ANTI-ANGINAL DRUGS

Angina pectoris is a pain syndrome due to induction of an adverse oxygen supply/demand

situation in a portion of the myocardium. It is mainly of two types-
a. Classical angina- It is the most common form of angina in which attacks are provoked
by exercise, emotion, eating etc. The main cause is atherosclerosis or arteriosclerosis of
large coronary arteries. The coronary obstruction is fixed and blood flow fails to increase
during increased demand and ischemic pain is felt.
b. Variant/Prinzmetal’s angina- In this case attacks occur at rest or during sleep and are
unpredictable. They are due to coronary vasospasm. Sometimes there is rapid increase in
duration and severity of attacks occurs due to rupture of an atheromatous plaque. As a
result platelet deposition initiated and progressive occlusion of the coronary artery
occurs.
Anti-anginal are the drugs which are used to treat angina pectoris.
CLASSIFICATION-
1. Nitrates-
a. Short acting, Rapid Onset: Glyceryl trinitrate (GTN) (Nitroglycerine), Amyl
nitirite.
b. Long acting, Slow Onset: Isosorbide dinitrate, Isosorbide mononitrate, Erythrityl
tetranitrate, Pentaerythritol tetranitrate.
2. β- blockers- Propanolol, Metoprolol, Atenolol, Nadolol, Bisoprolol and Celiprolol
3. Calcium channel blockers-
a. Phenylalkylamines – Verapamil
b. Benzothiazepine- Diltiazem
c. Dihydropyridines- Nifedipine, Felodipine, Amlodipine, Lacidipine, Benidipine.
4. Others-
a. Cytoprotective drugs: Trimetazidine, Ranolazine
b. Potassium channel openers- Nicorandil
c. Anti-platelet drugs: Aspirin, Ticlopidine, Clopidogrel, Dipyradamole, Cilostazol
d. Bradycardiac Drugs: Ivabradine
e. HMG-CoA Reductase Inhibitors: Statins
f. Drugs for Peripheral Vascular Disease: Naftidofuryl, Pentoxiphylline

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NITRATES
Organic nitrates which are polyol esters of nitric acid are potent vasodilators and have been used
in the treatment of angina-pectoris. The major action of all organic nitrates is direct smooth
muscle relaxation. Nitrates donot alter the response of the smooth muscle cells to various
parasympathomimetic and sympathomimetics agents.
Haemodynamic Action: Nitrate causes a relaxation of the systemic venous as well as arteriolar
bed. Venodilation causes peripheral pooling and a reduction in venous return and in cardiac
output. The relaxation is maximum in the large arteries. The blood pressure falls, the systolic
more than the diastolic and the reflex tachycardia occurs due to compensatory sympathetic over
activity. These actions on the venous (capacitance) and arteriolar (impedence) vascular beds
reduce respectively the preload and after load on the heart. Thus left ventricular work load and
energy expenditure thus decrease as a result of nitrate therapy.
Preload reduction- Nitrates dilate veins more than arteries which results in peripheral pooling
of blood and decreased venous return i.e. preload on heart is reduced. Moreover end diastolic
size and pressure is also reduced. Now, according to laplace relationship,

Wall tension = Intraventricular × Ventricular

Pressure radius
Thus, reduction in ventricular radium decreases the tension in the ventricular wall and hence
oxygen consumption is also reduced. Reduction in cardiac output occurs at rest but is less
marked during angina due to better ventricular emptying. The decrease in endiastolic blood
pressure abolishes the subendocardial crunch by restoring the pressure gradient across
ventricular wall due to which subendocardial perfusion occur during diastole.
Afterload reduction- Nitrates also produce some arteriolar dilatation which results in decrease
total peripheral resistance or afterload on heart. This action contributes to reduction in cardiac
work and thus oxygen demand is also reduced. But with large doses reflex sympathetic
stimulation occur which cause tachycardia and increased cardiac contractility. As a result cardiac
work increases and angina may be precipitated. Fainting and cold sweat occur due to cerebral
ischaemia.
GTN is predominantly a venodilator agent causing reduction of ventricular preload resulting in
decrease preload on the heart. Unlike sublingual nitrates inhalation of amyl nitrate which act

