ANTI-ANGINAL DRUGS

Prepared By- Mr. Soumyakanti Chatterjee

M. Pharm (Pharmacology)
 ANTIANGINAL DRUGS
Antianginal drugs are those that prevent , abort or terminate attacks of angina pectoris

Angina pectoris -Is a pain syndrome due to induction of an adverse oxygen supply/ demand
situation in a portion of the myocardium. Two Principal form are recognized:

classical angina (common form) 1. Attacks are predictably provoked (stable angina) by exercise,
emotion, eating or coitus and subside when the increased energy demand is withdrawn.
2. The underlying pathology is severe arteriosclerotic affliction of large coronary arteries which
run epicardially and send perforating branches to supply the deeper tissues.
 3. The coronary obstruction is 'fixed'; blood flow' fails to increase during increased demand
despite local factors mediated dilatation of resistance vessels and ischaemic pain is felt
4. Due to inadequacy of ischaemic left ventricle, the end diastolic left ventricular pressure
rises from 5 to about 25 mm Hg-produces subendocardial ‘crunch' during diastole (blood
flow to the subendocardial region occurs only during diastole ) and aggravate ischaemia in
this region
5. Thus, a form of acutely developing and rapidly reversible left ventricular failure results
which is relieved by taking rest and reducing the myocardial workload.

Variant/Prinzmetal's angina (uncommon form) Attacks occur at rest or during sleep and
are unpredictable. They are due to recurrent localized (occasionally diffuse) coronary vasospasm
which may be superimposed on arteriosclerotic coronary artery disease.

Unstable angina with rapid increase in duration and severity of attacks is mostly due to rupture
of an atheromatous plaque attracting platelet deposition and progressive occlusion of the
coronary artery; occasionally with associated coronary vasospasm.

Chronically reduced blood supply causes atrophy of cardiac muscle with fibrous replacement
(reduced myocardial work capacity + CHF) and may damage conducting tissue to produce
unstable cardiac rhythms.
Diagrammatic representation (coronary artery calibre changes in classical and variant angina)
 CLASSIFICATION
1. Nitrates
(a) Short acting: Glyceryl trinitrate (GTN, Nitroglycerine)
(b) Long acting: Isosorbide dinitrate (short acting by sublingual route), isosorbide
mononitrate
2. β blockers- propanolol, metoprolol, atenolol
3. Calcium channel blockers-
a) Phenyl alkylamine- verapamil
b) Benzothiazepine- diltiazem
c) Dihydropyridines- nifedipine, felodipine, amlodipine, nimodipine, lacidipine
4. Potassium channel opener- nicorandil
5. others- dipyridamole, trimetazidine, oxyphedrine
Clinical classification
Used to abort or terminate attack GTN, Isosorbide dinitrate (sublingually).
Used for chronic prophylaxis : All other drugs

NITRATES (GTN as prototype)

nonspecific smooth muscle relaxation.
Preload reduction The most prominent action is exerted on vascular smooth muscle. Nitrates
dilate veins more than arteries peripheral pooling of blood decreased venous
return i.e. Preload on heart is reduced end diastolic size and pressure are reduced
decreased cardiac work according to Laplace relationship-which describes the
effectiveness of ventricular wall tension in elevating intraventricular pressure and the extent
to which fibre shortening results in systolic ejection
reduction in ventricular radius decreases the tension that must be generated in the ventricular
Wall

hence decreased O2 consumption. Reduction in cardiac output (c.o.) occurs at rest but is less
marked during angina due to better ventricular emptying.

Afterload reduction

Nitrates also produce some arteriolar dilatation slightly decrease total peripheral
resistance ( t.p.r.) or afterload on heart.
BP falls somewhat; systolic more than diastolic
(reflex sympathetic activity tends to maintain diastolic BP). This action contributes to the
reduction in cardiac work which is directly proportional to aortic impedance
Redistribution of coronary flow
In the arterial tree, nitrates preferentially relax bigger conducting (angiographically visible)
coronary arteries than arterioles or resistance vessels. This pattern of action may cause
favourable redistribution of blood flow to ischaemic areas in angina patients.

