Dr. Hiwa K. Saaed
College of Pharmacy, University of Sulaimani28-Jun-14
Partial occlusion of coronary blood vessels
by atherosclerotic plaque occurs in ~75%
of adults in developed countries.
Symptoms may not manifest until late in the
history of the disease, but coronary
atherosclerosis can lead to:
Angina (ischaemic chest pain):
Myocardial infarction (heart attack): caused by the complete
occlusion of the coronary artery and associated death of
Is a characteristic sudden, severe, pressing-like substernal
chest pain radiating to the neck, jaw, back, and arms.
What is Angina?
ANGINA is pain or discomfort in the chest caused by
inadequate blood flow through the coronary blood vessels, is a
consequence of myocardial O2 demand exceeding
Is the principle symptom of ischemic heart disease
(IHD); This is sometimes called myocardial ischaemia
a spasm of the vascular smooth muscle
obstruction of blood vessels caused by
These transient episodes (15 seconds to 15 minutes) of
myocardial ischemia DO NOT cause cellular death, such
as occurs in myocardial infarction (MI).
Angina is often brought on by exertion or excitement
(when the O2 demands of the heart increase) from:
Types of Angina
Chronic stable angina
also called classic, typical, or effort angina
also called preinfarction or crescendo angina
also called Prinzmetal’s or variant angina
Stable angina: the most common (90%)
is chest pain caused by a temporary inadequacy of
blood flow to the myocardium
• Usually lasts 1-15 minutes, and is provoked by exercise,
stress, extreme cold or heat, heavy meals, alcohol, or
Rx: is promptly relieved by rest or nitroglycerin (a
• The underlying cause is usually occlusion of the
coronary arteries by atheroma - the narrowing of
blood vessels by deposits of fatty or fibrous material
B. Unstable angina
lies between stable angina and MI.
The pathology is similar to that involved in MI: a platelet-
fibrin thrombus associated with a raptured atherosclerotic
plaque, but without complete occlusion of the blood
1. chest pains occur with increased frequency
2. precipitated by progressively less effort.
3. The symptoms are NOT relieved by rest or nitroglycerin.
4. requires hospital admission and more aggressive therapy
to prevent death and progression to MI.
C. Prinzmetal's or variant or vasospastic
caused by spontaneous coronary artery spasm either at
work or at rest ...
the angina attacks are unrelated to physical activity, HR,
generally responds promptly to coronary vasodilators,
such as nitroglycerin and calcium-channel blockers.
but β-blockers are contraindicated???
Purpose of drug treatment
Minimize the frequency, duration and intensity of
Improve the patient’s functional capacity with as
few side effects as possible
Stop and regression of the disease process
Prevent or delay the worst possible outcome, MI
To reduce the cardiac workload and metabolic demand
To increase the perfusion of the heart muscle
To prevent myocardial infarction
Organic nitrates, Ca2+ antagonists, β-adrenoreceptor
Lipid lowering drugs, particularly statins, can be given if elevated
plasma cholesterol levels are detected
Antiplatelet drugs, especially low-dose (75mg) aspirin to reduce
the possibility of thrombosis.
Fibrinolytic drugs (e.g. heparin) are used in unstable angina
There are two treatment options:
1. Increase blood flow to ischemic heart muscle
2. Decrease myocardial oxygen demand
Glyceryl trinitrate, isosorbide mononitrate
Myosin Myosin P
Smooth muscle cell
Common nitrate preparations
Blood flow to
ischaemic area of
Glyceryl trinitrate can be taken by sublingual
tablet or spray
The effects start within minutes
and last ~30 min
Transdermal patches and i.v.
preparations are also available
Isosorbide mononitrate is a longer
acting preparation which is given orally
(half-life 4hrs), and slow release
preparations are available.
Side effects: nitrates can cause headache
because of the pronounced vasodilation, and
postural hypotension because of the drop in
Organic nitrates & nitrites
are simple nitric and nitrous acid esters of glycerol.
They differ in their volatility. For example,
1. isosorbide dinitrate and isosorbide mononitrate are
solids at room temperature,
2. nitroglycerin is only moderately volatile, and amyl
nitrite is extremely volatile.
They are effective in all types of angina pectoris.
