Intro to Antiarrhythmics

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Introduction to Antiarrhythmic Pharmacology (JiTT Reading)

Prerequisite reading: The wiki module on Cardiac Arrhythmia

[http://tmedweb.tulane.edu/pharmwiki/doku.php/cellular_basis_for_arrhythmias] .

Learning Objectives

By the end of the self study you should be able to:

1. List the three primary indications for treatment of cardiac arrhythmias.

2. List the primary channel or receptor mechanisms by which Class I, II , III and IV antiarrhythmic drugs produce

their effects

3. Recognize and categorize different antiarrhythmic drugs by their mechanism of action

4. Compare and contrast the different mechanisms by which Class I & Class III drugs increase the cardiac ERP

5. Explain how Class I & Class III drugs can acutely abolish a reentrant arrhythmia

6. Explain what antiarrhythmic drug class is contraindicated in the chronic treatment of patients with a history o

myocardial ischemia

7. Describe which drug class reduces the incidence of sudden death and reinfarction after an MI

8. List the primary drugs used for acute and chronic treatment of AV node reentry

9. Explain how Class Ia drugs can produce a dangerous increase in ventricular rate when used alone to treat atria

tachyarrhythmias.

10. Cite major side effects of major antiarrhythmic drugs that limit their clinical usefulness

11. Explain the multiple mechanisms by which amiodarone may exert its antiarrhythmic effects against atrial an

ventricular arrhythmias.

12. Describe two fundamentally different therapeutic goals of treatment that can be attempted to treat patients

with atrial fibrillation.

Drugs:

Class I:lidocaine, procainamide, (quinidine: rarely used)

Class II:propranolol, metoprolol

Class III:amiodarone, dronedarone, sotalol, ibutilide

Class IV:verapamil, diltiazem

Misc:adenosine

Abbreviations:

AFib - Atrial Fibrillation

APD Action Potential Duration

DAD Delayed After Depolarization

EAD Early After Depolarization

ERP Effective Refractory Period

Ih (or If) - the hyperpolarization activated (Na & K selective) pacemaker current

IKr - the rapid component of the delayed rectifier K current (HERG gene product)

NSR - Normal Sinus Rhythm

PSVT - Paroxysmal Supraventricular Tachycardia

VFib - Ventricular Fibrillation

VTach or VT - Ventricular Tachycardia

Three Primary Indications for Treatment of Cardiac Arrhythmias

Cardiac arrhythmias are a frequent problem in clinical practice. Not all arrhythmias require treatment with potentially

toxic antiarrhythmic drugs. Arrhythmias that typically require treatment fall into 3 basic categories:
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arrhythmias that decrease cardiac output (e.g. severe bradycardia, ventricular tachycardia or fibrillation)

arrhythmias that are likely to precipitate more serious arrhythmias (e.g. atrial flutter may lead to sustaine

ventricular tachycardia)

arrhythmias that are likely to precipitate an embolism due to creation of vascular stasis (e.g. chronic atria

fibrillation)

Other Therapeutic Modalities for Treatment of Arrhythmias

While drug therapy is still the most common method for treating arrhythmias, other non-pharmacological therapies arealso in current use. While detailed discussion of these treatments is beyond the scope of this course, they include:

DC cardioversion (wikipedia [http://en.wikipedia.org/wiki/Cardioversion]), implanting of a pacemaker, o

defibrillator device (ICD)

Carotid sinus massage ( vagal tone)

Surgical or catheter-mediated ablation of an ectopic focus, coronary bypass surgery

Lifestyle modification (avoiding events that aggravate an arrhythmia - e.g. exertion, emotional stress, non-idea

diet)

Commonly used procedure in Emergency Departments for patients with Paroxysmal SupraVentricular Tachycardi

(PSVT). Relatively safe, but should be avoided in patients with carotid artery disease rarely used alternatives include

the Valsalva maneuver, eye pressure (not real popular), placing the face in cold water, or giving a pressor agent.

The Most Commonly Used Antiarrhythmic Drugs

TABLE 1: Major Drug Categories

Drug Class Cellular Mechanism of Action Prototype Drugs

Ia Na channel blockers that APD Quinidine, Procainamide, Disopyramide

Ib Na channe l bl ock ers t hat sl ight ly APD Lidocaine, Mexiletine, Phenytoin

Ic Na channe l blockers that don' t change APD Propafenone, Flecainide

II -blockers Propranolol, Atenolol, Esmolol, Metoprolol

III P ro long A PD (K C hannel B lo ck ers) Amiodarone, Dronedarone, Sotalol, Ibutilide, Bretylium

IV L-type Ca channel blockers Verapamil, Diltiazem

Miscellaneous adenosine receptor agonist Adenosine

Miscellaneous vagal tone Digoxin

Amiodarone has Class I thru Class IV effects, but Class III effects seem to be most prominent.

Why Are There Different Classes of Antiarrhythmic Drugs?

Each class of antiarrhythmic drugs has different selective affinities for different cardiac ion channels and/o

adrenergic receptors.

Class I drugs: block cardiac Na channels (some drugs also block K channels see below).

Class II drugs: block beta-adrenergic receptors.

Class III drugs: block cardiac K channels (in particular the K channel that produces the rapidly activating K

current IKr).

Class IV drugs: block L-type Ca channels.

Note that the drugs in each class are only selective for blocking each ion channel or receptor subtype, and frequently

affect more than one channel or receptor. In particular, there is heterogeneity within the Class I drugs with regards to

their selectivity of effect on blocking Na channels vs K channels. These differences resulted in their grouping by

Vaughn-Williams into Class 1a, 1b & 1c subclasses based upon their in vitro effects on the ventricular action potentia

upstroke velocity (dV/dt-max) and action potential duration (APD) observed under normal physiological conditions

These in vitro effects result in corresponding effects on the QRS and QT durations in vivo:
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Figure 1. The effect of the subtypes of Class I drugs on the cardiac action potential & ECG intervals in the norma

heart in sinus rhythm. Drug effects on the action potential upstroke and conduction parameters in ischemic tissue

and/or at high heart rates is typically more significant.