Mechanism of relief of angina

1. The dilator effect on larger coronary vessels is the principal action of nitrates benefiting
variant angina by counteracting coronary spasm.
2. In classical angina undoubtedly the primary effect is to reduce cardiac work by action on
peripheral vasculature,
3. Though increased blood supply to ischaemic area may contribute.

Heart and peripheral blood flow

Nitrates have no direct stimulant or depressant action on the heart. They dilate cutaneous
(especially over face and neck flushing) and meningeal vessels followed
headache.
Splanchnic and renal blood flow decreases to compensate for vasodilatation in other areas.
Nitrates tend to decongest lungs by shifting blood to systemic circulation

Other smooth muscles

Bronchi, biliary tract and esophagus are relaxed; effect on intestine, ureter, uterus is variable
and insignificant.
 Mechanism of action
Organic nitrates are rapidly denitrated enzymatically in the smooth muscle cell to release
the reactive free radical nitric oxide (NO) which activates cytosolic guanylyl cyclase

increased cGMP
Causes dephosphorylation of myosin light chain kinase (MLCKP) through a cCMP dependent
protein kinase

Reduced availability of phosphorylated (active) MLCK interferes with activation of myosin

fails to interact with actin to cause contraction. Consequently relaxation occurs. Raised
intracellular cGMP may also reduce Ca++ entry-contributing to relaxation.
Pharmacokinetics
[Link] nitrates are lipid soluble:
2. well absorbed from buccal mucosa, intestines and skin .
3. All except isosorbide mononitrate undergo extensive and variable first pass metabolism in
liver.
4. They are rapidly denitrated by a glutathione reductase and mitochondrial dehydrogenase
Adverse effects
Mostly due to vasodilation
1. Fullness in head, throbbing headache; degree of tolerance develops on continue
2. Flushing, weakness, sweating, dizziness and fainting
3. Methemoglobinemia:
4. Rashes are rare

Interactions -- Sildenafil causes dangerous potentiation of nitrate action: severe hypotension,

MI and deaths are on record . A additive hypotension is also possible when nitrate is given
to a patient receiving other vasodilators.
USES
1. Angina pectoris
2. CHF and acute LVF
3. Myocardial infarction
4. Interventional cardiac procedures
5. Biliary colic
6. Esophageal spasm
7. Cyanide poisoning
β BLOCKERS

1. These drugs do not dilate coronaries or other blood vessels

2. Total coronary flow is rather reduced due to blockade of dilator β2 receptors.
3. However, flow to the ischaemic subendocardial area is not reduced because of favourable
redistribution and decrease in ventricular wall tension.
4. They act by reducing cardiac work and O2 consumption (decreased heart rate, inotropic state
and mean BP). This is marginal at rest. More importantly, β blockers limit increase in these
modalities that occurs during exercise or anxiety (due to antiadrenergic action on heart).
5. All β blockers are nearly equally effective in decreasing frequency and severity of attacks and
increasing exercise tolerance in classical angina,
6. Long term β blocker therapy lowers risk of sudden cardiac death among ischaemic heart
disease patients.

Calcium Channel Blockers

Three important classes of calcium channel blockers are exemplified by:
Verapamil-a phenyl alkylamine
Nifedipine- a dihydropyridine
Diltiazem- a hydrophilic benzothiazepine
PHARMACOLOGICAL ACTIONS AND ADVERSE EFFECTS
The common property of all three subclasses of CCBs is to inhibit Ca2++ mediated slow
channel component of action potential (AP) in smooth/ cardiac muscle cell. The two most
important actions of CCBs are:
(i) Smooth muscle (especially vascular) relaxation.
(ii) Negative chronotropic, inotropic and dromotropic action on heart.

