心血管药物Cardiovasculardrugs.ppt

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1、心血管药物心血管药物Cardiovascular drugsHeart Disease FactsHeart Disease FactsHeart disease is the leading causeleading cause of death for both men and women.More than halfMore than half of the deaths due to heart disease in 2009 were in men.About 600,000 Americans600,000 Americans die from heart disease each

2、 yearthats 1 1 in every 4 deathsin every 4 deaths.1Coronary heart disease is the most common type of heart disease,killing more than 385,000 people385,000 people annually.In the United States,someone has a heart attack every 34 secondsevery 34 seconds.Each minute,someone in the United States dies fr

3、om a heart disease-related event.Heart disease is the leading causeleading cause of death for people of most racial/ethnic groups in the United States,including African Americans,Hispanics,and whites.For Asian Americans or Pacific Islanders and American Indians or Alaska Natives,heart disease is sec

4、ond only to cancer.Coronary heart disease alone costs the United States$108.9 billion$108.9 billion each year.This total includes the cost of health care services,medications,and lost productivity.High blood pressure,high LDL cholesterol,and smoking are key heart disease risk factors for heart disea

5、se.About half of Americans(49%)have at least one of these three risk factors.Several other medical conditions and lifestyle choices can also put people at a higher risk for heart disease,including:DiabetesOverweight and obesityPoor dietPhysical inactivityExcessive alcohol useRisk FactorsRisk Factors

6、心血管药物心血管药物Cardiovascular drugs1.强心药强心药 Cardiotonic agents2.抗心绞痛药抗心绞痛药 Antianginal drugs3.抗心率失常药抗心率失常药 Antiarrhythmic drugs4.抗高血压药抗高血压药 Antihypertensive drugs5.抗高脂蛋白血症抗高脂蛋白血症 Antihyperlipoproteinemic drugs+_+_+_+_+_+_+_+_+_+_+_+_+_+_+_+_+Na+,K+-ATPaseATPNa+K+Ca+Cl-Na+K+K+跨膜电位mv-100-80-60-40-200+20复 极

7、 化去极化43210-心肌细胞膜电位与离子转运心肌细胞膜电位与离子转运零电位阈电位阈电位静息电位静息电位动作电位动作电位(actionpotential duration)细胞膜细胞膜0相：除极，Na+快速内流1相：快速复极初期，K+短暂外流2相：Ca2+及少量Na+经慢通道内流，K+外流3相：快速复极末期，K+外流4相：静息期复极过程膜电位恢复到-60-50mV时，细胞才对刺激产生动作电位。之前为Effective Refractory Period(ERP).ERP大：心肌不起反应的时间长不易发生快速性心律失常药物：影响心肌细胞膜的离子通道，改变离子流。I.强心药强心药 Cardioton

8、ic agents/正性肌力药正性肌力药 Inotropic agents 慢性或充血性心力衰竭(Congestive Heart Failure,CHF)诱发因素：心肌局部缺血、高血压、非阻塞性心肌病变，先天性心脏病*正性肌力药加强心肌收缩性*血管扩张剂、利尿药、血管紧张素转化酶抑制剂降低前、后负荷强心药*抑制膜结合Na+，K+-ATP酶活性的强心苷*b-受体激动剂*PDE(磷酸二酯酶)抑制剂*加强肌纤维丝对Ca2+敏感性的钙敏化药强心苷类强心苷类 Cardiac glycosidesH3COOOOH3COHHHOOH3COOH3COHHOOHOHHOHCH3H3CH3COOOOH3COHH

9、HOOH3COOH3COHHOOHOHH洋地黄毒苷洋地黄毒苷 Digitoxin地高辛地高辛 Digoxin抑制心肌细胞膜结合的Na+,K+-ATPase（逆浓度梯度主动转运3Na+出细胞外，2K+进入细胞内）使细胞内Na+增多，K+减少，并经Na+-Ca2+双向交换进一步导致细胞内Ca2+增加，使心肌收缩加强。Ca2+是触发心肌兴奋-收缩偶联的关键物质，胞浆内游离Ca2+能和心肌钙蛋白troponin结合，解除原肌球蛋白tropomyosin对actin和肌球蛋白myosin相互作用的抑制，使actin在横桥间滑动，化学能机械能强心苷类中毒引发心律紊乱，可用钾盐防止或缓解。F=60%80%治

10、疗血药浓度：0.51.5ng/mL中毒血药浓度：2ng/mlnarrow therapeutic index OHOOHCH3COOOOH3COHHOOOOCH3HOHHOHOHOHOHOHOH3COOOOH3COHHHOOH3COOH3COHOHOHHOHCH3HOHOHOHOO毛花苷C Lanatoside C毒毛花苷K Strophanthin K铃兰毒苷 ConvallatoxinOOOHCH3COHHOHOOHOHOH3COHH结构特征结构特征配糖基由糖苷基与配糖基两部分组成糖苷基部分：以1,4-糖苷键连接；糖基本身并无活性,糖越少，强心作用越强；苷元水溶性小，正性肌力作用减弱，脂溶

