Pharmacology lecture
Antianginal agents
22-28\12\2009
Angina Pectoris (Latin) = pain in the chest
Definition:
Sudden, sever, transient, pressing retrostrenal pain. Radiating to the
.
neck, jaw, left shoulder, and arm. Cardinal sign of coronary artery disease A problem of
O2 supply vs. O2 demand.
Pathophysiology
1- oxygen supply to the heart is insufficient to meet oxygen demand. Secondary to
atherosclerosis of the coronary arteries.
2- vasoconstriction, at an atherosclerosic site of the coronary arteries.
Types of Angina Pectoris
1- Stable Angina ( Classic exertional Angina).
1. most common form (90%)
 Coronary insufficiency due to vessel occlusion (atherosclerosis)
 Attacks usually occur during exercise (climbing stairs, etc.) when oxygen
demand exceeds supply
2- Variant Angina (Prinzmetal’s Angina)[rest angina]
2. Coronary insufficiency due to vasospasm (may be an effect produced by
atherosclerosis on vasomotor tone)
3. Attacks often occur during rest (e.g., at night)
3- Unstable Angina ( Accelarated Angina). (acute coronary
syndrome)
4. serious problem (impending MI)
5. Increased frequency & severity of attacks
6. Caused by atherosclerotic plaques, platelet aggregation at fractured
plaques & vasospasm
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Treatment Strategy
1- increase cardiac oxygen supply
2- decrease oxygen demand
Antianginal agents
1- Nitrites & Nitrates.
2- β-adrenergic blocking agents.
3- Calcium channel blocking agents.
4- Aspirin & anticoagulants.
5- Trimetazidine.
1- Nitrites & Nitrates
vascular smooth muscle
NO3Nitrate
RSH
Tissue
thioles
NO2-
NO
Nitrite
+
Guanylyl cyclase
c GMP
Vasodilation
Bound Ca2+
GTP
Ca2+
Mechanism of Action 1. release NO
Venodilation - primary mechanism
 Venodilation
results
in
decreased
“preload”
(decreased ventricular chamber size, end diastolic pressure, fiber
tension) = decreased work
 Decreased preload results in decreased O2 demand
 Reduction of afterload (arterial resistance) can be produced at
higher doses - can produce reflex tachycardia
2. Redistribution
of
coronary
blood
flow
with
nitrates
 Subendocardial regions are most ischemic
 Organic nitrates can selectively increase blood flow to ischemic
areas
 Total coronary flow is not increased
Nitroglycerin( Glyceryl trinitrate)



Significant first-pass metabolism of nitroglycerin occurs in the liver.
Sublingual tablet or spray acts with in (1-3min) for about 10-30 minutes.
Transdermal patches have a long duration of action(24 hours).
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Therapeutic uses





It is more useful in preventing attacks than in stopping them once they have
begun.
low doses (usually sublingual tablets) for acute attacks & for prophylaxis
patches used for prolonged prophylaxis
tablets – oral high dose;
Nitrates are the mainstay of therapy for the immediate relief of angina
Adverse Effects
Due to vasodilation, vessels relaxed




