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

Coronary vessels: blood supply for the heart 1. OVERVIEW

Coronary atherosclerosis: cause of cardiac ischemia cause of cardiac ischemia

Distribution of coronary arteries in the heart

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

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

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

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

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

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

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

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

Mechanism of the effect of nitroglycerin and other nitrates 2. Antianginal drugs

Mechanism of the effect of nitroglycerin and other nitrates

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

2.1 Other nitrates ( 硝酸异山梨酯 ) Isosorbide dinitrate ( 硝酸异山梨酯 ) (5- 硝酸异山梨酯 ) Isosorbide-5-mononirate (5- 硝酸异山梨酯 ) Compared with nitroglycerin: 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: Reducing oxygen demand: heart rate and contractility  heart rate and contractility  Increasing oxygen supply: Increasing oxygen supply: diastolic period  : perfusion time  diastolic period  : perfusion time  vascular tone in normal regions  : vascular tone in normal regions  : blood flow in ischemic regions  blood flow in ischemic regions  Others: Others: Improving myocardial metabolism Improving myocardial metabolism Inhibiting coagulation of platelets Inhibiting coagulation of platelets 2. Antianginal drugs

B. Clinical uses stable and unstable pectoris, especially associated with hypertension or arrhythmias, even with myocardial infarction ; but not used for variant angina pectoris 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 Dose individualization: starting from small dose Withdraw gradually and slowly: symptom rebound Withdraw gradually and slowly: symptom rebound Combination with nitroglycerin Combination with nitroglycerin 2. Antianginal drugs

2.3 Calcium channel blockers 2. Antianginal drugs

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

Actions of calcium channel blockers

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

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

Molsidomine （吗多明） Inhibiting adenosine uptake and cAMP degradationInhibiting adenosine uptake and cAMP degradation Inhibiting pletelet aggregationInhibiting pletelet aggregation Promoting collateral circulation after long-term usePromoting collateral circulation after long-term use Dipyridamole （双嘧达莫，潘生丁） Inhibiting adenosine uptake and cAMP degradation Inhibiting adenosine uptake and cAMP degradation Inhibiting pletelet aggregationInhibiting pletelet aggregation Promoting collateral circulation after long-term usePromoting collateral circulation after long-term use 2. Antianginal drugs

nitroglycerin  blockers Ca 2+ antagonists combination* nitroglycerin  blockers Ca 2+ 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 Ca 2+ antagonists (nifedipine; combination with verapamil/diltiazem not be recommendated) Caution: Combination may potentiate the antianginal effects, but may induce severe hypotension 3. Summary of antianginal drugs

Sammary Cardiovascular pharmacology

Overview of Cardiovascular Diseases Common Cardiac DiseasesCommon Cardiac Diseases Abnormal contractility ： Heart failuresAbnormal contractility ： Heart failures Abnormal rhythms ： ArrhythmiasAbnormal rhythms ： Arrhythmias Abnormal blood supply ： Ischemic heart diseasesAbnormal blood supply ： Ischemic heart diseases Myocardial disordersMyocardial disorders Common vascular diseasesCommon vascular diseases Abnormal systematic resistance ： HypertensionAbnormal systematic resistance ： Hypertension Dysfunction of coronary vessels ： Coronary vascular diseasesDysfunction of coronary vessels ： Coronary vascular diseases Dysfunction of cerebral vessels ： Cerebral ischemia, hemorrhageDysfunction of cerebral vessels ： Cerebral ischemia, hemorrhage Dysfunction of pulmonary vessels ： Pulmonary hypertensionDysfunction of pulmonary vessels ： Pulmonary hypertension Dysfunction of peripheral vessels: Peripheral vascular disorderDysfunction of peripheral vessels: Peripheral vascular disorder Arteriosclerosis: basis of most CVS diseasesArteriosclerosis: basis of most CVS diseases

Overview of Cardiovascular Drugs Classification based on target organs/tissuesClassification based on target organs/tissues Heart ： Heart failures, arrhythmias, cardiac ischemiaHeart ： Heart failures, arrhythmias, cardiac ischemia Vessels ： Vasodilatation, vasoconstriction, arteriosclerosisVessels ： Vasodilatation, vasoconstriction, arteriosclerosis Classification based on the mechanismsClassification based on the mechanisms Ion channels ： Ca 2+, Na +, K + channelsIon channels ： Ca 2+, Na +, K + channels Receptors ： Adrenoceptors, AT 1 receptors, etc.Receptors ： Adrenoceptors, AT 1 receptors, etc. Enzymes ： ACEI, Na + -K + -ATPase, HMG-CoA reductaseEnzymes ： ACEI, Na + -K + -ATPase, HMG-CoA reductase Others ： DiureticsOthers ： Diuretics

Cardiovascular Drugs Antiarrhthemic drugsAntiarrhthemic drugs Classification; Typical drugs and their propertiesClassification; Typical drugs and their properties Antihypertensive drugsAntihypertensive drugs Classification; Properties of 6 main drug classesClassification; Properties of 6 main drug classes Drugs for treating heart failureDrugs for treating heart failure Classification; ACEIs,  blockers, cardiac glycoideClassification; ACEIs,  blockers, cardiac glycoide Antiatheroscleotic drugsAntiatheroscleotic drugs HMG CoA reductase inhibitors (statins)HMG CoA reductase inhibitors (statins) Antianginal drugsAntianginal drugs Nitroglycerin;  blockers; Ca 2 + antagonistsNitroglycerin;  blockers; Ca 2 + antagonists