Vasodilators & the Treatment of Angina Pectoris

Introduction The name angina pectoris denotes chest pain caused by accumulation of metabolites resulting from myocardial ischemia. 临床表现：阵发性的胸骨后压榨性疼痛并向左上肢放射。

2. classfication 劳累性心绞痛：心肌耗氧量增加时诱发。休息或硝酸甘油可以缓解。 自发性心绞痛：与心肌耗氧量无明显关系。安静时也可以发生。硝酸甘油不能缓解。 混合性心绞痛

PATHOPHYSIOLOGY OF ANGINA Determinants of Myocardial Oxygen Demand Determinants of Coronary Blood Flow & Myocardial Oxygen Supply 心肌氧供 动静脉氧压差 冠状动脉血流量 心舒张时间 冠状动脉血流 冠脉阻力 心肌基本代谢 冠脉灌注 心室壁张力 侧支循环 心肌氧耗 射血时间 心率 心收缩力 Determinants of Vascular Tone

影响心肌耗氧量及供氧量的因素

心肌氧需 血供、氧供失平衡 冠状动脉供血 心肌暂时缺血缺氧 decrease myocardial oxygen requirement increase oxygen delivery

抗心绞痛药的共同作用机理 1.舒张冠脉，增加心肌氧供血供 2.降低心肌耗氧量 3.抗血栓形成 舒张静脉降低前负荷 扩张小动脉降低后负荷 减慢心率 抑制心肌收缩力 3.抗血栓形成 降低心室壁张力

Calcium channel blockers Others DRUGS USED TO TREAT ANGINA Nitrates & Nitrites -blockers Calcium channel blockers Others

1. NITRATES & NITRITES (硝酸酯类及亚硝酸酯类) Nitroglycerin(硝酸甘油 ) Isosorbide dinitrate(硝酸异山梨酯) Isosorbide mononitrate(单硝酸异山梨酯) Amyl nitrite (亚硝酸戊酯) Pentaerythritol (季戊四醇)

Mechanism of action of nitrates, nitrites, and other substances in vascular smooth muscle cells. Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in vascular smooth muscle cells. Steps leading to relaxation are shown with blue arrows. MLCK*, activated myosin light-chain kinase. Nitrosothiols (SNOs) appear to have non-cGMP-dependent effects on potassium channels and Ca2+-ATPase. GC*, activated guanylyl cyclase; PDE,phosphodiesterase; eNOS, endothelial nitric oxide synthase; mtALDH2, mitochondrial aldehyde dehydrogenase-2; ROCK, Rho kinase.

硝酸甘油 ( nitroglycerin ) （1） Drug Action A. Decrease myocardial oxygen requirement 舒张全身静脉和动脉 改善左室顺应性：有利于血液从心外膜流向心内膜缺血区。 B. Increase oxygen delivery 扩张冠状动脉：对较大冠脉也有舒张作用 保护缺血的心肌细胞，减轻缺血损伤。

B. Antianginal drugs 扩张侧支循环

C. Action on platelets The increase in cGMP that results is responsible for a decrease in platelet aggregation. Unfortunately, recent prospective trials have established no survival benefit when nitroglycerin is used in acute myocardial infarction. In contrast, intravenous nitroglycerin may be of value in unstable angina, in part through its action on platelets.

（2） Clinical Use 各种类型心绞痛：舌下含服 急性心肌梗塞，减少梗死范围 还可用于心衰、呼衰和肺动脉高压的患者 （3）不良反应 血管扩张引起的皮肤潮红。 大剂量会引起体位性低血压。反射性导致心肌耗氧量增加，加重心绞痛。 反复使用易产生耐受性。 血管机制和非血管机制

OTHER NITRO-VASODILATORS Nicorandil(尼可地尔) A nicotinamide nitrate ester Mechanism: activation of cardiac KATP channels. Clinical studies ： it reduces both preload and afterload. It also provides some myocardial protection. it reduces relative risk of fatal and nonfatal coronary events. approved for use in the treatment of angina in Europe and Japan but has not been approved in the USA.

2. BETA-BLOCKING DRUG 普萘洛尔 (Propranolol) 美托洛尔（metoprolol） 阿替洛尔（atenolol）

普萘洛尔 (Propranolol) （1）药理作用： 降低心肌耗氧量：与其负性频率和负性肌力有关 改善心肌缺血区血供 降低心肌游离脂肪酸含量、促进氧解离，增加氧供

普萘洛尔 (Propranolol) （2）临床应用： 用于硝酸酯类不敏感或疗效差的稳定型心绞痛疗效较好 对伴有心律失常或高血压的心绞痛效果好 对冠状动脉痉挛诱发的变异型心绞痛不宜使用。α受体占优势后加重痉挛。 目前主张β拮抗药和硝酸酯类合用

常用药物 β拮抗药 硝酸酯类 心室容积增大和心室射血时间延长 心率加快和心肌收缩性增强 加重心绞痛

3. CALCIUM CHANNEL-BLOCKING DRUGS 维拉帕米 地尔硫卓 硝苯地平

A simplified diagram of smooth muscle contraction and the site of action of calcium channel-blocking drugs. Contraction is triggered (red arrows) by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium combines with calmodulin to form a complex that converts the enzyme myosin light-chain kinase to its active form (MLCK*). The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Other proteins, including calponin and caldesmon (not shown), inhibit the ATPase activity of myosin during the relaxation of smooth muscle. Interaction with the Ca2+-calmodulin complex reduces their interaction with myosin during the contraction cycle. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle (blue arrows) by accelerating the inactivation of MLCK and by facilitating the expulsion of calcium from the cell (not shown). cGMP facilitates relaxation by the mechanism shown in Figure 12–2. ROCK, Rho kinase.

（1）Mechanism： Decrease myocardial contractile force=> reduces myocardial oxygen requirements. Calcium channel block in arterial smooth muscle =>decreases arterial and intraventricular pressure. Some of these drugs (eg, verapamil, diltiazem) also possess a nonspecific antiadrenergic effect, which may contribute to peripheral vasodilation

（2）organ effect： Smooth muscle: Vascular smooth muscle appears to be the most sensitive, but similar relaxation can be shown for bronchiolar, gastrointestinal, and uterine smooth muscle. In the vascular system, arterioles appear to be more sensitive than veins; Dihydropyridines>diltiazem and verapamil

（2）organ effect： Cardiac muscle Reduce cardiac contractility in a dose-dependent fashion. Reduce the oxygen requirement Verapamil and diltiazem block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selectively than do the dihydropyridines.

（3）Clinical Uses ： 伴有支气管哮喘的患者有效。 预防或治疗心绞痛，特别是变异型心绞痛疗效最佳。 对稳定型心绞痛及急性心肌梗死等也有效。 对心肌抑制作用较弱，较少诱发心衰。 心肌缺血伴外周血管痉挛性疾病有效。

其他抗心绞痛药物 卡维地洛：去甲肾上腺素能神经受体阻断药，又具有抗氧化作用。用于心绞痛、心功能不全和高血压治疗。

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