Headache.
Facial flushing
Orthostatic Hypotension
Dizziness.
 Reflex Tachycardia ((baroreceptor mediated, lowered Bp => reflex to
increase Bp)
Tolerance. If tolerance develops, it can be reversed by withholding nitrates
(nitrates free interval). Until the sulfhydryl content of VSM has been replenished.
Can have anginal rebound during nitrate-free intervals.
lsosorbide dinitrate
lsosorbide dinitrate is an orally active nitrate.
The drug is not readily metabolized by the liver or smooth muscle
It has a lower potency than nitroglycerin in relaxing vascular smooth muscle.
Prophylactic uses.
Onset (20-40 min).
Duration ( 4-6 hr).
Amyl nitrate
Amyl nitrate is extremely volatile.
High chance of abuse.
Route is by inhalation.
Onset (0.5 min).
Duration (3-5 min).
Emergency uses.
2- β-adrenergic blocking agents:
β- blockers reduce Anginal pain by decreasing cardiac oxygen demand, due to
reduced heart rate (esp. during exercise).
Reduced blood pressure (esp. systolic) during exercise.
Mechanism of action.
This is accomplished primarily through blockade of β1 receptors in the heart,
which decreases heart rate and contractility.
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β- blockers can reduce oxygen demand further by causing a modest reduction in
arterial pressure (afterload).
Commonly Used β-adrenergic blocking agents.
Propranolol is the prototype of this class of compounds, but other β-blockers,
such as metoprolol and atenolol are equally effective.
However, agents with intrinsic sympathomimetic activity (for example,
pindolol and acebutolol)
Therapeutic uses
are less effective and should be avoided.
1. Only for prophylaxis of exertional angina
2. Ineffective (or contraindicated) for variant angina (may make attacks worse)
3. Often combined with other drug types.
Adverse effects
1. Bronchoconstriction (nonselective).
2. Fatigue, insomnia
3. Hypoglycemia (nonselective).
4. Sever myocardial depression & heart failure.
Contraindication
1.
2.
3.
4.
They are contraindicated in patients with:
Diabetes,
Peripheral vascular disease,
Chronic obstructive pulmonary disease.
3- Calcium Channel Blockers (CCBs).
These agents block the channels that carry slow inward Ca++ currents in
vascular smooth muscle and cardiac muscle
Resulting actions include the decrease of conduction velocity, reduction of
automaticity, and coronary and peripheral arterial dilitation
These effects lead to an increase of coronary blood flow and a decrease in
myocardial oxygen demand.
Examples: nifedipine, verapamil, diltiazem, amlodipine
Mechanisms of action








Block Ca entry into cell which is important for contractile action in heart.
Produce decreased contractility.
Vasodilation, (Arteriolar dilation).
O2 Demand - probably “most” important
Decreased HR
Decreased contractility
Decreased afterload (TPR, BP)
little effect on venous resistance vs. arterial
Increase coronary blood flow (useful in vasospastic angina)
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


Nifedipine:
exerts a greater effect on smooth muscle in the peripheral
vasculature, functions mainly as an arteriolar vasodilator.
This drug has minimal effect on cardiac conduction or heart rate.
Nifedipine is administered orally and has a short half-life (about 4 hours)
requiring multiple dosing.
Therapeutic uses

nifedipine is useful in the treatment of variant angina caused by spontaneous
coronary spasm.
Side Effect



Can cause flushing, headache, hypotension, and peripheral edema
as side effects of its vasodilation activity.
may cause reflex tachycardia if peripheral vasodilation is marked
resulting in a substantial decrease in blood pressure.
Gingival hyperplasia, & dysgeusia
Dental Considerations: Calcium Channel Blockers
There are no significant drug interactions reported
Gingival hyperplasia can occur in patients taking calcium channel
blockers; close monitoring and encouragement of optimal oral hygiene
is necessary
Verapamil: mainly affects the myocardium, slows cardiac
conduction directly and thus decreases heart rate and oxygen demand,
but it is a weaker vasodilator.
Side Effect
Verapamil is contraindicated in patients with preexisting depressed
cardiac function or AV conduction abnormalities.
It also causes constipation. Verapamil should be used with caution in
digitalized patients, since it increases digoxin levels.
Diltiazem: is intermediate in its actions, it has cardiovascular effects
that are similar to those of verapamil.
It reduces the heart rate, although to a lesser extent than verapamil, and
also decreases blood pressure.
In addition, diltiazem can relieve coronary artery spasm and is
therefore particularly useful in patients with variant angina.
The incidence of adverse side effects is low.
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 Note : nitroglycerin,  blockers; CCBs in refractory
pts ( combined)
4-
Aspirin & anticoagulants.
Unstable Angina : recurrent ischemic episodes at rest
Recurrent thrombotic occlusions
Platelet aggregation.
1- aspirin
2- i.v.
heparin
3- antiplatelet drugs (clopidogrel, others)
5-
Trimetazidine, Ranolazine
A novel anti ischemic drug.
Mechanism of action is unclear.
Are metabolic modulators.
They are known as pFOX inhibitors because they partially inhibit the
fatty acid oxidation pathway in myocardium.
Well tolerated.
Minor side effect.
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