Antianginal Drugs

Coronary artery disease

• Angina Pectoris (Ischemic Heart Disease)
• Acute Coronary Syndrome
• Unstable Angina
• Angina pectoris refers to a
strangling or pressure-like
pain caused by cardiac
ischemia. The pain is
sometimes perceived in the
neck, shoulder and arm, or
epigastrium.
• .
• Antianginal drugs are those that prevent, abort or
terminate attacks of angina pectoris.
• Types of angina
– Atherosclerotic angina (classic angina [common form]):
Attacks are predictably provoked (stable angina) by
exercise, emotion, eating or coitus and subside when the
increased energy demand is withdrawn.
– Rest, by reducing cardiac work, usually leads to complete
relief of the pain within 15 min.
– Atherosclerotic angina constitutes about 90% of angina
cases.
• Types of angina
– Vasospastic angina (rest
angina, variant angina, or
Prinzmetal’s angina
[uncommon form]):
– Attacks occur at rest or
during sleep and are
unpredictable. Vasospastic
angina is responsible for less
than 10% of angina cases.

Coronary artery calibre changes in

classical and variant angina
• Types of angina
– Unstable angina (crescendo angina, also known as acute
coronary syndrome): It is characterized by increased
frequency and severity of attacks that result from a
combination of atherosclerotic plaques, platelet
aggregation at fractured plaques, and vasospasm.
 Treatment of Angina Pectoris
• Drugs used in angina exploit two main strategies:
– reduction of oxygen demand
– increase of oxygen delivery to the myocardium
 Classification of antianginal drugs
• Nitrates
– Short acting: Glyceryl trinitrate (GTN, Nitroglycerine)
– Long acting: Isosorbide dinitrate (short acting by
sublingual route), Isosorbide, mononitrate, Erythrityl
tetranitrate, Pentaerythritol tetranitrate
• β Blockers: Propranolol, Metoprolol, Atenolol and others.
• Calcium channel blockers
– Phenyl alkylamine: Verapamil
– Benzothiazepine: Diltiazem
– Dihydropyridines: Nifedipine, Felodipine, Amlodipine,
Nitrendipine, Nimodipine, Lacidipine, Lercanidipine,
Benidipine
• Potassium channel opener: Nicorandil
• Others: Dipyridamole, Trimetazidine, Ranolazine,
Ivabradine, Oxyphedrine

• Clinical classification
• Used to abort or terminate attack: GTN, Isosorbide
dinitrate (sublingually).
• Used for chronic prophylaxis: All other drugs.
 Nitrates/ Organic Nitrates
• Preload reduction: Peripheral pooling of blood → decreased
venous return (preload reduction).

• Afterload reduction: Nitrates also produce some arteriolar

dilatation → slightly decrease total peripheral resistance or
afterload on heart.

• Redistribution of coronary flow: In the arterial tree, nitrates

preferentially relax bigger conducting (angiographically visible)
coronary arteries than arterioles or resistance vessels.
 Mechanism of action:
• The organic nitrate agents are prodrugs that are sources
of NO. NO activates the soluble isoform of guanylyl
cyclase, thereby increasing intracellular levels of cGMP.
In turn, cGMP promotes the dephosphorylation of the
myosin light chain and the reduction of cytosolic Ca2+ and
leads to the relaxation of smooth muscle cells in a broad
range of tissues.
References: Eschenhagen T. Treatment of Ischemic Heart Disease. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds.
Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
Mechanism of action:
Mechanism of vascular smooth
muscle relaxant action of
nitrodilators like glyceryl trinitrate
and calcium channel blockers

• (- - -→) Inhibition
• CAM—Calmodulin;
• NO—Nitric oxide
• MLCK—Myosin
• light chain kinase
• MLCK-P—Phosphorylated MLCK
• GTP—Guanosine triphosphate;
• cGMP—Cyclic guanosine
monophosphate

References: Tripathi, K. (2013). Essentials of medical pharmacology (7th ed.). New Delhi: Jaypee Brothers.
Adverse effects:

• Headache is the most common adverse effect of nitrates.

High doses of nitrates can also cause postural
hypotension, facial flushing, and tachycardia.

• Phosphodiesterase type 5 inhibitors such as sildenafil

potentiate the action of the nitrates.
.

