Institute of Pharmacology welcome! Lou Haiyan Institute of Pharmacology

Antianginal Drugs

Section I Introduction of angina pectoris

Angina pectoris Definition Angina pectoris is a primary symptom of myocardial ischemia, which is the severe chest pain that occurs when coronary blood flow is inadequate to supply the oxygen required by the heart.

Angina pectoris Typical Symptom a heavy strangling(窒息样) or pressure-like pain, sometimes may feel like indigestion, usually located in substernal (胸骨下) area or precardium , but sometimes radiating to the left shoulder, left arm, jaw , neck, epigastrium(上腹部) or back.

Classifications of angina 1) Angina pectoris of effort (劳累性心绞痛, Classic angina) ① Stable angina pectoris (稳定型心绞痛) ② Initial onset angina pectoris (初发型 心绞痛) ③ Accelerated angina pectoris (恶化型

2) Angina pectoris at rest (自发性心绞痛) ①Angina decubitus (卧位型心绞痛) ②Prinzmetal’s variant angina pectoris (变异型心绞痛) ③Intermediate syndrome (中间综合征) ④Postinfarction angina (梗死后心绞痛) 3) Mixed type angina pectoris (混合性 心绞痛)

Clinical Classifications of angina Stable angina pectoris Unstable angina pectoris Prinzmetal’s Variant angina pectoris

1.Stable angina Is caused by narrowed arteries due to atherosclerosis Occurs when the heart works harder Episodes of pain tend to be alike Usually lasts a short time Is relieved by a rest or angina medicine

2. Unstable angina Often occurs at rest Is more severe and lasts longer than stable angina Episodes of pain tend to be changing in the character, frequency, duration as well as precipitating factors is caused by episodes of increased coronary artery tone or small platelet clots occurring in the vicinity of an atherosclerotic plaque. is associated with a high risk of myocardial infarction and death.

3. Variant angina Usually occurs at rest Tend to be severe Is relieved by angina medicine (vasodilators) Is caused by a transient spasm in a coronary artery

Pathophysiology of angina An imbalance between the myocardial oxygen supply and demand. O2 demand O2 supply >

The difference of Arteriovenous Pathophysiology The difference of Arteriovenous oxygen pressure O2 demand supply Wall tension Heart rate Contractility Coronary blood flow Angina Aortic Diastolic pressure Coronary Vascular resistance Ventricular Pressure Volume > the duration of diastole

Indirect measure of myocardial oxygen consumption Three product: systolic blood pressure × heart rate x ejection time Double product: heart rate x systolic blood pressure

影响心肌供氧和耗氧的主要因素及药物的作用 影响因素 药物作用 供氧 氧的摄取率 冠脉血流量 扩张冠脉，增加供血 耗氧 心室壁张力 扩张外周血管，↓心脏负荷 心率 抑制心脏，减慢心率 心肌收缩力 减弱心肌收缩力

Treatment of angina Lifestyle changes Nitrates Medication β-blockers Calcium channel blockers Surgery : CABG ( coronary artery bypass graft) PTCA (percutaneous transluminal coronary angioplasty)

Section II Organic nitrates Key structure: -O-NO2 Nitroglycerin Isosorbide dinitrate Isosorbide mononitrate

Pharmacological actions 1. Dilate vascular smooth muscle, decrease myocardiac oxygen consumption dilate veins dilate arteries

at minimal effective dose: Ventricular volume wall tension dilate veins blood returning to heart preload Ventricular volume wall tension at higher dose: dilate arteries peripheral resistance afterload myocardial oxygen consumption. wall tension

2. Increase blood supply to ischemic area Increase subendocardium blood flow Redistribution of coronary blood flow Increase embranchment cycle in ischemic area

ventricular wall tension dilate veins blood returning to heart blood flows from epicardium to endocardium LVEDV and LVEDP dilate arteries ventricular wall tension

Nitroglycerin Non-ischemic region ischemic region Non-ischemic region ischemic region

3. Protect the ischemic cardiac myocytes, inhibit platelet aggregation and adhesion，decrease ischemic damage

Mechanisms of action cGMP smooth muscle relaxation Nitrates NO cGMP platelet PGI2; CGRP CGRP：calcitonin gene-related peptide smooth muscle relaxation

