心血管.ppt

CHAPTER 11 CARDIOVASCULAR DRUGS （心血管药物）,1,Heart diseases are grouped into three major disorders: cardiac failure, ischemia (with angina as its primary symptom), and cardiac arrhythmia. 心血管药物：作用于心脏或血管系统，改进心脏功能，调节心脏血液的总输出量，或改变循环系统各部分的血液分配。,2,SECTION 1 cardiotonic agents SECTION 2 antianginal drugs SECTION 3 antiarrhythmic drugs SECTION 4 antihypertensive drugs SECTION 5 antilipidemic drugs,3,SECTION 1 CARDIOTONIC AGENTS （强心药）,I Cardiac glycosides（强心苷类） II、Nonglycoside（非苷类） 1. Phosphodiesterase inhibitor (磷酸二酯酶抑制剂) 2. b-agonists 3. Calcium sensitizers (钙敏化剂),4,Cardiac failure can be described as the inability of the heart to pump blood effectively at a rate that meets the needs of metabolizing tissues. This is found to be a direct result of a reduced contractility of the cardiac muscles, especially those of the ventricles (心室). The cardiac output decreases, and the blood volume of the heart increases (hence the name congested). As a result, the systemic blood pressure and the renal blood flow are both reduced, which often lead to the development of edema in the lower extremities and the lung (pulmonary edema) as well as renal failure.,5,Congestive heart failure（ CHF, 充血性心力衰竭）：心脏收缩力严重损害，可引起慢性心力衰竭，心脏不能把血液泵到外周部位，无法满足机体代谢的需要。 CHF起因：心肌部分缺血、高血压、非阻塞性心肌病变及先天性心脏病。,6,P282 强心药可加强心肌收缩力的药物，正性肌力药（positive inotropic agents）。,作用途径： l 抑制膜结合的Na+, K+-ATP酶的活性（强心苷类） l b-受体，特别是b1-受体激动作用（b-受体激动剂） l 激活腺苷环化酶，使cAMP水平增高，从而促进钙离子进入心脏细胞膜，增强心肌收缩力（磷酸二酯酶抑制剂） l 加强肌纤维丝对Ca2+的敏感性（钙敏化剂）,7,I Cardiac glycosides（强心苷类）,A group of drugs known as the cardiac glycosides were found to reverse most of these symptoms and complication. The cardiac glycosides occur mainly in plants and in rare case in animals. 洋地黄、铃兰毒毛旋花子、黄花夹竹桃、福寿草和万年青等有毒植物，蟾蜍等动物。 强心苷类小剂量有强心作用，使心肌的收缩作用加强，脉搏加速，但大剂量则能使心脏中毒而停止跳动。,8,Digitoxin (洋地黄毒苷) Lanatoside C (毛花苷C),9,-Strophanthin-K (毒毛花苷K) Convallatoxin (铃兰毒苷),10,Methyldigoxin (甲基地高辛) *Digoxin (地高辛),11,Cardiac glycosides are composed of two portions: the sugar and the nonsugar (the aglycone) moiety. The aglycone portion of the cardiac glycosides is a steroid nucleus with a unique set of fused rings, which makes these agents easily distinguished from other steroids. Rings A-B and C-D are cis fused, and ring B-C has a trans configuration. Such ring fusion gives the aglycone nucleus the characteristic U shape. The steroid nucleus also carries, in most cases, two angular methyl groups at C-10 and C-13. Hydroxyl groups are located at C-3, the site of the sugar attachment, and C-14. The latter hydroxyl is normally unsubstituted.,12,Additional hydroxyl groups may be found at C-12 and C-16, the presence or absence of which distinguishes the important genins. These additional hydroxyl groups have significant impact on the partitioning and kinetics of each glycoside. The lactone ring at C-17 is a major structural feature