Treatment of Arrythmias

Note: All anti-arrhythmic drugs have the potential to be lethal

4 classes of anti-arrhythmic drugs – Vaughn-Williams Classification

Class I – block Na/K channels Þ modify fast inward current through Na channels Þ slows conduction (AV node)

Ia – block Na (2+) and K (1+) with slightly more emphasis on Na (2+ vs 1+)

Effect on: Sinus rate (-Ý ); PR interval (Ý ); QRS complex duration (Ý ); QT interval (Ý Ý ); JT interval (Ý Ý )

Effect on: phase 0 of action potential – moderate depression ß ß

Effect on: phase 3 of action potential – prolong Ý Ý Ý

Use Dependence – these drugs bind to the Na receptors during systole therefore the effects of these drugs are much greater Þ give these drugs with caution

Quinidine – lengthens repolarization phase by prolonging the plateau stage

The oldest antiarrhythmic drug; natural alkaloid of cinchona bark and an optical isomer of quinine

Adverse effects – Cardiovascular toxicity (hypotension, conduction block in AV node and ventricles, Ý Ý QRS complex duration, ventricular arrhythmias); Cinchonism (tinnitus, visual disturbances, vertigo, diplopia, N/V, diarrhea); Thrombocytopenia (ß platelets); Bleeding in patients who take oral anticoagulants

Patients taking Digoxin may experience a rise in serum Digoxin level Þ digitalis toxicity

Procainamide

Toxicity – Cardiovascular toxicity similar to that of Quinidine (no interaction with Digoxin); Granulocytopenia (ß WBCs); Lupus Erythematosus (fever arthralgia, arthritis, pleuritis, serum antinuclear Ab’s)

Procainamide and Quinidine Þ used to treat a wide variety of reentrant tachyarrhythmias Þ "broad spectrum" antiarrhythmic agents Þ Supraventricular arrhythmias (Atrial Fibrillation, Atrial Flutter, Atrial Tachycardia, Atrial premature beats) and Ventricular arrhythmias (Ventricular premature beats and Ventricular Tachycardia); IV Procainamide is indicated in emergency therapy

Adverse effects – proarrhythmic (can cause supraventricular or ventricular arrhythmias)

Disopyramide (Norpace) Þ effective against most supraventricular and ventricular arrhythmias that respond to quinidine; Also has prominent anticholinergic effects

Adverse effects – arrhythmias and conduction disturbances similar to quinidine; may precipitate or exacerbate CHF in patients with depressed left ventricular function (due to its negative inotropic effects)

Ib – block Na (1+) with little effect on K channel

Effect on: PR interval (--); QRS complex duration (--); QT interval (-ß ); JT interval (-ß )

Effect on: phase 0 of action potential – weak depression ß

Effect on: phase 3 of action potential – shorten ß

Only useful for Ventricular arrhythmias; ineffective in the treatment of supraventricular tachyarrhythmias

Lidocaine Þ effective for acute treatment of serious ventricular arrhythmias (especially those caused by digitalis toxicity or recent MI); administered intravenously

Adverse effects – CNS depression, muscular fasciculations and then tonic, clonic convulsions; no adverse cardiovascular effects; no negative inotropic effects

Mexiletine and Tocainide – structural analogs of Lidocaine; unlike Lidocaine however, they have a high bioavailabilty when given orally thus can be used for the chronic suppression of ventricular arrhythmias

Phenytoin

Ic – block Na (3+)

Effect on: PR interval (Ý Ý ); QRS complex duration (Ý Ý ); QT interval (Ý ); JT interval (--)

Effect on: phase 0 of action potential – strong depression ß ß ß

Effect on: phase 3 of action potential – little effect Ý ß

Used to treat atrial fibrillation and/or flutter

Flecainide (Tambocor) – a fluorinated local anesthetic analog of Procainamide Þ prominent Na channel blocking action

Treatment for: Supraventricular Arrhythmias (suppress Atrial Fibrillation, Atrial Flutter, Atrial Tachycardia, AV nodal reentry, and AV reentry involving an accessory AV connection) and Ventricular Arrhythmias (ventricular premature beats, non-sustained ventricular tachycardia, sustained ventricular tachycardia or fibrillation)

Adverse effects – transient CNS symptoms (dizziness); cardiovascular toxicity; may precipitate or exacerbate CHF in patients with depressed ventricular function (due to its negative inotropic effects); proarrhythmic (can cause supraventricular or ventricular arrhythmias)