11、性增加，易进CNS，中枢毒副作用五元环（植物）cardenolide六元环（动物）bufadienolide3糖苷基：多为D-glucose,D-digitoxose,L-Rhamnose,D-Cymarose;常见糖苷基常见糖苷基OHOHOHOHOOHOOHH3COHHOOOHH3COCH3HOOOHH3CHOHOOHb b-D-洋地黄毒糖b b-D-葡萄糖-L-鼠李糖b b-D-加拿大麻糖甾核立体构象：顺反顺甾核立体构象：顺反顺 OHCH3HCH3HOHHHcis-trans-cis19181716151413121110987654321ABCD通常通常3 3b b位有位有OHOH，与糖

12、苷，与糖苷基连接，转为基连接，转为 构型则构型则失活失活通常通常1414位有位有OHOH，若，若脱水成双键脱水成双键（8,14 8,14 oror14,1514,15）则失）则失活。活。C14C14应保持应保持spsp3 3杂化杂化在甾核的其它位置在甾核的其它位置上可引入上可引入OHOH通常通常1010b b，1313b b有两个甲基，有两个甲基，称称19-CH319-CH3和和18-18-CH3CH319-CH319-CH3氧化为氧化为19-CH2OH19-CH2OH或或19-19-CHOCHO，活性升高；，活性升高；若氧化为若氧化为19-19-COOHCOOH，则活性，则活性大大降低大大降

13、低19-CH319-CH3脱除，脱除，活性大大降低活性大大降低卡烯内酯卡烯内酯 Cardenolide 蟾二烯羟酸内酯蟾二烯羟酸内酯 BufadienolideOOOHRHOOO19181716151413121110987654321ABCD2021222324232221201717b b位：位：,b b-不饱和内酯环不饱和内酯环内酯环变为内酯环变为17 位，则活性降低位，则活性降低双键被饱和，或内酯环打开，活性均显著降双键被饱和，或内酯环打开，活性均显著降低或消失；低或消失；,b b不饱和氰基取代，保留活性不饱和氰基取代，保留活性双键：双键：5,6 5,6 和和16,17 16,17 保

14、保留作用留作用8,9 8,9 丧失强丧失强心作用心作用Phosphodiesterase inhibitorsPDE以多种同工酶形式存在于人体细胞中，其中位于心肌细胞膜上的PDE-对于cAMP具有高亲和性和专一性。PDE-是cAMP和cGMP的降解酶，其活性被抑制将增加胞内cAMP的量，高浓度的cAMP激活多种蛋白激酶，使心肌膜上钙通道开放，促Ca2+内流，促进心肌纤维收缩，发挥正性肌力作用和血管舒张作用，达到强心的目的。药用：选择性PDE-抑制剂 氨力农 Amrinone（副作用多）HNNNCOCH3HNNH2NONHNHCONOCH3CH2NHNHCOOH3CH3CS依洛昔酮 Enoxim

15、one，可长期口服，耐受良好米力农Milrinone，活性增强1020X匹洛昔酮Piroximone，比enoximone强510XCH2CH2NHHOHOCHCH2CH3CH2OHCH2CH2NH2HOHOCH2CH2NHCH2CHCH3OCH3OOHOHCH2CH2NHCH3(CH3)2CHCO(CH3)2CHCOOOb b1 adrenoceptor agonists多巴胺 Dopamine，加快心律副作用多巴酚丁胺 Dobutamine，口服无效，体内由Catechol-O-methyltransferase催化代谢异波帕胺 Ibopamine地诺帕明 Denopamine,口服有效扎

16、莫特罗 Xamoterol,双重作用（交感神经功能低下时，产生正性肌力作用和频率，亢进时负性肌力作用），不适用于重症CHF普瑞特罗 Prenalterol,选择性b1受体激动剂,对b2无明显作用，治疗伴有心肌梗死的心力衰竭HOOCH2CHCH2NHCH(CH3)2OHHOOCH2CHCH2NHCH2CH2NHCOHNOO心绞痛是冠状动脉供血不足引起的心肌急剧的、暂时的缺血和缺氧综合征。改善心肌的血氧供需矛盾与消除冠状动脉痉挛是目前治疗心绞痛的药理基础。*通过舒张冠状动脉、解除冠状动脉痉挛或促进侧枝循环的形成而增加冠状动脉供血*通过舒张静脉，减少回心血量、降低前负荷*舒张外周小动脉、降低血压，减轻后负荷，降低心室壁肌张力，减慢心率及降低心肌收缩性等降低心肌对氧的需求 II.II.抗心绞痛药抗心绞痛药 AntianginalAntianginal drugs drugs1 NO供体药物2 钙拮抗剂Calcium antagonists3 b-受体阻断剂 b-Blockers（见抗肾上腺素药物）2.1 NO舒张血管作用过程舒张血管作用过程血管内皮细胞血管内皮细胞合成并释放合成并释放血管内皮舒