Smooth muscle
Smooth muscles depolarise primarily by inward Ca2+ movement through voltage sensitive
channel.

These Ca2+ ions trigger release of more Ca 2+ from intracellular stores and together bring
about excitation-contraction coupling through phosphorylation of myosin Light chain

CCBs cause relaxation by decreasing intracellular availability of Ca2+. They markedly relax
arterioles but have mild effect on veins.

Extravascular smooth muscle (bronchial, biliary, intestinal, vesical, uterine) is also relaxed.
The dihydropyridines (DHPs)have the most marked smooth muscle relaxant and
vasodilator action
Heart
In the working atrial and ventricular fibres, Ca2+ moves in during plateau phase of AP-
releases more Ca+ from sarcoplasmic reticulum

contraction through binding to troponin , allowing interaction of myosin with actin. The
CCBs would thus have negative inotropic action.

The 0 phase depolarization in SA and A-V nodes is largely Ca2+ mediated. Automaticity and
conductivity of these cells appear to be dependent on the rate of recovery of the Ca2+
channel.

The L-type Ca ion channels activate as well as inactivate at a slow rate. Consequently, Ca
ion depolarized cells (SA and A-V nodal) have a considerably less steep 0 phase and longer
refractory period.

channel to the state from which it can again be activated by membrane depolarization
is delayed by verapamil and to a lesser extent by diltiazem (resulting in depression of
pacemaker activity and conduction), but not by DHPs
Moreover, charmel blockade by verapamil is enhanced at higher rates of stimulation, that by
nifedipine is independent of frequency, while diltiazem is intermediate.

Thus, verapamil slows sinus rate and A-V conduction, but nifedipine does not effect of diltiazem
on sinus node automaticity and A-V conduction is similar to that of verapamil.

The DHPs are more selective for smooth muscle L channels: at concentrations which cause
vasodilatation they have negligible negative inotropic action

Verapamil
1. It dilates arterioles and has some α adrenergic blocking activity-decreases t.p.r. but
BP is only modestly lowered.
2.. The HR generally decreases A-V conduction is slowed, but c.o. is maintained by reflex
sympathetic stimulation and reduction in aortic impedance.
3. Ventricular contractility may be markedly impaired in CHF patients. Coronary flow is
increased
Adverse effects
1. Nausea, constipation and bradycardia are more common than other CCBs, while
flushing, headache and ankle edema are less common.
2. Hypotension is occasional and tachycardia (common with DHPs) is absent
Interactions-
1. Verapamil should not be given with β blockers-additive sinus depression conduction defects or
asystole may occur
2. It increases plasma digoxin level by decreasing its excretion: toxicity can develop.
3. It should not be used with other cardiac depressants like quinidine and disopyramide

Diltiazem
1. lt is a less potent vasodilator nifedipine and verapamil,
2. Modest negative inotropic action, but direct depression of SA node and A-V conduction are
equivalent to verapamil.
3. Usual clinical doses produces consistent fall in BP with little change or decrease in HR.
4. Large dose or i.v. injection decreases total peripheral resistance markedly which may elicit
reflex cardiac effects. It dialates coronaries.

Adverse effects
1. Incidence of side effects is low, but the profile is similar to verapamil.
2. Like verapamil, it also increases plasma digoxin.
3. Diltiazem should not be given to patients with preexisting sinus, A-V nodal or myocardial
disease. Only low doses should be given to patients on β blockers.
Nifedipine
1. It is the prototype DHP with a rapid onset and short duration of action.
2. The overriding action of nifedipine is arteriolar dilatation that causes total peripheral
resistance decreases BP falls.
3. The direct depressant effect on heart requires much higher dose, but a weak negative
inotropic action can be unmasked after β blockade.
4. As discussed above, it doesnot depress SA node or A-V conduction. Reflex sympathetic
stimulation of heart predominates that produces tachycardia, increased contractility and c.o.
(no decrease in venous retum along with lowering of afterload aid increase in c.o.).
5. Coronary flow is increased.
6. Nifedipine has mild natriuretic action, but significant diuresis does not occur

