段时间。相对不应期内产生兴奋称为期前兴奋。Causes of arrhythmias Many factors influence the normal rhythm of electrica

53、l activity in the heart. Arrhythmias may occur because pacemaker cells fail to function properly or because of a blockage in transmission through the A-V node. A second mechanism for the generation of arrhythmias is from a phenomenon called reentry. Factors that initiate arrhythmia Underlying diseas

54、es such as atherosclerosis (动脉硬化), hyperthyroidism(甲状腺机能亢进), or lung disease may also be initiating factors. Some of the more common arrhythmia are those termed ectopic (异位的), which occur when electrical signals spontaneously arise in regions other than the pacemaker and then compete with the normal

55、 impulses. Myocardial ischemia, excessive myocardial catecholamine(儿茶酚胺) release, stretching of the myocardium, and cardiac glycoside toxicity have all been shown to stimulate ectopic foci. 1. Classification of antiarrhythmic drugs by action mechanism 1. Ion channel blockers (离子通道阻滞剂)：blockers of so

56、dium channel, potassium channel and calcium channel (钠离子通道阻滞剂、钾通道阻滞剂 、钙通道阻滞剂 ) receptor antagonists(受体拮抗剂)Classification by Vaughan-Williams and action mechanism of antiarrhythmic drugsclassdrugsaction mechanismIIAQuinidineProcainamideBlocking Na+ influx IB LidocaineMexiletineBlocking sodium channel

57、sIC FlecainideProlonging conductionII Adrenergic blockersPropranolol Inhibitoring sympathetic nerves III potassium blockers Amiodarone Blocking K+ flux, prolonging APD and ERPIV Calcium antagonists Verapamil Diltiazem Blocking Ca2+ influx to reduce cardiac dilation period and to decrease AV conducti

58、on 2. Ion channel blockers(1) Ion channels (2) Blockers of sodium channel (I)Class I drugs are generally local anesthetics acting on nerve and myocardial membranes.Class I decrease the maximal rate of depolarization and increase the threshold (阈值) of excitability, increase the effective refractory p

59、eriod（有效不应期）, decrease conduction velocity, and decrease spontaneous diastolic(心脏舒张的) depolarization in pacemaker cell. This class is further subclassified into classes IA, IB, and IC based on the primary pharmacologic effect. A. A sodium channel blockersIA适度阻滞Na通道，减少除极时Na的内流，降低电子电位振幅，减慢传导速度；降低自律性；间

60、接抑制K+外流。Quinidine (奎尼丁)化学名：(9S)-6-甲氧基-脱氧辛可宁-9-醇(9S)-6-methoxy-cinchonan-9-olChemical StructureQuinidine is a member of a family of alkaloids found in Cinchona(金鸡纳树) bark. It is diastereomers(非对映体) of quinine.Quinidine is composed of a quinoline (喹啉) ring and the bicyclic quinuclidine ring (奎宁环) syst