Classification Of ANTI-ARRHYTHMIC DRUGS / Pharmacology of ANTI-ARRHYTHMIC DRUGS / ANTI-ARRHYTHMIC DRUGS

 

ANTI-ARRHYTHMIC DRUGS               

Introduction

Arrhythmia is a common disorder of cardiac excitation, which may be benign but

may also be fatal ( e.g., ventricular fibrillation following a heart attack).

Antiarrhythmic drugs are used to control or correct cardiac rhythm.

Four types of arrhythmias are:

1) Atrial fibrillation,

2) Bradycardia,

3) Tachycardia, and

4) Ventricular arrhythmias. 

 The symptoms of arrhythmias are:

1) Shortness of breath,

2) Feeling tired or light-headed,

3) Rapid thumping in chest or palpitations,

4) Chest pain, and

5) Losing consciousness.

 

1.5.2. Classification

The classification of antiarrhythmic drugs is as follows:

1.5.3. Sodium Channel Blockers (Class I)

Sodium channel blockers are the most wi dely used antiarrhythmic agents. They

act by blocking myocardial Na + ion channels. They are mainly used for the

treatment of supraventricular, nodal and ventricular arrhythmias , especially after

MI and DC shock.

1.5.3.1. Mechanism of Action

          Antiarrhythmic activity of sodium channel blockers is due to:

1) Decrease in inflow of sodium during phase 0 which slo ws the maximum rate

of depolarisation,

2) Decrease in excitability and conduction velocity,

3) Prolongation of effective refractory period, and

4) Decrease in slope of phase 4 spontaneous depolarisation (automaticity).

 

1.5.3.2. Therapeutic Uses

The sodium channel blockers have the following therapeutic uses:

1) Treatment of supraventricular, nodal and ventr icular arrhythmias, especially

after MI and DC shock.

2) After treatment of atrial flutter and fibrillation to maintain sinus rhythm.

1.5.3.3. Adverse Effects

The adverse effects of sodium channel blockers are marked depression of AV

conduction, hypotension, bradycardia, anorexia, nausea, and vomiting.

1.5.3.4. Individual Drugs

Class I antiarrhythmic agents are further classified into:

1) Moderate (Class IA): These drugs slow the rate of rise of action potential

and prolong the duration of action potential. They block Na+ ion channels and

prolong the repolarisation time.

Examples

i) Quinidine:

          It is the prototype of Class IA drug. Because of its

concomitant Class III activity, it can precipitate arrhythmias such as
polymorphic ventricular tachycardia ( torsades de pointes ), which ca n
degenerate into ventricular fibrillation. Due to the toxic effects, the
clinical uses of quinidine are replaced with calcium antagonists (like
amiodarone and verapamil).  

• Mechanism of Action: 

Quinidine binds to open and inactivated Na+ ion
channels to pr event the influx of Na+ ions; thus slowing down the rapid
upstroke during phase 0. It also reduces the slope of phase 4 spontaneous
depolarisation and inhibits potassium channels. These actions result in
slow conduction velocity and increased refractoriness. 

• Therapeutic Uses: 

Quinidine is used in the treatment of a wide variety
of arrhythmias including atrial, AV -junctional, and ventricular
tachyarrhythmia. It is used to maintain sinus rhythm after direct -current
cardioversion of atrial flutter or fibrilla tion and to prevent frequent
ventricular tachycardia.

• Adverse Effects

a) A potential adverse effect of quinidine is development of arrhythmia

(torsades de pointes).

b) It may cause SA and AV blockage or asystole.

c) At toxic levels, it may induce ventricular tachycardia.

d) Nausea, vomiting, and diarrhoea are commonly observed.

e) In l arge doses , it may induce the symptoms of cinchonism ( e.g.,

blurred vision, tinnitus, headache, disorientation, and psychosis).

f) It has a mild α-adrenergic blocking action as w ell as an atropine-like

effect.

g) It can increase the steady -state concentration of digoxin by

displacement of digoxin from tissue -binding sites (minor effect) and

by decreasing digoxin renal clearance (major effect). 

