《心血管药物》PPT课件.ppt

Chapter 12Cardiovascular DrugsCardiovasculardiseasesnCardiovascular diseases include hypertension(高血压高血压),hyperlipidemia(高血脂高血脂),angina(心绞痛心绞痛),atherosclerosis(动脉粥样硬化动脉粥样硬化),coronary diseases(冠心病冠心病),hypotension(低血压低血压),cardiac arrhythmias(心率失常心率失常),heart failure(心力衰竭心力衰竭),and certain vascular disorders.Cardiovascular DrugsnCardiovascular drugs 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 drugsnCardiac drugs include cardiac agents(强心药强心药),antianginal drugs(抗心绞痛药抗心绞痛药),antiarrhythmic agents(抗心率失常药抗心率失常药),antihypertensive agents(抗抗高血压药高血压药),hypolipidemic drugs(降血脂药血脂药).Section 1 Cardiac AgentsnCardiac 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 failure，CHF）nCHF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。nCHF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 CHFnCardiac Agents nVasodilatorsnDiureticsnAngiotensin-converting enzyme inhibitors(ACEI)The Sorts of Cardiac Agentsn1.Cardiac glycosidesn2.Phosphodiesterase inhibitors n3.Calcium sensitizersn4.Adrenergic agonists 1.Cardiac glycosides(强心苷类)nCardiac glycosides have applied for heart failure for more than hundred years.Today they are still important drugs to treated heart failure.n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。n主要缺点：安全范围小，强度不够大，且具有吸收、消除途径及速度方面的缺点。Digoxinn(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 nDigoxin is absorbed and distributed in tissues rapidly.It is excreted in prototype by kidney.nDigoxin 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 clinicnThere 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(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配糖基部分配糖基部分steroid nucleus nStereo-structure of steroid nucleus cis-A/B,trans-B/C,cis-C/D.,unsaturated lactonenFive-member(plant):Cardenolide(卡烯内酯)nSix member(animal):Bufadienolide(蟾二烯羟酸内酯)Sugar moietiesThe function of chemical structurenAglycone steroid nucleus which convey the pharmacological activity of these compounds.nAn unsaturated lactone ring which conveys cardiotonic(强心的)activity.nSugar moieties which modulate potency and pharmacokinetic distribution.2）The Action MechanismnCardiac 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 out of the cell by the Na+/Ca2+exchanger during diastole(心脏舒张).nConsequently,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 glycosidesn1.C17-,unsaturated lactonen2.steroid nucleus;n3.C19-CH3;n4.C14-OH;n5.C3-O-sugar.Figure of cardiac glycosides and Na+,K+/ATPase actionMethyldigoxintoxicity2.Phosphodiesterase inhibitor,PDEInPDEI is a sort of new cardiac drugs having different action mechanism with cardiac glycosides.nExamples of PDEI include amrinone(氨力农)and milrinone(米力农).nThese have been developed as a result of the many adverse effects and problems associated with cardiac glycosides.nThere is no evidence that these improve the mortality.The Action MechanismnPhosphodiesterase is responsible for the degradation of cAMP;Thus,inhibiting this enzyme raises cAMP levels and causes increase in myocardial(心肌)contractility and vasodilatation(血管舒张).nCardiac 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 force of cardiac contractionPhosphodiesterase,PDEnPDE has three types:PDE-,.nPDE-,which both have different subtypes,dont have speciality on cAMP.nPDE,which only has a subtype,possesses high speciality and affinity on cAMP.Amrinone(氨力农)nAmrinone is the first PDEI drug in clinical use in 1978.Pharmacology of AmrinonenAmrinone is short acting and is administered intravenously.nIt is given for severe acute heart failure that is resistant to other drugs.nIt has several adverse effects.These include nausea and vomiting,arrhyth-mias,liver dsyfunction,abdominal pain,and hypersensitivity.Milrinone(米力农)n化学名：1,6-二氢-2-甲基-6-氧-(3,4-双吡啶)-5-氰,又名米利酮。n1,6-dihydro-2-methyl-6-oxo-3,4-bipyridine-5-carbonitrile,corotropePharmacology of MilrinonenMilrinone is long acting and is administered orally.nMilrinone has high speciality on PDE-.So it is 1020 fold effective than amrinone.nIts adverse effects are less than amrinone,but it has potent arrhythmias possibility.Enoximone(依洛昔酮）nEnoximone is a potent selective inhibitor.nIt is administered orally for a long period.3.Calcium sensitizers(钙敏化剂)n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)n能增加收缩蛋白对Ca2+敏感性，在不增加Ca2+浓度的情况下，提高心肌收缩力。