Antianginal Drugs

ANGINA
• Angina pectoris refers to a strangling or
pressure-like pain caused by cardiac ischemia.
The pain is usually located substernally but is
sometimes radiates to the neck, shoulder and
arm, or epigastrium.
 Antianginal Drugs
• Antianginal drugs are those that prevent, abort or
terminate attacks of angina pectoris.
• Types of angina
1) Stable 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when the increased energy demand is withdrawn.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.
2) Vasospastic angina (rest angina, variant angina, or
Prinzmetal’s angina [uncommon form]): occurs due
to spasm of coroanry artery . Attacks occur at rest or
during sleep and are unpredictable. Vasospastic
angina is responsible for less than 10% of angina
cases.

3) 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
1) Nitrates
– Short acting: Glyceryl trinitrate (GTN, Nitroglycerine)
– Long acting: Isosorbide dinitrate (short acting by
sublingual route), Isosorbide mononitrate, Erythrityl
tetranitrate, Pentaerythritol tetranitrate
2) β Blockers: Propranolol, Metoprolol, Atenolol and others.
3) Calcium channel blockers
– Phenyl alkylamine: Verapamil
– Benzothiazepine: Diltiazem
– Dihydropyridines: Nifedipine, Felodipine, Amlodipine,
Nitrendipine, Nimodipine, Lacidipine, Lercanidipine,
Benidipine
 Classification of antianginal drugs
4) Potassium channel opener: Nicorandil
5) 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
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—Myosinlight chain kinase
• MLCK-P—Phosphorylated MLCK
• GTP—Guanosine triphosphate;
• cGMP—Cyclic guanosine
monophosphate
 Nitrates/ Organic Nitrates
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.
 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.
 Nitrates/ Organic Nitrates
Pharmacokinetics:
• Organic nitrates are lipid soluble, well absorbed from
buccal mucosa, intestines and skin. They are given
sublingually during acute attack.
• Isosorbide Mononitrate has highest oral bioavailability
 Nitrates/ Organic Nitrates
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. To preclude the
dangerous hypotension that may occur, this combination
is contraindicated.
 Nitrates/ Organic Nitrates
Tolerance:
• Tolerance to the actions of nitrates develops rapidly as the
blood vessels become desensitized to vasodilation.
Tolerance can be overcome by providing a daily “nitrate-
free interval” to restore sensitivity to the drug.

Dependence:
• Sudden withdrawal after prolonged exposure has resulted in
spasm of coronary and peripheral blood vessels.
Withdrawal of nitrates should be gradual.
 Nitrates/ Organic Nitrates
Uses:
• Angina pectoris: GTN produces relief within 3 min in 75%
patients, the rest may require another dose or take longer
(upto 9 min).
• Acute coronary syndromes: Nitrates are useful by
decreasing preload as well as by increasing coronary flow.
• Myocardial infarction (MI): GTN is frequently used during
evolving MI with the aim of relieving chest pain,
pulmonary congestion and limiting the area of necrosis by
favourably altering O2 balance in the marginal partially
ischaemic zone.
 Nitrates/ Organic Nitrates
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).
• The nonselective are particularly prone to worsen variant
angina due to unopposed α receptor mediated coronary
constriction that may accentuate the coronary spasm.
 Calcium channel blockers

– Phenyl alkylamine: Verapamil

– Benzothiazepine: Diltiazem

– Dihydropyridines: Nifedipine, Felodipine, Amlodipine,

Nitrendipine, Nimodipine, Lacidipine, Lercanidipine,
Benidipine
 Calcium channel blockers
Pharmacological actions:
• Smooth muscle: The CCBs cause relaxation by decreasing
intracellular availability of Ca2+. They markedly relax
arterioles but have mild effect on veins.The
dihydropyridines (DHPs) have the most marked smooth
muscle relaxant and vasodilator action; verapamil is
somewhat weaker followed by diltiazem.
 Calcium channel blockers
Pharmacological actions:
• Heart: The CCBs have negative inotropic, chronotropic,
dromotropic action hence decreases the O2 demand of
the myocardium.
• Verapamil has greater negative inotropic effects than
amlodipine, but it is a weaker vasodilator.
 Calcium channel blockers
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.
 Calcium channel blockers
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.
 Calcium channel blockers
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.
• 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.
 Calcium channel blockers
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
• Adverse effects – Due to vasodilation
Postural hypotension, reflex tachycardia
Bradycardia, palpitation, Ankle edema
- GI effects : Nausea, vomitting , constipation
 Potassium Channel Openers
Nicorandil:
• Antianginal action of nicorandil is mediated through ATP
sensitive K+ channels (KATP) thereby hyperpolarizing vascular
smooth muscle.
• So cell cant depolarise and volatge sensitive Ca channel cant
open and ca cant enter for contraction .
• It also releases NO like nitrates and causes vasodilation.
• 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.
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