Antianginal Drugs

1. Angina pectoris

• Angina pectoris, commonly

known as angina, is severe
chest pain due to ischemia (a
lack of blood, hence a lack of
oxygen supply) of the heart
muscle, generally due to
obstruction or spasm of the
coronary arteries (the heart's
blood vessels).
• It is caused by coronary blood
flow that is insufficient to meet
the oxygen demands of the
myocardium, leading to
ischemia.
• The imbalance between oxygen delivery and
utilization may result during exertion, from a
spasm of the vascular smooth muscle, or from
obstruction of blood vessels caused by
atherosclerotic lesions.
• These transient episodes (15 seconds to 15
minutes) of myocardial ischemia do not cause
cellular death, such as occurs in myocardial
infarction.
• Options other than medications for treating
angina include angioplasty and coronary
artery bypass surgery.
 2. Major risk factors

• Age (≥ 55 for men, ≥ 65 for women)

• Cigarette smoking
• Diabetes mellitus (DM)
• Dyslipidemia
• Family History
• Hypertension (HTN)
• Kidney disease
• Obesity
• Physical inactivity
• Medications
 3.Types of Angina
A. Stable angina
• Stable angina is the most common form of angina and,
therefore, is called typical angina pectoris.
• It is characterized by a burning, heavy, or squeezing feeling
in the chest.
• It is caused by the reduction of coronary perfusion due to a
fixed obstruction produced by coronary atherosclerosis.
• The heart becomes vulnerable to ischemia whenever there
is increased demand, such as that produced by physical
activity, emotional excitement, or any other cause of
increased cardiac workload.
• Typical angina pectoris is promptly relieved by rest or
nitroglycerin (a vasodilator).
 B. Unstable angina

• Unstable angina lies between stable angina on the one

hand and myocardial infarction on the other.
• In unstable angina, chest pains occur with increased
frequency and are precipitated by progressively less
effort.
• The symptoms are not relieved by rest or
nitroglycerin.
• Unstable angina requires hospital admission and
more aggressive therapy to prevent death and
progression to myocardial infarction.
C. Prinzmetal's or variant or vasospastic angina

• Prinzmetal's angina is an uncommon pattern of episodic

angina that occurs at rest and is due to coronary artery
spasm.
• Symptoms are caused by decreased blood flow to the heart
muscle due to spasm of the coronary artery.
• Although individuals with this form of angina may have
significant coronary atherosclerosis, the angina attacks are
unrelated to physical activity, heart rate, or blood pressure.
• Prinzmetal's angina generally responds promptly to
coronary vasodilators, such as nitroglycerin and calcium-
channel blockers.
 D. Mixed forms of angina

• Patients with advanced coronary artery

disease may present with angina episodes
during effort as well as at rest, suggesting the
presence of a fixed obstruction associated
with endothelial dysfunction.
 Treatment
Drugs Classification

Three classes of drugs, used either

alone or in combination, are
effective in treating patients with
angina.