TABLE 2: Class 1 Subclasses

Subclass QRS QT Currents

blocked Explanation

Ia Na & Kr Large block of both open Na & K Channels at normal heart rates, hence both QRS & QT affected

Ib Na High affinity for open & inactiv ated Na channels with rapid unbinding during diastol e, hence litt le cumulative

effect on QRS in NSR also blocks the small Na plateau current which shortens the APD

Ic Na Large block of open Na channels & very slow unbinding during diastole, QRS markedly prolonged during NSR

Class Ia drugs are those which prolong both the QRS and QT of the normal heart. These drugs prolong the QT an

cellular APD because they block the rapid potassium current (IKr) at therapeutic concentrations. In addition these

drugs also block cardiac Na channels in the open state, and then dissociate slowly & incompletely during diastoli

intervals in-between beats. Hence block accumulates with each successive beat, resulting in enough Na channel block

at normal sinus rates to significantly widen the QRS.

Class Ib drugs are those which have little effect on the QRS of normal heart hearts at normal heart rates, and

slightly shorten the QT. These drugs interact with sodium channels in both the open and inactivated state, bubecause the time that Na channels spend in the open state is so brief (~1 msec) under normal conditions, and because

Na channels remain inactivated for several hundred milliseconds during each action potential, the contribution of drug

interaction with inactivated channels is much greater than with open channels (Matsubara et al, 1987 Clarkson et al.

1988). Because most drug binding occurs after the upstroke, when Na channels are inactivated, and these drug

rapidly unbind at normal diastolic potentials, there is little residual Na channel block by the time of the next action

potential at normal heart rates (see below). (However, block can accumulate at very high heart rates, when th

diastolic interval is short, or when the diastolic membrane potential becomes significantly depolarized, as this slows the

rate of drug dissociation from Na channels)(Hume & Grant, 2012). In addition, because most of the interaction of clas

Ib drugs occurs during the plateau, they have very little effect on tissue with short action potential durations, such as

atrial tissue. In addition, atrial tissue is unlikely to become ischemic (due to differences in wall thickness & vesse

physiology). As a result, Class Ib drugs are ineffective in treating atrial tachy-arrhythmias at non-toxic

concentration . The slight reduction of the QT by Class Ib drugs results from their effect to block the small residua


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Figure 2. Three mechanisms by which antiarrhythmic drugs can affect automaticity. In the absence of drug th

ectopic pacemaker utilized Ih to spontaneously depolarize to threshold, more rapidly than the normal sinus pacemake

Class I antiarrhythmic drugs can decrease the automaticity of an ectopic pacemaker by either 1) blocking the Ipacemaker current (thereby decreasing the slope of diastolic depolarization), 2) shifting the threshold for action

potential generation to a more positive potential (increasing threshold) by blocking excitable Na channels, and/or 3

increasing APD (by blocking IKr). In this hypothetical example, ischemic damage to sympathetic nerves results in

denervation supersensitivity that increases the expression of beta receptors, and reduces the density of pre-synapti

neuronal NET (norepinephrine reuptake transporters), which makes the zone over-react to circulating catecholamine

during fight-or-flight situations. This creates at least a transient ectopic foci.

Treatment of Arrhythmias Induced by Abnormal Forms ofAutomaticity

Arrhythmias believed to be due to Early Afterdepolarizations (EAD's)(e.g. patients with drug-induced long QT syndrome or Torsade dePointes) are typically treated by correcting imbalances in K+ or Mg2+

levels, withdrawal of the drug suspected of causing the condition, orincreasing the heart rate by isoproterenol infusion or ventricularoverdrive pacing. Arrhythmias induced by DAD's (e.g. patients withdigitalis overdose or intracellular Ca overload) may be treated bycorrection of electrolyte (K or Ca) levels, blocking the effects ofcatecholamines, reductions in heart rate, lowering of plasma digoxinlevels, or administration of lidocaine or phenytoin to decrease Nainflux.

B. Increasing the ERP (by State-Dependent Binding to Na Channels)

Class I antiarrhythmic drugs and related local anesthetic drugs bind to a receptor site within the cardiac sodium


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channel. Since Na channels constantly fluctuate between 3 different states (Rested, Open and Inactivated) during each

cardiac cycle, the conformation of the Na channel and its drug receptor both undergo state-dependent conformationa

changes with each heart beat. Because of this, drug affinity for the Na channel & its binding site within the channel is

state-dependent - the affinity of drug for its Na channel receptor is different for each channel state. Class I drug

have a very low affinity for rested channels, but a high affinity for channels in either open or inactivated states.

Figure 3. The Modulated Receptor Hypothesis. Drugs (D) can bind to Na channels in their three primary state

(R:Rested O:Open and I:Inactivated). Clinically useful drugs have a low affinity for rested channels (as indicated by

the arrows), and a high affinity for Na channels when they are in either the open and/or inactivated state. As a result

drug binding occurs during an action potential when high affinity states are occupied, and drug dissociation occurs a

diastolic potentials when the low affinity rested state is occupied. The rate at which drug dissociation occurs is voltage

dependent because the kinetics of channel gating for drug-associated channels is voltage dependent, similar to drug

free channels, although the gating kinetics are much slower for drug-associated channels (Hondeghem & Katzung

1977 Hume & Grant, 2012).

The fraction of drug-occluded channels increases during each action potential upstroke and plateau phase (when

channels temporarily exist in high-affinity open and inactivated states). During diastole, the fraction of drug-occluded

channels decreases time-dependently as channels return to the low-affinity rested state. As a result, at therapeuti

drug levels there is a cyclical pattern of drug binding and unbinding that takes place during each beat of the heart (se

Figure 4)(Hondeghem & Katzung, 1977 Hume & Grant, 2012).

Each drug has its own unique characteristics in terms of its affinity for different channel states, and its kinetics o

binding and unbinding to each state. For example, recovery from channel block at a normal diastolic resting potentia

occurs with a time constant of a few hundred milliseconds for most Class Ib drugs (e.g. lidocaine), whereas the time

constants for unblocking by Ia drugs (e.g. 7 seconds for quindine) and Class Ic drugs (e.g. 20 seconds for flecainide) are

much longer. This tends to give each Na channel blocker somewhat unique properties at the cellular level.


