ANGINA

and
ANTIANGINAL
DRUGS
AIMS AND OBJECTIVES

The primary symptom of Ischemic

Heart Disease, Angina Pectoris is
caused by transient episodes of
Myocardial Ischemia. These episodes
are due to an imbalance in the
Myocardial Oxygen Demand – Supply
relationship.
Pharmacologic therapies include the
nitrates, the Ca+2 Channel Blockers
and the -Adrenergic Blocking Agents.
The pharmacology of Nitrates
(Nitrovasodilators) is discussed. The
role of -Blockers and Ca+2 channel
blockers has also been briefly
reviewed.
ANGINA
THE PRINCIPAL SYMPTOM OF ISCHAEMIC
HEART DISEASE.
SUDDEN SEVERE PRESSING SUBSTERNAL
PAIN, THAT OFTEN RADIATES TO THE LEFT
SHOULDER, AND ALONG THE FLEXOR
SURFACE OF THE LEFT ARM.
Typical angina is induced by:
Exercise, Emotions, Eating
TYPICAL
ISCHEMIC
CARDIAC
PAIN

Davidson
19th Ed. P 373.
TYPES OF ANGINA

1. Atherosclerotic Angina
Atherosclerotic angina is also known
as Angina of Effort or Classical
Angina. It is associated with
Atheromatous Plaques that partially
occlude one or more coronary
arteries.
When cardiac work increases (e.g., in
exercise), the obstruction of flow
results in the accumulation of acidic
metabolites and ischemic changes, that
stimulate myocardial pain endings.
Rest usually leads to prompt relief of the
pain within a few minutes.
Atherosclerotic angina constitutes about
90% of angina cases, and may persist for
years with little change.
It may deteriorate into Unstable Angina.
2. Vasospastic Angina
Vasospastic angina is also known as
Rest Angina, Variant Angina, or
Prinzmetal’s Angina.
It involves reversible spasm of
coronary arteries, usually at the site of
an atherosclerotic plaque. Spasm may
occur at any time, even during sleep.
Vasospastic angina may deteriorate
into Unstable Angina.
3. Unstable Angina
Also known as Crescendo
Angina, or Acute Coronary
Syndrome. It is characterized by
increased frequency and
severity of attacks caused by
repeated episodes of diminished
coronary flow, that result from a
combination of: -
i. Atherosclerotic plaques
ii. Platelet aggregation at fractured
plaques, and
iii.Vasospasm
Unstable Angina is thought to be
the immediate precursor of a
myocardial infarction and is treated
as a medical emergency.
Fixed Stenosis Dynamic Stenosis
Predictable Unpredictable

Davidson 19th ed. P 375

 CAUSES OF ANGINA
IMBALANCE BETWEEN OXYGEN
DEMAND AND SUPPLY

Oxygen Demand = Oxygen Supply

≠

Coronary
Cardiac
Blood
Work ISCHAEMIA Supply

ANGINA
STRATEGY FOR TREATMENT
INCREASE
BLOOD FLOW (CORONARY)

DECREASE
1. HEART RATE
2. FORCE OF MYOCARDIAL
CONTRACTION
3. PRELOAD
4. AFTERLOAD
ANTIANGINAL DRUGS
The Rule
All approved antianginal drugs function by
improving the balance of myocardial oxygen
supply and demand, by one or both of the
following actions: -
1. Improvement in Myocardial arterial supply
This is achieved by increase in coronary
arterial blood flow, due to dilatation of
coronary arteries.
2. Decrease in O2 demand
This is achieved by reducing cardiac work
due to: -
a) Decrease in preload, after load, heart rate
and cardiac contractility
b) Reduction in double product
_____________________________________
Double product = Systolic BP x Heart rate
 Drugs used in Angina Pectoris

Vasodilators Cardiac Depressants

Nitrates Ca+2 Channel -Blockers

Blockers
NITROVASODILATORS AVAILABLE
FOR CLINICAL USE
1. Amyl Nitrite (Inhalation)
2. Nitroglycerin (Glyceryl Trinitrate) [Angised]
i. Tablet for sublingual use
ii. Sustained Release Capsule or Tablet
iii. Ointment applied to skin every 4 to 8
hours
iv. Intravenous (5g/minute)
v. Transdermal disc
vi. Buccal (Transmucosal) tablet
3. Isosorbide Dinitrate (Isordil)
Tablets
i. Sublingual ii. Chewable
iii. Oral iv. Sustained release
4. Isosorbide Mononitrate (ISMO)
i. Tablets for sublingual use
ii. Sustained release Tablets or Capsules
5. Erythrityl Tetranitrate (Cardilate)
i. Tablet for sublingual use
ii. Oral Tablet or Capsule
Nitrovasodilators
(Mechanism of Action)

