1. Antianginal Drugs 抗心绞痛药 Antianginal Drugs

2. What’s Angina pectoris Cause and the classification of angina pectoris : – Atheromatous obstruction of the large coronary vessels (atherosclerotic angina, classic angina); 劳累性心绞痛：稳定型，初发型，恶化型 – Transient spasm of localized portions of the large coronary vessels (angiospastic or variant angina); 自发性心绞痛：卧位型，变异型，急性冠脉功能不全，梗死后心绞痛 – Both causes 混合性心绞痛 Unstable angina pectoris: initial onset type; accelerated type; spontaneous type initial onset type; accelerated type; spontaneous type associated with atheroscleosis plaque and thrombus formation associated with atheroscleosis plaque and thrombus formation may lead to myocardial infarction may lead to myocardial infarction Overview

3. Coronary vessels: blood supply for the heart Overview

4. Coronary atherosclerosis: cause of cardiac ischemia cause of cardiac ischemia Overview

6. Distribution of coronary arteries in the heart

7. Primary cause of angina pectoris: – In classic angina, the imbalance occurs when the myocardial oxygen requirement increases; “angina of effort” – In variant angina, oxygen delivery decreases as a result of reversible coronary vasospasm. “vasospastic or Prinzmetal's angina” oxygen requirement  oxygen supply  imbalance Overview

8. preloadafterload

9. 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 Myocardial oxygen supply is increased by: Dilating conduct coronary arteries Dilating conduct coronary arteries (  coronary blood flow) (  coronary blood flow) Promoting regional distribution Promoting regional distribution (  in ischemic regions) (  in ischemic regions) Treatments: Non-drug treatment: 经皮冠状动脉成形术 (percutaneous transluminal coronary angioplasty, PTCA), 冠脉搭桥术 ( coronary artery bypass graft surgery, CABG ) Drug treatment Wall tension  Overview

10. Antianginal Drugs Antianginal drugs: Organic nitrates Organic nitrates   receptor blockers   receptor blockers Calcium channel blockers Calcium channel blockers Anti-platelet agents ACEIs Fish oil Effects of antianginal drugs: Reducing oxygen demandsReducing oxygen demands Increasing oxygen supplyIncreasing oxygen supply Others: Anti- platelet coagulation and thrombus formationOthers: Anti- platelet coagulation and thrombus formation

11. Nitrates & Nitrites Quick tolerance and cross-tolerance; Pharmacokinetic factors determine the selection; nitroglycerin

12. - Pharmacokinetics Low oral bioavailability (eg, nitroglycerin and isosorbide dinitrate, typically < 10–20%). Sublingual is normally used. Transdermal and buccal absorption from slow release preparations. Amyl( 戊基 ) nitrite and related nitrites can be used with inhalation route. Duration of effect is very brief (Unchanged nitrate t1/2=2-8 minutes, partially denitrated metabolites longer t1/2= 3 hrs). So micro-pump is very common in hospital usage. Nitrates & Nitrites

13. - 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  Alleviating ischemic injury Alleviating ischemic injury Anti- platelet coagulation Anti- platelet coagulation Nitrates: Nitroglycerin ( 硝酸甘油 )

14. Influence of organic nitrates and dipyridamole on the blood supply of ischemic area Nitrates: Nitroglycerin ( 硝酸甘油 )

15. Intracellular Ca 2+ release ↓ ， extracellular Ca 2+ influx ↓ Intracellular [Ca 2+ ] ↓ The production of PGE or PGI2 and membrane hyper-polarization may also be involved. Mechanism of the effect of nitroglycerin and other nitrates

16. - Clinical uses Angina pectoris: all kinds, especially stable type Angina pectoris: all kinds, especially stable type Heart failure Heart failure - Adverse reactions Symptoms due to vasodilation: headache, postural Symptoms due to vasodilation: headache, postural hypotension, etc. hypotension, etc. Increase in heart rate and contractility 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 supplement of agents containing – SH (captopril, NAC), VitC (captopril, NAC), VitC Nitrates: Nitroglycerin ( 硝酸甘油 )

17. 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 Nitrates

18. - 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 Increase oxygen supply Increase oxygen supply Inhibiting coagulation of platelets Inhibiting coagulation of platelets  receptor blockers

19. - 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 - 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 Cardiac depression Cardiac depression Inducing asthma Inducing asthma Combination with nitroglycerin Combination with nitroglycerin  receptor blockers

20. - 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 Inhibiting coagulation of platelets Inhibiting coagulation of platelets Protecting ischemic myocardial cells Protecting ischemic myocardial cells - Clinical uses stable and variant type: stable and variant type: nifedipine, verapamil, diltiazem nifedipine, verapamil, diltiazem unstable type: unstable type: verapamil, diltiazem verapamil, diltiazem Calcium channel blockers

22. - Toxicity Cardiac depressionCardiac depression, including cardiac arrest, bradycardia, atrioventricular block, and heart failure. Relatively short-acting calcium channel blockers have the potential to enhance the risk of adverse cardiac events. Slow-release and long-acting vasoselective calcium channel blockers are usually well tolerated. Patients receiving  -adrenoceptor-blocking drugs are more sensitive to the cardiodepressant effects of calcium channel blockers. Tolerable toxicity: flushing, dizziness, nausea, constipation, and peripheral edema. Calcium channel blockers

23. Other drugs Angiotensin converting enzyme inhibitors (ACEI) Nicorandi ( 尼可地尔 ) a potassium channel opener Molsidomine （吗多明） Producing NO → stimulate guanylyl cyclase (GC) →increase cGMP → relaxes vascular smooth muscle Dipyridamole （双嘧达莫，潘生丁） Inhibiting adenosine uptake and cAMP degradation Inhibiting adenosine uptake and cAMP degradation Inhibiting pletelet aggregation Inhibiting pletelet aggregation

24. 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 Summary of antianginal drugs

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