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Figure 4. Modulated Receptor Hypothesis based computer-simulation of time-dependent changes in Na channel stateand lidocaine block of Na channels associated with the cardiac action potential. Lidocaine binds to Na channels in open

(O) and inactivated (I) states but has very low affinity for channels in the rested (R) state. As indicated (middle)

channels are in a rested state during diastole, open transiently during the upstroke, and are in an inactivated state

during the plateau. As shown at the bottom, all channels are in a drug-free state after a long rest, but lidocaine binding

to open and inactivated channels develops rapidly during the action potential. The extent of rapid open channel block is

clipped due to the open state being relatively short lived (~1 msec). Drug-channel interaction continues to progres

during the plateau as lidocaine binds to inactivated channels. In the absence of drug, Na channels normally rapidly

return to the rested (excitable) state at the end of phase 3 (with a time constant of ~20 msec), resulting in the end o

the ERP very near the end of the normal APD. However, the process by which excitability recovers is different in the

presence of drug, because a large fraction of Na channels become drug-associated during a single beat, and drug

dissociation during diastole is relatively slow compared to the recovery from inactivation of drug-free channels (e.g

lidocaine dissociates with a time constant of ~150 msec). This relatively slow process of unblocking extends the ERP to

well beyond the duration of the APD, and suppresses the formation of early extrasystoles. The time-dependent

dissociation of drug from channels also results in an accumulation of drug-associated (blocked) channels at high hear

rates where the unblocking process becomes incomplete in-between beats (the steady-state effect on the upstroke

velocity or conduction is hence rate-dependent). However, for lidocaine the process of drug dissociation is mostly

complete by the end of a normal diastolic interval, resulting in little cumulative block at the time of each action

potential upstroke at normal resting heart rates. Hence normal therapeutic concentrations of lidocaine have little effect

on the QRS, despite the fact that ~80% of Na channels become blocked by the end of a typical ventricular action

potential.

To summarize, there are three basic consequences of this state- and time-dependent nature of drug-channe

interaction in normal heart tissue:

1. Increase in ERP. A critical number of channels must exist in an unblocked rested state to allow conduction o

an action potential to occur. Since drug unbinding is not instantaneous, some channels will be blocked at the


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end of the action potential (see Figure 4). This decrease in the fraction of Na+ conducting channels at the end

of phase 3 will increase the effective refractory period to a time point beyond the end of the action potential (i.e

both the ERP and ERP/APD ratio increase). If the ERP is increased beyond the conduction time around a

reentrant circuit, reentry can no longer occur.

2. Selective block of early extrasystoles. Due to the time-dependence of drug unbinding, the fraction o

blocked channels will be greater during early vs. late diastolic intervals (see Figure 4). This can result in a

selective suppression of conduction of early extrasystoles. This selectivity is highest for Class Ib drugs, and

minimal for Class Ic drugs. The kinetics of drug unbinding during diastole also become slower as the resting

membrane potential is made more depolarized (see Figure 4). This leads to in an increased accumulation o

blocked channels in depolarized cells.

3. Dependence of drug effect on heart rate. As the heart rates is increased the diastolic interval will shorten

resulting in progressively incomplete drug unbinding, and a rate-dependent increase in drug effect to slow

conduction.

4. Selective depression of conduction in depolarized tissue. If the resting membrane potential become

depolarized, some channels will exist in a high-affinity inactivated state at all times. Since drugs bind tightly to

inactivated channels, this results in a selective depression of conduction in depolarized tissue (see Figures 5&6)

This can abolish reentry by converting a depolarized (partially ischemic) zone from a region of unidirectiona

block to a region of bidirectional block by making it totally inexcitable.

Figure 5. Effect of diastolic membrane potential on lidocaine dissociation from Na channels (channel unblocking

Normal ventricular tissue has a diastolic resting potential near -85 mV, whereas chronically ischemic tissue is more

depolarized (e.g. -60 mV). Upper right: the time constant for lidocaine dissociation from Na channels is highly voltage

dependent, with the time constant becoming progressively larger at more depolarized potentials. This is also illustrated

at the bottom which shows a pair of ventricular action potentials recorded from normal & ischemic tissue, and the


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percent of Na channels blocked by lidocaine as a function of time. There is a more marked drug effect in ischemic tissue

due to both an increased percentage of inactivated & blocked channels at depolarized potentials, and slower unbinding

kinetics following a previous action potential. Conduction it the sick (depolarized) tissue is selectively depressed. (Figure

is adapted from Sampson & Kass, 2011 and Hume & Grant, 2012).

Figure 6. Selective Depression of Excitability in Partially Depolarized Tissue. The graphs are reproduce

transmembrane recordings from an ischemic and normal zones of an epicardial ventricular muscle preparation showing

the effects of propafenone (2 ug/ml) perfusion for 30 minutes. The sketch at the top shows the recording sites. Lef

Panel: the ischemic myocardial cells in the absence of drug showed a more depolarized resting potential & reduce

action potential amplitude. Right Panel: propafenone produced a markedly larger depressant effect on action potentia

properties (upstroke velocity and amplitude) in the ischemic zone compared to normal tissue. Reproduced from RH

Zeiler et al. (Am J Cardiol 198454:424-429).

C. How Class I Drugs Prevent/Abolish Reentry

Most clinically significant arrhythmias are caused by reentry, and reentry has 3 primary criteria for it to occur:

Table 3: 3 Requirements for Reentry

1. Multiple conduction pathways

2. Unidirectional conduction block (conduction block in one direction, but not the other)

3. CT>ERP: Conduction time around the circuit must be greater than the ERP of any cell in the circuit

By substantially increasing the ERP (an effect that is typically largest in ischemic depolarized tissue), Class I drugs can

cause the ERP within the circuit to be greater than the conduction time around the circuit (abolishing criteria #3). In

addition, by reducing the excitability of ischemic zones, Class I drugs may also produce a conduction block in both


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directions, which would abolish criteria #2 as well. The take home message is, through their time & voltage-dependen

effect on Na channels, Class I drugs may reduce the likelihood that reentry can occur by increasing the ERP.

Figure 7. Effect of Class I antiarrhythmic agents on reentrant excitation. Left: Reentrant excitation in the absence o

drug. A region of subendocardial ischemia causes membrane depolarization and inactivation of Na channels

Consequently normal excitation delivered the Purkinje fibers is not strong enough to penetrate into healthy

myocardium below. Conduction progressively slows (as indicated by the wavy line) and eventually is blocked, producing

a block in one direction (unidirectional block) as indicated by the red line. Meanwhile the stimulus conducted by othe

normal pathways succeeds in depolarizing a large mass of ventricular tissue that can add together to produce a large

retrograde stimulus that can conduct slowly through the ischemic zone into the normal Purkinje tissue above, and

establish a reentrant circuit. This can produce a stable arrhythmia such as a ventricular tachycardia (VTach). Right

Class I drugs will selectively increase ERP and depress conduction, an effect that is more marked in depolarized tissue

(Figures 5&6). Class I drugs can also affect action potential duration to a variable extent (as indicated by the orange

arrow at top, right). Class Ia drugs block IKr to prolong the APD, an effect that also contributes to prolonging the ERP.