The pharmacological effects of

Nitrovasodilators appear to be
identical to those of EDRF*
Which has been shown to be NO i.e.
Nitric Oxide.
These agents lead to the formation of
the reactive free radical NO* which
interacts with
GUANYLYL CYCLASE

Activation of Cyclic
GMP Dependent
Protein Kinase
Increased cGMP Leads To
Dephosphorylation Of
Myosin Light Chain

Which Leads To Relaxation

Of Smooth Muscle
PHARMACOLOGICAL ACTIONS
CARDIOVASCULAR SYSTEM
A) THE ROLE IN THE MANAGEMENT
OF ANGINA
1. DECREASE IN O2 DEMAND:
a) Smooth muscle relaxation (veins)
leads to venodilatation, which results
in reduced cardiac size, and reduced
cardiac output through reduced
preload.
b) Reduced after load from arteriolar
dilatation may contribute to an
increase in ejection and a further
decrease in cardiac size. Arteriolar
dilatation also leads to reduced
peripheral resistance, and fall in
blood pressure.
These changes contribute to an overall
reduction in cardiac work and, therefore,
reduction in oxygen requirement.

Thus the primary mechanism of

therapeutic benefit in atherosclerotic
angina is reduction in the oxygen
requirement.
2. INCREASE IN CORONARY BLOOD
FLOW:
A secondary mechanism, namely an
increase in coronary flow, via collateral
vessels in ischemic areas, has also been
proposed. In vasospastic angina a
reversal of coronary spasm and increase
in coronary blood flow has been
demonstrated.
Note:-
It has been shown that of the
vascular beds the veins are the
most sensitive, arteries less and
arterioles least sensitive.
B) BLOOD PRESSURE

As discussed above, these agents

produce a fall in blood pressure.
Hypotension is usually associated with
reflex tachycardia. These drugs don’t
produce a direct effect on the heart.
Tachycardia can be prevented by the
concomitant administration of a  receptor
blocking agent.
OTHER EFFECTS
a) Nitrates relax the smooth muscle
of Bronchi, GIT and Genitourinary
Tract, but these effects are too
small to be clinically useful.
Intravenous Nitroglycerine
(sometimes used in unstable
angina) reduces platelet
aggregation.
b) Exercise Tolerance: Patients are
able to exercise for a longer
period after the administration of
Nitrovasodilators.
THERAPEUTIC USES

1. Angina
2. Congestive Cardiac Failure – The
utility of nitrovasodilators to
relieve pulmonary congestion, and
to increase cardiac output in
congestive heart failure, is well
established.
Higher doses of Organic Nitrates may
reduce blood pressure to such an
extent that coronary flow is
compromised: reflex tachycardia and
adrenergic enhancement of
contractility also occur. These effects
may initiate an Anginal Attack.
Beneficial and Deleterious
Effects of Nitrates in the
Treatment of Angina
Beneficial
Results
Effects
Decreased ventricular
volume
Decreased arterial Decreased myocardial
pressure oxygen requirement
Decreased ejection
time
Vasodilatation of Relief of coronary
epicardial coronary artery spasm
arteries
Beneficial
Effects Results

Increased collateral Improved perfusion to

flow ischemic myocardium

Decreased left Improved

ventricular diastolic subendocardial
pressure oxygen requirement
Deleterious Results
Effects
Reflex tachycardia

Reflex increase in Increased myocardial

contractility oxygen requirement

Decreased diastolic
perfusion time due to Decreased coronary
tachycardia perfusion
Effect of Nitrate and Dipyridamole (Persantine) in CAD
CAD: Coronary Artery Disease
SIDE EFFECTS

