Drugs used in angina pectoris

Antianginal drugs

Learning Objectives

Describe the antianginal mechanism of Nitrites, β-blockers and CCBs

Clarify the vasodilatory mechanism of NOSelect antianginal agents for the treatment

of different types of angina pectoris

By the end of this class, you can…

Methods for treatment

■ To improve perfusion:

■ To reduce metabolic demand

Factors affecting myocardial oxygen demand and oxygen supply

Oxygen demand

Oxygen supply=

>

Coronary blood flow

Regional myocardial distribution

Ventricular volume

LV pressure

Wall tension

Heart rate

Contractile state

Aortic pressure

Coronary vascular resistance

Drugs classifications

▲ Organic nitrates: Nitroglycerin▲ Calcium antagonists▲ β-Receptor blockers

Chemical structures of two nitrates

Nitroglycerin Isosorbide dinitrate (IDSN)

-O-NO2

Longer lasting effectRapid onset effect

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

Nitroglycerin

↓ SHNO/SNO

↓+guanylate cyclase

↓+ cGMP ↑ 5’GMP

Concentration of Ca2+ in VSMC↓

PDE

Inhibition platelet

Ca2+ influx↓ Ca2+ efflux↑ Activation of protein kinase

VASODILATION

Organic nitrates

Pharmacological effects and mechanism:

■ dilate peripheral vein preload

■ dilate peripheral artery afterload■ Dilate coronary artery perfusion of

ischemic myocardium

Oxygen consumption

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

" Decrease in the effect of a drugwhen administered in a long-acting form"

" Decrease in the effect of a drugwhen administered in a long-acting form"

NITRATESTOLERANCE

NITRATESTOLERANCE

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

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

NITRATES

CONTRAINDICATIONS

NITRATES

CONTRAINDICATIONS

Previous hypersensitivity

Hypotension ( < 80 mmHg)

1st trimester of pregnancy

Previous hypersensitivity

Hypotension ( < 80 mmHg)

1st trimester of pregnancy

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

ß-ADRENERGIC BLOCKERSCONTRAINDICATIONS

ß-ADRENERGIC BLOCKERSCONTRAINDICATIONS

Hypotension: BP < 100 mmHg

Bradycardia: HR < 50 bpm

Chronic bronchitis, ASTHMA

Severe chronic renal insufficiency

Hypotension: BP < 100 mmHg

Bradycardia: HR < 50 bpm

Chronic bronchitis, ASTHMA

Severe chronic renal insufficiency

  Nitrates alone

β-blockers

Combined nitrates with β-blockers

Heart rate Reflex increase

Decrease Decrease

Arterial pressure

Decrease Decrease Decrease*

End-diastolic volume

Decrease Increase None or decrease

Contractility Reflex increase

Decrease None

Coronary vasospasm

Decrease Increase None

Effects of nitrates alone and with β-blockers in angina pectoris

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

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

Other drugs for angina

■ Anti-platelet drugs: aspirin, persantin

■ Chinese medicine: salvia miltiorrhiza, panax notoginseng -promoting blood circulation to remove blood

stasis

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

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

The Original Question from Step1-USMLE

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.

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.