1. Institute of Pharmacology
welcome!
Lou Haiyan
Institute of Pharmacology

2. Antianginal Drugs

3. Section I Introduction of angina pectoris

4. 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.

5. 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.

6. 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

7. 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)

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

9. 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

10. 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.

11. 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

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

13. 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

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

15. 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

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

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

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

19. 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

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

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

23. Nitroglycerin
Non-ischemic region
ischemic region
Non-ischemic region
ischemic region

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

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

26. (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

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

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

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

30. 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

31. Drug interaction
Sidenafil (Viagra)
PDE inhibitor

32. Section III Beta-adrenoceptor Blocking Drugs

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

34. 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

35. 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

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

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

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

39. 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

40. Section IV Calcium channel-blocking drugs

41. 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

42. 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

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

44. 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

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

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

47. 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.

48. 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.

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

50. 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.