A Caveat on Tissue Selectivity - Class Ibs are effective only against ventriculararrhythmias:

Not all Class I antiarrhythmics are equally effective against atrial vs. ventricular arrhythmias.Class Ib drugs (lidocaine, mexiletine, phenytoin) are generally not effective againstsupraventricular arrhythmias. In contrast, Class Ia drugs (quinidine, procainamide) areeffective against both atrial and ventricular arrhythmias.

The proposed explanation for this difference is that Class Ib drugs bind primarily to Nachannels in the inactivated state, a state that Na channels exist in during the actionpotential plateau. Atrial cells have a very short plateau duration (e.g. 1/3rd the duration ofventricular myocytes). Only a small amount of Class Ib drug binding can therefore develop inatrial cells during normal sinus rhythm (in contrast to ventricular cells). Class Ia and Ic drugsbind much more extensively to open Na channels (a state occupied during the action


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potential upstroke), and their effect is therefore much less dependent on the length of theaction potential plateau.

The Curtailed Use of Class I Drugs - Following the CAST Trials

In 1986 the National Heart, Lung and Blood Institute instituted two Cardiac Arrhythmia Suppression Trials (CAST 1 &

2). In both trials Class Ic drugs encainide, flecainide & moricizine effectively suppressed asymptomatic ventricula

arrhythmias but increased arrhythmic death 3.6-fold compared to placebo-treated patients. (Encainide and moricizine

have since been withdrawn from the market). A meta-analysis of 61 randomized clinical trials involving 23, 486patients showed that the routine use of Class I drugs in high risk patients (e.g. survivors of myocardial infarction) i

associated with an increased risk of death (McAlister & Teo 1997). As a result, the current standard of care is tha

Class I drugs have no role in the prevention of cardiac arrhythmias (and sudden cardiac death) in post-

MI patients, and are not recommended in the primary prevention of sudden cardiac death (Zipes et a

2006). A hypothetical mechanism of drug-induced proarrhythmia is illustrated in Figure 8. At present, beta blockers

are the only antiarrhythmic drugs recommended for the prevention of sudden cardiac death in post-MI patients.

Figure 8. One possible mechanism for proarrhythmic side effects of Class I drugs. Left Panel: In the absence of drug

the presence of mild subendocardial ischemia is sufficient to slow conduction by partially inactivating Na channels, bu

is not enough to produce conduction block. This is a region that has the potential to produce reentry in the presence o

Na channel blockers, or worsening of ischemia. Right Panel: In the presence of a Class I drug, Na current amplitude i

reduced in the ischemic zone, resulting in conduction block for the wavefront coming from small Purkinje fiber

endings. Conduction succeeds from the opposite direction because of the much larger electrical stimulus produced by

depolarization of a large ventricular mass.

Clinical Indications for Class I Antiarrhythmics
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Table 4: Clinical Indications for Class I Drugs

Procainamide:

Most atrial and ventricular arrhythmias in patients without a history of

ischemic heart disease

Drug of 2nd or 3rd choice in the CCU for the treatment of sustained

ventricular arrhythmias following an MI (amiodarone & lidocaine are preferred)

Quinidine:

used primarily for malaria, but not for arrhythmias due to its side effects,

proarrhythmia & better drug options being availableLidocaine:

Drug of 2nd choice (vs amiodarone) to terminate VTach and prevent

VFib after DC cardioversion

Used only in a hospital setting (not effective orally)

Ineffective against atrial arrhythmias

Flecainide & Propafenone:

Supraventricular arrhythmias in patients without a history of ischemic heart

disease

Class II Drugs (-Blockers)

Beta blockers prevent or terminate tachyarrhythmias caused by increased sympathetic tone, excessively high levels o

circulating plasma catecholamines, or tissue supersensitivity to catecholamines. (The latter may develop following

myocardial infarction that damages sympathetic nerves within the wall of the heart, resulting in a denervation

supersensitivity in regions distal to the lesion.) By reducing the effects of catecholamines they may act to:

reduce pacemaker automaticity (by blocking catecholamine stimulation of Ih and ICa)

reduce Delayed After Depolarizations (DADs) by antagonizing adrenergic increases in Ca influx throug

L-type Ca channels. (Cai-overload may occur in ATP-depleted cells in an ischemic environment, or cells exposed

to toxic levels of digitalis)

Table 5: Clinical Indications for Class II Drugs (-blockers)

Prevent re-infarction & sudden death in patients with a history of CHF or MI

(clinical trials have documented a reduced risk of re-infarction & sudden or arrhythmic

death)

Treat exercise-induced arrhythmias

Prevent occurrence of AVN reentry (e.g. patients with Paroxysmal SupraVentricular

Tachycardia)

Control ventricular rate in patients with supraventricular tachyarrhythmias

by increasing the AVN ERP

Propranolol

Propranolol is a non-selective 1/2 blocker, and was the first beta blocker developed. Most beta blockers (selective or

non-selective) share similar clinical efficacy against cardiac arrhythmias.

Metoprolol

Metoprolol is a commonly used 1-selective beta blocker.

Carvedilol

Carvedilol is a nonselective 1/2 blocker that also blocks -receptors, IKr, and at higher doses blocks L-type Ca


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channels, the transient outward current (Ito) and IKs. In addition it has antioxidant effects and inhibits endothelin.

Class III Drugs (Drugs that Selectively Increase APD)

Class III drugs significantly prolong the action potential duration (APD) by blocking IKr (the rapi

component of the delayed rectifier current). Class Ia drugs also share this same effect. Prolongation of the APD

indirectly results in an increase in the ERP due to the longer plateau phase and the resulting delay i

repolarization. The increase in ERP is thought to be the primary mechanism by which Class III drugs (such

as amiodarone) can exert an antiarrhythmic effect - by making ERP greater than the Conduction Time around

reentrant circuit (Figure 9).

Figure 9.Effect of Class III antiarrhythmic agents on reentrant excitation. Left: Reentrant excitation is present at th

Purkinje fiber - Ventricular myocardial boarder. This can produce a sustained ventricular arrhythmia such as ventricula

tachycardia (VTach). Right: Class III agents block IKr and prolong the APD in the normal region of the heart, resulting

in an increased ERP. This effect can prevent or abolish reentry by making ERP greater than the conduction time (CT

around a reentrant circuit.

