1. Drugs used in angina pectoris
Antianginal drugs

2. Learning Objectives
By the end of this class, you can…
Describe the antianginal mechanism of Nitrites, β-blockers and CCBs
Clarify the vasodilatory mechanism of NO
Select antianginal agents for the treatment of different types of angina pectoris

5. Methods for treatment
To improve perfusion:
To reduce metabolic demand

6. Factors affecting myocardial oxygen demand and oxygen supply
Regional
myocardial
distribution
Contractile
state
Heart
rate
Oxygen
demand
Oxygen
supply
Coronary
vascular
resistance =
Ventricular
volume
>
Wall
tension
Coronary
blood flow LV
pressure
Aortic
pressure

7. Drugs classifications
Organic nitrates: Nitroglycerin
Calcium antagonists
β-Receptor blockers

8. Chemical structures of two nitrates
Nitroglycerin
Isosorbide dinitrate (IDSN)
Rapid onset effect
Longer lasting effect
-O-NO2

9. Mechanism of action in VSM
NO(EDRF) activate GC increase c-GMP activate cGMP- dependent kinase decrease Ca induce de-phosphorylation of the myosin light chain relaxation

10. Concentration of Ca2+ in VSMC↓
Nitroglycerin
↓ SH
NO/SNO ↓+
guanylate cyclase
cGMP ↑ ’GMP
Concentration of Ca2+ in VSMC↓
PDE
Activation of
protein kinase
Inhibition
platelet
Ca2+ influx↓
Ca2+ efflux↑
VASODILATION

11. Organic nitrates Pharmacological effects and mechanism:
dilate peripheral vein preload
dilate peripheral artery afterload
Dilate coronary artery perfusion of
ischemic myocardium
Oxygen
consumption

12. Pharmacokinetics:
very low bioavailability per os
Sublingual Rapid onset(2~5min)
Acute adverse effects: postural hypotension, throbbing headache
Tolerance : depletion of free –SH (hydrosulfuryl ) groups

13. NITRATES TOLERANCE " Decrease in the effect of a drug
when administered in a long-acting form"
Develops with all nitrates
Is dose-dependent
Disappears in 24 h. after stopping the drug
Tolerance can be avoided
- Using the least effective dose
- Creating discontinuous plasma levels
Treatment of Heart Failure.
Nitrates: Tolerance
Repetitive administration of nitrates over days is accompanied by a reduction in intensity and duration of its effects (tolerance), that obligates sequential increases in dose to obtain the desired effect. Nitrate tolerance appears with all nitrates, crosses over from one nitrate preparation to another (explaining the poor effect that IV NTG can have in patients on oral nitrate therapy), and is not dose dependent. Additionally, tolerance appears within 8-24 hours of administration of preparations that allow for maintenance of stable plasma nitrate levels (i.v., patch), but disappears rapidly (<48hrs) after stopping treatment. Increasing dosage does not overcome the tolerance effect. Tolerance can be avoided, however, by using the lowest effective dose, and by avoiding continuous plasma levels (drug-free periods).

14. NITRATES CONTRAINDICATIONS
Previous hypersensitivity
Hypotension ( < 80 mmHg)
1st trimester of pregnancy

15. β-Receptor blockers Pharmacological effects: Myocardial contractility
Heart rate
Clinic use : stable and unstable angina
Propranolol not for variant angina because of coronary artery contraction due to its β-receptor blocked and α -receptor relatively activated.
Oxygen
consumption

16. ß-ADRENERGIC BLOCKERS
CONTRAINDICATIONS
Hypotension: BP < 100 mmHg
Bradycardia: HR < 50 bpm
Chronic bronchitis, ASTHMA
Severe chronic renal insufficiency
Treatment of Heart Failure. Beta-Blockers: Contraindications
Contraindications to beta-blocker therapy in heart failure patients are the same as those for the general population.

17. Effects of nitrates alone and with β-blockers
in angina pectoris
Nitrates alone
β-blockers
Combined nitrates with β-blockers
Heart rate
Reflex increase
Decrease
Arterial pressure
Decrease*
End-diastolic volume
Increase
None or decrease
Contractility
None
Coronary vasospasm

18. Pharmacological effects of CCB
Cardiac contractility,
heart rate
Peripheral vessels dilation , afterload
dilate coronary artery, release its spasm
Ca2+ overload apoptosis,necrosis
Myocardial oxygen
consumption

19. Calcium channel blockers
Clinic use : variant angina
Nifedipine not for unstable angina?
Reflex increase in heart rate and cardiac contractility
How to control ?
β-Receptor blockers

20. Other drugs for angina Anti-platelet drugs: aspirin, persantin
Chinese medicine:
salvia miltiorrhiza, panax notoginseng
-promoting blood circulation to remove blood stasis

21. Non-Pharmacologic Management
Limit alcohol
No high saturated fat/high cholesterol foods
Maintain normal blood lipid levels
Maintain blood pressure within normal range
Regular exercise
Optimal weight
Maintain blood glucose within normal range
No tobacco 21

22. The Original Question from Step1-USMLE
A 60 y-o woman with a history of smoking presents with the chief complaint of chest pain that occurs at night while at rest. A treadmill test is negative. A 24 hr holter recording reveals transient ST elevation and AV block (suggestive of occlusion of her right coronary artery) that are temporally associated with anginal attacks. A coronary angiography with provocative testing with acetylcholine injection reproduces her chest pain & ECG changes. Which drug will be contraindicated in her treatment?
A. diltiazem
 B.  isosorbide dinitrate
 C.  metoprolol
 D. nitroglycerin sublingually
 E.  verapamil

23. Features & diagnosis of Variant angina
Symptoms typically occur at rest, rather than on exertion (thus attacks usually occur at night).
The treadmill stress test is always negative.
It is associated with specific ECG changes (elevation rather than depression of the ST segment).
The gold standard is coronary angiography with injection of provocative agents into the coronary artery. Depending on the local protocol, provocation testing may involve substances such as ergonovine, methylergonovine or acetylcholine.

24. Beta blockers (both beta-1 selective and nonselective types) are contraindicated in vasospastic angina because of the concern about blocking beta-2 receptors in coronary arteries, and leaving "alpha receptors unopposed"...resulting in enhanced likelihood of vasospasm.