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very rapidly, has preferential systemic arteriolar dilator action which thereby primarily lowers
the impedence or afterload to ventricular ejection. Rapid arteriolar dilation causes distinct fall in
blood pressure and marked rise in compensatory sympathetic over-activity. Consequent
tachycardia will increase the need of oxygen by myocardium.
Coronary Circulation: A decrease in the coronary resistance and an increase in the total
coronary flow have been noticed. Moreover the total coronary blood flow falls concomitantly
with the reduction in blood pressure. Thus nitrates causes dilatation of large coronary arteries,
dilatation of collateral vessels and redistribution of the coronary blood flow with improved
perfusion of ischemic subendocardial areas in the myocardium. On chronic administration
nitrates promotes the development of inter-arterial anastomoses within the myocardium and
increases the survival rate.
Mechanism of action

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Organic nitrates are rapidly denitrated enzymatically in the smooth muscle cell to release the
reactive free radical nitric oxide (NO) which activates cytosolic gunaylyl cyclase. The gunaylyl
cyclase in turn converts GTP into cGMP and causes dephosphorylation of myosin light chain
kinase (MLCK). Reduced availability of phosphorylated MLCK interferes with activation of
myosin and thus fails to interact with actin to cause contraction. Moreover raised intracellular
cGMP may also cause Ca++ entry and thus contributing to relaxation.
Adverse effects-
a. Fullness, headache, weakness, sweating, palpitation, dizziness and fainting.
b. Methemoglobinemia.
c. Tolerance & dependence: Tolerance may result from a reduced capacity of the vascular
smooth muscle to convert nitroglycerin to NO. Multiple mechanisms have been proposed to
account for nitrate tolerance, including
 Volume expansion
 Neurohumoral activation
 Cellular depletion of sulfhydryl groups and the generation of free radicals
 Inactivation of mitochondrial aldehyde dehydrogenase, an enzyme implicated in
biotransformation of nitroglycerin
Uses-
a) Angina pectoris- Nitrates are effective in classical as well as variant angina. For terminating
an attacks sublingual GTN tablet or spray is taken on required basis.
b) Acute coronary syndromes-The syndrome is characterized by rapid worsening of angina
status of patient or myocardial infarction. The nitrates prevent further coronary occlusion,
increase coronary blood flow and decrease myocardial stress.
c) Myocardial infarction- The drug relieves the chest pain and limits the area of necrosis by
favourably altering oxygen balance.
d) Congestive heart failure (CHF)& Left ventricular failure- Nitrates afford relief by
venous pooling of blood and thus reduce venous return or preload. As a result end diastolic
volume is decreased & left ventricular function is improved.
e) Biliary colic and Esophageal spasm.
f) Cyanide poisoning-

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Haemoglobin
Sodium nitrite

Methaemoglobin
Cyanide

Cyanomethaemoglobin
Sodium thiosulfate

Sod.thiocynate + Methaemoglobin

Excreted in urine.
ΒETA BLOCKERS
Beta blockers abolish the exercise and emotional excitement induce angina by normalizing heart
rate, blood pressure, myocardial contractility and oxidative metabolism.
 These agents by blocking β2- receptors reduced the total coronary flow. However, flow to the
ischaemic area is not reduced because of decrease in ventricular wall tension.
 Thus, they act by reducing cardiac work and oxygen consumption i.e. heart rate, inotropic
state and mean BP is decreased.
 Like the nitrates beta blockers increase the exercise tolerance. They also prevent arrhythmias
precipitated by exercise and emotion and by other conditions associated with excessive
sympathetic discharge.
 They reduce the frequency of attacks and decrease the GTN dependence. The net effect is a
beneficial reduction in cardiac work load and myocardial oxygen consumption.
 In angina pectoris, β- blockers are to be taken on a regular basis and sudden discontinuation
after chronic use may precipitate severe attacks or even MI.
 β- blocker reduce myocardial oxygen demand and afford additional benefit by reducing risk
of sudden cardiac death.
 Βeta blockers decrease the frequency and severity of attacks in classical angina.