of the cardiac aglycones. In most cases, cardiac glycosides of plant origin, the cardinolides（卡烯内酯）, possess a five-membered, a,b-unsaturated lactone ring, whereas those derived from animal origin, the bufadienolides（蟾二烯羟酸内酯）, possess a six-membered lactone ring with two conjugated double bonds.,13,Cardenolide Bufadienolide (卡烯内酯) (蟾二烯羟酸内酯),14,The hydroxyl group at C-3 of the aglycone portion is usually conjugated to a monosaccharide or a polysaccharide with b-1,4-glucosidic linkages. The number and identity of sugars vary from one glycoside to another as detailed subsequently. The most commonly found sugars in the cardiac glycosides are D-glucose, D-digitoxose, L-rhamnose and D-cymarose.,15,D-glucose D-digitoxose （-D-葡萄糖） （-D-洋地黄毒糖） L-rhamnose D-cymarose （-L-鼠李糖） （-D-加拿大糖）,16,Biochemical mechanism of action p284,Receptor: Na+, K+-ATPase enzyme At the resting state , the concentration of sodium is high outside the cell. On membrane depolarization, sodium fluxes-in, leading to an immediate elevation of the action potential, elevated intracellular sodium triggers the influx of Ca+, results in efflux of potassium out of the myocardium. The Na+/K+ exchange requires energy and is catalyzed by the enzyme Na+, K+-ATPase .cardiac glycosides are proposed to inhibit this enzyme with net result of reduced sodium exchange with potassium.,17,i.e., increased intracellular sodium, which , in turn, results in increased intracellular calcium. Elevated intracellular calcium concentration triggers a series if intracellular biochemical events that ultimately result in an increase in the force of the myocardial contraction, or a positive inotropic effect.,18,II、Nonglycoside（非苷类） 1. Phosphodiesterase inhibitor (磷酸二酯酶抑制剂) 2. b-agonists 3. Calcium sensitizers (钙敏化剂),19,II Nonglycoside（非苷类） 1. Phosphodiesterase inhibitor (PDEI, 磷酸二酯酶抑制剂),20,This agent and related compounds are thought to elicit their effects by the inhibition of a specific phosphodiesterase (phosphodiesterase fraction III) in the myocardium. This inhibition leads to elevated levels of cyclic adenosine monophosphate (cAMP), which through complex chain of biochemical events leads to an increase in muscle contractility.,Amrinone produced both positive inotropic and concentration-dependent vasodilatory effects. Despite similar positive inotropic action of the cardiac glycosides, amrinone appears to act through a distinctly different mechanism.,21,氨力农(Amrinone),*米力农(Milrinone) 1,6-dihydro-2-methyl-6-oxo-3,4-bipyridine-5-carbonitrile Milrinone produces similar pharmacologic effects and probably acts through the same mechanism as amrinone. Milrinone is of an order of magnitude more potent than amrinone and is better tolerated, with no apparent thrombocytopenia (血小板减少症）or gastrointestinal disturbances.,22,Enoximone(依洛昔酮) Piroximone(匹罗昔酮) Bemarinone(贝马力农) Vesnarinone(维司力农),23,p287,2. b-agonists 