Part 6 Antianginal Drugs Organic nitrates  receptor blockers Calcium channel blockers

1. OVERVIEW Coronary vessels: blood supply for the heart

Coronary atherosclerosis: cause of cardiac ischemia

Distribution of coronary arteries in the heart

Ischemia (angina pectoris ): imbalance between oxygen demand and supply

1. OVERVIEW Classification of angina pectoris: Exertional angina (劳累性心绞痛) Stable angina (稳定性心绞痛) Initial onset angina (初发型心绞痛) Accelerated angina (恶化性心绞痛) Spontaneous angina (自发性心绞痛) Angina decubitus (卧位型心绞痛) Variant [or vasospastic] angina (变异性[痉挛性]心绞痛) Acute coronary insufficiency (急性冠脉功能不全) Postinfarction angina (梗死后心绞痛) Mixed angina (混合性心绞痛) Unstable angina (不稳定性心绞痛): link of stable angina and myocardial infarction

1. OVERVIEW Myocardial oxygen demand is chiefly determined by: Contractility Heart rate Wall tension Preload (venous return ) Afterload (arteriolar resistance) afterload preload

1. OVERVIEW Myocardial oxygen demand is diminished by: Reducing contractility Reducing heart rate Reducing the preload Reducing the afterload Wall tension 

1. OVERVIEW Myocardial oxygen supply is chiefly determined by: AV oxygen difference Regional myocardial distribution coronary blood flow: vascular resistance, artery pressure

1. OVERVIEW Effects of antianginal drugs: Reducing oxygen demands Reducing heart rate and contractility Dilating systemic arteries and veins (  wall tension by lowering heart loads) Increasing oxygen supply Dilating conduct coronary arteries (  coronary blood flow) Promoting regional distribution (  in ischemic regions) Others: Anti-platelet coagulation and thrombus formation

2. Antianginal drugs 2.1 Nitrates Nitroglycerin (硝酸甘油) A. Pharmacological actions Dilating vessels and reducing heart loads wall tension ; reflex tachycardia Redistribution of coronary circulation dilating conduct artery: collateral circulation  reducing wall tension: blood flow in ischemic subendocardial area 

2. Antianginal drugs Influence of organic nitrates and dipyridamole on the blood supply of ischemic area

Mechanism of the effect of nitroglycerin and other nitrates [Ca2+]i  Mechanism of the effect of nitroglycerin and other nitrates

2. Antianginal drugs B. Clinical uses C. Adverse reactions Angina pectoris: all kinds, especially stable type Heart failure：reducing heart loads due to vasodilation C. Adverse reactions Increase in heart rate and contractility Symptoms due to vasodilation: headache, flash, postural hypotension, collapse, ect. Others: methaemoglobinaemia（高铁血红蛋白） Tolerance : avoiding steady-state plasma concentration; supplement of agents containing –SH (captopril)

2. Antianginal drugs 2.1 Other nitrates Isosorbide dinitrate (硝酸异山梨酯) Isosorbide-5-mononirate (5-硝酸异山梨酯) Compared with nitroglycerin: Orally active Similar but weaker effect Acting slowly but lasting longer Larger individual variation and more adverse effects

2. Antianginal drugs 2.2  receptor blockers A. Pharmacological action Reducing oxygen demand: heart rate and contractility  Increasing oxygen supply: diastolic period : perfusion time  vascular tone in normal regions : blood flow in ischemic regions  Others: Improving myocardial metabolism Inhibiting coagulation of platelets

2. Antianginal drugs B. Clinical uses C. Notes stable and unstable pectoris, especially associated with hypertension or arrhythmias, even with myocardial infarction; but not used for variant angina pectoris C. Notes Dose individualization: starting from small dose Withdraw gradually and slowly: symptom rebound Combination with nitroglycerin but without verapamil Contraindicated in heart depression, asthma, and so on

