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BASIC SCIENCE REVIEW

Pharmacotherapy of Cardiac Arrhythmias—BasicScience for Clinicians

JUAN SHU, M.D.,*,# JUN ZHOU, M.D.,†,# CHINMAY PATEL, M.D.,‡

and GAN-XIN YAN, M.D., PH.D.*,‡,§From the *The First Hospital of Xi’an Jiaotong University, Xi’an, China; †Department of Pharmacology, School of Medicine, Xi’an Jiaotong University, Xi’an, China; ‡Main Line Health Heart Center and Lankenau Institute forMedical Research, Wynnewood, Pennsylvania; and §Jefferson Medical College, Thomas Jefferson University,Philadelphia, Pennsylvania

Cardiac arrhythmias occur in approximately 5.3% of the population and contribute substantially tomorbidity and mortality. Pharmacological therapy still remains the major approach in management of pa-tients with nearly every form of cardiac arrhythmia. Effective and safe management of cardiac arrhythmiaswith antiarrhythmic drugs requires understanding of basic mechanisms for various cardiac arrhythmias,clinical diagnosis of an arrhythmia and identification of underlying cardiac diseases, pharmacokinetics,and antiarrhythmic properties of each individual antiarrhythmic drug. Most cardiac arrhythmias occur via one of the two mechanisms: abnormal impulse formation and reentry or both. Antiarrhythmic drugs

primarily work via influencing cardiac automaticity or triggered activity or by their effects on effectiverefractoriness of cardiac cells. Proarrhythmic effects of antiarrhythmic drugs are also briefly discussed inthis review article. (PACE 2009; 32:1454–1465)

antiarrhythmic drugs, arrhythmias, atrial fibrillation, automaticity , reentry , triggered activity

Introduction

The heart functions as a pump, moving the blood through the circulatory system. Normalpump function of the heart is not only depen-dent on its mechanical properties but also requiresproper impulse propagation through its special-ized conducting system that brings about the syn-

chronized contraction and relaxation. Abnormalgeneration and propagation of the electrical im-pulses, i.e., cardiac arrhythmias, occurs approx-imately in 5.3% of the population, or 14.4 mil-lion people annually in the United States alone,and profoundly affects morbidity and mortality(www.wrongdiagnosis.com/lists/preval.htm). De-spite recent advances in invasive electrophys-iologic interventions, pharmacotherapy still re-mains the primary approach in the managementof various cardiac arrhythmias.

Optimal management of cardiac arrhythmiaswith antiarrhythmic drugs requires an in-depthknowledge of the following key aspects: (1) mech-anisms for the initiation and maintenance of var-ious cardiac arrhythmias; (2) clinical diagnosisof an arrhythmia and identification of underly-

#The authors have contributed equally to the work.

Address for reprints: Juan Shu, M.D., The First Hospitalof Xi’an Jiaotong University, Xi’an 71006, China. E-mail:[email protected]

Received June 29, 2009; accepted July 29, 2009.

doi: 10.1111/j.1540-8159.2009.02526.x

ing cardiac diseases; (3) pharmacokinetics of indi-vidual antiarrhythmic drugs; and (4) antiarrhyth-mic and proarrhythmic properties of individualdrugs. Identification of patients that require in-vasive electrophysiologic intervention and theirtimely referral to an arrhythmia specialist is alsoimperative.

This review article will encompass a brief discussion of the cellular mechanisms of ar-rhythmogenesis, diagnosis of common cardiacarrhythmias, pharmacokinetic and electrophys-iologic properties, and classification of antiar-rhythmic drugs. Management of common cardiacarrhythmias with antiarrhythmic drugs is dis-cussed in the later part of the article. We attemptto provide adequate practical information to facil-itate optimal use of antiarrhythmic drugs for com-monly encountered cardiac arrhythmias.

Mechanisms Underlying Cardiac Arrhythmias

The origin cardiac arrhythmias and drug-induced proarrhythmias can be divided in two ma-jor categories: abnormal impulse formation (i.e.,enhanced automaticity and triggered activities)and reentry (Fig. 1).1 Some arrhythmias may orig-inate via one mechanism and are then maintainedvia other. For example, torsades de points (TdP)is precipitated by early afterdepolarization (EAD)-induced triggered activity and then maintained viareentry. All of the arrhythmic drugs have an ef-fect either on one or more membrane ion currents,or on a cardiac receptor that indirectly alters ion

C2009, The Authors. Journal compilation C2009 Wiley Periodicals, Inc.