Extracellular Potassium & Ischemic Damage Reduce Class III Drug Effects

In direct contrast to Na channel blockers, Class III drugs (e.g. sotalol) have been shown to produce much less effect on

ischemic tissue compared to normal tissue (Figure 10A). The more pronounced the ischemic injury, or presence o

hyperkalemia, the less drug effect is observed (Patterson et al, 2007). These effects appear to be due to a combination

of mechanisms:

infarcted myocardial cells have a reduced expression of the IKr channel gene (Jiang et al, 2000) Class III drugs
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cannot produce an effect if their target is not expressed

hyperkalemia increases IKr amplitude (Yang & Roden, 1996)

hyperkalemia also independently reduces the effect of drugs that block IKr (e.g. quinidine & sotalol) by shifting

their dose-response curve to the right (Figure 10B)(Yang & Roden, 1996)

This can also explain why hypokalemia is associated with an increased likelihood for producing Torsade de pointes, since

it will increase drug effects to the point of producing early after depolarizations (EADs). This interaction can be

reproduced in both isolated Purkinje fibers and transmural myocardial preparations in vitro (Roden & Hoffman, 1985

Antzelevitch & Burashnikov, 2011).

Figure 10. Both ischemic injury and hyperkalemia reduce the effect of Class III drugs. Panel A: Microelectrod

recordings showing the effects of sotalol on normal epicardium and ischemically injured epicardium. Sotalol prolongs

the APD in normal tissue, but produces little effect in a region previously exposed to 4 days of ischemia in situ. Note

that the recording conditions, including potassium concentration (4 mM) were identical in both situations. (Adaptedfrom Patterson et al, 2007). Panel B: Concentration-response relationship for quinidine block of IKr in the presence o

different extracellular K concentrations. Raising external potassium significantly reduced the effect of quinidine, and

lowering potassium concentration intensified quinidine effect. Similar effects were observed with the IKr-selective

blocker dofetilide (Adapted from Yang & Roden, 1996).

Amiodarone & Dronedarone

The most commonly used Class III drug is amiodarone. It is also one of the most commonly used drug

for chronic treatment of arrhythmias. It is effective against both ventricular and atrial arrhythmias.

Amiodarone has some unusual characteristics including a very long half life of several weeks, and a relative lack

of selectivity between multiple antiarrhythmic targets. At therapeutic doses it blocks Na, K, and Ca


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channels, as well as and -adrenergic receptors. It is in essence a nonselective antiarrhythmicshotgun. While several of its multiple effects likely contribute to its clinical efficacy as an antiarrhythmic, its ability to

prolong the APD is considered to be most important by many, hence its classification as Class III drug.

Amiodarone has multiple effects on thyroid function that can cause either hypothyroidism (most commonly), o

hyperthyroidism. The structure of amiodarone contains two iodine molecules, and when taken at therapeutic dose

results in a large intake of inorganic iodine. The normal daily iodine intake is ~0.3 mg, whereas a normal 200 mg

maintenance dose releases 6 mg of iodine following hepatic metabolism. In normal patients, high levels of iodine

typically contribute to a transient inhibition of thyroid hormone synthesis due to an auto-regulatory mechanism within

the thyroid (the Wolff-Chaikoff effect). Amiodarone also blocks the conversion of T4 to T3 and one of its activ

metabolites blocks T3-receptor binding to nuclear receptors (Ross, 2012). These mechanisms are responsible fo

amiodarone's hypothyroid side effects.

In contrast, in iodine-deficient patients, or patients with latent Graves' disease the excess iodine from amiodarone

provides increased substrate, resulting in enhanced thyroid hormone production and hyperthyroidism (Ross, 2012).

Skin deposits of the drug can result in a photodermatitis that causes a gray-blue tint of the skin when exposed t

sunlight.

Corneal microdeposits are present in most patients, but are considered a benign side effect.

Pulmonary fibrosis is another (potentially lethal) side effect associated with amiodarone, and is seen primarily in

patients taking very high doses of the drug it is rarely seen with commonly used doses.

Dronedarone is a newer analog of amiodarone that lacks iodine atoms, and has a similar lack of selectivity fo

blocking different ion channels and adrenergic receptors. It has a half life of 24 hours, and lacks the thyroid andpulmonary toxicity. It has been approved by the FDA for the treatment of atrial fibrillation. The drug also carries a

black box warning against its use in acute decompensated or advanced (class IV) heart failure because of a

increased risk of mortality observed in clinical trials (Hume & Grant, 2012).

A Caveat on Drug Selectivity

Other antiarrhythmic drugs are not perfectly selective either. For example, at therapeuticdoses quinidine has a blocking effect on K and Ca channels, and in high doses Ca-channelblockers such as verapamil and diltiazem also block Na channels. Everything is relative,and it depends on the dose!

Sotalol

Sotalol is Class III antiarrhythmic that consists of a mixture of stereoisomers, one of which (d-Sotalol) selectively

blocks IKr, and the other (l-sotalol) is a non-selective beta blocker. The clinical use of sotalol has been limited by both

its antiarrhythmic efficacy (a common issue for most antiarrhythmics), and its Class III-related associated side effect o

Torsade de pointes (1.5-2% incidence). There is a Black Box Warning that when patients are to be initiated on sotalo

therapy, they should be monitored for at least 3 days in a facility that can provide cardiac resuscitation and continuou

electrocardiographic monitoring. It is indicated for both life-threatening ventricular arrhythmias and maintenance o

normal sinus rhythm in patients with atrial fibrillation/flutter.

Ibutilide

Ibutilide shares a similar ~2% incidence of producing Torsades de pointes. It is indicated as an i.v. injection for the

rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm. Patients with atrial arrhythmias o

longer duration are less likely to respond.

Table 6: Clinical Indications for Class III Drugs

Sotalol:

Adjuvant drug to reduce ICD (implantable cardioverter-defibrillator) shocks in

patients with an ICD

Drug of 2nd choice to prevent the re-occurrence of atrial fibrillation (rhythm

control)

Amiodarone:

Acute suppression of post-MI ventricular arrhythmias in the Coronary


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Care Unit

Adjuvant drug to reduce ICD shocks in patients with an ICD

Viable alternative in post-MI patients not eligible for (or have access to)

an ICD to prevent recurrent ventricular tachycardia (it does not produce an

increase in mortality in patients with coronary artery disease or heart failure)

Drug of choice to maintain normal sinus rhythm in patients with atrial

fibrillation (rhythm control)

Ibutilide:

Drug-induced conversion of AFib to normal sinus rhythm (with a short

term risk of producing Torsade)

Class IV Drugs (Ca Channel Blockers)

Ca channels behave much like Na channels: their behavior is voltage-dependent and is governed by movement o

activation and inactivation gates. However, Ca channels have a more positive threshold for activation, and slowe

kinetics of opening and inactivating. In normal atrial and ventricular cells, their primary function is to produce the

action potential plateau and modulate the strength of muscle contraction. However, in the more depolarized regions o

the SAN and AVN, they are also responsible for conduction and refractoriness.

