drugs used in angina pectoris antianginal drugs. learning objectives describe the antianginal...
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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.