• Atherosclerotic disease, also known as coronary artery disease
(CAD) or ischemic heart disease (IHD), is the most common
cause of mortality worldwide.
• Atherosclerotic lesions in coronary arteries can obstruct blood
flow, leading to an imbalance in myocardial oxygen supply and
demand that presents as
– stable angina (ischaemic chest pain)
– an acute coronary syndrome
• unstable angina.
• myocardial infarction (MI) (heart attack): caused by the complete
occlusion of the coronary artery and associated death of tissue
• Spasms of vascular smooth muscle may also impede cardiac
blood flow, reducing perfusion and causing ischemia and
• Is a characteristic sudden, severe, pressing-like substernal
chest pain radiating to the neck, jaw, back, and arms.
Patients may also present with dyspnea or atypical
symptoms such as indigestion, nausea, vomiting, or
• is caused by inadequate blood flow through the coronary
blood vessels, is a consequence of myocardial O2 demand
• Transient, self-limited episodes (15 seconds to 15 minutes)
of myocardial ischemia (stable angina) do not result in cellular
death; such as occurs in myocardial infarction (MI).
• however, acute coronary syndromes and chronic ischemia can
lead to deterioration of cardiac function, heart failure,
arrhythmias, and sudden death.
Types of Angina
Angina pectoris has three patterns:
1. stable, effort-induced, classic, or typical angina.
2. unstable angina, preinfarction or crescendo angina.
3. Prinzmetal, variant, vasospastic, or rest angina.
They are caused by varying combinations of increased
myocardial demand and decreased myocardial
Stable angina: the most common (90%)
is chest pain caused by a temporary inadequacy of
blood flow to the myocardium, The underlying cause is
usually occlusion of the coronary arteries by
Usually lasts 1-15 minutes, and is provoked by
exercise, stress, extreme cold or heat, heavy meals,
alcohol, or smoking.
Rx: is promptly relieved by rest or nitroglycerin (a
(Acute coronary syndrome)
• 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 vessel.
1. chest pains occur with increased frequency, duration, and intensity.
2. precipitated by progressively less effort.
3. Any episode of rest angina longer than 20 minutes, any new-onset
angina, any increasing (crescendo) angina, or even sudden
development of shortness of breath is suggestive of unstable
4. The symptoms are NOT relieved by rest or nitroglycerin.
5. requires hospital admission and more aggressive therapy to prevent
death and progression to MI.
Prinzmetal's or variant or vasospastic 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 from the 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.
• generally responds promptly to coronary vasodilators, such as
nitroglycerin and calcium-channel blockers.
• but β-blockers are contraindicated???
Determinants of the volume of oxygen required by the heart.
Determinant of myocardial O2 demand
Preload- diastolic filling pressure (blood volume and venous tone)
Afterload-peripheral vascular resistance
1. Increase blood flow to ischemic heart muscle and/or
2. Decrease myocardial oxygen demand
Four types of drugs, used either alone or in combination,
are commonly used to manage patients with stable
angina: β-blockers, CCBs, organic nitrates, and the
sodium channel blocking drug, ranolazine. These agents
help to balance the cardiac oxygen supply and demand equation by
affecting blood pressure, venous return, heart rate, and contractility.
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
A newer Therapeutic strategies
• Trimetazidine: Partial fatty acid oxidation inhibitors (pFOX
inhibitors). A newer strategy attempts to increase the
efficiency of oxygen utilization by shifting the energy
substrate preference of the heart from fatty acids to
• Ranolazine: inhibition of late sodium current.
• Ivabradine: selectively reduces heart rate with no other
detectable hemodynamic effects, act by inhibition of the SA
pacemaker current, If.
• Nicorandil, Potassium channel activators,
Nitroglyserin, Isosorbid dinitrat, Isosorbid mononitrate
• They are effective in all types of angina pectoris.
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
Redistribution blood flow
• 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
• activates guanylate cyclase
(GC) and increases the cGMP.
• dephosphorylation of the
myosin light chain, vascular
smooth muscle relaxation.
Pharmacokinetics of Nitroglycerin
• Prototype: nitrate
• 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
• Oral isosorbide dinitrate undergoes denitration to two
mononitrates, both of which possess antianginal activity.
Common nitrate preparations
Glyceryl trinitrate can be taken by sublingual tablet or
The effects start within minutes and last ~30 min
Transdermal patches and I.V preparations are also
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 in about 30% - 60% of patients because of
the pronounced vasodilation.
High doses can cause postural hypotension, flushing &
• 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
• 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
• Atenolol, metoprolol, propranolol, bisoprolol
• 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
• 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.
• Side Effects:?
Mechanism of Action
• Suppress the activation of the heart by blocking B1 receptors
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
III. Reduce the work of the heart by decreasing COP and causing a
slight decrease in BP
• ↓ HR,
• ↓systolic wall tension,
• ↑perfusion time
Reasons for Using Nitrates and β-Blockers in
Combination in Angina
• β-Blockers prevent reflex tachycardia and contractility
produced by nitrate-induced hypotension.
• Nitrates prevent any coronary vasospasm produced by β-
• 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 : amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil
Mechanism of Action
• 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. Cause peripheral arterial vasodilation
• Reduce myocardial contractility (-ve inotropic action)
• Result: decreased myocardial oxygen demand
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.
• ↓ afterload,
• coronary vasodilation
Verapamil & deltiazem:
Calcium Channel Blockers
a dihydropyridine derivative
• a dihydropyridine derivative.
• functions mainly as an arteriolar vasodilator.
• This drug has minimal effect on cardiac conduction or heart
• Used in variant angina caused by spontaneous coronary
• Other members of this class, amlodipine, nicardipine, and
felodipine, have similar cardiovascular characteristics except
for amlodipine, which does not affect heart rate or cardiac
Calcium Channel Blockers
B- nondihydropyridine derivative/ Verpamil
• The diphenylalkylamine
• slows cardiac atrioventricular (AV) conduction directly,
• and decreases HR, contractility, BP, and oxygen demand.
• 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 digoxin levels.
• It also causes constipation.
Calcium Channel Blockers
C- nondihydropyridine derivative/ Deltiazem
• Its cardiovascular effects similar to verpamil
• Reduce the HR but lesser than verpamil
• Reduce BP
• Relieve coronary artery spasm so used in variant angina
• Can be used in angina in patients with concomitant diseases
I. First-line agents for treatment of:
3. supraventricular tachycardia
II. Short-term management of atrial fibrillation and flutter
Very acceptable side effect and safety profile, May cause:
• hypotension, palpitations, tachycardia or bradycardia, constipation,
Newer Antianginal Drugs
Sodium Channel Blocker, Ranolazine
• Ranolazine inhibits the late phase of the sodium current (late
INa), improving the oxygen supply and demand equation.
• Inhibition of late INa reduces intracellular sodium and calcium
overload, thereby improving diastolic function.
• It has antianginal as well as antiarrhythmic properties.
• Ranolazine is extensively metabolized, mainly by the CYP3A
family and also by CYP2D6. It is also a substrate of P-
glycoprotein. As such, ranolazine is subject to numerous drug
• ranolazine can prolong the QT interval.