There are at least two subtypes of Ca channels present in cardiac tissue (designated as L and T types). L type channels

are found in both ventricular and atrial cells, whereas T type channels are believed to also be expressed in the SA node

and AV node. L-type Ca channels are blocked by therapeutic levels of organic Ca channel blockers such as verapami

and diltiazem. These drugs block L-type Ca channels in a state-dependent manner much like Class I drugs

block Na channels. (As yet there are no clinically approved T-type Ca channel blockers). The primary cellula

mechanism of action of Ca channel blockers is to slow AVN conduction and increase the AVN ERP (see Figure 11)

Clinically, L-type Ca channel blockers are primarily used to:

Prevent re-occurrence (prophylaxis) of AVN reentry (by AVN ERP) e.g. Paroxysmal SupraVentricula

Tachycardia

Control ventricular rate in patients with atrial tachyarrhythmias (by AVN ERP)


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Figure 11. Effects of 10-20 mg diltiazem (D), 10 mg verapamil (V) and 1 mg nifedipine (N) on the ERP of the AVN iclinical cases. Thick red lines denote mean values. C=control. The direct suppressive effect of nifedipine on the AVN i

overcome by a reflex increase in sympathetic tone as the result of a fall in blood pressure. Nifedipine is a more poten

hypotensive agent than diltiazem or verapamil. (Adapted from C. Kawai et al. Circulation, 63:1035-1042, 1981.)


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Figure 12. Treatment of Paroxysmal SupraVentricular Tachycardia (PSVT) caused by AV node reentry. Left PanelReentry can occur in the AV node when a dispersion of refractory periods develops in different pathways due to

acquired or congentital pathology (see arrhythmias). Events that increase vagal tone will transiently increase the AV

node ERP and can break a reentrant circuit. These include carotid artery massage or performing a Valsalva maneuver

Adenosine i.v. is the recommended treatment for acute conversion of AV nodal reentry back to sinus

rhythm. Non-dihydropyridine calcium channel blockers and beta blockers are used prophylactically to

prevent the recurrence of PSVT. Right Panel: Reestablishment of normal sinus rhythm in response to an increas

in AV node ERP, and breaking the reentrant loop. ECG recording obtained from wikipedia[http://en.wikipedia.org/wiki/File:SVT_Lead_II-2.JPG]

Table 7: Clinical Indications for Class IV Drugs

Verapamil & Diltiazem:

Prophylaxis against re-occurrence of Paroxysmal Supraventricular

Tachycardia (PSVT)

Drugs of 2nd choice after adenosine for acute conversion of PSVT to sinus

rhythm (adenosine has better outcomes & less severe or prolonged side

effects)

Control of ventricular rate in patients with chronic atrial

fibrillation/flutter)

Prevent acute MI secondary to coronary artery spasm

Treatment of idiopathic outflow tract VT

Verapamil-sensitive idiopathic left ventricular fascicular VT

Alternative drugs for treatment of catecholaminergic polymorphic VT in

patients intolerant to beta-blockers
http://en.wikipedia.org/wiki/File:SVT_Lead_II-2.JPGhttp://tmedweb.tulane.edu/pharmwiki/doku.php/cellular_basis_for_arrhythmias


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Adenosine

Adenosine i.v. is the preferred treatment for ACUTE drug-induced conversion of AV node reentry to sinu

rhythm. Adenosine has a half life of a few seconds, and produces an effect on the AV node that is essentially identica

to that of acetylcholine. Adenosine binds to adenosine receptors in heart tissue and activates the same G-protein

modulated signal transduction pathway as does acetylcholine (including activation of a large G-protein modulated

potassium conductance). Adenosine has a higher success rate in converting patients with PSVT back to sinus rhythm

and side effects that are short lived compared to verapamil or diltiazem.

Note that maneuvers to abolish the arrhythmia by increasing vagal tone (such as carotid sinus massage or a Valsalva

maneuver) are typically attempted first before deciding to administer adenosine or other drugs. Drugs are used if these

attempts are unsuccessful. In addition DC cardioversion can be used if the patient is hemodynamically unstable, and

requires immediate treatment.

Digoxin (Increased Vagal Tone)

Although not classified as an antiarrhythmic agent, low doses of digoxin produces a cardioselective increase in vaga

tone to the heart. This effect results from multiple effects of digoxin including:

sensitization of baroreceptors

stimulation of central vagal nuclei

facilitation of muscarinic transmission at the neuro-cardiac junction

An increase in vagal tone will increase the AVN ERP and decrease automaticity in areas where vagal innervation is rich

(primarily in the SAN and atria). Digoxin is often used in the treatment of patients with systolic heart failure who

have atrial fibrillation, to slow ventricular rate to


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Figure 13. Effect of quinidine on atrial and ventricular rate when used alone to treat atrial flutter. A dog was placeunder alpha-chloralose anesthesia and atrial flutter was induced by programmed electrical stimulation of the atrium a

a frequency of 20 Hz after first crushing the atrial muscle between the superior and inferior vena cavae. The atria

flutter was stable with an atrial rate of 400 beats/min. The ventricular rate was stable at 200 beats/min due to a 2:

AV block. An i.v. infusion of 3 mg/kg quinidine was administered whereupon the atrial rate began to diminish

However, at the same time the ventricular rate also rose dangerously high to near 300 beats/min as the degree of AV

block diminished to near 1:1. Shortly afterwards there was an arrest of the atrial flutter, and both atrial and ventricula

rates fell to a stable level of 120-150 beats/min. Repeated attempts to re-initiate flutter (S) were unsuccessful. Th

experimental preparation closely duplicates the response in clinical cases. (Reproduced from Goodman & Gilman's The

Pharmacological Basis of Therapeutics, 5th edition, 1975.)