These agents lower the oxygen

demand of the heart by affecting
blood pressure, venous return,
heart rate, and contractility.
 Treatment
1. Organic Nitrates
• Organic nitrates (and nitrites) used in the
treatment of angina pectoris are simple nitric
and nitrous acid esters of glycerol.
• These compounds cause a rapid reduction in
myocardial oxygen demand, followed by rapid
relief of symptoms.
• They are effective in stable and unstable
angina as well as in variant angina pectoris.
 A. Mechanism of action (MOA)
• Nitrates decrease coronary vasoconstriction
or spasm and increase perfusion of the
myocardium by relaxing coronary arteries.
• In addition, they relax veins, decreasing
preload and myocardial oxygen
consumption.
• Organic nitrates, such as nitroglycerin,
which is also known as glyceryl trinitrate,
are thought to relax vascular smooth muscle
by their intracellular conversion to nitrite
ions, and then to nitric oxide, which in turn
activates guanylate cyclase and increases
the cells' cyclic guanosine monophosphate
(GMP). Elevated cGMP ultimately leads to
dephosphorylation of the myosin light Effects of nitrates and nitrites on
chain, resulting in vascular smooth muscle smooth muscle. cGMP = cyclic
relaxation guanosine 3', 5'-monophosphate.
B. Effects on the cardiovascular system
• All these agents are effective, but they differ in
their onset of action and rate of elimination.
• For prompt relief of an ongoing attack of
angina precipitated by exercise or emotional
stress, sublingual (or spray form) nitroglycerin
is the drug of choice.
• At therapeutic doses, nitroglycerin has two major
effects. First, it causes dilation of the large veins,
resulting in pooling of blood in the veins.
• This diminishes preload (venous return to the
heart) and reduces the work of the heart.
• Second, nitroglycerin dilates the coronary
vasculature, providing an increased blood supply
to the heart muscle. Nitroglycerin decreases
myocardial oxygen consumption because of
decreased cardiac work.
 C. Pharmacokinetics
• The time to onset of action varies from 1 minute
for nitroglycerin to more than 1 hour for
isosorbide mononitrate.
• Significant first-pass metabolism of nitroglycerin
occurs in the liver. Therefore, it is common to take
the drug either sublingually or via a transdermal
patch, thereby avoiding this route of elimination.
• 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.
 Time to peak effect and duration of
action for some common organic nitrate
preparations
 D. Adverse effects
• The most common adverse effect
of nitroglycerin, as well as of the
other nitrates, is headache.
• High doses of organic nitrates can
also cause postural hypotension,
facial flushing, and tachycardia.
• Sildenafil (Viagra) potentiates the
action of the nitrates. To preclude
the dangerous hypotension that
may occur, this combination is
contraindicated.
 2. β-Adrenergic Blockers
• The β-adrenergic blocking
agents decrease the oxygen
demands of the myocardium
by lowering both the rate and
the force of contraction of the
heart.
• They suppress the activation of
the heart by blocking β1
receptors, and they reduce the
work of the heart by
decreasing heart rate,
contractility, cardiac output,
and blood pressure.
• With β-blockers, the demand for oxygen by the
myocardium is reduced both during exertion and at
rest.
• Propranolol is the prototype for this class of
compounds, but it is not cardioselective. Thus, other β-
blockers, such as metoprolol or atenolol, are preferred.
• All β-blockers are nonselective at high doses and can
inhibit β2 receptors. This is particularly important to
remember in the case of asthmatics.
• Agents with intrinsic sympathomimetic activity (for
example, pindolol) are less effective and should be
avoided in angina.
• The β-blockers reduce the frequency and severity of
angina attacks. These agents are particularly useful in
the treatment of patients with myocardial infarction
and have been shown to prolong survival.
• The β-blockers can be used with nitrates to
increase exercise duration and tolerance. They
are, however, contraindicated in patients with
asthma, diabetes, severe bradycardia,
peripheral vascular disease, or chronic
obstructive pulmonary disease.
• Note: It is important not to discontinue β-
blocker therapy abruptly. The dose should be
gradually tapered off over 5 to 10 days to
avoid rebound angina or hypertension.
 3. Calcium-Channel Blockers
• Calcium is essential for muscular contraction. Calcium
influx is increased in ischemia because of the
membrane depolarization that hypoxia produces.
• In turn, this promotes the activity of several
adenosine triphosphate consuming enzymes, thereby
depleting energy stores and worsening the ischemia.
• The calcium-channel blockers protect the tissue by
inhibiting the entrance of calcium into cardiac and
smooth muscle cells of the coronary and systemic
arterial beds.
• All calcium-channel blockers are therefore arteriolar
vasodilators that cause a decrease in smooth muscle
tone and vascular resistance.
• Verapamil mainly affects the myocardium, whereas
nifedipine exerts a greater effect on smooth muscle in
the peripheral vasculature.Diltiazem is intermediate
in its actions.
• All calcium-channel blockers lower blood pressure.
They may worsen heart failure due to their negative
inotropic effect.
• Variant angina caused by spontaneous coronary
spasm rather than by increased myocardial oxygen
requirement is controlled by organic nitrates or
calcium-channel blockers; β-blockers are
contraindicated.
 A. Nifedipine
• Nifedipine, a dihydropyridine derivative, functions mainly as
an arteriolar vasodilator. This drug has minimal effect on
cardiac conduction or heart rate.
• 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.
• Nifedipine is administered orally, usually as extended-
release tablets.
• It undergoes hepatic metabolism to products that are
eliminated in both urine and the feces.
• The vasodilation effect of nifedipine is useful in the
treatment of variant angina caused by spontaneous
coronary spasm.
• Nifedipine can cause flushing, headache, hypotension, and
peripheral edema as side effects of its vasodilation activity.
• As with all calcium-channel blockers,
constipation is a problem. Because it has little
to no sympathetic antagonistic action,
nifedipine may cause reflex tachycardia if
peripheral vasodilation is marked.
• The general consensus is that short-acting
dihydropyridines should be avoided in
coronary artery disease.
 B. Verapamil
• The diphenylalkylamine verapamil slows cardiac
atrioventricular (AV) conduction directly, and decreases
heart rate, contractility, blood pressure, and oxygen demand.
• Verapamil causes greater negative inotropic effects than
nifedipine, but it is a weaker vasodilator.
• The drug is extensively metabolized by the liver; therefore,
care must be taken to adjust the dose in patients with liver
dysfunction.
• 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 patients taking digoxin, because verapamil
increases digoxin levels.
 C. Diltiazem
• Diltiazem has cardiovascular effects that are similar to
those of verapamil. Both drugs slow AV conduction and
decrease the rate of firing of the sinus node pacemaker.
• Diltiazem 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, therefore, is particularly useful in patients with variant
angina. It is extensively metabolized by the liver.
• The incidence of adverse side effects is low (the same as
those for other calcium-channel blockers). Interactions with
other drugs are the same as those indicated for verapamil.
Some common adverse
effects of the calcium-
channel blockers
END