 

ii) Procainamide: 

It is a derivative of the local anaesthetic procaine and

shows actions similar to those of quinidine.

Mechanism of Action: Procainamide stabilises the neuronal membrane

by inhibiting the ionic fluxes required for the initiation and conduction of

impulses, thereby affecting local anaesthetic action.

Therapeutic Uses: Procainamide can be given in place of quinidine as it is

better tolerated in the treatment of atrial fibrillation and flutter. It is an

alternative to lidocaine in preventi on and treatment of frequent VPBs

(Ventricular Premature Beats) and sustained tachycardia after MI. Its use is

also declining because of frequent dosing and unacceptable adverse effe cts.

Adverse Effects: With chronic use, procainamide causes a high

incidence of side effects, including a reversible lupus erythematous -like

syndrome. Toxic concentrations of procainamide may cause asystole or

induction of ventricular arrhythmias. CNS side effects include

depression, hallucination, and psychosis.

 

2) Weak (Class IB):

 

The characteristic effects of these drugs are reduced rate of rise of action potential and reduced or unchanged APD ( Action PotentialDuration). The drugs of Class IB rapidly associate and dissociate from the sodium channels. Thus , their actions are m anifested when the cardiac cells
are depolarised or firing rapidly. 
Examples
i) Lidocaine: 
It is a local anaesthetic which shortens phase 3 repolarisation
and decreases the duration of action potential . Lidocaine is useful in
treating ventricular arrhythmias. It was the drug of choice for emergency
treatment of cardiac arrhythmias. It does not slow down conduction, thus
has a little effect on the AV junction arrhythmia.
Lidocaine in higher doses causes cardiac and CNS manifestations. SA
nodal arrest and hypotension may also occur. Paraesthesia, tremor (facial
twitching), vomiting, light headedness, slurred speech, and convulsions

also occur commonly. 

3) Strong (Class IC): 

Drugs of this class are powerful blockers of fast Na + ion

channels, and thus reduce upstroke of AP in normal and diseased

myocardium. There is dela yed inactivation of slow Na + ion channels during

down slope of AP , and this result in prolongation of APD. In addition, there

is inhibition of delayed rectifier K + current (less K + efflux), so the APD is

prolonged in His Bundle and Purkinje fibre system.

These changes create heterogeneity of impulse conduction, non -uniform

slowing and unidirectional block predisposing to development of re -entry 

(proarrhythmic potential). Arrhythmias are more likely to occur in structural

heart disease, sympathetic over activity and at faster heart rates.

 1.5.4. Beta -Blockers (Class II)

The Beta -blockers or β-adrenergic receptor blockers produce some important

electrophysiological effects. They are highly effective in arrhythmias in which

excess of catecholamine plays a role after MI, CHF, pheochromocytoma, anxiety,

anaesthesia and postoperative period, exercise and mitr al valve prolapse. Excess

of cAMP is considered to be responsible for causing ischemia induced

ventricular fibrillation.

1.5.4.1. Mechanism of Action

• Reduction in intracellular Ca ++ ions leads to reduced phase 2 of AP. There is

reduction in SA nodal automaticity, slowing of conduction, and prolongation of

ERP (Effective Refractive Period ) in AV node. They counteract catecholamine

induced after depolarisations (arrhythmias) by reducing cAMP and Ca ++ ion

accumulation. 

• -blockers are also effective prophylactically in suppressing supraventricular

tachycardia because they suppress automaticity of ectopic foci and slow AV

nodal conduction , thereby reducing ventricular response in atrial fibrillation.

They reduce cardiac contractility and blood pressure.