Propafenone

Encainide

Class II – b blockers Þ prevent or blunt arrhythmogenic effects of catecholamines Þ work at AV node to slow conduction through it

They prevent the arrhythmia-inducing effects of the sympathetic nervous system (among these are the sympathetic-induced increases in automaticity of the sinus node or ectopic pacemakers due either to normal or abnormal automaticity). Also, they have antiarrhythmic actions on the AV node in the reentrant circuit, or to slow the ventricular response rate to atrial fibrillation, atrial flutter, or atrial tachycardia

Effect on: PR interval (Ý ); QRS complex duration (--); QT interval (--); JT interval (--)

Propranolol

Treatment for: Atrial arrhythmias (inappropriate sinus tachycardia, paroxysmal atrial tachycardia, paroxysmal atrial fibrillation due to sympathetic activation; atrial arrhythmias which accompany hyperthyroidism; reduce ventricular rate during atrial flutter or fibrillation (adjunct to digitalis therapy); AV nodal reentry and AV reentry tachycardia; Ventricular arrhythmias; Prevention of sudden cardiac death

Adverse effects – cardiovascular problems attributable to sympathetic blockade (depression of myocardial contractility, effects on electrical activity of the heart, hypotension); contraindicated in asthma patients

Acebutalol

Esmolol

Class III – prolong the QT interval Þ prolong action potential duration and refractory period Þ effect K channels (prolongs repolarization)

Effect on: PR interval (Ý ); QRS complex duration (Ý ); QT interval (Ý Ý ); JT interval (Ý Ý )

Amiodarone – weak Na, Ca, and b blocker

Ability to prolong time for repolarization of atrial and ventricular tissues and thereby prolong the effective refractory period.
Because of its high incidence of adverse effects, it is mainly used for life threatening arrhythmias that have been proven to be refractory to other antiarrhythmic drugs
Only approved by the FDA for oral administration in the treatment of life-threatening ventricular arrhythmias

Treatment for: Supraventricular arrhythmias (atrial flutter or fibrillation – slows ventricular response at rest and with exercise, may convert the arrhythmia to sinus rhythm, effective in maintaining sinus rhythm in patients with paroxysmal atrial fibrillation or flutter, also effective in preventing recurrences of atrial tachycardia; AV nodal reentrant tachycardia or AV reentry tachycardia involving accessory AV connection); Ventricular arrhythmias

Drug interactions – digoxin-amiodarone interaction (may lead to digitalis toxicity); amiodarone-warfarin interaction (potentiates the anticoagulant effect by decreasing warfarin metabolism)

Adverse effects – ocular complications; skin reactions; thyroid disorders (hypo/hyperthyroidism); pulmonary toxicity (most responsible for the associated deaths); cardiac toxicity; hepatic toxicity; muscle weakness

(Torsades de pointes – increased QT interval and polymorphic ventricular tachycardia; thought to result from triggered activity due to early afterdepolarizations)

Sotalol – real b blocker – has half the strength of Propanolol; main concern is hypokalemia

Prolongs repolarization and the effective refractory period of cardiac muscle by blocking the delayed rectifier K channels that are responsible for phase 3 repolarization of the action potential

Treatment for: Supraventricular (Atrial) Arrhythmias (prevent the onset of paroxysmal arrhythmias caused by sympathetic activation and slowing the ventricular rate in the absence of converting flutter or fibrillation to sinus rhythm; preventing paroxysmal and sustained atrial flutter and fibrillation or converting these arrhythmias to sinus rhythm because it plongs the atrial refractory period); Ventricular Arrhythmias

Adverse effects – proarrhythmic; torsades de pointes; hemodynamic effect; beta receptor blocking effects (sinus bradycardia, AV block, exacerbation of heart failure)

Ibutilide – blocks the slow Na channel; used intravenously for atrial fibrillation and flutter

Dofetilide

Class IV – Ca channel blocking drugs Þ modify inward current through slow Ca channels Þ also work at the AV node

Effect on: PR interval (Ý ); QRS complex duration (--); QT interval (--); JT interval (--)

Verapamil – primary effect on the heart is an interaction with the secondary inward channel to decrease inward Ca current Þ effective in treating arrhythmias caused by slow responses and afterdepolarizations and also abnormal automatic rhythms (spontaneous phase 4 depolarization initiated at a reduced maximal diastolic potential)

Treatment for: Supraventricular arrhythmias (paroxysmal AV nodal reentry tachycardia and AV reentry tachycardia involving an accessory AV connection); useful for slowing the ventricular response rate to atrial flutter or fibrillation by its effects on the AV node; ineffective against almost all ventricular arrhythmias except right ventricular outflow tract tachycardia (due to triggered activity)

Adverse effects – depress myocardial contractility and CO

Diltiazem

Mechanisms of Action of the Antiarrhythmic Drugs

exert their therapeutic effects by altering electrical activity in the cells critically involved in causing the arrhythmia. Thus may act on the following mechanisms

(1) Abnormal impulse generation = Automatic (normal, abnormal) and Triggered (early and delayed afterdepol.)

