Description
Introduction
The rhythm and normal heart rate may be affected by some diseases and drugs.
This condition is termed cardiac arrhythmia in which certain disorders affect
the normal mechanical activ ity of heart. A specific sequence of electrical
activation determines the normal mechanical activity of the heart; this sequential
electrical activation is the same for all myocardial cells during each beat and it
initially begins at the SA node and ends w ith depolarisation of the ventricle.
Therefore, any alteration in conduction automaticity refractory period of the
myocardial cells may result in arrhythmia.
Drugs which have the ability to revert any irregular cardiac rhythm or rate to
normal are known as anti-arrhythmic or anti-dysrhythmic or anti-fibrillatory
drugs. The properties of an ideal antiarrhythmic drug are:
1) It should be highly efficient in controlling symptoms and improving survival
in both supraventricular and ventricular arrhythmias.
2) It should have no negative effect.
3) It should produce a favourable effect on myocardial oxygen consumption.
4) It should produce both oral and intravenous activity.
5) It should have a wide therapeutic range.
7.1.2. Classification
The anti-arrhythmic drugs are classified as shown in table 7.1:
Table 7.1: Classification of Anti-Arrhythmic Drugs
Classes Actions Drugs
I Membrane stabilising agents
(Na+
channel blockers)
A. Moderately decrease dv/dt
of 0 phase,
Quinidine, Procainamide, Disopyramide, and
Moricizine.
B. Little decrease in dv/dt of 0
phase,
Lignocaine, Mexiletine, and Phenytoin.
C. Marked decrease in dv/dt
of 0 phase.
Propafenone, Flecainide, and Encainide.
II Antiadrenergic agents (β-
blockers)
Propranolol, Esmolol, and Sotalol (also class
III).
III Agents widening AP (prolong
re-polarisation and ERP)
Amiodarone, Bretylium (also class II) , and Dofetilide. IV Calcium channel blockers Verapamil and Diltiazem.
Note: Class IA agents also have Class III prop erty; Propranolol also has Class I action;
Sotalol and Bretylium have Class II and Class III actions.
Mechanism of Action
The mechanism of action of anti-arrhythmic drugs is as follows:
1) Sodium Channel Blockers: This group of anti -arrhythmic drugs is
commonly used. The mechanism of action of sodium channel blockers
includes blockade of myocardial Na+
channels. The anti-arrhythmic activity
of these drugs is the result of the following conditions:
i) Decrease in inflow of sodium during phas e 0 slows the maximum rate of
depolarisation,
ii) Decrease in excitability and conduction velocity,
iii) Prolongation of effective refractory period, and
iv) Decrease in slope of phase 4 spontaneous depolarisation (automaticity).
Class I drugs are sub -divided into the following sub-classes on the basis of
their mechanism of action:
Class IA Prolongs the refractory period; moderately depresses conduction;
used in supraventricular and ventricular arrhythmias.
Class IB Shortens the refractory period; minimally depresses conduction; used
in ventricular arrhythmias.
Class IC Negligible effect on refractory pe riod; markedly depresses
conduction; used in supraventricular and ventricular arrhythmias.
2) -Blockers: The electrophysiological effects of β-adrenergic receptor
blocking drugs pl ay a significant role. Due to β1 blockade, phase 4 of the
action potential becomes less steep. A small decrease in the level of Ca ++
ions within the cells reduces phase 2 of the action potential. Also, the SA
node automaticity decreases, con duction in AV node slows down, and ERP
(Effective Refractive Period) in AV node prolongs. The catecholamine
induced after depolarisations (arrhythmias) is counteracted by these agents
by reduction in the accumulated cAMP and Ca++ ions.
Arrhythmias mediate d by excessive catecholamines, e.g., early after MI,
CHF, pheochromocytoma, anxiety, exercise, anaesthesia , post-operative
period, and mi tral valve prolapse are most effectively managed by β-
blockers.
3) Potassium Channel Blockers: The mechanism of action of C lass III anti –
arrhythmic drugs involves blockade of potassium channels. Therefore, the
outward flow of K
+ ions is diminished during re-polarisation of cardiac cells.
The duration of action potential is prolonged without any alteration in the
resting membrane potential or phase 0 of depolarisation. However, the effective refractory period is prolonged and the refractoriness is increased.
All drugs belonging to this class of anti -arrhythmic agents are potent
inducers of arrhythmias.