1.5.4.2. Therapeutic Uses

At present -blockers are considered to be better antiarrhythmic agent s because

they improve survival, have broader spectrum of antiarrhythmic action, and are

comparatively safer. In addition , they act synergistically with many other

antiarrhythmic agents reducing their arrhythmogenic potential.

1.5.4.3. Adverse Effects

Some common adverse effects of β-blockers are:

1) Worsening of CHF,

2) Bronchospasm,

3) Cardiac conduction blocks,

4) Bradycardia

5) Peripheral vasospasm,

6) Insomnia, and

7) Hypotension

1.5.4.4. Individual Drugs

Some commonly used β-blockers are described below:

1) Propranolol: It reduces sudden arrhythmic death after myocardial infarction.

It reduces the mortality rate after a heart attack by preventing ventricular

arrhythmia.

• Propranolol acts by binding at β1-adrenergic receptors in the heart by

competing with the sympathomimetic neurotransmitters (catecholamine s),

thus inhibiting sympathetic stimulation. This reduces the resting heart rate,

cardiac output, systolic and diastolic blood pressure, and reflex orthostatic

hypotension.

• Propranolol is used therapeutically for the management of hypertension,

angina pec toris (with the exception of variant angina ), tachyarrhythmia,

myocardial infarction, tachycardia or tremor associated with anxiety, panic,

hyperthyroidism, or lithium therapy , migraine, cluster headache , and

hyperhidrosis.

• The adverse effects caused by p ropranolol include insomnia, vivid dre ams

and nightmares as it can cross the BBB much easily as compared to the less

lipophilic β-blockers due to high lipophilic nature.

2) Metoprolol: It is a -adrenergic antagonist used for the treatment of cardiac

arrhythmia. Like propranolol, it can also b e metabolised easily and can

penetrate CNS. It reduces the risk of bronchospasm.

• Metoprolol is a β1-selective adrenergic receptor blocker, but at higher plasma

concentrations it also inhibits β2-adrenoreceptors located in the bronchial and

vascular musculature.

• Metoprolol is used in the treatment of acute myocardial infarction, angina

pectoris, heart failure, and mild to moderate hypertension. It is also used for

the treatment of supraventricular and tachyarrhythmia, and as prophylaxis for

migraine.

• Common adverse effects of metoprolol include d izziness or lightheadedness,

tiredness, depression, nausea, dry mouth, stomach pain, and vomiting.

1.5.5. Potassium Channel Blockers (Class III)

Class III agents block K+ ion channels, thus the outward potassium current during

re-polarisation of cardiac cells diminishes. These agents prolong the duration of

action potential without altering p hase 0 of depolarisation or the resting

membrane potential. They prolong the effective refractory period and increase

refractoriness. All class III drugs have the potential to induce arrhythmias.

1.5.5.1. Mechanism of Action

Blocking of K+ ion channels in phase 3 of the action potential reduces the efflux

of K+ ions from the myocyte; t hus slowing down the repolarisation rate of the

cell and increasing the length of plateau phase of the action potential. These

actions result in increase of the refractory period of atrial, ventricular and

Purkinje cells as well as increase of the QT interval.

1.5.5.2. Therapeutic Uses

Potassium channel blockers are used to treat:

1) Recurrent ventricular fibrillation,

2) Unstable ventricular tachycardia, and

3) Atrial fibrillation.

1.5.5.3. Adverse Effects

Common adverse effects of potassium channel blockers are p ulmonary fibrosis,

photosensitivity, corneal micro deposits, hypothyroi dism, and peripheral

neuropathy, AV block, bradycardia, ventricular arrhythmia s, bronchospasm, and

severe hypotension.

1.5.5.4. Individual Drugs

Some commonly used potassium channel blockers are discussed below:

1) Amiodarone: It is a potent and broad spectrum antiarrhythmic agent, having

cardiac and extracardiac actions.