4.Adrenergic Agonistsn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。nExamples 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)nDobutamine is a selective agonist of cardiac 1 receptor.nIt is given for heart failure.But it is short acting,and no effective orally.Denopamine(地诺帕明）nDenopamine has distinct positive inotropic action when given orally and doesnt increase heart rate.Section 2 Antianginal DrugsnAngina is the primary symptom of ischemic heart disease,characterized by a sudden,server pain originating in the chest,often radiating to the left shoulder and down the left arm.nAngina is the symptom of the coronary artery.nThe latter is the supply route of blood carrying oxygen from the left ventricle to all heart tissues,including the ventricle themselves.Oxygen supplyingnWhen the coronary artery becomes less efficient in supplying blood and oxygen to the heart,the heart is said to be ischemic(short in oxygen).nMyocardial ischemia (心肌缺血)occurs when the oxygen is not efficient to meet the myocardial(心肌的)workload.nThis can occur because of atherosclerotic narrowing of the coronary circulation(typical)or vasospasm(血管痉挛)of the coronary artery(variant).Oxygen requirements nThe 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 resistance of the blood flow.Antianginal DrugsnTherapy 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 vasodilating,O2preloadheart ratethe force of cardiac contraction afterloadThe class of Antianginal Drugsn 1.NO donor drugsn 2.Calcium antagonits(calcium channel blockers)n adrenergic antagonists(-adrenergic blockers)(1)The Development of NO donor drugs nOrganic nitrates have dominated the treatment of acute angina over 100 years after the antiaginal effect of amyl nitrite(亚硝酸异戊酯)was first observed in 1857.nAlthough 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 class of choice to treat acute anginal episode.Chemistry of nitratesnOrganic nitrates are esters of simple organic alcohols or polyols with nitric acid.Nitrates in clinical use todayThe chemical natures of nitrates nVolatility(挥发性)nHydrolysis nExplosive properties nThe nonpolar nature Pharmacologic actions of nitratesnThe 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 nitratesnPrevention therapy requires a long-acting preparation with more emphasis on duration and less emphasis on onset.nThe duration of nitrate action is strongly influenced by metabolism.nAll 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 tissues,such as the blood vessels themselves.The onset of organic nitrate actionnThe onset of organic nitrate action is influenced not only by the special agent chosen,but also by the routine of administration.nSublingual(舌下)administration is used predominantly for a rapid onset of action.nFor the treatment of acute anginal attacks,a rapid-acting preparation is required.The duration and onset of nitrates action Nitroglycerin（硝酸甘油）n1,2,3-propanetriol trinitraten1,2,3-丙三醇三硝酸酯nVolatility,hydrolysis,explosive properties,nonpolar nature.体内作用n舌下含服通过口腔粘膜快速吸收，生物利用度可达80%。n本品为短效、速效抗心绞痛药物，能直接松弛血管平滑肌，使心绞痛缓解，用于各种心绞痛。Isosorbide Dinitraten1,4;3,6-dianhydro-D-glucitol-2,5-dinitrate.n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。n本品具有冠脉扩张作用，是长效抗心绞痛药。Isosorbide mononitraten1,4;3,6-dianhydro-D-glucitol-5-mononitraten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 NitratesnNitrates release NO,which dilates blood vessel.nThe 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.nThe balance between oxygen supply(by vasodilating the coronary artery)and oxygen demand(by decreasing the myocardial workload)is restored.n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 n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。n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n本品为潜在NO供体，在体内经代谢释放出NO而起作用。n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。