ANTIARRHYTHMIC DRUGS

• Arrhythmia/ 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 & Delayed after-

depolarisation

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

blockB. Re-entry

- Circus movement- Reflection

Normal To Pathologic cardiac Rythm

Specific Arrhythmias Supraventricular Arrhythmias

Sinus tachycardia - high sinus rate of 100-180 beats/min as occurs during exercise or other conditions that lead to

increased SA nodal firing rate Atrial tachycardia - a series of 3 or more consecutive

atrial premature beats occurring at a frequency >100/min;

Paroxysmal atrial tachycardia (PAT) of sudden onset, disappearance

Atrial flutter - sinus rate of 250-350 beats/min. Atrial fibrillation - uncoordinated atrial depolarizations. AV blocks - a conduction block within the AV node (or

occasionally in the bundle of His) that impairs impulse conduction from the atria to the ventricles

Ventricular premature beats (VPBs) - caused by ectopic ventricular foci; characterized by widened QRS.

Ventricular tachycardia (VT) - high ventricular rate caused by aberrant ventricular automaticity or by intraventricular reentry; can be sustained or non-sustained (paroxysmal); characterized by widened QRS; rates of 100 to 200 beats/min; life-threatening.

Ventricular flutter - ventricular depolarizations >200/min.

Ventricular fibrillation - uncoordinated ventricular depolarizations

Pharmacologic Rationale & Goals

The ultimate goal of antiarrhythmic drug therapy:o Restore normal sinus rhythm and conductiono Prevent more serious and possibly lethal

arrhythmias from occurring. Antiarrhythmic drugs are used to:decrease conduction velocity alter the excitability of cardiac cells by changing

the duration of the effective refractory period suppress abnormal automaticity

Pharmacologic Rationale Some drugs block fast sodium channels that determine how fast the

membrane depolarizes (slope of phase 0, Vmax) & conduction velocity Sodium channel blockers (Group I) reduce conduction velocity to

abolish tachyarrhythmias caused by reentry circuits Antiarrhythmic drugs affect cardiac refractoriness by changing

ERP/APD via potassium channels and delay repolarization of action potentials (phase 3)

This would inhibit reentry tachycardias Slow inward Ca channel blockers reduce SAnodal firing rate by

slowing the rate of rise of depolarizing pacemaker potentials (phase 4 depolarization)

These drugs also reduce conduction velocity Ca-dependant tissue including the AV & SA nodal cells

Blockers of beta1-adrenoceptors can indirectly alter membrane ion conductance, particularly calcium and potassium conductance

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

Class Basic Mechanism/Actions

I Na+ Channel blockade

   IA    - moderate    Moderate reduction in phase 0 slope; increase APD/ERP.

   IB    - weak Small reduction in phase 0 slope; reduce APD/ ERP

IC - strong Pronounced reduction in phase 0 slope; no effect on APD/ERP

II β-ADR blockers

Block sympathetic activity; reduce rate & conduction

III K+-channel blockade

Delay re-polarization (phase 3), increase APD/ERP

IV Ca2+channel blockade

L-Ca2+channel blockade most effective at SA & AV nodes; reduce rate and conduction

1 .Class I ANTIARRHYTHMIC DRUGS Na+-Channels Blockers

• Drugs in this class are blockers of voltage-operated fast 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)

• Group IA drugs have additionally moderate K+

channel blockade

Class IA Drugs Quinidine, Procainamide, Disopyramide

• Class IA agents slow the phase 0/reduction of Vmax of the cardiac action potential (conduction velocity)

• They prolong muscle action potential & ventricular effective refractory period (refractoriness)

• 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• Pharmacokinetics:• Procainamide has good oral bioavailability• Procainamide is frequently used as IV slow route to

avoid hypotension• Procainamide is metabolized into N-acetylprocainamide

(NAPA), an active class III meatbolite mailnly cleared via the kidney, (dose adjustment in kidney failure)

• Quinidine has good oral bioavailability & metabolized mainly in liver

Class IA Drugs Uses• Class IA drugs are effective in treatment of both

supraventricular and ventricular arrhythmias• Quinidine rarely used for supraventricular arrhythmias• Oral quinidine/procainamide are used with class III

drugs in refractory ventricular tachycardia patients with implantable defibrillator

• IV procainamide used for hemodynamically stable ventricular tachycardia

• IV procainamide used for acute conversion of atrial fibrillation including WPW syndrome

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 At high levels, asystole or induction of

ventricular arrhythmias Hypersensitivity reactions including drug fever

and rarely agranulocytosis. 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, ibulitide• Uses:They are used in the treatment of ventricular

arrhythmias, especially ventricular fibrillation or tachycardia

Supra-ventricular tachycardiaAmiodarone 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

Adenosineo Adenosine activates A1-purinergic receptors

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

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

o It is used only by slow intravenous boluso It has only low-profile toxicity being ultra-short

acting of 15 seconds duration

• Compare between class

IA, IB, and IC drugs as regards effect on Na+ channel & ERP

• Sodium-channel blockade: IC > IA > IB

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