Dependence:
• Sudden withdrawal after prolonged exposure has resulted
in spasm of coronary and peripheral blood vessels.
Withdrawal of nitrates should be gradual.
Uses:
• Angina pectoris
• Acute coronary syndromes.
• Myocardialinfarction(MI):
Uses:
• CHF and acute LVF: Nitrates afford relief by venous
pooling of blood → reduced venous return (preload) →
decreased end diastolic volume → improvement in left
ventricular function.
• Biliary colic
• Esophageal spasm
• Cyanide poisoning: Nitrates generate methaemoglobin
• which has high affinity for cyanide radical and forms
cyanomethaemoglobin.
 β Blockers
• The β-adrenergic blockers decrease the oxygen demands
of the myocardium by blocking β1 receptors, resulting in
decreased heart rate, contractility, cardiac output, and
blood pressure.
• All β blockers are nearly equally effective in decreasing
frequency and severity of attacks and in increasing
exercise tolerance in classical angina, but cardioselective
agents (atenolol, metoprolol) are preferred over
nonselective β1 + β2 blockers (e.g. propranolol).
• Agents with intrinsic sympathomimetic activity (ISA) such
as pindolol should be avoided in patients with angina and
those who have had a MI.
Calcium channel blockers
– Phenyl alkylamine: Verapamil

– Benzothiazepine: Diltiazem

– Dihydropyridines: Nifedipine, Felodipine, Amlodipine,

Nitrendipine, Nimodipine, Lacidipine, Lercanidipine,
Benidipine
Pharmacological actions:

• Smooth muscle: The CCBs cause relaxation by decreasing

intracellular availability of Ca2+. The dihydropyridines
(DHPs) have the most marked smooth muscle relaxant
and vasodilator action; verapamil is somewhat weaker
followed by diltiazem.
Pharmacological actions:

• Heart: Calcium influx is increased in ischemia because of

the membrane depolarization that hypoxia produces. 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 and
decreases smooth muscle tone and vascular resistance,
afterload.
Phenyl alkylamine: Verapamil:
• It dilates arterioles and decreases total peripheral
resistance.
• It slows atrioventricular (AV) conduction directly and
decreases heart rate, contractility, blood pressure, and
oxygen demand.
• It also has some α adrenergic blocking activity.
• Verapamil has greater negative inotropic effects than
amlodipine, but it is a weaker vasodilator.
• Verapamil should not be given with β blockers, digoxin,
cardiac depressants like quinidine and disopyramide.
Benzothiazepine: Diltiazem:
• Diltiazem also slows AV conduction, decreases the rate of
firing of the sinus node pacemaker, and is also a coronary
artery vasodilator.
• Diltiazem can relieve coronary artery spasm and is
particularly useful in patients with variant angina.
• It is somewhat less potent vasodilator than nifedipine and
verapamil, and has modest direct negative inotropic
action, but direct depression of SA node and A-V
conduction are equivalent to verapamil.
Dihydropyridine (DHP) calcium channel blockers: Nifedipine:
• Nifedipine is the prototype DHP with a rapid onset and short
duration of action. It causes arteriolar dilatation and decreases
total peripheral resistance.
• Nifedipine is usually administered as an extended-release oral
formulation.
• It causes direct depressant action on heart in higher dose.

• ADR: Frequent side effects are palpitation, flushing, ankle

edema, hypotension, headache, drowsiness and nausea.
Nifedipine has paradoxically increased the frequency of angina
in some patients.
Other dihydropyridine (DPH) calcium channel blockers:
• Amlodipine, an oral dihydropyridine, functions mainly as
an arteriolar vasodilator.
• Nitrendipine, is a calcium channel blocker with aditional
action of vasodilatation action. Vasodilation action is due
to release NO from the endothelium and inhibit cAMP
phosphodiesterase.
• Lacidipine, is a highly vasoselective newer DHP.
• Nimodipine, is short-acting DHP which penetrates blood-
brain barrier very efficiently due to high lipid solubility.
• DPH with long duration of action: Lercanidipine,
Benidipine.
Uses:
• Calcium channel blockers can be safely given to patients
with obstructive lung disease and peripheral vascular
disease in whom β blockers are contraindicated.
• CCB are used for the treatment of
– angina pectoris
– hypertension
– cardiac arrhythmias
– hypertrophic cardiomyopathy
 Potassium Channel Openers
Nicorandil:
• Antianginal action of nicorandil is mediated through ATP
sensitive K+ channels (KATP) thereby hyperpolarizing
vascular smooth muscle.
• Nicorandil is well absorbed orally, nearly completely
metabolized in liver and is excreted in urine. Administered
i.v. during angioplasty for acute MI, it is believed to
improve outcome.
• ADR: Flushing, palpitation, weakness, headache,
dizziness, nausea and vomiting.
 Other antianginal drugs

Dipyridamole • Dipyridamole inhibits platelet aggregation

• It is a powerful coronary dilator
Trimetazidine • This antianginal drug acts by nonhaemodynamic
mechanisms.
• The mechanism of action of trimetazidine is uncertain, but
it may improve cellular tolerance to ischaemia by
inhibiting mitochondrial long chain 3-ketoacyl-
CoAthiolase.
Ranolazine • This novel antianginal drug primarily acts by inhibiting a
late Na+ current (late INa) in the myocardium.
Ivabradine • This ‘pure’ heart rate lowering antianginal drug has
been introduced recently as an alternative to β blockers.
• It blocks cardiac pacemaker (sino-atrial) cell ‘f’ channels.
Oxyphedrine • Improve myocardial metabolism.