2. Antianginal drugs 2.3 Calcium channel blockers

2. Antianginal drugs 2.3 Calcium channel blockers A. Pharmacological actions Reducing myocardial oxygen remand: heart loads : nifedipine heart rate and contractility : verapamil and diltiazem Increasing myocardial blood supply Protecting ischemic myocardial cells Inhibiting coagulation of platelets

Actions of calcium channel blockers

Selective calcium channel blockers Dihydropyridines (二氢吡啶类): nifedipine 硝苯地平 rapid, hypotension, reflex tachycardia amlodipine 氨氯地平 high bioavailability, t1/2 40-50 h, long-acting, less influences on heart rate and blood pressure Phenylalkylamines (苯烷胺类): verapamil 维拉帕米 reducing oxygen demands, antiarrhythmia Benzothiazepines (苯硫卓类): diltiazem 地尔硫卓 weaker for heart depression and vasodilation; suitable for variant angina pectoris

2. Antianginal drugs B. Clinical uses stable and variant type: nifedipine, verapamil, diltiazem unstable type: verapamil, diltiazem Actions of DHP (like nifedipine) are similar to those of nitroglycerin Actions of verapamil are similar to those of  blockers Actions of diltiazem are intermedial in both above drugs

3. Summary of antianginal drugs nitroglycerin  blockers Ca2+ antagonists combination* Heart rate     Contractility    / Wall tension   / / Oxygen demand     Blood pressure     : increase,  : markedly increase; : decrease,  : markedly decrease; : variable according to the dose and effect of each drug ; *  blockers combined with nitroglycerin or Ca2+ antagonists (nifedipine; combination with verapamil/diltiazem not be recommendated) Caution: Combination may potentiate the antianginal effects, but may induce severe hypotension

2. Antianginal drugs 2.4 Other drugs ACEIs （血管紧张素转化酶抑制药） Treating hypertension and preventing ischemic heart disease Reducing heart loads Inhibiting cardiac remodeling Nicorandil （尼可地尔） Opening ATP-sensitive K+ channel (KATP) Lowering intracellular Ca2+ Providing NO (like nitroglycerin) Inducing ischemic preconditioning

2. Antianginal drugs Molsidomine （吗多明） Dipyridamole （双嘧达莫，潘生丁） Promoting collateral circulation Similar to nitroglycerin Used in stable angina Dipyridamole （双嘧达莫，潘生丁） Inhibiting adenosine uptake and cAMP degradation Inhibiting pletelet aggregation Small doses, long-term oral administration

Cardiovascular pharmacology Summary

Overview of Cardiovascular Diseases Common Cardiac Diseases Abnormal contractility：Heart failures Abnormal rhythms：Arrhythmias Abnormal blood supply：Ischemic heart diseases Myocardial disorders Common vascular diseases Abnormal systematic resistance：Hypertension Dysfunction of coronary vessels：Coronary vascular diseases Dysfunction of cerebral vessels：Cerebral ischemia, hemorrhage Dysfunction of pulmonary vessels：Pulmonary hypertension Dysfunction of peripheral vessels: Peripheral vascular disorder Arteriosclerosis: basis of most CVS diseases

Overview of Cardiovascular Drugs Classification based on target organs/tissues Heart：Heart failures, arrhythmias, cardiac ischemia Vessels：Vasodilatation, vasoconstriction, arteriosclerosis Classification based on the mechanisms Ion channels：Ca2+, Na+, K+ channels Receptors：Adrenoceptors, AT1 receptors, etc. Enzymes：ACEI, Na+-K+-ATPase, HMG-CoA reductase Others：Diuretics

Cardiovascular Drugs Antiarrhthemic drugs Antihypertensive drugs Classification; Typical drugs and their properties Antihypertensive drugs Classification; Properties of 6 main drug classes Drugs for treating heart failure Classification; ACEIs,  blockers, cardiac glycoide Antiatheroscleotic drugs HMG CoA reductase inhibitors (statins) Antianginal drugs Nitroglycerin;  blockers; Ca2+ antagonists