Negative Inotropic Action

This side effect is especially important when treating patients with systolic heart failure (low ejection fraction). Drugs

with a clinically significant negative inotropic effect (in decreasing order of severity) include:

Ca channel blockers (verapamil, diltiazem)

-blockers (propranolol)

Class Ia drugs (disopyramide, quinidine, procainamide)- which partially block L-type Ca channels

Bronchoconstriction

Important in patients with asthma.

drugs with -2 blocking actions (propranolol, higher doses of -1 selective blockers)


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Neurologic side effects (stimulation or depression, convulsions)

Class Ib drugs (lidocaine, phenytoin, mexiletine)

Proarrhythmia (producing new arrhythmias)

Class I & Class III antiarrhythmics have the ability to produce new arrhythmias by several possible mechanisms

(Average incidence is 10%). These include:

converting an area of depressed conduction in partially depolarized tissue to one of unidirectional block, which

would mimic the same event that can be produced by worsening of ischemia (see Figure 8).

increasing the dispersion of refractoriness (variability of ERP values in different regions of the heart) a

condition that predisposes the heart to reentry whenever there are multiple conduction pathways present, as

illustrated by reentry that can occur in the AV node (see Fig 5B&C in the Arrhythmia wiki document).

production of Early After Depolarizations (EADs). EADs are widely believed to be the mechanism underlying the

formation of Torsade de Pointes

Drugs, EADs, Dispersion of Repolarization & Torsade

Torsade can be produced by more than 40 drugs that block IKr (the rapid component of repolarization current in

ventricular myocytes). This includes Class Ia & most Class III drugs. Quinidine syncope(fainting) is typically causeby this arrhythmia. This is one reason why patients being initialized on most Class Ia or Class III drugs are hospitalized

for the first day or two when initializing treatment (when this event is most likely to occur). Amiodarone is an

exception it has a very low incidence of producing Torsade, perhaps because it behaves like a pharmacologica

shotgun - it blocks multiple currents, including those that contribute to the depolarizing upstroke of action potentials

that produce EADs. Torsade is potentially life-threatening and is treated as a medical emergency.

Several lines of evidence implicate that either Early After Depolarizations (EADs) or enhanced transmural dispersion o

repolarization can result in the triggered activity that is the genesis of Torsade de pointes:

The conditions that elicit EADs in tissue preparations in vitro (slow stimulation rates, low extracellular potassium

levels, and treatment with APDprolonging drugs)(Fig 14A) are also associated with a higher incidence o

Torsade de pointes in patient populations.

Heterogeneity in action potential duration results in a myocardium that is more vulnerable to reentranexcitation, a second likely cause of torsade de pointes. As illustrated in Figure 14B, M cells have an action

potential duration that prolongs disproportionately compared to other cell types in response to a slowing of hear

rate and/or the presence of drugs that prolong the APD (Anzelevitch & Burashnikov, 2011). M cells are

sensitized to the effects of APD-prolonging drugs (e.g. blockers of IKr) due to a larger expression of both an

inward plateau Na current and a Na-Ca exchange current, and a smaller slow potassium current (IKs) compared

to other ventricular myocytes (Anzelevitch & Burashnikov, 2011). Hypokalemia would also increase the effect o

APD-prolonging drugs (see Fig 15B).
http://tmedweb.tulane.edu/pharmwiki/doku.php/cellular_basis_for_arrhythmias#psvt


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Figure 14. Two proposed mechanisms for formation of Torsade. Panel A: Isolated Purkinje fiber preparation. Th

combination of APD-prolonging drugs, hypokalemia and bradycardia can result in the formation of EADs and TriggereBeats in isolated Purkinje fiber preparations. EADs develop when the balance of currents active during phase 2 or 3

shifts in the inward (vs. outward) direction. Panel B: Slowing of the heart rate in the presence of an APD-prolongin

drug can enhance the normal transmural dispersion of repolarization that normally exists between mid

myocardial cells (M cells) and epicardial or endocardial cells (Antzelevitch & Fish, 2001). Cells from the mid-wall region

have a longer APD compared to endocardial or epicardial cells, and greater sensitivity to the effects of APD-prolonging

drugs. Under the combination of such drugs and slowing of the heart rate, the M cell APD widens disproportionately

resulting in an abnormally large dispersion of APD values between regions (as indicated by the width between the two

vertical lines). A dispersion of repolarization can induce a spread of current from the depolarized M cell region to th

epicardial region that has regained its excitability (Antzelevitch & Burashnikov, 2011). The source for depolarization can

be either the L-type Ca current, Na-Ca exchange current, or a late plateau Na current (indicated by the red arrow)

(Figure modified after Roden, 2004).

Drug Specific Side Effects

Class Ia

Quinidine

Cardiac:

negative inotropic action

vagolytic

snycope and Torsade de pointes

Non-Cardiac:


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Cinchonism (tinnitus, visual disturbances, hearing loss, g.i. upset)

g.i. upset (nausea, vomiting, diarrhea) w/o cinchonism

thrombocytopenia

hypersensitivity reactions

Procainamide

Cardiac:

Negative inotropic action similar to quinidine

Weak ganglionic blocking effect that is vagolytic & can cause hypotensionProcainamide is converted to N-acetylprocainamide (NAPA) which has Class III actions (including

proarrhythmia) and has a longer half life than procainamide. NAPA levels accumulate with chronic

therapy

Non-Cardiac:

Lupus erythematosus-like syndrome that occurs in 20-25% of all patients on drug therapy for mor

than 1 year

Class Ib

Lidocaine

Non-Cardiac:

CNS excitation and/or depression (drowsiness, dissociation), nausea, tremor, vertigo, metallic taste

numb lips, visual and hearing disturbances.

High concentrations (> 9 g/ml) may cause convulsions & respiratory depression/arrest inhibitory

centers in the CNS are typically inhibited first, resulting in seizure activity respiratory depression occur

at higher doses

Class Ic

Propafenone

Cardiac:proarrhythmia in patients with ischemic heart disease

beta-blocking effect can cause 1st or 2nd degree AVN block

Non-Cardiac:

aggravation of bronchospasm

Class II

Propranolol

bradycardia, hypotension, left ventricular failure, AVN block, bronchospasm

Class III

Amiodarone

corneal microdeposits in most patients

peripheral neuropathy

PULMONARY FIBROSIS (rare with normal therapeutic doses, but potentially fatal)

disturbed thyroid function (hypo- or hyper-thyroidism)

photosensitivity with blue-gray discoloration

may precipitate heart failure

very rare incidence of Torsade de Pointes (compared to other drugs)


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Dronedarone

lacks iodine & thyroid side effects

Sotalol

non-selective beta blockade (one enantiomer is a beta-blocker, the other blocks IKr)

Torsade de pointes

Ibutilide

Torsade de pointes in 4-8% of patients (reserved for acute conversion of AFib to sinus rhythm)

Class IV

Verapamil & Diltaizem

Cardiac:

negative inotropic, AVN block, sinus arrest,

Non-Cardiac:

peripheral vasodilation, constipation

Misc

Adenosine

transient ~10 second depression of SA node & AV node, hypotension

syncope (administer with patient in a horizontal position!)

