ANTIARRHYTHMIC DRUGS

Arrhythmia or dysrhythmia means an abnormal or irregular heart beat

Arrhythmias may originate in the atria, SA node or AV node, whereby they are known as supra-ventricular arrhythmias or in the ventricles giving rise to the life-threatening ventricular arrhythmias

Causes of Arrhythmias Arteriosclerosis Coronary artery spasm Heart block (mostly AV

block) Myocardial ischemia

Mechnisms of Arrhythmogenesis

I. Abnormal Impulse Generation

II. Abnormal Impulse Conduction

A. Automatic rhythms:- Enhanced normal

automaticity- Abnormal automaticityB. Triggered rhythms

-Early after-depolarisation - Delayed after- depolarisation

A. Conduction blockFirst-, second-, third–degree

blockB. Re-entry

- Circus movement- Reflection

ANTIARRHYTHMIC DRUGS

Most antiarrhythmic drugs are pro-arrhythmic

Only ß-blockers are proved to reduce mortality in post-myocardial infarction patients

They are classified according to Vaughan William into four classes according to their effects on the cardiac action potential

1. Class I ANTIARRHYTHMIC DRUGS:

Drugs in this class are blockers of voltage-operated Na+ channels in the myocardial membrane

They show (class IA & IB) preferential selectivity to Na+ channels in the open or inactivated closed states

Hence, they have better degree of blockade in tissues that are frequently depolarized or use-dependent or state-dependent

They decrease conduction velocity in non-nodal tissue (atrial and ventricular muscle, purkinje conducting system)

Class IA Drugs

Quinidine is the prototype of this class

Class IA agents slow the phase 0/reduction of Vmax of the cardiac action potential

They prolong muscle action potential and increase ventricular effective refractory period

They decrease the slope of Phase 4 spontaneous depolarization, tending to suppress enhanced normal automaticity-induced arrhythmias

Class IA Drugs

They possess intermediate rate of association and dissociation with sodium channels

Agents of Class IA: Quinidine Procainamide Disopyramide Uses: Class IA drugs are used in treatment of both

atrial and ventricular arrhytmias

Class IA Drugs ToxicityQuinidine

A-V block at higher plasma levels At toxic levels, ventricular

tachycardia and torsade de pointes ventricular arrhythmia

Increasing digoxin plasma concentration by displacing digoxin from binding sites in addition to decreased digoxin renal clearance

Cinchonism occurs at large dose levels (blurred vision, tinnitus, headache, psychosis and gastrointestinal upset)

Digoxin is administered before quinidine to prevent the conversion of atrial fibrillation or flutter into paradoxical ventricular tachycardia. Quinidine shortens of A-V nodal refractoriness by atropine-like effects

Procainamide 1. At high levels, asystole or induction of

ventricular arrhythmias 2. Hypersensitivity reactions including drug

fever and rarely agranulocytosis. 3. Systemic lupus erythromatosus (SLE)-

like (arthralgia, fever & pleural-pericardial inflammation)

The SLE is dose- and time-dependent, and usually disappears upon drug stop

It is most common in patients with slow hepatic acetylation resulting in higher plasma level of the parent drug

Disopyramide 1. Anticholinergic side-effects 2. Induction of ventricular arrhythmias in

patients with prolonged QT interval 3. Similar to quinidine, disopyramide may

induce ventricular arrhythmia if used alone in the treatment of fibrillation

Class IB Drugs They shorten Phase 3

repolarisation and decreases the duration of the cardiac action potential

They suppress arrhythmias caused by abnormal automaticity (c.f. quinidine suppresses enhanced normal automaticity-induced arrhythmias)

They show rapid association & dissociation with Na+ channels with appreciable degree of use-dependence

Agents of Class IB

Lidocaine It should be used by

intravenous route because of its extensive first-pass metabolism

Lidocaine is the drug of choice in emergency treatment of ventricular arrhythmias

Mexiletine and tocainide These are the oral analogs

of lidocaine Mexiletine is used for

chronic treatment of ventricular arrhythmias associated with previous myocardial infarction

Tocainide is used for ventricular tachyarrhythmias but its use is limited by its pulmonary toxicity that may lead to pulmonary fibrosis

UsesThey are used in the treatment of ventricular arrhythmias arising during myocardial ischemia or due to digoxin toxicityThey have little effect on atrial or AV junction arrhythmias

Class IC Drugs They markedly slow Phase 0 fast

depolarization They possess slow rate of

association and dissociation with sodium channels

They markedly slow conduction in the myocardial tissue

They only have minor effects on duration of action potential and refractoriness

They reduce automaticity by increasing the threshold potential rather than decreasing the slope of Phase 4 spontaneous depolarization

Class IC Drugs Agents of Class IC: Flecainide & propafenone Uses: They are broad-spectrum but only approved for refractory

ventricular arrhythmias Flecainide is a particularly potent suppressant of premature

ventricular contractions Toxicity and Cautions for Class IC Drugs: They are severe proarrhythmic drugs causing severe

worsening of a preexisting arrhythmia or de novo occurrence of life-threatening ventricular tachycardia

In patients with frequent PVCs following MI, flecainide increased mortality compared to placeboNotice: Class 1C drugs are particularly of low safety and have shown even to increase mortality when used chronically after MI