1) Severe throbbing headache: -

This is due to the dilatation of
meningeal vessels.
2) Flushing of neck, face and
clavicular area: - Due to
dilatation of cutaneous
vessels.
3) Postural Hypotension: - Due to
pooling of blood in the veins. These
drugs should not be administered in
standing position.
4) Reflex Tachycardia and Aggravation
of Angina: - High doses of organic
nitrates may reduce blood pressure
to such an extent that coronary flow
is compromised.
 Reflex tachycardia and adrenergic
enhancement of contractility also
occur. These effects may initiate an
Anginal Attack.
5) Withdrawal symptoms: - A few days
break in chronic exposure may lead
to death due to Infarction.
Don’t Withdraw Nitrates Abruptly.
5) Methemoglobinaemia: - Nitrates can
produce methemoglobinaemia at
high blood concentrations.
TOLERANCE

Sublingual organic nitrates should

be taken at the time of an anginal
attack or in anticipation of exercise
or stress. Such intermittent
treatment results in reproducible
cardiovascular effects.
However, frequently repeated or
continuous exposure to high doses
leads to a marked decrease in the
magnitude of most of their
pharmacological effects. This
phenomenon is known as
TOLERANCE.
The therapeutic significance of this
phenomenon has increased as the oral,
transdermal and intravenous
administration of higher doses has
become prevalent. An effective
approach is to interrupt therapy for 8-
12 hours each day.
NITROGLYCERIN
In human beings peak concentrations of
nitroglycerin are found in plasma with in 4
minutes of sublingual administration. Because
of its rapid action, long established efficacy
and low cost, nitroglycerin is the most useful
drug among the organic nitrates that can be
given sublingually.
NITROGLYCERIN

An initial dose of 0.3 mg often relieves

pain with-in 3 minutes. Anginal pain may
be prevented when the drug is used
prophylactically prior to exercise or
stress.
ISOSORBIDE DINITRATE
Sublingual administration produces
maximum concentrations in plasma by
6 minutes.

ISOSORBIDE MONONITRATE (ISMO)

This agent is available in tablet forms.
It has excellent bioavailability after oral
administration.
Time to peak
effect and
duration of
action for
some common
organic nitrate
preparations.
OTHER DRUGS
-BLOCKERS
These drugs decrease heart rate and force of
myocardial contraction. They also produce
fall in blood pressure. They, therefore,
decrease the myocardial O2 demand, by
decreasing the work load on the heart.
Propranolol is the prototype. Atenolol and
Metoprolol are also effective. These drugs are
orally administered and are used for
prophylaxis.
A judicious combination of Propranolol with
Nitroglycerin is able to prevent attacks of
angina in nearly 85% of patients.
The combination of -blockers and nitrates
is useful because the adverse undesirable
compensatory effects evoked by nitrates
(tachycardia and increased cardiac force)
are prevented or reduced by -blockers.
Ca+2 CHANNEL BLOCKERS
Verapamil and Diltiazem decrease myocardial
contractile fore, decrease cardiac output and
decrease O2 demand. These drugs also
produce increase in coronary flow by
producing relaxation of coronary arteries.
The effect of Nifedapine is more prominent on
coronary arteries, and it inhibits coronary
arterial vasospasm.
They are, therefore, effective in both
angina of effort and variant angina.
Nifedapine can be used safely with -
blockers.
Ca+2 channel blockers are effective as
prophylactic therapy. In atherosclerotic
angina, these drugs are particularly
valuable when combined with Nitrates.
NON PHARMACOLOGICAL THERAPY

Myocardial revascularization by Coronary

Artery Bypass Graft (CABG) and Percutaneous
Transluminal Coronary Angioplasty (PTCA)
have become important in the treatment of
severe angina. These are the only methods
capable of consistently increasing coronary
flow in atherosclerotic angina.
QUESTIONS
1. The route of administration of
Amyl nitrite is: -
a) Inhalation
b) I/V
c) Oral
d) Sublingual
e) Transdermal
2. The antianginal effect of Propranolol
may be attributed to which one of the
following: -
a) Block of exercise induced tachycardia
b) Decreased endiastolic ventricular
volume
c) Dilatation of constricted coronary
vessels
d) Increased cardiac force
e) Increased resting heart rate
3. The major common determinant of
myocardial oxygen consumption is: -
a) Blood volume
b) Cardiac output
c) Diastolic B.P.
d) Heart rate
e) Myocardial fiber tension
4. Which of the following is not a
component of the side effects of
organic nitrates?
a) Headache
b) Flushing
c) Reflex tachycardia
d) Hypertension
e) Methemoglobinemia