288,The myocardium has mostly b-adrenergic receptors of b1 subtype. It has been found that stimulation of these receptors by a variety of b-adrenergic agonists produces a potent positive inotropic response.,24,Dobutamine (多巴酚丁胺) Dobutamine is a prime representative of dopamine derivatives. It is a potent b1-adrenergic agonist. Its beneficial effects, although largely attributed to its b1agonistic activity on the myocardium, are likely the composite of a variety of actions on the heart and the peripheral vasculature. Short duration ,cannot be used orally,25,Ibopamine (异波帕胺) Denopamine (地诺帕明) Abbot-4(谷多巴胺双醋酸酯) Dopexamine (多培沙明),26,Butopamine(布托巴胺) Xamoterol(扎莫特罗) Prenalterol(普瑞特罗),27,3. Calcium sensitizers (钙敏化剂) p289,钙敏化剂是一类能增加肌纤维对Ca2+敏感性的药物，能使生理浓度的游离Ca2+产生更强的张力，与肌节增长的效应相似，又称收缩蛋白Ca2+敏感性调节剂。 Sulmazole (硫马唑) Esomazole (伊索马唑),28,*Pimobendan (匹莫苯) 苯并咪唑-哒嗪酮衍生物，具有强而持久的正性肌力效应，不仅是钙敏化剂，还选择性地抑制PDE-III的活性。,29,SECTION 2 ANTIANGINAL DRUGS （抗心绞痛药）,Organic nitrates and nitrites (硝酸酯及亚硝酸酯类) 2. Calcium channel blockers （钙拮抗剂） 3. b-Adrenergic blocking agents,30,Angina pectoris is the disease of the coronary artery（冠状动脉）. The latter is the supply route of blood carrying oxygen from the left ventricle（左心室）to all heart tissues, including the ventricles themselves. When the coronary artery becomes less efficient in supplying blood and oxygen to the heart, the heart is said to be ischemic (short in oxygen). Angina is the primary symptom of ischemic heart disease, characterized by a sudden, severe pain originating in the chest, often radiating to the left shoulder and down the left arm.,31,心绞痛的发作是由于心肌急剧的暂时性缺血和缺氧所引起，是冠心病的常见病。治疗心绞痛的合理途径是增加供氧或降低耗氧。现有药物通过降低心肌耗氧量而达到缓解和治疗的目的。,32,1. Organic nitrates and nitrites (硝酸酯及亚硝酸酯类),Amyl Nitrite(亚硝酸异戊酯) * Nitroglycerol(硝酸甘油) Erythrityl Tetranitrate PentaerythritolTetranitrate (丁四硝酯) (戊四硝酯),33,* Isosorbide Dinitrate (硝酸异山梨酯) 1,4:3,6-dianhydro-D-glucitol-2,5-dinitrate 冠脉扩张作用，长效抗心绞痛药，预防心肌梗塞。 Isosorbide Mononitrate Mannitol Hexanitrate (单硝酸异山梨醇) (硝甘露醇),34,*Nitroglycerin 硝酸甘油,浅黄色无臭代甜味的油状液体，低温下凝固成两种形式，一种是稳定的双棱形晶体，一种为不稳定的三斜晶体。有挥发性。能吸收空气中的水分成塑胶状，遇热和撞击下易发生爆炸。 中性和弱酸性条件下稳定，碱性条件下迅速分解。 体内代谢生成1，2-和1，3-甘油二硝酸酯，甘油单硝酸酯，甘油，代谢物经尿和胆汁排出体外 用途：直接松弛血管平滑肌，特别是小血管平滑肌，使全身血管扩张，外周阻力减少，静脉回血量减少。心排出量降低，心脏负荷减轻，减少心肌耗氧量，从而缓解心绞痛。 用于心绞痛性发作治疗，也用于急性左心衰竭的治疗，可舌下含服,35,* Isosorbide dinitrate 硝酸异山梨酯,1,4:3,6-dianhydro-D-glucitol-2,5-dinitrate 1,4:3,6-二脱水-D-山梨醇二硝酸酯，又名消心痛，硝异梨醇 本品在丙酮或氯仿中易溶，乙醇中略溶。室温干燥状态稳定，遇强热会发生爆炸。加水和硫酸水解生成硝酸，缓缓加入硫酸亚铁试液，接界面显棕色。 血管扩张药，用于缓解和预防心绞痛，也用于充血性心力衰竭，本品扩张血管平滑肌的作用比硝酸甘油更显著，且持续时间长，能明显的增加冠脉流量，降低血压。,36,作用机制,血管内皮细胞能释放扩血管物质内皮舒张因子（endotheliumderived relaxing factor, EDRF），即NO。NO由内皮细胞中的L-精氨酸-NO合成途径产生，从内皮细胞弥散到血管平滑肌细胞，激活鸟苷酸环化酶，增加细胞内cGMP的含量，从而激活依赖于cGMP的蛋白激酶，促使肌球蛋白去磷酸化，松弛血管平滑肌。硝基类扩冠药在平滑肌细胞及血管内皮细胞中产生NO而舒张血管。硝酸酯类与血管平滑肌细胞的硝酸酯受体结合，并被硝酸酯受体的巯基还原成NO或SNO。