Class II ANTIARRHYTHMIC DRUGS (β-adrenergic blockers)

β-Adrenergic blockers produce both negative inotropic & chronotropic effects

They diminish phase 4 spontaneous depolarization suppressing automaticity and prolonging AV conduction

Uses They are used in treatment

of increased sympathetic activity-induced arrhythmias such as stress- and exercise-induced arrhythmias

Treatment of atrial flutter and fibrillation

AV nodal tachycardia

Class II ANTIARRHYTHMIC DRUGS

Propranolol: was proved to reduce the incidence of sudden arrhythmatic death after myocardial infarction

Metoprolol & Pindolol Metoprolol and other selective β1-adrenergic

blockers reduce the risk of bronchospasm Pidolol, having additional partial agonistic activity,

may decrease the frequency of cardiac failure Esmolol: Esmolol is a very short-acting β1-adrenergic

blocker that is used in the by intravenous route in acute arrhythmias occurring during surgery or emergencies

Class III ANTIARRHYTHMIC DRUGS

Class III antiarrhythmic drugs prolong phase 3 depolarization, without altering phase 0 upstroke or the resting membrane potential

They prolong both the duration of the action potential and the effective refractory period (ERP)

Their mechanism of action is still not clear but it is thought that they block potassium channels

Class III ANTIARRHYTHMIC DRUGS

Drugs of Class III: Sotalol, bretylium, amiodarone, ibulitideUses: They are used in the treatment of

ventricular arrhythmias, especially ventricular fibrillation or tachycardia

Supra-ventricular tachycardia Amiodarone usage is limited by its wide

range of side effects

Class III ANTIARRHYTHMIC DRUGSSotalol (Sotacor)

Sotalol is a β-adrenergic blocker that also prolongs the duration of action potential and refractoriness in all cardiac tissues

Sotalol suppresses Phase 4 spontaneous depolarization and possibly producing severe sinus bradycardia

The β-adrenergic blockade combined with prolonged action potential duration may of special efficacy in prevention of sustained ventricular tachycardia

It may induce the polymorphic torsade de pointes ventricular tachycardia

Bretylium It is generally administered parenteraly because of poor GIT

absorption Long-term oral use is associated with painful parotid

enlargement as well as severe postural hypotension

Class III ANTIARRHYTHMIC DRUGSAmiodarone (Cordarone)

Amiodarone is a drug of multiple actions and not well understood It is extensively taken up by tissues, especially fatty tissues, and has a half-

life of up to 60 days Amiodarone antiarrhythmic effect is complex comprising class I, II, III,

and IV actions• Prolongation of action potential duration and refractoriness is the main• It slows cardiac conduction, works as Ca2+ channel blocker, and as a weak

β-adrenergic blocker Amiodarone Toxicity Amiodarone has wide-spectrum toxicity Most common include GI intolerance, tremors, ataxia, dizziness, hyper-or

hypothyrodism Corneal microdeposits may be accompanied with disturbed night vision Other common side effects include liver toxicity, photosensitivity, gray facial

discoloration, neuropathy, muscle weakness, and weight loss The most dangerous side effect is pulmonary fibrosis which occurs in 2-

5% of the patients

Class IV ANTIARRHYTHMIC DRUGS (Calcium Channel Blockers)

Calcium channel blockers decrease inward Ca2+ currents resulting in a decrease of phase 4 spontaneous depolarization

They slow conduction in Ca2+ current-dependent tissues like AV node

Verapamil and diltiazem, but not nifedipine (or the other dihydropyridine Ca2+ antagonists), are representative of this class being more effective on the heart than blood vessels

Class IV ANTIARRHYTHMIC DRUGS

Verapamil and diltiazem bind only to open depolarized voltage-operated Ca2+ channels, and hence preventing re-polarization until the drug dissociates from the channels.

Therefore, they are use-dependent blocking rapidly beating heart since in a normally-paced heart, Ca2+ channels have enough time to repolarize and the drug to dissociate from the channel before the next conduction cycle

Verapamil and diltiazem slow conduction and prolong effective refractory period in Ca2+ current-dependent tissues like AV node

Class IV ANTIARRHYTHMIC DRUGS

Verapamil & diltiazem are more effective in treatment of atrial than ventricular arrhythmias.

They are used in treatment of supra-ventricular tachycardia preventing the occurrence of ventricular arrhythmias

They are used in treatment of atrial flutter and fibrillation

Both drugs are contraindicated patients with pre-existing depressed heart function because of their negative inotropic activity

Both drugs may cause bradycardia, and asystole especially when given in combination with β-adrenergic blockers

Miscellaneous Antiarrhythmic Drugs

Adenosine Adenosine activates A1-purinergic receptors

decreasing the SA nodal firing and automaticity, reducing conduction velocity, prolonging effective refractory period, and depressing AV nodal conductivity

It is the drug of choice in treatment of supra-ventricular tachycardia

It is used only by intravenous route It has only low-profile toxicity being ultra-short

acting of 15 seconds duration

Sodium-channel blockade:   IC > IA > IB

Increasing the ERP:IA>IC>IB (lowered)