Antianginal Drugs Section I Introduction of angina pectoris.
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Transcript of Antianginal Drugs Section I Introduction of 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 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.