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 Cardio selective agents like atenolol is preferred over non- selective β1 & β2blockers like
propranolol.
 Adverse effects include precipitation of CHF and development of severe syncope.

CALCIUM CHANNEL BLOCKERS-

The calcium channel blockers (CCBs) block voltage dependent L-type calcium channels and thus
reduce frequency of the opening of these channels in response to depolarization. Thus inhibit
calcium mediated channel component of action potential in smooth/cardiac muscle cells and
heart which result in marked decrease in the transmemebrane calcium current in vascular smooty
muscle, cardiac muscle, SA node and AV node.
VOLTAGE SENSITIVE CALCIUM CHANNELS
Properties L (Long Lasting) T (Transient) N (Neuronal) P/Q & R
Activation High Low High High
Threshold
Inactivation Slow Fast Medium Slow
State
Location Cardiac & smooth SA node, Thalamic Neurons in CNS & Cerebellar and
muscle, SA & AV node and other neurons Secretory glands Purkinje neurons
Function Regulate excitation Regulate pacemaker Modulates Modulates
contraction coupling, activity, Regulate T transmitter release transmitter
Regulate pacemaker current & repetitive release
activity, Regulate spikes in thalamic
conduction velocity nuclei
Blockers CCB Ethosuximide, Gabapentin Toxin of funnel
Flunarizine web spider

Cardiovascular actions:
Negative ionotropic effects: These drugs depress the contractility of myocardium and decrease
the cardiac work and myocardial oxygen consumption. Verapamil is more potent negative
ionotropic agent than nefidipine and hence should not be combined with beta blockers in the

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treatment of angina of effort. However nefidipine and other CCB has been used together with
beta blockers.
Anti-arrhythmic effects: CCB decrease the rate of discharge of the SA node, suppress ecotopic
pacemaker activity, increase the refractoriness of the AV node and slow the conduction of a
propagated impulse in the myocardium. The slowing of conduction prevents re-entrant
excitation. This effect plus the improvement of cardiac ischaemia account for the potent anti-
arrhythmic activity. Verapamil can aggravate AV block so it must be used cautiously in patient
with depressed AV conduction. So nifedipine is indicated in such patients.
Effect on Coronary Arteries: These drugs are more potent than nitroglycerine as coronary
artery dilator. CCB dilates both large epicardial branches and small intramyocardial coronary
arteries. CCB dilates both even in the presence of coronary artery spasm. Further they can
prevent the spasm even in diseased atherosclerotic coronary arteries. Nefidipine ia amore potent
coronary vasodilator than verapamil.
Effect on Peripheral Blood Vessels: CCB relax the vascular smooth muscle in systemic as well
as pulmonary arterial circulation. They thus decrease the vascular resistance and the blood
pressure in both these territories. They have been used with beneficial effect in the treatment of
hypertension. Further reduction in the afterload contributes to their efficacy in angina of effort.
Nefidipine is a more potent vasodilator than verapamil. The reduction in blood pressure is
accompanied by reflex tachycardia in case of nefidipine but not in the case of verapamil which
suppress the SA node. They have little effect on the venous bed and do not alter the cardiac
preload.
Smooth muscles- Smooth muscles depolarize primarily by inward calcium movement through
voltage sensitive channel. These calcium ions trigger excitation-contraction mechanism through
phosphorylation of myosin light chain. CCBs cause relaxation by decreasing intracellular
availability of calcium.
Heart- The CCBs have negative inotropic action. The zero phase depolarization in SA and AV
node is largely calcium mediated. Automaticity and conductivity of the cells appear to be
dependent on the rate of recovery of the calcium channel.
 The L-type calcium channel present in heart muscles activates as well as inactivate at slower
rate. Thus, calcium depolarized cells have less steep O phase and longer refractory period.

