13 抗心肌缺血药物-2011-10-17

null抗缺血性心肌病药 Drugs used in myocardial ischemia抗缺血性心肌病药 Drugs used in myocardial ischemia陈小平概 述概 述病理: 弥漫性纤维化所致心肌缺血 病因: 冠状动脉粥样硬化（coronary atherosclerosis）、冠脉痉挛（coronary vasospasm）和血栓（thrombosis）形成 症状：心绞痛（angina pectoris）, 胸骨下急性、严重的压榨样疼痛，放射痛，老年人和糖尿病患者常见。null病理生理机制: 心肌氧供需失平衡 代谢产物堆积：乳酸、丙酮酸、组胺、K+等心绞痛的分类心绞痛的分类劳累型心绞痛（effort angina） 变异型心绞痛（variant angina） 不稳定型心绞痛（unstable angina）null劳累型心绞痛（effort angina）: 最常见，发作时持续3 ~ 5 min 劳累、锻炼或情绪激动等 HR 心肌收缩力   心肌耗氧 舌下含服硝酸甘油缓解 动脉粥样硬化性心绞痛或经典心绞痛null自发性心绞痛（angina at rest）： 休息时或夜间发作 严重且持久，舌下含服硝酸甘油不能缓解 冠脉储存降低所致 冠脉自发性痉挛（spontaneous spasm），做梦或夜间血压降低，回心血量增加不稳定型心绞痛（unstable angina）不稳定型心绞痛（unstable angina）病理改变： 内皮下出血 动脉粥样硬化斑快破裂 血小板聚集和血栓形成null心肌缺血的直接原因: 心肌氧的供需失衡 Increase in oxygen demand (氧需求增加) Decrease in oxygen supply by the coronary flow (氧供给减少)Myocardial ischemia (angina)决定心肌耗氧量因素决定心肌耗氧量因素 室壁张力（ventricular wall tone）： T = P  R T 与室内压 (P) 和心室半径（R）呈正比 2. 每分射血时间: = Heart rate X 每搏射血时间null心肌收缩力和收缩速度 Contractility, velocity   Oxygen demand  决定心肌供氧量因素:决定心肌供氧量因素: 与心肌灌注量及氧摄取有关（a function of myocardial oxygen delivery and extraction）null氧摄取（extraction of oxygen）  75% oxygen is extracted (nearly maximal) under normal status 冠脉流量（coronary artery flow） 灌注压（perfusion pressure） 舒张期时程（diastole duration） Coronary vascular bed resistance 药物治疗策略（ treatment strategy）药物治疗策略（ treatment strategy）减少心肌耗氧（decrease oxygen demand） 增加心肌氧供应（increase oxygen supply） 改善心肌代谢（ameliorate myocardium metabolism） 抑制血小板集聚、抗血栓形成（inhibition of platelet aggregation and anti-thrombosis）Drugs for angina硝酸酯类（nitrates）: nitroglycerin 受体阻断药（-AR blockers): propranolol 钙通道阻滞药（calcium channel blockers）: verapamil, nifedipine, diltiazem 其他: antiplatelet (aspirin), K+ channel opening drugs（nicorandil) Drugs for anginaNitrates (硝酸酯类)Nitrates (硝酸酯类)Nitroglycerin (硝酸甘油) Isosorbide Dinitrate (硝酸异山梨酯) Isosorbide Mononitrate (单硝酸异山梨酯) Pentaerithrityl Tetranitrate (戊四硝酯) Amyl Nitrite (亚硝酸异戊酯) Mannityl Nitrate (甘露六硝酯) Clonitrate (氯硝甘油)nullA. Actions of nitroglycerinA. Actions of nitroglycerin 扩张静脉（dilation of veins） 静脉容量   回心血量   前负荷  ， 室壁张力  ，射血时间  ，心输出量   心肌耗氧  null舒张动脉（dilation of artery） 后负荷   射血完全  心室舒张末压力   心肌耗氧量  大剂量：反射性交感神经兴奋，心动过速，心肌收缩力增强，oxygen requirement 冠脉循环的特点：冠脉循环的特点：3. 增加心内膜下缺血区的血液灌注（increases subendocardial perfusion in ischemia region）自心外膜垂直穿透心室壁 心内膜下易缺血null网状分布，储备能力弱 舒张期灌注增加，收缩期锐减； 收缩期1/4，舒张期 3/4 HR   心室舒张期时程   冠脉血流 null回心血量   心室充盈压   舒张期室壁张力   室壁对血管的侧压力  心内膜下血液灌注 血液再分布, 增加缺血区血液灌注（redistributes coronary flow, increases ischemic region perfusion）血液再分布, 增加缺血区血液灌注（redistributes coronary flow, increases ischemic region perfusion）5. 开放侧枝循环（opens lateral circus）5. 开放侧枝循环（opens lateral circus） 冠状动脉侧枝间普遍存在侧枝循环  侧枝循环开放可增加缺血区血液供应 null6. 心肌保护作用（myocardial protectionLow dose reduces ischemic damage，ameliorates LV function 缩小梗死范围（narrows MI region），改善左室重构（improves LV remodeling），  MI mortality (死亡率) 舒张肺血管（dilates pulmonary vasculatures） ameliorates pulmonary ventilationNO release   CGRP and PGI2   protective on myocardiumnullMechanism of action of nitritesMechanism of action of nitritesEndothelial cellsNOGuanylyl cyclase*Guanylyl cyclase (鸟苷酸环化酶)GTPcGMPGMPMyosin-LCMyosin-LC-PO4Myosin-LCActinContractionRelaxationMLCK++?PDEPharmacokinetics of nitroglycerinPharmacokinetics of nitroglycerinLow bioavailability (about 8%) when orally administrated 舌下给药（sublingual route）: absorbed rapidly，efficiently, onset of action: 1~2 minutes, lasts for 25 min 谷胱甘肽-有机硝酸还原酶和醛脱氢酶（ALDH2) 催化代谢生成二硝酸甘油和单硝酸甘油。