1454 November 2009 PACE, Vol. 32



MANAGEMENT OF CARDIAC ARRHYTHMIA

Figure 1. Classification of cardiac arrhythmias according to predominant cellular mechanisms.Note that cellular mechanisms for some arrhythmias may be multiple. For example, arrhythmiaslike atrial fibrillation and torsades de pointes originate via triggered activity but are maintained by reentry. (Modified and reproduced with permission from Antzelevitch.1)

currents. Their antiarrhythmic effects are con-ferred by their effects on cardiac automaticity ortriggered activities, prolonging action potential ef-fective refractoriness, or changing properties of

specialized conduction tissue such as the sino-atrial node (SA) or the atrio-ventricular (AV) node.This section will provide a brief overview of ionicand cellular mechanisms underlying arrhythmo-genesis and also antiarrhythmic and proarrhyth-mic effects of drug.

Abnormal Impulse Formation

Abnormal Automaticity

Some cardiac cells, including SA node, AVnode, and His-Purkinje fibers, possess theability togenerate spontaneous action potentials under nor-mal conditions—so-called pacemaker cells. Under

normal conditions, SA node displays the high-est intrinsic rate and hence, governs the normalheart rate. The intrinsic rate of SA node can be en-hanced by β-adrenergic agonists or slowed down

by an increase in parasympathetic tone. Normalautomaticity of cardiac cells is the consequence of spontaneous diastolic depolarization caused by anet inward current during phase 4 of action poten-tial. Abnormal automaticity, which is due to eitherenhanced normal automaticity or spontaneous ac-tivity in ventricular and atrial myocardium, mayoccur with heightened β-adrenergic tone, or dur-

ing reduced resting membrane potentials such asischemia or infarction (Fig. 2A).1,2

Cardiac arrhythmias originating principallydue to enhanced automaticity include focal atrial

tachycardias, junctional tachycardias, and accel-erated idioventricular rhythm.1

Afterdepolarization and Triggered Activity

Afterdepolarization can be divided into twosubclasses: EADs and delayed afterdepolariza-tions (DADs). EADs are the oscillatory potentialsduring action potential phase 2 or phase 3 prob-ably due to ICa,l reactivation.1,3,4 EADs classicallyoriginate from M cells or endocardial cells in set-ting of disproportional action potential prolonga-tion due to drugs that block IKr; however, it can

be seen in the setting of altered electrolytes, hy-

poxia, acidosis, increased catecholamines, and un-der conditions of ventricular hypertrophy or heartfailure.5,6 Such EADs not only increase the disper-sion of repolarization but can propagate and gener-ate new action potential in nearby cells manifest-ing as an R-on-T ectopic that is capable of initiatingTdP (Fig. 2C).5

DADs are oscillations of the membrane thatoccur after completion of repolarization and areproduced by enhanced Na+/Ca++ exchange cur-rent secondary to oscillatory release of calciumfrom the sarcoplasmic reticulum under conditions

PACE, Vol. 32 November 2009 1455



SHU, ET AL.

Figure 2. Cellular mechanisms of abnormal impulse formation. (A) Normal automaticity of spontaneously depolarizing pacemaker cell is shown in solid lines.When progressive increase in net inward current during phase 4 of repolarization reaches the threshold

of intracellular calcium overload, such as withthe use of digitalis or extensive sympatheticstimulation (Fig. 2B).7,8 Faster cardiac pacingoften terminates arrhythmias mediated via EADs

but accelerate or precipitate the arrhythmia driven by DADs.

Clinical arrhythmias caused by DAD-inducedtriggered activity include paroxysmal atrial tachy-cardia, fascicular tachycardia, and bidirectionalventricular tachycardia (VT) in the setting of digitalis toxicity; idiopathic ventricular tachycar-dia; and possibly exercise-induced, adenosine-sensitive ventricular tachycardia.1 Antiarrhyth-mic drugs like calcium channel and β-adrenergic

blockers suppress DADs and, therefore, DAD-mediated arrhythmias.