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 The recovery process which restores the channel to the state from which it can again be
activated by membrane depolarization is delayed by verapamil and diltiazan.
 On other hand, dihydropyridines like nifedipine have no such effect. These are more
selective for smooth muscles.
Verapamil
It causes:
 Suppression of SA and AV node
 AV block
 Coronary and peripheral vasodilation
 Potent anti-arrhythmic effect
 Potent negative inotropic effect
The drug cause dilation of arteriols and blocks α- adrenergic receptors. The heart rate decreases
and A-V conduction is slowed. Verapamil should not be given with β- blockers as the
combination may cause sinus depression and asystole may occur. It also increases plasma
digoxin level by decreasing its excretion and thus toxicity may develop.
Adverse effects- Nausea, constipation, bradycardia, flushing, headache and ankle edema.
Cardiac arrest may occur on i/v administration.
Diltiazem It is less potent vasodilator than nifedipine and verapamil. The drug produces negative
inotropic action and direct depression of SA node and A-V conduction.
Adverse effects- Similar to verapamil.
Nifedipine The drug causes reduction in blood pressure through arteriolar dilation and decrease
total peripheral resistance. It has weak negative inotropic action but do not depress SA node and
AV node conduction. As a result reflex sympathetic stimulation occurs due to which tachycardia,
increased contractility and cardiac output occurs. Coronary flow is increased.
Nitrendipine The drug additionally release NO from the endothelium and inhibit cAMP
phosphodiestrase. Thus it is more potent vasodilator.
USES
a) Angina pectoris- All CCBs are effective in reducing frequency and severity of classical as
well as variant angina. The capacity of CCBs to prevent arterial spasm is responsible for the
beneficial effect in variant angina.

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b) Hypertension- Nefidipine, Verapamil and other drugs are considered as first line drugs for
hypertension.
c) Cardiac arrythmais- Verapamil and diltiazem are highly effective in PSVT.
d) Hypertropic cardiomyopathy- CCBs cause –ve inotropic action.

Verapamil Diltiazem Nifedipine Amlodipine

Chemical class Diphenylalkulamine Benzithiazepine Dihydropyridine Dihydropyridine
Vasodilation ++ + +++ +++
Anti-arrhythmic + + - -
effect
Negative ++ + ± ±
inotropic effect
Heart rate ↓ ↓/N ↑ N
Blocks AV +++ ++ - -
conduction
Adverse effects AV block, AV block, Palpitation, nausea Palpitation, nausea
constipation, nausea hypotension hypotension, edema hypotension, edema

POTASSIUM CHANNEL OPENERS

Potassium ions control the resting membrane potential. Since intracellular concentration of
potassium ions is much higher compared to extracellular, the potassium channel openers cause
an efflux of potassium and hyperpolarisation occurs. Such an effect indirectly opposes the
opening of voltage gated calcium channels which require depolarization above a certain
threshold membrane potential for activation. This result in a fall of cytosolic calcium
concentration with a reduction of cellular contractile activity at the myocardial and vascular
level.
Certain drugs which are currently recommended as potassium channel opener includes
nicorandil, pinacidil and cromakalim. The drug acts by opening the potassium channels which
results in outflow of K+ ions and thus causing hyperpolarisation.
Nicordinal- It is a potent anti-anginal drug which activates ATP sensitive K+ channels thus
hyperpolarizing vascular smooth muscles. It reduces pre and afterload and produces coronary

