Download antianginal drugs

ANTIANGINAL DRUGS
Section I
Introduction
1. Angina pectoris: Angina pectoris is a primary symptom of myocardial, which is the severe chest
pain that occurs when coronary blood flow is inadequate to supply the oxygen required by the
heart.
2. The classifications of angina
1) Stable angina
2) Unstable angina
3) Variant angina (Prinzmetal’s angina)
3. The pathophysiology mechanism of angina
An imbalance between the myocardial oxygen supply and demand (The myocardial oxygen
demand exceeds supply).
Determinants of myocardial oxygen supply:
1) the difference of arteriovenous oxygen pressure: The heart’s oxygen needs are relatively high,
and it extracts approximately 70-90% of the available oxygen even under conditions of no stress.
2) coronary blood flow: Coronary blood flow is directly related to the perfusion pressure (aortic
diastolic pressure), the duration of diastole and Coronary Vascular resistance.
Determinants of myocardial oxygen demand:
1) ventricular wall tension:
Intraventricular pressure; Ventricular volume
2) heart rate
3) ventricular contractility
Section II Organic nitrates
Nitroglycerin
1.
Pharmacokinetics
Absorption: first-pass elimination is large, bioavailability 10-20%，small dose sublingual route is a
preferred. take effect after 1~3 min, last time: 20~30 min. Metabolism: in liver, be dinitrated by
glutathione-nitrate reductase; Excretion: by kidney。
Other routes of administration available for nitroglycerin include transdermal and buccal absorption
from slowrelease preparations.
2.
Pharmacological action
Basic action: Relax smooth muscle, specially vascular smooth muscle
(1)
Dilate peripheral vessels, decrease myocardial oxygen consumption.
at minimal effective dose:
dilate veins
blood returning to heart
cardiac preload
wall tension
at higher dose:
1
dilate arteries
(2)
peripheral resistance
cardiac afterload
Dilate coronary artery, increase the blood supply to ischemic area.
selectively dilate epicardium vessels, conductance vessels and side vessels
redistribution of coronary blood flow
(3)
LVEDP, increase blood perfusion of subendocardium, improve the compliance of left-ventricle.
Dilate veins
blood returning to heart
Dilate arteries
CO
LVEDV and LVEDP
ventricle wall stress
(4) Protect the ischemic cardiac myocytes, decrease ischemia damage.
release of PGI2 and CGRP; inhibite of platelet aggregation
3.
Parmacological mechanism
Nitrates are exogenous donors of nitric oxide (NO). They are metabolized to release NO by
biochemical pathway. NO is a potent vasodilator. That is the basic mechanism of action of nitrates.
intracellular Ca2+
cGMP
Nitrates
NO
cGMP
smooth muscle relaxation
inhibit platelet aggregation
PGI2; CGRP
CGRP
4.
KATP
K+efflux
Ca2+influx
vasodilation
Clinical uses
(1)All types of angina； stable angina：first choice
(2)Acute myocardia infarction (3)CHF (4)Pulmonary artery high pressure
5.
Adverse reactions
(1) Acute adverse reactions: Flushed appearance; Tachycardia;
Orthostatic hypotension; Throbbing headache; Methemoglobinemia
(2) Tolerance:
The requirement for the dose of a drug becomes higher to achieve the same pharmacological effect.
Mechanism:
 Blood vessel tolerance:
 Fake tolerance:
Management:
-SH consumption
reflex sympathetic excitation
Diet: (rich in -SH); change dosing interval; Avoid large dose；combine with ACEI;
antioxidant.
* a nitrate-free period of at least 8 hours between doses should be observed to reduce or prevent
tolerance.
Isosorbide dinitrate
2
High bioavailability, take effect is slow, last long.
Used in prophylaxis attack of angina.
Isosorbide mononitrate
Section III β-adrenoceptor blocking drugs
1.
The mechanism of antiangina
(1) Decrease myocardial oxygen consumption
Block β-adrenoceptor,
myocardial contractility and heart rate
(2) Improve blood and oxygen supply to ischemia area
Lower heart rate, prolong diastolic perfusion time, endocardium flow
(3) Improve myocardial metabolism;
FFA level
(4)Promote oxygen to dissociate from oxygenated hemoglobin(HbO2)
2. Clinical uses
All β-blockers are effective in the prophylaxis of stable angina attacks, but ineffective against the
variant form. Because the blockage of β2-receptor can cause vasoconstriction in coronary artery, which
is the cause of variant angina. The combination of β-blockers and nitrate is useful because the adverse
effects evoked by the nitrates are prevent or reduced by β-blockers.
(1) stable and unstable angina
(2) myocardia infarction: caution:
contractility
(3) Do not used to variant angina
3. Combines with nitrates
Nitrates+
Nitrates alone
β-blokers
β-blokes
Heart rate
reflex increase
decrease
decrease
Arterial pressure
decrease
decrease
decrease
End-diastolic volume
Contractility
decrease
reflex increase
Ejection time
decrease
increase
none or decrease
decrease
none
increase
none
Section IV Calcium channel-blocking drugs
1.
The mechanism of antiangina
(1) Decrease myocardial oxygen consumption
Decrease heart rate and contractility; vasodilation; antisympathetic action
(2) Improve the blood supply to the ischemia
Dilate coronary artery, decrease the platelet aggregation
(3) Protect ischemic cardiac myocytes
3
(4) Antiatherosclerosis
2.
Clinical uses
First choice for variant angina, also used in stable and unstable angina.
4