• Amiodarone prolongs the APD of atrial and ventricular tissues by blocking

delayed rectifier K+ ion current. The blocking of K + ion channel prevents K+

ion efflux, thus the down slope of phase 3 of action potential is delayed. It

also blocks the Na+ ion channels increasing their inactivation time in phase 3

thus prolonging APD. The Na+ ion channels get recovered very quickly from

this blockage. Amiodarone also blocks Ca++ ion channels resulting an altered

phase 4 of AP. It actively inhibits abnormal automaticity and slows

conduction by prolonging ERP in all tissues.

• Following are the common therapeutic uses of amiodarone:

i) Suppressing of chronic at rial fibrillation and for maintaining NSR after

cardioversion.

ii) Preventing recurrent ventricular extra systoles and VT alone or as an

adjunct to Implanted Cardioverter Defibrillator (ICD).

iii) It is also used for suppressing atrial fibrillation in WPW syndrome.

 

 The adverse effects caused by amiodarone may be cardiac and extra-cardiac:

i) Cardiac adverse effects include hypotension (due to direct myoca rdial

depression), vasodilation, bradycardia, and QT prolongation.

ii) If used for a long-term, amiodarone give some extra-cardiac adverse

effects like pulmonary fibrosis, corneal micro deposits and halos in

visual fields, optic neuritis, hepatic dysfunction, peripheral neuropathy,

proximal muscle weakness, photodermatitis, slate blue discoloration of

skin, testicular failure, and thyroid malfunction.

 

2) Sotalol: It is a non -selective -blocker with no intrinsic sympathomimetic

activity. The L-isomer of sotalol has class II antiarrhythmic action , while D and

L-isomers show class III antiarrhythmic action. It blocks the+ K ion channels and

inhibits delayed rectifier K+ ion current. It prolongs APD in atrial and ventricular

tissues. It reduces automaticity and slows down the AV nodal conductio n.

Sotalol is therapeutically used as an alternative to quinidine for treating

recurrent or sustained VT and can be given in structural heart disease (where

flecainide is not effective). It is also used in tachyarrhythmia in WPW

(Wolff-Parkinson-White) syndrome.

The common adv erse effects of sotalol include b radycardia, depression of

cardiac contractility, CHF, dose-dependent TDP, fatigue, and bronchospasm.

 1.5.6. Calcium Channel Blockers (Class IV)

The drugs included in CCBs are verapamil, diltiazem, and bepridil (blocks Na +

ion channels also).

1.5.6.1. Mechanism of Action

CCBs block the slow in ward calcium channels, and slow down the conduction

through the AV node.

1.5.6.2. Therapeutic Uses

CCBs are used to treat atrial fibrillation and flutter, prinzmetal and variant angina

and unstable or chronic stable angina pectoris, and hypertension.

1.5.6.3. Adverse Effects

CCBs give rise to dizziness, hypotension, bradycardia, oedema, constipation, AV

block, ventricular systole, ventricular fibrillation, and nausea.

1.5.6.4. Individual Drug - Verapamil

• Verapamil blocks L -type voltage operated Ca +2 ion channels in activated and

inactivated state. Since Ca +2 ions are the main ion participating in the generation

of AP in slow automatic tissues of SA and AV nodes, verapamil has predominant

depressant effects on these pacemakers. I t slows automaticity and increases

refractoriness. It also blocks the re-entry in AV node.

• Verapamil also suppresses EADs (Early After Depolarisations ) and DADs

(Delayed After Depolarisations), which are calcium dependent. These effects cause

bradycardia, prolongation of PR interval , and reduction in anterograde impulses

from atria to ventricles, thus slowing ventricular rate in atrial fibrillation/flutter. It

also has negative inotropic and peripheral vasodilatory effects .

• Verapamil is used in the treatment of hypertension, angina, and cluster headache

         prophylaxis.

• The adverse effec ts caused by verapamil include c onstipation, heartburn,

       dizziness or light headedness, headache, slow heartbeat, blurred vision, nausea,

       loss of appetite, rash, and fever.