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delataion. The drug also opens myocardial mitochondrial K+sensitive-ATP channels and protects
myocardium by ischaemia and reduces myocardial stunning, arrhythmias and infarct size. Like
nitrates, this drugs cause release of NO and thus relaxes blood vessels by increasing cGMP
concentration. The drug produces arteriolar and venodilation as well which improves the
coronary flow. Therefore the drug combines an activation of potassium channel with nitric acid
donor action. Nicorandil increases coronary blood flow without causing coronary steal
phenomenon and without producing significant cardiac effects on contractility, conduction, heart
rate and blood pressure.
Adverse effects- Palpitation, weakness, headache, dizziness, nausea and vomiting.
Clinical Applications
 Angina Pectoris
 Hypertension
 CHF
 Bronchial Asthma
 Erectile dysfunction
 Peripheral vascular disease
 AMI
CYTOPROTECTIVE DRUGS
Trimetazidine
It is a new calcium channel blocker belonging to piperazine group. It is type of cellular anti-
ischaemic drug that has cytoprotective effects on myocardial energy metabolism. The drug
prevents the degradation of membrane unsaturated fatty acids by lipid peroxidation and thus
reduces myocardial oxygen demand. It also inhibits the superoxide cyto-toxicity to protect the
myocardium from the harmful effects of ischaemia. In the presence of ischaemia it maintains LV
functions without affecting heamodynamics. The drug reduced the frequency of angina attacks
and increase exercise capacity by
a. Inhibiting mitochondrial long chain 3-Ketoacyl-CoA-thiolase (LC3-KAT), an enzyme
involved in fatty acid metabolism or oxidation. Thus in myocardium fatty acid metabolism is
reduced while glucose metabolism is increased. Thus oxygen demand is reduced in
ischaemic myocardium.

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b. Limiting intracellular acidosis and Na+, Ca++ accumulation during ischaemia.

c. Protection against free radical induced membrane damage.
Adverse effects- Tinnitus, Visual disturbances, dizziness.
Clinical Application In angina pectoris and post-MI patients
Ranolazine
The drug mainly acts by inhibiting the inward sodium current during ischemia. As a result the
calcium load in cardiac muscle is reduced indirectly via Na-Ca exchanger. The drug prolongs the
exercise tolerance to angina without affecting heart rate and blood pressure. The main side effect
includes prolongation of QT interval. Actually the drug does not relieves angina but reduces the
incidence of serious ventricular arrhythmia in patients with post acute coronary syndrome.
DIRECT BRADYCARDIAC AGENTS
Ivabradine: The drug blocks hyperpolarization activated current through sodium channels
present in the SA node. These channels get activated during ischaemic episodes. Inhibition of the
current by the drug decreases the myocardial oxygen demand by decreasing the heart rate.there is
no negative inotropic effect or reduction in blood pressure or any rebound on cessation of
therapy. The most prominent side effect includes disturbances in nocturnal vision with flashing
lights which may impair driving at night.
DIPYRIDAMOLE-
The drug inhibits adenosine deaminase and also phosphodiesterase which leads to an
accumulation of adenosine and cAMP respectively. These mediators then inhibit platelet
aggregation and may also stimulate release of PGI2. It is a powerful coronary dilator which
increases total coronary flow by preventing uptake and degradation of adenosine. Adenosine is a
mediator which regulates coronary flow in response to ischaemia. This drug is primarily used in
prophylaxis of coronary and cerebral thrombosis in post-MI and post-stroke as well as to prevent
thrombosis with prosthetic heart valves.
 It dilates resistance vessels.
 Moreover dipyridamole inhibits platelet aggregation by potentiating PGI2 and increasing
cAMP in platelets.
 The drug is mainly used in cerebral thrombosis and post-MI and post stroke patients.
The side effects includes headache, tachycardia and GIT distress.

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DRUGS FOR PERIPHERAL VASCULAR DISEASE

Pentoxiphylline (Oxypentifylline): It is a theobromine analogue and inhibits phosphodiesterase
enzyme. It is a blood viscosity reducing agent and improves blood flow in ischaemic area
through microcirculation. It does not exhibit coronary steal phenomenon. The drugs apart from
anti-angina effect also used to reduce peripheral claudication, non-haemorrhagic stroke, chronic
cerebrovascular insufficiency, obstructive circulatory disturbances of retina, to improve sperm
motility and diabetic neurophathy.
Naftidofuryl is a 5-HT2A receptor antagonist and is used in angina and improves exercise
tolerance.

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