此外，能扩张冠状动脉，改善心肌缺血症状。n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 nThe myocardium and vascular smooth muscle contraction depend on calcium influx for contraction.nInhibition of calcium ion(Ca2+)influx into myocardial and vascular cells may be advantageous in preventing angina.nBecause of the dependency of the myocardium contraction on calcium,these drugs have a negative inotropic effect on the heart.Action mechanismnInhibition of Ca2+influx into vascular muscles by the calcium channel blockers leads to vasodilation,particularly in the arterial smooth muscles.nThe venous 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 nCa2+是心肌和血管平滑肌兴奋-收缩偶联的关键物质。n 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 心肌收缩力减弱，心率减慢;钙拮抗剂钙拮抗剂具有具有抗心绞痛抗心绞痛、心律失常心律失常和和高血压高血压作用，作用，是一类治疗缺血性心脏病的重要药物。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n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。n受体调控的钙通道(receptor-operated calcium channels)Class of calcium channel blockers n(1)Selective calcium channel blockers n(2)Noselective calcium channel blockers (非选择性钙通道阻断剂)(1)Selective calcium channel blockers nA.Dihydropyridines(二氢吡啶类)nB.Aralkylamine derivatives(芳烷基胺类)nC.Benzothiazepine derivatives(苯并硫氮杂卓类)A.Dihydropyridines,DHPnThe dihydropyridines have much less effect on the cardiac tissues and higher specificity for the vascular bed.(L-calcium channels)nSo the dihydropyridine are more frequently used as antianginal and antihypertensive agents.Nifedipine（硝苯地平）n1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester.n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。Nicardipine（尼卡地平）nNicardipine 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.n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）n第三代钙通道阻滞剂，长效、耐受性好、生物利用度高。nIt may be used for patients with angina or hypertension.SARs of DHPn(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。n(2)活性与二氢吡啶环C-4的扭角有关，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)nVerapamil are clinically used in the management of angina,hypertension,and cardiac arrhythmia.Varapamil（维拉帕米）n-3-2-(3,4-dimethoxyphenyl)ethylmethyl-aminopropyl-3,4-dimethoxy-(1-methyl ethyl)benzeneacetonitrile hydrochloridePharmacologic effects nVarapamil have a chiral center,possessing distinct stereo-selectivity.nLevorotatory(R)isomer is preferred drug in treatment of supraventricular tachycardia(室上性室上性心动过速心动过速).nThe dextrorotatory(S)isomer is about an order of magnitude more potent as a calcium channel blocker than R isomer as antianginal and antihypertensive agent.C.Benzothiazepine(苯并硫氮卓类)derivativesnDiltiazem is clinically used in the management of angina,hypertension,and cardiac arrhythmia.Diltiazem hydrochride(盐酸地尔硫卓)n2S-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n2S-cis-3-(acetyloxy)-5-2-(dimethylamino)ethyl-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiozepin-4(5H)-one hydrochloridePharmacologic effects nDiltiazem has two chiral centers(2,3),and 2S,3S isomer is clinically used for supraventricular(室上性)arrhythmia,angina and hypertension.nDiltiazem is subject to fairly rapid first-pass metabolism.Metabolism of Diltiazem临床用途n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n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 blockersn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。n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，从而减少心肌耗氧量，缓解心绞痛。Adrenergic blockersnThe use of-adrenernic blockers as antianginal agents is limited to the treatment of exertion-I angina.nPropranolol is the prototype drug in the class.nAlthough these agents may be used alone,they are often used in combination therapy with nitrates,calcium channel blockers,or both.Section 3 Antiarrhythmic Drugsn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n心动过缓型 常用阿托品或异丙肾上腺素治疗。n心动过速型l 窦性心动过速l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）l 室性心动过速（室速）及心室纤颤（室颤）心脏内兴奋的传导Arrhythmic diseasenArrhythmia is an alteration in the normal sequence of electrical 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;however,both the atria（心房）and the ve