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Antianginal drugs 抗心绞痛药物

Antianginal drugs 抗心绞痛药物. Huifang Tang Department of pharmacology Zhejiang University School of Medicine tanghuifang@zju.edu.cn. Overview Antianginal drugs - Organic nitrates - β -blockers - Calcium channel blockers Combination of antianginal drugs.

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Antianginal drugs 抗心绞痛药物

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  1. Antianginal drugs 抗心绞痛药物 Huifang Tang Department of pharmacology Zhejiang University School of Medicine tanghuifang@zju.edu.cn

  2. Overview • Antianginal drugs -Organic nitrates - β-blockers - Calcium channel blockers • Combination of antianginal drugs

  3. Overview:Angina pectoris 心绞痛 The name angina pectoris denotes chest paincaused 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。 • most common cause of angina is atheromatous obstruction of the large coronary vessels (coronary artery disease, CAD).

  4. Symptoms: Sudden, uncomfortable pressure, fullness, squeezing or severe substernal pain, radiating to the left arm, shoulders, neck, etc.

  5. Classification of angina pectoris: Effort angina （classic angina） Caused by atherosclerosis plaque and/or thrombus formation Caused by spontaneous spasm of coronary arteries • Stable angina pectoris • Unstable angina pectoris • initial onset type(初发型) • accelerated type(恶化型) • spontaneous type(自发型) • angina at rest(卧位型) • Variant angina （变异型） • Mixed angina pectoris

  6. Extreme weather Strong emotion Excessive exercise Excessive food intake Excessive smoking • Stable and unstable angina pectoris usually occur on following conditions • Variant angina: usually occur when a person is at rest between midnight and 8am

  7. How does angina pectoris happen? Demand of the myocardium for oxygen 动脉粥样硬化斑块和血栓形成 Normal Ischemia 冠脉痉挛 Oxygen delivery to the myocardium by the coronary circulation

  8. Factors disturb the balance between oxygen demand and delivery • Demand • Preload (venous return ) • Afterload (arteriolar resistance) • Heart rate • Delivery • Atherosclerosis plaque • Thrombus • Spasm of coronary arteries

  9. 影响心肌耗氧量及供氧量的因素

  10. 心肌耗氧量=收缩压×心率×左心室射血时间 心肌氧需 冠状动脉供血 血供、氧供失平衡 心肌暂时缺血缺氧 decrease myocardial oxygen requirement increase oxygendelivery

  11. Strategies for angina treatment Decrease the oxygen demand and/or increase the delivery BY - Dilating arteries, especially coronary arteries, including relieving spasm and opening collateral circulation - Dilating veins - Cardiac inhibition: decrease HR, contractility, tensility of myocardium - Antiatherosclerosis and prevention of thrombosis

  12. Antianginal drugs • Organic nitrates • -receptor blockers • Calcium channel blockers • Other drugs (ACEIs, nicorandil尼可地尔, molsidomine吗多明)

  13. 硝酸酯类药物的百年发展历程

  14. Organic nitrates （硝酸酯类） • Actions • Dilate vessels: • - Dilate veins and arteries, decrease pre/after-load and cardiac oxygen demand • - Dilate coronary arteries, epicardial vessels and open collateral circulation, redistribute blood to ischemic area • - Decrease LVFP, increase blood to subendocardial area • Protect myocardial cells against ischemic injury • Anticoagulation of platelets Nitroglycerin（NTG, 硝酸甘油） Isosorbide dinitrate（硝酸异山梨酯，消心痛） Isosorbide mononitrates（ISMN, 单硝酸异山梨酯）

  15. Organic nitrates 动脉 输送血管 阻力血管 扩张侧支循环 CAD: coronal artery disease

  16. Organic nitrates 硝酸异山梨酯 Isosorbide dinitrate 硝酸甘油 Nitroglycerin 单硝异山梨酯 Isosorbide mononitrate

  17. Organic nitrates Clinical uses • Angina pectoris • Acute myocardial infarction • Chronic heart failure • Acute respiratory failure and pulmonary arterial hypertension

  18. Organic nitrates Adverse effects • Symptoms due to vasodilation: headache, tachycardia, postural hypotension, increase in intraocular and/or intracranial pressure, and facial flushing • Allergy • Methaemoglobinaemia (高铁血红蛋白血症，at very high doses)

  19. Organic nitrates Tolerance • Easily induced by repeated uses • Minimized by • - provision of daily “nitrate-free interval” • - supplement of –SH (food, drugs)（N乙酰半胱氨酸，蛋氨酸）, Vc Drug interactions • Antihypertensive drugs • Alcohol, Viagra and similar drugs

  20. β-blockers Propranolol Metoprolol Atenolol 普萘洛尔 美托洛尔 阿替洛尔 Actions - 1R : Inhibit cardiac contractility, decrease O2 demand - 2R: Increase blood supply to ischemic area: perfusion time , vascular tone in normal tissues  - 3R: Improve myocardial metabolism (FFA )

  21. 心肌收缩力↓ →心室容积↑ →射血时间↑ 心肌收缩力↓ 肌纤维缩短速度↓ HR↓ 收缩压↓ 心肌氧需 冠状动脉供血 • Decrease the oxygen demand -1-R 耗氧 耗氧 • Increase the delivery • -2-R or + -R →冠脉收缩 冠脉血流重分布 缺血区阻力<非缺血区 增加缺血区灌注 • HR ↓ → 舒张期 ↑ 增加心内膜供血

  22. Angina pectorisβ-blockers 冠脉血流重分布 非缺血区 缺血区 非缺血区 缺血区

  23. β-blockers Contraindications: Clinical uses: - stable and unstable angina pectoris, especially associated with hypertension or arrhythmias, even with myocardial infarction. - NOT used for variant angina.

  24. Calcium channel blockers, CCBs - Decrease myocardial oxygen consumption - Increase myocardial blood supply: dilate coronary vessels, open collateral circulation - Protect ischemic myocardial cellsby inhibiting Ca2+ overload - Inhibit coagulation of platelets Actions contributing to anti-anginal effect :

  25. 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 Cardiac muscleReduce 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.

  26. Calcium channel blockers, CCBs Clinical uses: - Stable and unstable angina: ver, dil, nif+  blockers - Variant angina: nif, dil, ver

  27. Calcium channel blockers, CCBs Contraindications: - hypotension - severe heart failure - sinus bradycardia - atrioventricular block Adverse effects: - peripheral edema - sympathetic excitation (nif) - cardiac inhibition (ver, dil) - hypotension (nif)

  28. Combination of anti-anginal drugs Caution: Hypotension,low cardiac perfusion, bradycardia, A-V block

  29. Treatment of angina in patients with concomitant diseases

  30. Treatment algorithm for improving symptoms in patients with stable angina. Treatment algorithm for improving symptoms in patients with stable angina.

  31. Nicorandil尼可地尔 独特双重机制的钾通道开放剂

  32. New idea for the treatment of Angina pectoris

  33. 雷诺嗪

  34. 参考文献 Cher-Rin Chong, Gao J Ong & John D Horowitz (2016) Emerging drugs for the treatment of angina pectoris, Expert Opinion on Emerging Drugs, 21:4, 365-376, DOI: 10.1080/14728214.2016.1241231

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