Treatment of Atrial Fibrillation Antiarrhythmics in ClinicaContext

Atrial fibrillation (AFib) is the most common cardiac arrhythmia, currently affecting more than 2 millionAmericans. It is rarely a one-time event. Patients who develop AFib once tend to be predisposed to developing it again

& again (which is what is meant by the phrase AFib begets AFib). Current research indicates that this is primarily

due to a change in the expression of ion channels that is caused by fibrillation (which may be mediated by changes in

intracellular calcium caused by rapid pacing). This electrical remodeling creates an electrical substrate that is

conducive to producing reentry. Some of the characteristics associated with AFib are:

Symptoms: palpitations, dyspnea, fatigue, decreased exercise tolerance, chest pain

ECG: lack of P waves, irregularly irregular timing between QRS complexes & pulse pressure. The QRS complex

& T waves are typically normal in duration & shape

Risk factors: hypertension, age, CHF, previous AFib

Associated Pathology: atrial dilation, fibrosis, myocyte apoptosis

Complications: thromboembolism (due to vascular stasis in left atrium) & strokeCommon Origin & Mechanism: in patients with heart failure, an electrical focus around a lef

pulmonary vein combined with an abnormal atria ablation of tissue around the pulmonary vein is one

form of current therapy for patients with combined AFib & heart failure (Khan et al., 2008).

There are two approaches to the treatment of AFib: rate control, allowing AFib to persist but controlling the

ventricular rate by drugs affecting the AV node ERP, and rhythm control with cardioversion to normal sinus rhythm

& chronic treatment with antiarrhythmic drugs to prevent the reoccurrence of AFib.

Arguments in favor of rate control include: 1) its easily achievable in most patients 2) avoidance of use o

antiarrhythmic agents with less desirable side effects/toxicity 3) risk of stroke can be reduced by anticoagulan

therapy.

Arguments in favor of rhythm control include: 1) rhythm control reduces the odds of thromboembolism 2)


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was thought that patients who remain in AFib have a worse outcome than those treated with drugs that maintain a

sinus rhythm. (Of course! Who would argue with that?.but what does the evidence say???)

In 2008, the results of two studies, one in North America, and one in Europe were published in the New England

Journal of Medicine. In both studies, rhythm control provided no advantage over ventricular rate control with respect to

survival (Fig 15A). On the basis of these results, rate control is currently considered an equally safe approach for the

treatment of AFib, and rhythm control (if it is used) can be abandoned early if it is not fully satisfactory (e.g. th

patient cannot tolerate the side effects of the drugs used to suppress AFib). Surgical procedures (e.g. Mini Maze

procedure) [http://youtu.be/DWXvDXXflmc] involving catheter ablation of ectopic foci around the pulmonary veins ma

also be successful in patients with otherwise relatively normal hearts.

Figure 15.Panel A: Kaplan-Meier Estimates of Death from Cardiovascular Causes (Primary Outcome). Among 137

patients with atrial fibrillation and congestive heart failure who were followed for a mean of 37 months, 182 patients

(27%) in the rhythm-control group died from cardiovascular causes, as compared with 175 patients (25%) in the rate

control group (hazard ratio, 1.06 95% confidence interval, 0.86 to 1.30). (From Roy et al, 2008). Panel B: Kaplan

Meier Estimates of the Percentage of Patients Remaining Free of Recurrence of Atrial Fibrillation in the two treatmen

groups (hazard ratio for recurrence among patients in the amiodarone group, 0.43 [95 percent confidence interval

0.32 to 0.57]). Follow-up began 21 days after randomization (designated day 0). (From: Roy et al, 2000).

Currently amiodarone appears to be superior to other antiarrhythmics in preventing the reoccurrence o

AFib (Figure 15B).

Initial conversion from AFIb to sinus rhythm can be achieved by either DC defibrillation or by an i.v. bolus of the drug

Ibutilide (a Class III drug which typically isnt used for any other indication due to high risk of Torsade de pointesTorsade occurs within a few hours in ~2% of patients given a single bolus of ibutilide.) Patients who are placed on rate

control treatment are typically given maintenance therapy with either verapamil, diltiazem, a beta blocker or digoxin

(digoxin use is more common if the patient has systolic HF).

WARNING: Patients who have had AFib for more than 2-3 days duration must be adequately

anticoagulated, generally for 2 weeks prior to attempting cardioversion. If emergency cardioversion

considered, a transesophageal echocardiogram can be used to determine the presence or absence of left atrial thrombi

Treatment Summary
http://youtu.be/DWXvDXXflmc


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References:

Antzelevitch C, Burashnikov A (2011): Overview of basic mechanisms of cardiac arrhythmia. Card Electrophysio

Clin 3(1): 23-45.

Antzelevitch C, Fish J (2001): Electrical heterogeneity within the ventricular wall. Basic Res Cardiol 96:517-527

Clarkson CW, Follmer CH, et al (1988): Evidence for two components of sodium channel block by lidocaine in

isolated cardiac myocytes. Circ Res 63(5):869-78.

Hondeghem LM, Katzung BG (1977): Time- and voltage-dependent interactions of antiarrhythmic drugs with

cardiac sodium channels. Biochim Biophys Acta 472:373-398

Hume JR, Grant AO (2012) [http://libproxy.tulane.edu:2048/login?url=http://www.accessmedicine.com/content.aspx

aID=55822358]: Agents used in cardiac arrhythmias (Chapter 14). In: Basic and Clinical Pharmacology. 12e

Katzung BG, Masters SB, Trevor AJ (Editors). McGraw-Hill / Lange.

Kawai C, Konishi T et al (1981): Comparative effects of three calcium channel antagonists, diltiazem, verapam

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Khan MN, Jais P et al (2008): Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Eng

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Patterson E, Scherlag BJ, Lazzara R et al (2007): Electrophysiologic actions of d,l-sotalol and GLG-V-13 in

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Roden DM, Hoffman BF (1985): Action potential prolongation and induction of abnormal automaticity by low
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quinidine concentrations in canine Purkinje fibers: relationship to potassium and cycle length. Circ Res. 56:857

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Roden DM (2004): Drug-induced prolongation of the QT Interval. New Engl. J. Med. 350:10131022.

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Roy D, Talajic M et al (2000): Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atria

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