Nitrates: Effects on CVS
at therapeutic doses :has 2 major effects
a) Dilation of the large veins resulting in pooling of
blood in the veins which diminish the preload and
reduces the work of the heart
b) Dilates the coronary vasculature providing increased
blood supply to the heart muscle
The total effect is a decrease in myocardial oxygen
consumption because of decreased cardiac work
A. Mechanism of action
relax vascular smooth muscle by
their intracellular conversion to
nitrite ions, to nitric oxide,
activates guanylate cyclase (GC)
and increases the cGMP.
dephosphorylation of the myosin
light chain, vascular smooth
Pharmacokinetics of Nitroglycerin
significant first-pass effect metabolism of
nitroglycerin occurs in the liver with PO forms
Therefore, it is common to take the drug
either sublingually or via a transdermal patch,
The time to onset of action varies from 1
minute for nitroglycerin to more than 1 hour
for isosorbide mononitrate.
Isosorbide mononitrate owes its improved
bioavailability and long duration of action to
its stability against hepatic breakdown.
Oral isosorbide dinitrate undergoes
denitration to two mononitrates, both of which
possess antianginal activity.
Nitrate Side Effects
long acting preparations cause headache in
about 30% - 60% of patients
high doses can cause postural hypotension,
flushing & tachycardia
Tolerance develops rapidly. The blood vessels become
desensitized to vasodilation.
providing a daily “nitrate-free interval” to restore
sensitivity to the drug.
This interval is typically 10 to 12 hours, usually at night,
because demand on the heart is decreased at that time.
Nitroglycerin patches are worn for 12 hours then
removed for 12 hours.
However, variant angina worsens early in the morning,
perhaps due to circadian catecholamine surges.
Therefore, the nitrate-free interval in these patients
should occur in the late afternoon.
Antianginal Agents: Beta Blockers
atenolol, metoprolol, propranolol, nadolol
Are used only for prophylactic therapy of angina;
they are of no value in an acute attack
Effective in preventing exercise-induced angina
But are ineffective against the vasospastic form
Mechanism of Action
Suppress the activation of the heart by blocking
I. Decrease the HR, resulting in:
1. decreased myocardial oxygen demand.
2. increased oxygen delivery to the heart.
II. Decrease myocardial contractility, helping to
conserve energy or decrease demand
III. Reduce the work of the heart by decreasing
COP and causing a slight decrease in BP
Cardioselective β-blockers, such as metoprolol or
atenolol, are preferred.
Thus, Propranolol is not preferred
Agents with intrinsic sympathomimetic activity (for
example, pindolol) are less effective and should be
avoided in angina.
The dose should be gradually tapered off over 5 to 10
days to avoid rebound angina or hypertension.
Reasons for Using Nitrates and β-Blockers in
Combination in Angina
β-Blockers prevent reflex tachycardia and
contractility produced by nitrate-induced
Nitrates prevent any coronary vasospasm
produced by β-Blockers.
Nitrates prevent increases in left ventricular filling
pressure or preload resulting from the negative
inotropic effects produced by β-Blockers .
Calcium Channel Blockers (CCBs)
ex : verapamil, deltiazem, nifidipine
Calcium is essential for muscular contraction.
The CCBs protect the tissue by inhibiting the
entrance of Ca+2 into cardiac and smooth muscle
cells of the coronary and systemic arterial beds.
All CCBs are therefore arteriodilators that cause a
decrease in vascular resistance.
1. Verapamil mainly affects the myocardium,
2. whereas nifedipine exerts a greater effect on
smooth muscle in the peripheral vasculature.
3. Diltiazem is intermediate in its actions.
They lower blood pressure may worsen heart
failure due to their -ve inotropic effect.
Calcium Channel Blockers
a dihydropyridine derivative.
functions mainly as an arteriolar
This drug has minimal effect on cardiac
conduction or heart rate.
Used in variant angina caused by
spontaneous coronary spasm
Other members of this class, amlodipine,
nicardipine, and felodipine,
have similar cardiovascular characteristics
except for amlodipine, which does not
affect heart rate or cardiac output.
slows cardiac atrioventricular (AV)
and decreases HR, contractility, BP, and
causes greater -ve inotropic effects than
nifedipine, but it is a weaker vasodilator.
is extensively metabolized by the liver.
is contraindicated in patients with
preexisting depressed cardiac function or
AV conduction abnormalities.
Drug Interaction: verapamil increases
It also causes constipation.
Its cardiovascular effects similar to verpamil
Reduce the HR but lesser than verpamil
Relieve coronary artery spasm so used in
Can be used in angina in patients with
Therapeutic Uses of deltiazem
I. First-line agents for treatment of:
3. supraventricular tachycardia
II. Short-term management of atrial fibrillation
Very acceptable side effect and safety profile,
tachycardia or bradycardia,