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 pectorisTypical 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 心绞痛 )

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 pectorisPrinzmetal’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.

>>OO22

demanddemand

OO22

supplysupply

Pathophysiology

The difference of Arteriovenous

oxygen pressureO2

demand

O2

supply

Wall tension

Heart rate

Contractility

Coronary blood flow

AnginaAngina

Aortic Diastolicpressure

Coronary Vascular

resistanceVentricularPressure

VentricularVolume

>>

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:

dilate veins blood returning to heart

preload Ventricular volume wall tension

at higher dose:

dilate arteries peripheral resistance

afterload wall tension myocardial oxygen

consumption.

2. Increase blood supply to ischemic area

Increase subendocardium blood flow

Redistribution of coronary blood flow

Increase embranchment cycle in ischemic area

blood flows from epicardium to

endocardium

dilate veins blood returning to heart

LVEDV and LVEDP

dilate arteries ventricular wall tension

Non-ischemic region

ischemic region

Non-ischemic region

ischemic region

NitroglycerinNitroglycerin

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

Mechanisms of action

cGMP

Nitrates NO cGMP platelet

PGI2; CGRP

CGRP ： calcitonin gene-related peptide

smooth musclerelaxation

Nitrates

NO

Guanylyl cyclase* Guanylyl cyclase

GTP cGMP PDE

GMP

Ca2+ (intracellular)

MLCK*MLC MLC-PO4 MLC

Actin

Contraction Relaxation

Mechanisms of action

(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 vasodilationFlushed appearanceThrobbing headacheOrthostatic 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 consumptionFake tolerance: reflex sympathetic excitationManagement: 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

Selective β1-blokers:

Atenolol, Metoprolol, Acebutolol

Antianginal actions

1. 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 action2. Improve blood supply to the ischemic area decrease myocardial oxygen consumption, prom

ote 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 decreaseArterial pressure decrease decreaseEnd-diastolic volume decrease increaseContractility reflex increase decreaseEjection 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 myocytesAntiatherosclerosis

Clinical uses

Antianginal effect is similar to β-blokers,

but have many virtuesSuit for the anginal patient with asthmaVariant angina first choiceSuit for the anginal patient with surroundi

ng blood vessel spasm

Nifedipine

Variant angina strongest actionStable angina

Combined with β-blokers

Verapamil

Weaker for dilating peripheral vesselsInhibit the heartUsed for stable angina and variant angina

combined with other drugsContraindications:

heart failureatrioventricular blockade

Diltiazem

Moderate , used for all types of anginaAnginal patient with heart failure, atriove

ntricular 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.