,37,2. Calcium channel blockers（钙拮抗剂）,The second major therapeutic approach to the treatment of angina is the use of calcium channel blockers. Calcium ions are known to play a critical role in many physiologic functions. Physiologic calcium is found in a variety of locations, both intracellular and extracellular. Because Calcium plays such a ubiquitous role in normal physiology, the overall therapeutic effect of the calcium channel blockers is often the composite of numerous pharmacologic actions in a variety of tissues. The most important of these tissues associated with angina are the myocardium and the arterial vascular bed.,38,Because of the dependence of the myocardium contraction on calcium, these drugs have a negative inotropic effect on the heart. Vascular smooth muscle also depends on calcium influx for contraction. Inhibition of calcium channel blockers leads to vasodilation, particularly in the arterial smooth muscles. The venous（静脉） beds appear to be less affected by the calcium channel blockers. The negative inotropic effect and arterial vasodilation result in decreased heart workload and afterload. The preload is not affected because of lesser sensitivity of venous bed to the calcium channel blockers.,39,钙离子是心肌和血管平滑肌兴奋-耦联中的关键物质，钙拮抗剂抑制细胞外钙离子内流，使心肌和血管平滑肌细胞内缺乏足够的钙离子，导致心肌收缩力减弱，心率减慢，心输出量减少，同时，血管松弛，外周血管阻力降低，血压下降，因而减少心肌做功力和耗氧量。钙拮抗剂在临床上除抗心绞痛外，还有抗心率失常和抗高血压的作用，是一类治疗缺血性心脏病的重要药物。,40,Calcium channel blockers are used clinically as antianginal, antiarrhythmic, and antihypertensive agents. The most common side effects of the calcium channel blockers include dizziness, hypotension, headache, and peripheral and pulmonary edema.,41,（1）Dihydropyridines, DHP (二氢吡啶类),Dihydropyridines have much less effect on the cardiac tissues and higher specificity for the vascular bed. Dihydropyridines are most frequently used as antianginal and antihypertensive agents.,42,*Nifedipine (硝苯地平) 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester 心痛安，利心平，第一代DHP的代表，血管扩张作用强烈，作用是硝酸甘油的20倍；适于冠脉痉挛所致心绞痛。用于预防和治疗冠心病、心绞痛，对顽固性、重度高血压有疗效。,43,*Nicardipine (尼卡地平) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl-2-methyl-(phenylmethyl)-amino-ethyl ester 第二代DHP，两种结晶；平稳降压，降低心肌耗氧量，减轻左室负荷及增加心输出量，适用于各种缺血性脑血管疾病，风湿性心脏病及各类型心绞痛。,44,Amlodipine Nisoldipine (氨氯地平) (尼索地平) Amlodipine起效较慢，但持续时间长。 Nisoldipine适用于治疗心衰和高血压危象，作用迅速。,45,SAR of DHP,l 1,4-二氢吡啶环是必需结构，吡啶无活性，1位N不被取代为佳 l 2,6-位取代基应为低级烷烃 l 3,5-位取代基酯基是必要结构，-COCH3, -CN活性降低 l 若C4有手性，立体结构有选择作用 l 4位取代苯基上以邻、间位取代为宜,46,（2）Aralkylamine derivatives (芳烷基胺类),* Verapamil (维拉帕米，异搏定，戊脉胺) 5-(3,4-dimethoxyphenethyl)methylamino-2-(3,4-dimethoxyphenyl)-2-isopropylvalero-nitrile,47,Verapamil is structurally characterized by a central basic nitrogen to which alkyl and aralkyl groups are attached. Verapamil affects both the heart and the arterial bed and is clinically used in the management of angina, hypertension, and cardiac arrhythmia. 