中国科学技术大学：心血管药物（PPT课件讲稿）Cardiovascular drugs

心血管药物 Cardiovascular drugs Heart disease facts Heart disease is the leading cause of death for both men and women More than half of the deaths due to heart disease in 2009 were in men about 600, 000 Americans die from heart disease each year-that's 1 in every 4 deaths. I Coronary heart disease is the most common type of heart disease killing more than 385, 000 people annually. In the United States, someone has a heart attack every 34 seconds Each minute. someone in the United states dies from a heart disease-related event Heart disease is the leading 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 second only to cancer Coronary heart disease alone costs the United States $108. 9 billion each year. This total includes the cost of health care services medications, and lost productivity

心血管药物 Cardiovascular drugs Heart Disease Facts • Heart disease is the leading cause of death for both men and women. More than half of the deaths due to heart disease in 2009 were in men. • About 600,000 Americans die from heart disease each year—that’s 1 in every 4 deaths. 1 • Coronary heart disease is the most common type of heart disease, killing more than 385,000 people annually. • In the United States, someone has a heart attack every 34 seconds. Each minute, someone in the United States dies from a heart disease-related event. • Heart disease is the leading 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 second only to cancer. • Coronary heart disease alone costs the United States $108.9 billion each year. This total includes the cost of health care services, medications, and lost productivity

Risk factors High blood pressure, high Ldl cholesterol, and smoking are key heart disease risk factors for heart disease. 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: Diabetes Overweight and obesity Poor diet Physical inactivity Excessive alcohol use

High blood pressure, high LDL cholesterol, and smoking are key heart disease risk factors for heart disease. 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: Diabetes Overweight and obesity Poor diet Physical inactivity Excessive alcohol use Risk Factors

心血管药物 Cardiovascular drugs 1.强心药 Cardiotonic agents 2.抗心绞痛药 Antianginal drugs 3.抗心率失常药 Antiarrhythmic drugs 4.抗高血压药 Antihypertensive drugs 5.抗高脂蛋白血症 Antihyperlipoproteinemic drugs

心血管药物 Cardiovascular drugs 1. 强心药 Cardiotonic agents 2. 抗心绞痛药 Antianginal drugs 3. 抗心率失常药 Antiarrhythmic drugs 4. 抗高血压药 Antihypertensive drugs 5. 抗高脂蛋白血症 Antihyperlipoproteinemic drugs

心肌细胞膜电位与离子转运 0相:除极,Na+快速内流 零电位1相:快速复极初期,K短暂外流 跨0 2 2相:Ca2及少量Na经慢通道内流 膜 K外流 电 -20 去 复 位 0极 极 3相:快速复极末期,K外流 化 化\3 my -60 4相:静息期 阌电位 静息电位4 复极过程膜电位恢复 100 到-60-50mV时,细胞 动作电位 actionpotential duration)才对刺激产生动作电 位。之前为 Effective Na cl ca K Na, K-ATPase Refractory Period (ERP).ERP大:心肌不 细胞膜 ++++++ 起反应的时间长→不 易发生快速性心律失 K K Na 常 药物:影响心肌细胞膜的离 子通道,改变离子流

_+_+ +_ +_ +_ _+ +_ + _ + _ + _ + _ + _ + _ + _ +_ _ +_ + Na + , K + -ATPase ATP Na + K+ Ca C ++ l N - a + K+ K+ 跨 膜 电 位 mv -100 -80 -60 -40 -20 0 +20 复 极 化 去 极 化 4 3 2 1 0 - - - - - - - 心肌细胞膜电位与离子转运 零电位 阈电位 静息电位 动作电位(actionpotential duration) 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

L强心药 Cardiotonic agents/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Nat,K-ATP酶活性的强心苷 *β-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

I. 强心药 Cardiotonic agents / 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 Cardiac glycosides 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NaCa2双向交换进步导致细 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。Hsc H3C 洋地黄毒苷 Digitoxin H3c H3C H3C H OH OH OH OH Hac 地高辛 Digoxin Hac H3C H F=60‰80% 治疗血药浓度:0.51.5ng/mL OH narrow therapeutic index 中毒血药浓度:2ng/ml

强心苷类 Cardiac glycosides H3C O O O O H3C OH H H O O H3C O O H3C OH HO OH OH H OH CH3 H3C H3C O O O O H3C OH H H O O H3C O O H3C OH HO OH OH H 洋地黄毒苷 Digitoxin 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% 治疗血药浓度：0.5~1.5ng/mL narrow therapeutic index 中毒血药浓度：2ng/ml

OH 毛花苷 C Lanatoside c H OH H3C H?c H3C HO OH OH H3C OHCH H2c H OH OCH3 毒毛花苷 K Strophanthin K

O HO OHC H3C O O O O H3C OH H O O O OCH3 H OH HO HO HO HO HO HO H3C O O O O H3C OH H H O O H3C O O H3C OH OH OH H OH CH3 HO HO HO HO O 毛花苷C Lanatoside C 毒毛花苷K Strophanthin K

结构特征 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,脂溶性增加,易进CNS,中枢毒副作用 五元环(植物) cardenolide 六元环(动物) bufadienolide 糖苷基:多为D- glucose,D digitoxose, L-Rhamnose, D- ymarose, OUCH HRC O H OH HO O 配糖基 HO OH 铃兰毒苷 Convallatoxin

铃兰毒苷 Convallatoxin O O OHC H3C OH H OH O O HO HO H3C OH H 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，脂溶性增加，易进CNS，中枢毒副作用 五元环（植物）cardenolide 六元环（动物）bufadienolide 3 糖苷基：多为D-glucose, D￾digitoxose,L-Rhamnose, D￾Cymarose;

常见糖苷基 HrC HO HO OH HO HO OH HO β-D洋地黄毒糖 β-D-葡萄糖 H3CT-OOH HO HO OH HO OH OCH3 aL-鼠李糖 β-D-加拿大麻糖

常见糖苷基 O HO HO HO HO OH O OH H3C OH HO O OH H3C OCH3 O OH HO H3C HO HO OH b-D-洋地黄毒糖 b-D-葡萄糖 -L-鼠李糖 b-D-加拿大麻糖

甾核立体构象:顺-反-顺 通常10β,13B 有两个甲基, 称19-CH和18 CH3 18 19-CH3氧化为 19-CH20H或19 CH 13 CH0,活性升高; 若氧化为19 10 H C\17 CO0H,则活性 B 大大降低 H 14D 16 19-CH3脱除, 7 活性大大降低 通常14位有OH,若 HO 脱水成双键 (△8,14 cis- trans- cis or△1415)则失 活。C14应保持s3 通常3β位有OH,与糖苷 杂化 基连接,转为a构型则 在甾核的其它位置 失活 上可引入OH

甾核立体构象：顺－反－顺 OHCH3 H CH3 HOH H H cis-trans-cis 19 18 1716 15 14 13 12 11 10 9 8 7 6 54 321 A B C D 通常 3 b位有OH，与糖苷 基连接，转为 构型则 失活 通常14位有OH，若 脱水成双键 （△8,14 or △14,15）则失 活。C14应保持sp3 杂化 在甾核的其它位置 上可引入OH 通常10 b ，13 b 有两个甲基， 称19-CH3和18 - CH3 19 -CH3氧化为 19 -CH2OH 或19 - CHO，活性升高； 若氧化为19 - COOH，则活性 大大降低 19 -CH3脱除， 活性大大降低