Adverse effects
1. Frequent side effects are palpitation, flushing, ankle edema, hypotension, headache,
drowsiness and nausea, can be minimized by low starting dose, fractionation of dose or use
of retard formulation.
2. Nifedipine has paradoxically increased the frequency of angina in some patients. Higher
mortality among post MI patients has been confirmed. However, it has been safely
administered with B blockers and digoxin.
3. By its relaxant effect on bladder nifedipine can increase urine voiding difficulty in elderly
males. It has also been reported to hamper diabetes control by decreasing insulin release
PHARMACOKINETICS of calcium channel blocker
1. All are 90-100% absorbed orally, peak occurring at 1-3 hr (except amlodipine 6-9 hr). The
oral bioavailability of Ca ion channel blockers is incomplete with marked inter- and intra-
individual variations.
2. This is due to high first pass metabolism (modest and less variabie for amlodipine).
3. All are highly plasma protein bound (min.: diltiazem 80%, max.: felodipine 99%)
4. The Ca ion c channel blockers are high clearance drugs with extensive tissue distribution.
5. > 90% metabolized in liver and excreted in urine.
6. Some metabolites are active. The eliminatiion are in the range of 2-6 hr, but that of
amlodipine is exceptionally long followed by lacidipine nitrendipine and felodipine.
7. On chronic use verapamil decreases it own metabolism-bioavailability is nearly doubled and
t1/2 is prolonged.

USES (calcium channel blockers)

Calcium channel blockers can be safely given to patients with obstructive lung disease and
peripheral vascular disease in whom β blockers are contraindicated. The problem of rebound
worsening of angina on withdrawal after chronic use is less with CCBs than with β blockers

1. Angina pectoris: All CCBs are effective in reducing frequency and severity of classical as
well as variant angina.
Benefit in classical angina appears to be primarily due to reduction in cardiac work: mainly
as a result of reduced afteload, Though, they can increase coronary flow in normal
individuals, this is unlikely to be significant in patients with fixed arterial obstruction.
Exercise tolerance is increasead
Myocardial infarction: The concensus opinion against use of CCBs in MI, but verapamil/
diltiazem may be employed for secondary prophylaxis when β blockers are contraindicated
CCBs are not a first line treatment of unstable angina;maybe used as add on therapy to nitrates
when coronary vasospasm is prominent and is not counteracted by nitrate alone. Use of
Nifedipine /DHPs in non β blocked patients is to be avoided.
2 Hypertension: DHPs, diltiazem and verapamil are among the first line drugs for hypertension
3. Cardiac arrhythmias : Verapamil and diltiazem are highly effective in PSVT and for control
of ventricular rate in supraventricular arrhythmias
4. Hypertrophic cardiomyopathy: The negative inotropic action of verapamil can be salutary
in this condition.
5. Other uses : Nifedipine is an altemative drug for premature labour. Verapamil has been used
to suppress migraine and nocturnal leg cramps.