左旋体是室上性心动过速的首选药物，右旋体用于治疗心绞痛。,48,Gallopamil (戈洛帕米) 左旋体有效 Emopamil (依莫帕米)左旋体活性大于右旋体 Falipamil (法利帕米),49,(3) Benzothiazepine derivatives (苯并硫氮杂卓类),* Diltiazem (地尔硫卓) d-cis-2-(4-甲氧基苯基)-3-乙酰氧基-5-(2-二甲基氨基乙基)-2,3-二氢-1,5-苯并硫氮杂卓-4(5H)-酮 Diltiazem适用于缺血性心脏病、运动性心绞痛及陈旧性心肌梗塞引起的心绞痛。,50,Metabolism of Diltiazem,脱乙酰基,脱O-甲基,脱N-甲基,Synthetic route of Diltiazem,Nictiazem (尼克硫卓),(4) Miscellaneous calcium channel blockers (其它类钙拮抗剂),Diphenylpiperazine derivatives (二苯基哌嗪类)：对血管平滑肌钙通道有抑制作用。 氟桂利嗪(Flunarizine),Cinnarizine(桂利嗪) Lidoflazine(利多氟嗪) 对缺血性脑缺氧引起的脑损失和代谢异常有效，也可增加脑血流量，减轻脑血管痉挛脑水肿。,55,Bepridil (苄普地尔) Bepridil 抑制钠、钾通道，并具有扩张外周和冠脉血管，增加冠脉血管作用，用于治疗冠心病、高血压、心率不齐和心绞痛。,Perhexiline (哌克昔林),Perhexiline 扩张冠脉血管，增加冠脉血流量，改善心肌供氧，适用于抗心绞痛和抗心率不齐。,Prenylamine (普尼拉明) 对冠脉有持续扩张作用，对心绞痛、心肌梗死及心率失常有效。,3. b-Adrenergic blocking agents,The use of b-Adrenergic blockers as antianginal agents is limited to the treatment of exertion-induced angina. Although these agents may be used alone, they are often used in combination therapy with nitrates, calcium channel blockers, or both. In several instances, combination therapy was found to provide more improvement than did either agents alone.,Dipyridamole (双嘧达莫) Dipyridamole is generally used prophylactically, but its efficacy in reducing the incidence and severity of anginal attacks is not universally accepted.,60,SECTION III ANTIARRHYTHMIC DRUGS （抗心律失常药),1. Ion channel blockers (1) Sodium channel blockers (2) Calcium channel blockers (3) Potassium channel blockers 2. b-Adrenergic blocking agents 3. SAR of antiarrhythmic drugs,Arrhythmia is an alteration in the normal sequence of electrical impulse activation that leads to the contraction of 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 so-called pacemaker cells in the A-V and S-A nodes; however, both the atria and the ventricles are also involved.,心律失常是心动规律和频率的异常，心房和心室正常激活和运动顺序发生障碍，是严重的心脏疾病，分为心动过速和心动过缓型两种。起搏细胞功能失调或房室节传导阻滞都可引起心律失常，冲动形成障碍和冲动传导障碍或二者兼有均可引起。,Normal cardiac contractions are largely a function of the action of a single atrial pacemaker, a fast and generally uniform conduction in predictable pathways, and a normal duration of the action potential and refractory period. It is widely accepted that most currently available antiarrhythmic drugs may be classified into four categories, grouped based on their effects on the cardiac action potential and consequently on the electrophysiologic properties of the heart.,Classification of antiarrhythmic agents,I Sodium channel blockers (钠通道阻断剂) II -adrenergic receptor blocking agents(b阻断剂) III agents for the prolongation of duration of action potential(延长动作电位时程药物) IV Calcium channel blockers (钙拮抗剂),65,作用机制,l 降低自律性，抑制快反应细胞4相Na+内流或抑制慢反应细胞4相Ca2+内流而降低自律性，促进K+外流，增大最大舒张电位，使其远离阈电位，也可降低自律性。 l 减少后除极与触发活动，早后除极，迟后除极 l 改变膜反应性而改变传导性，增强膜反应性改善传导或减弱膜反应性 l 改变有效不应期（effective refractory p