Download ① Stable angina pectoris

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
心绞痛)
2) Angina pectoris at rest (自发性心绞痛)
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
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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
Pathophysiology
The difference of
Arteriovenous
oxygen pressure
Contractility
Heart rate
O2
demand
>
O2
supply
Wall tension
Coronary blood flow
Angina
Ventricular
Pressure
Ventricular
Volume
the duration
of diastole
Aortic
Diastolic
pressure
Coronary
Vascular
resistance
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
供氧
氧的摄取率
冠脉血流量
耗氧
心室壁张力
心率
心肌收缩力
药物作用
扩张冠脉，增加供血
扩张外周血管，↓心脏负荷
抑制心脏，减慢心率
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
preload
blood returning to heart
Ventricular volume
wall tension
at higher dose:
dilate arteries
afterload
peripheral resistance
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
dilate veins
blood returning to heart
LVEDV and LVEDP
dilate arteries
ventricular wall tension
blood flows from epicardium to
endocardium
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
Nitrates
NO
cGMP
smooth muscle
relaxation
cGMP
platelet
PGI2; CGRP
CGRP：calcitonin gene-related peptide
Mechanisms of action
Nitrates
NO
Guanylyl cyclase*
GTP
Guanylyl cyclase
cGMP
PDE
GMP
Ca2+ (intracellular)
MLCK*
MLC
MLC-PO4
Actin
Contraction
MLC
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
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 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
alone
Heart rate
reflex increase
Arterial pressure
decrease
End-diastolic volume
decrease
Contractility
reflex increase
Ejection time
decrease
β-blokers
alone
decrease
decrease
increase
decrease
increase
synergism
Section IV Calcium channelblocking 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 βblockers 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 βblockers should be considered; calcium channel
blockers should be added in refractory cases.