(MLCK-myosin light chain kinase Mechanisms of action Nitrates NO Guanylyl cyclase* Guanylyl cyclase GTP cGMP PDE GMP Ca2+ (intracellular) MLCK* MLC MLC-PO4 Actin Contraction Relaxation (MLCK-myosin light chain kinase

Pharmakinetics Absorption oral bioavailability 10-20% sublingual route: t1/2 2~4min Metabolism liver Excretion kidney

Clinical uses All types of angina sublingual Acute myocardial infarction iv Congestive heart failure (CHF) load

Adverse reactions Respond to vasodilation Flushed appearance Throbbing headache Orthostatic hypotension Tachycardia Methemoglobinemia

Tolerance The requirement for the dose of a drug becomes higher to achieve the same pharmacological effect. Mechanism: Blood vessel tolerance: -SH consumption Fake tolerance: reflex sympathetic excitation Management: Diet: (rich in -SH) change dosing interval: * a nitrate-free period of at least 8 hours between doses should be observed to reduce or prevent tolerance. Avoid large dose

Drug interaction Sidenafil (Viagra) PDE inhibitor

Section III Beta-adrenoceptor Blocking Drugs

Drugs Nonselective β-blokers: Propranolol, Pindolol, Timolol Atenolol, Metoprolol, Acebutolol

Antianginal actions Decrease myocardial oxygen consumption blockβ- R decrease heart rate, contractility, and blood pressure decrease myocardial oxygen consumption blockβ- R increase in end-diastolic volume, ejection time increase myocardial oxygen consumption total effect: decrease

Antianginal action 2. Improve blood supply to the ischemic area decrease myocardial oxygen consumption, promote the blood supply to the compensative dilating ischemic area decrease heart rate, increase diastolic perfusion time, blood flow from epicardium to endocardium increase embranchment cycle in ischemic area

Antianginal action 3. Decrease myocardial free fatty acid, improve myocardial metabolism 4. Promote oxygen to dissociate from oxygenated hemoglobin (HbO2)

Disadvantage 1. decrease contractility eject time , ventricular volume O2consumption 2. blockβ2- R on coronary artery coronary artery contract coronary blood flow

Clinical uses Stable and unstable angina Myocardial infraction Combined with nitroglycerin Variant angina pectoris not used

β-blokers combines with nitrates Nitrates β-blokers alone alone Heart rate reflex increase decrease Arterial pressure decrease decrease End-diastolic volume decrease increase Contractility reflex increase decrease Ejection time decrease increase synergism

Section IV Calcium channel-blocking drugs

Mechanisms of Antianginal actions Decrease myocardial oxygen consumption heart rate and contractility; vasodilation; antisympathetic action Improve the blood supply to the ischemia Dilate coronary artery, decrease the platelet aggregation Protect ischemic cardiac myocytes Antiatherosclerosis

Clinical uses Antianginal effect is similar to β-blokers, but have many virtues Suit for the anginal patient with asthma Variant angina first choice Suit for the anginal patient with surrounding blood vessel spasm

Nifedipine Variant angina strongest action Stable angina Combined with β-blokers

Verapamil Weaker for dilating peripheral vessels Inhibit the heart Used for stable angina and variant angina combined with other drugs Contraindications: heart failure atrioventricular blockade

Diltiazem Moderate , used for all types of angina Anginal patient with heart failure, atrioventricular blockade caution

Other Antianginal Drugs Dipyridamole(双嘧达莫) Nicorandil（尼可地尔） Molsidomine（吗多明） ACEI

Section V summary Angina of Effort (stable angina) nitrates, calcium channel blockers, and β-blockers are all useful in prophylaxis in patients with angina of effort. For maintenance therapy of chronic stable angina, long-acting nitrates, calcium channel-blocking agents, or β-blockers may be chosen.

The combination of a β-blocker with a Nitrates or a β-blocker with a calcium channel blocker or two different calcium channel blockers has been shown to be more effective than individual drug used alone. If response to a single drug is inadequate, a drug from a different class should be added to maximize the beneficial reduction of cardiac work while minimizing undesirable effects.

Vasospastic Angina Nitrates and the calcium channel blockers are effective drugs for relieving and preventing ischemic episodes in patients with variant angina.

Unstable Angina In patients with unstable angina，anticoagulant and antiplatelet drugs play a major role in therapy. Aggressive therapy with antilipid drugs, heparin, and antiplatelet agents is recommended. In addition, therapy with nitroglycerin and β-blockers should be considered; calcium channel blockers should be added in refractory cases.