RATIONAL DRUG COMBINATIONS

for chronic prophylaxis of angina, sublingual short-acting nitrate is allowed on as and when
required basis to abort and terminate anginal attacks when they occur
When monotherapy is unable to provide adequate relief in tolerated doses, concurrent use
of 2 or 3 drugs may be tried.
I. β blocker + long-acting nitrate combination is rational in classical angina because:
(a) Tachycardia due to nitrate is blocked by β blocker.
(b) The tendency of β blocker to cause ventricular dilatation is counteracted by nitrate.
(c) The tendency of β blocker to reduce total coronary flow is opposed by nitrate.
II. Combination of a slow acting DHP (in place of nitrate) with β blocker. However, verapamil
or diltiazem should not be used with β blocker since their depressant effects on SA and A-V
node may add up.
III. Nitrates primarily decrease preload, while CCBs have a greater effect on afterload. Their
concurrent use may decrease cardiac work to an extent not possible with either drug alone. This
combination may be especially valuable in severe vasospastic angina.
IV In the most severe and resistant cases of classical angina, combined use of all the three
classes is indicated. Since their primary mechanism of benefit is different, supraadditive
results may be obtained.
•Nitrates primarily decrease preload.
•CCBs mainly reduce afterload + increase coronary flow.
•β blockers decrease cardiac work primarily by direct action on heart.
Verapamil/diltiazem should be avoided in such combinations.

POTASSIUM CHANNEL OPENERS

1. Minoxidil and diazoxide are K+ channel openers which were used earlier in severe
hypertension and hypertensive emergencies
2. Novel K+ channel openers like nicorandil, pinacidil, cromakalim

Intracellular concentration of K+ is much higher (150 mM) compared to extracellular (4-5

mM)

K+ channel opening results in outflow of K+ ions and hyperpolarization

There are multiple types of K+ channels, e.g. voltage dependent, Ca2+ activated, receptor
operated, ATP sensitive, Na+ activated and cell volume sensitive which serve diverse functions
and exhibit different sensitivities to drugs.

The most prominent action of K+ channel openers is smooth muscle relaxation-vascular

as well as visceral
(Diazoxide and some other K+ channel openers reduce insulin secretion, while sulfonyl ureas
(glibenclamide) cause hypoglycaemia by blocking K+ channels in pancreatic β cells and
promoting insulin release.)
Nicorandil
This novel antianginal drug activates ATP sensitive K + channels

Hyperpolarizing vascular smooth muscle

Like nitrates it also acts as NO oxide donor-relaxes blood vessels by increasing cGMP. Thus,
arterial dilatation is coupled with venodilatation and Coronary flow is increased.

Side effects are flushing, palpitation, weakness, headache, dizziness, nausea and vomiting.

OTHER ANTIANGINAL DRUGS

Dipyridamole-
It is a powerful coronary dilator;
increases total coronary flow by preventing uptake and degradation of adenosine which is a
local mediator involved in auto regulation of coronary flow in response to ischaemia.
It dilates resistance vessels and abolishes autoregulation, but has no effect on larger
conducting coronary vessels. Cardiac work is not decreased because of venous return is not
reduced
It does not afford symptomatic benefit or avert ECG changes of angina.
The pharmacological success but therapeutic failure of dipyridamole has been explained on
the basis of coronary steal phenomenon
Coronary haemodynamics
A. In classical angina
B. Selective nitrate action on conducting vessels which along with ischemic dilatation of
resistance vessels increase flow to the subendocardial region and it relief to angina.
C. Dipyridamole action on all resistance vessels increases blood flow to nonischaemic zone to
the detriment of ischaemic zone that develops coronary steal

•Coronary steal phenomenon refers to the phenomenon in which small vessel dilation and an
increase in flow to an area already well-perfused myocardium leads to a decrease in flow to
another area of myocardium with borderline perfusion and limited coronary reserve.
•Coronary steal can occur between 2 arteries connected by collateral vessels (intercoronary
steal) or from subendocardium to subepicardium distal to a coronary stenosis (transmural
steal).
The pharmacological success but therapeutic failure of dipyridamole has been explained on the
basis of coronary Steal phenomenon.

By dilating resistance vessels in non-ischaemic zone as well, it diverts the already reduced
blood flow away from the ischaemic zone
Dipyridamole inhibits Platelet aggregation by potentiating PGI2 and increasing cAMP in
platelets, it enhances anti-aggregatory influences

Dipyridamole employed for prophylaxis of coronary and cerebral thrombosis in post-Ml and
poststroke patients, as well as to prevent thrombosis in patients with prosthetic heart valves