As the potassium channels are blocked during phase 3 of the action potential,
the efflux of K
+ ions f rom the myocyte is slowed down. This in turn
diminishes the rate of cellular repolarisation, resulting in a lengthened
plateau phase of the action potential. The refractory period of atrial,
ventricular and Purkinje cells is increased by these drugs, along with an
increase in the QT interval, as evident on an ECG.
4) Calcium Channel Blockers: The mechanism of action of this group of anti –
arrhythmic agents involves blockade of slow inward calcium channels. Also,
conduction through the AV node is slowed down. The calcium channel
blockers, e.g., verapamil, diltiazem, and bepridil (blocks sodium channels
also), are included in this group.
7.1.4. Uses
Therapeutic uses of anti-arrhythmic agents are:
1) Sodium Channel Blockers: Presently, these drugs are considered better
anti-arrhythmic agents because of a broad spectrum of their anti-arrhythmic
action, the improvement they show in terms of patient survival, and the ir
safety compared to other anti -arrhythmic agents. When administered with
several other anti-arrhythmic drugs, these agents act in synergism and further
reduce their arr hythmogenic potential (a tendency to produce cardiac
arrhythmia).
2) β-Blockers: The property of blocking β1-receptors plays a significant role in
anti-arrhythmic drugs. Though a β-blocker possessing membrane stabilising
property (i.e., propranolol) is desired, yet it is not a requirement. On the other
hand, an Intrinsic Sympathomimetic Activity (ISA) is not desirable. Sotalol
is an anti-arrhythmic agent possessing properties of both class II and class III
drugs. Esmolol is an ultra -short acting β-blocker whic h is administered
intravenously.
Drugs like propranolol, metoprolol, and esmolol are often used for treating
the following conditions:
i) Sinus tachycardia causing palpitations and nervousness in anxiety neurosis,
ii) Exercise induced paroxysmal atrial tachycardia,
iii) Tachyarrhythmia in mitral valve prolapse,
iv) Recurrent VT (metoprolol),
v) Amiodarone induced VT,
vi) Tachycardia in hereditary prolonged QT syndrome,
vii) Tachyarrhythmia in pheochromocytoma,
viii) Atrial fibrillation (may be used with digoxin),
ix) Frequent APBs causing palpitations, and
x) Digitalis-induced supraventricular tachycardia.
3) Potassium Channel Blockers: These anti -arrhythmic drugs are employed
for treating atrial fibrillation, recurrent ventricular fibrillation, and unstable
ventricular tachycardia.
4) Calcium Channel Blockers: These anti-arrhythmic drugs are employed for
treating prinzmetal, variant angina, unstable or chronic stable angina,
hypertension, and atrial fibrillation.
7.1.5. Structure-Activity Relationship
The SAR of different anti-arrhythmic types is explained below:
1) Sodium Channel Blockers: The activity of sodium channel blockers can be
varied by making the following changes in their structure:
i) The activity is enhanced by substituting ethyl group at the ortho position.
ii) Desirable compounds are yielded by replacing the pyridyl group with
acyclic amines. A potent compound is obtained if the replacement is done
with cyclohexyl group. Pentenamide showed a longer duration of action
than disopyramide.
iii) The potency of 2-pyridyl is more than that of the other isomers.
iv) By varying the amino group using di -isopropylamine and 2,6 –
dimethylpiperidine groups yields a correlation between n values and
ventricular arrhythmias.
2) β-Blockers: The activity of β-blockers can be varied by making the
following changes in their structure:
i) The antagonistic property is due to the presence of O CH2 group
between the aromatic ring and the ethylamino side chain.
ii) The β-blocking activity is retained by replacing the catecho l hydroxyl
group with chlorine or phenyl ring.
iii) The β-blocking activity is decreased by N, N-di substitution. While the
same activity is maintained by adding phenylethyl, hydroxyl
phenylethyl or methoxy phenylethyl groups to amine as a part of
molecule.
iv) The β-blocking activity is also due to the presence of two carbon side
chains.
v) For the β-blocking activity to be optimum, the N atom should be of
secondary amine.
vi) For optimum affinity, the hydroxyl group of the carbon side chain
should be of S-configuration (e.g., Levobunolol and Timolol).
vii) The potency of aryloxy propanolamines is more than that of the aryl
ethanolamines.
viii) The β-blocking activity decreases if the ethereal oxygen in aryloxy
propanolamines is replaced with S, CH2, or NCH3.
ix) Isopropyl and tertiary b utyl group are the most effective amino group
substituents.
Subject:- Medicinal chemistry 2
Semester:- Sem 5
Course:- Bachelor of pharmacy