(2) Abnormal impulse conduction = Block and Unidirectional block and reentry (unidirectional block and slow conduction)

Automatic arrhythmias – Normal mechanism

Class I drugs significantly depress or abolish impulse initiation in ectopic pacemakers by ß the depolarizing inward Na current Þ depressed slope of spontaneous diastolic (phase 4) depolarization.

Quinidine and Procainamide also shift the threshold voltage to less negative values so that it takes longer for spontaneous diastolic depolarization to reach threshold and fire, thereby causing slowing of the pacemaker by yet another mechanism.
In therapeutic concentrations, these drugs have little effect on sinus node automaticity

Class II drugs may depress automaticity caused by sympathetic stimulation

Class III and Class IV drugs do not significantly depress normal automaticity

Automatic arrhythmias – Abnormal mechanism

Class IV drug – Verapamil which blocks the slow inward current, abolishes automatic activity caused by the abnormal mechanism at low levels of membrane potential

Class III drug – Amiodarone has some slow channel blocking effects thus may also stop abnormal automaticity

Triggered Rhythms

Class III and IV drugs – If caused by early afterdepolarizations because the action potentials triggered by early afterdepolarizations are often caused by slow inward current

Class IV drug – If caused by delayed depolarizations because they decrease intracellular Ca

Class I drug – If caused by delayed depolarizations because they block the Na channels which indirectly decrease intracellular Ca and prevent triggered activity via an effect on Na/Ca exchange; Class IV has a more potent effect

Arrhythmias caused by abnormal impulse conduction; Unidirectional block and reentry

For reentrant excitation to occur: 1) there must be unidirectional block; 2) the returning impulse must not be blocked by encountering cells that still are refactory; ALSO, the presence of an area of slow conduction in the reentrant circuit must be present in virtually all clinically important reentrant rhythms

A drug might terminate a reentrant rhythm by acting on any one of these variables in the following ways:

Disposes of unidirecitonal block – The area of unidirectional block might change to either bidirectional block or bidirectional conduction

Encounters refactory tissue – The velocity of conduction of the circulating reentrant wave front might increase in all or a portion of the reentry loop so that the returning impulse encounters tissue which has not had time to repolarize OR The duration of refractoriness might increase sufficiently so that the returning impulse encounters refractory tissue

Presently, unsure whether any drugs convert unidirectional block to bidirectional conduction or abolish reentrant arrhythmias by speeding conduction in reentrant pathways

The Na channel blocking drugs (Class I) and the slow channel blocking drugs (Class IV) often will slow and block conduction in reentrant circuits of some reentrant rhythms

Example – can give a drug to slow conduction Þ originally 250ms refractory period, circuit returns in 280ms therefore need to prolong the time it takes for circuit to return in order to prevent re-entry

Class I drugs depress the fast inward Na current responsible for the depolarization phase of the action potential without altering resting potential.

This effect is much greater on diseased fibers with depressed fast responses in reentrant pathways than on normal fibers Þ depression of the already depressed Na current will further slow conduction Þ prevent generation of an action potential Þ blocked conduction in the reentrant pathway.

Class IV drugs should be very effective in slowing conduction and blocking reentry caused by slow responses, but not reentry caused by depressed fast responses

Many antiarrhythmic drugs prolong the refractory period thus causing block of the returning (reentering) impulse

Example – can give a drug to prolong wavelength Þ originally 250ms refactory period, circuit returns in 280ms therefore need to prolong the refactory period to 300ms to prevent re-entry

Class I drugs delay reactivation of the Na channels even after the cardiac fibers have repolarized.

Class III drugs prolong the refractory period by delaying repolarization (significantly prolong A/P duration)

Safety Factor for Conduction – there lies an area that slows down the conduction wavefront somewhere in the middle of the circuit Þ the addition of these drugs strengthens this area and no longer allows the wavefront to pass through Þ the wavefront is no longer strong enough to excite the tissue ahead of it Þ thus breaking the circuit Þ terminating the arrythmias