Therapeutic usesTherapeutic uses各类心绞痛  Effort angina (劳累型心绞痛)  Variant angina (变异型心绞痛)  Unstable angina (不稳定型心绞痛) 急性心肌梗死（acute MI） 充血性心力衰竭（chronic congestive heart failure）: relieve pulmonary congestion, increase COAdverse reactionAdverse reaction颜面潮红、(心动过速 搏动性头痛，诱发(青光眼 直立性低血压)、(晕厥 呕吐、紫绀，大剂量可诱发或加重心绞痛Contraindications: 颅内高压、青光眼null耐受性（tolerance） 与巯基耗竭和NO释放减少有关 存在交叉耐受（cross tolerance ） 补充含巯基药物预防 小剂量间歇给药：intervals > 8 hDrug-drug interactionDrug-drug interactionDrug metabolizing enzyme inducers (phenobarbital) accelerate metabolism Ethanol inhibits metabolism  Hypotensive effect of tricyclic antidepressant Decrease the metabolism of inhalational anesthetics Cautious when combined with morphineIsosorbide dinitrate (硝酸异山梨酯，消心痛) and pentaerythrityl tetranitrate (戊四硝酯)Isosorbide dinitrate (硝酸异山梨酯，消心痛) and pentaerythrityl tetranitrate (戊四硝酯)Long acting nitrates Use for prophylaxis of angina Act slowly when sublingually administrated Not as well as NTG for acute episode Metabolites of isosorbide dinitrate: isosorbide 5-mononitrate or isosorbide mononitrate (单硝酸异山梨酯） -receptor blockers-receptor blockersPropranolol (普萘洛尔) Atenolol (阿替洛尔) Metoprolol (美托洛尔) Nadolol (纳多洛尔) Carteolol (卡替洛尔) Bisoprolol (比索洛尔) Labetalol (拉贝洛尔)A. Therapeutic usesA. Therapeutic uses劳累性心绞痛和不稳定性心绞痛有效 预防性用药 心绞痛伴高血压和(心律失常； 心肌梗死的次级预防 禁忌证：变异性心绞痛B. Actions and mechanismsB. Actions and mechanisms1. 阻断儿茶酚胺的作用 HR,  BP,  心肌收缩力Myocardial oxygen demand  End-diastolic volume  Ejection timeMyocardial oxygen demand Effect of nitrates alone and in combination with -blockers in anginaEffect of nitrates alone and in combination with -blockers in angina2. 增加缺血区域血液供应2. 增加缺血区域血液供应null改善心肌代谢 乳酸和FFA生成  心肌缺血所致 K+丢失  心肌细胞对葡萄糖的利用  保护线粒体的功能禁忌证: 哮喘、心动过缓、房室传导阻滞、病窦综合症、左心室衰竭Cautions in clinic useCautions in clinic use有效剂量存在个体差异 小剂量开始 (10~20mg increase /day) 逐渐停药，避免反跳Calcium channel blockersCalcium channel blockersRepresentative drugs: Verapamil (维拉帕米), nifedipine (硝苯地平), amlodipine (氨氯地平), diltiazem (地尔硫卓) Therapeutic uses:Variant and effort angina Unstable angina Patients with asthma (哮喘), arrhythmia (心律失常) and hypertension (高血压)作用机制：作用机制：减轻Ca+ 超负荷：保护线粒体的功能及能量供应 降低心肌对O2 的需求：抑制心肌收缩，降低外周血管阻力，改善心肌工作效率 舒张CA，增加缺血区域血液供应 抑制血小板聚集：促进内源性 NO释放，增强CCB的直接舒血管作用null Nifedipine Variant angina Stable angina: combined with -blockers Angina accompanied by atrioventricular block Verapamil Stable and unstable angina Angina accompanied with arrhythmia Be cautious when in combination with -blockers Diltiazem Stable and unstable anginaOther anti-angina drugsOther anti-angina drugsAspirin: 75~160 mg/d, 抗血小板聚集； Dilazep (地拉齐普): 迅速、持久、选择性地舒张CA，用于心绞痛和慢性心功能不全（与强心苷合用）； Molsidomine (吗多明): 舒张容量血管和阻力血管，降低心脏前后负荷； Nicorandil (尼可地尔)：升高细胞内cGMP，激活K+通道， 舒张CA，用于心绞痛、轻中度高血压，不产生耐受性。Combined use of antianginal drugs Combined use of antianginal drugs -AR blockers with nitrates: Decrease myocardium oxygen demand -AR blockers antagonist the reflexed increased in HR Nitrates narrow ventricular volume and shorten ejection time caused by -AR blockers Both decrease BP and lead to decrease in CA perfusion, begin with low dose nullCalcium channel blockers with nitrates: CCBs dilate small artery and CA Nitrates mainly dilate venous CCBs: gently and long-acting is better, such as amlodipinenullCCBs with -AR blockers: Better antianginal effect used together Combination of Nifedipine or amlodipine with -AR blockers show good efficiency and tolerance in clinic Verapamil or diltiazem induce bradycardia, atrioventricular conduct block and heart failure when combined with  receptor blockers, should be used cautiously and begin with low dose.