Reentry

The electrical cycle of cardiomyocyte consistsof two phases: depolarization and repolarizationand this cycle is initiated by an impulse originat-ing from SA node. Whereas complete depolariza-tion of the entire heart takes only about 80 ms, therepolarization lasts for more than a couple hun-dred milliseconds. During repolarization phase,the cardiac cells are refractory to new electrical ex-citation. Hence, the first electrical impulse dies outafter normal activation of the heart before the sec-ond sinus impulse arrives. Reentrant arrhythmiasoccur if a propagating impulse fails to extinguishand causes re-excitation of the cardiac tissues that

potential (solid red line), it leads to opening of fast sodium channel and generates action potential. In-creasedautomaticity leads to higherrate of spontaneous

firing than normal (dashed lines). (B) Delayed afterdepolarization (dashed lines) are spontaneous oscillationsof membrane after completion of repolarization. Whenit reaches the threshold potential (solid red line), it initi-ates spontaneous action potential. (C) Early afterdepo-larization (dashed line) is spontaneous membrane os-cillation during phase 3 of repolarization. Upper cell (dashed line) that fails to complete repolarization due to

EADs, causes the lower cell (solid line) to fire repeatedly generating extra beats. (D) Reentry generating extra beat between tissue planes I and II. As shown in figure, action

potential A (in tissue plane I) excites the tissue plane II,giving rise to B. Before dying out, B can re-excite tissue

plane 1 (dashed red arrow) and give rise to C (dashed black line). Actionpotential C can travelback to plane 2,giving rise to D, thus causing sustained rhythm. In or-der for this to maintain, time required by an impulse totransverse the circuit should be longer than refractory

period of the potentially re-excitable tissue. (Modified and reproduced from Nattel and Carlsson.46)





have regained excitability after expiration of theeffective refractory period (Fig. 2D). Reentry can

be divided into two categories based on reentrantroutes: anatomic and functional.1

The development of a reentrant arrhythmiavia an anatomical reentrant circuit is dependenton (1) penetration of an electrical impulse into thereentrant circuit in which unidirectional conduc-tion block is present, and this unidirectional blockis functional; (2) the wavelength of the reentrantimpulse; and (3) the size of the circuit that is nor-mally constant. The wavelength of the reentrantwavefront is equal to the product of the conduc-tion velocity times the effective refractory periodof myocardial tissue in the pathway. The wave-length of the reentrant wavefront should be signif-icantly less than the pathlength so that a spatial ex-citable gap is present between the crest and the tailof the reentrant wavefront for the maintenance of

circus movement. Therefore, slow conduction likemyocardial ischemia facilitates the developmentof reentrant arrhythmias by reducing the wave-length of the circulating wavefront, so that reentrycan occur in a small circuit.

Functional reentry occurs without the in-volvement of anatomic obstacles and is commonlyassociated with the presence of enhanced disper-sion of repolarization. It should be emphasizedthat the first electrical impulse that enters the reen-trant circuit can be generated by enhanced au-tomaticity or by triggered activity. For example,atrial fibrillation (AF) can be initiated by triggeredactivity in the pulmonary veins and sustained by

functional reentry.9

Reentrant arrhythmias include sinus nodalreentry, atrial flutter, AF, some forms of atrialtachycardia, AV nodal reentry, AV reentry,monomorphic ventricular tachycardia due to scartissues of myocardial infarction or surgery, ven-tricular fibrillation (VF), and polymorphic ventric-ular tachycardia.

Proarrhythmias

Proarrhythmic and antiarrhythmic effects of a drug are the two sides of the same coin. An-tiarrhythmic drugs that are intended to suppress

arrhythmias may potentially worsen a preexistingarrhythmia or cause a new arrhythmia. The mech-anisms responsible for cardiac arrhythmias arecomplicated, and any intervention may be antiar-rhythmic in some circumstances and proarrhyth-mic in others.

Atrial Proarrhythmias

When class I antiarrhythmic drugs are usedfor the treatment of supraventricular tachycardia,they can cause atrial flutter, often with slower rates(approximately 200 beats/min). This is classically

seen in patients with AF treated with class Ic drugslike flecainide and propafenone that markedlyslow the propagating velocity of reentrant wave-fronts. Because sodium channel blockers have lit-tle effect on AV node, atrial flutter in such casemay be associated with 1:1 AV conduction withsignificantly high ventricular rate. This tachycar-dia sometimes mimics ventricular tachycardia es-pecially when there is widening of the QRS com-plex as a result of use-dependent inhibition of thefast sodium current. Therefore, dosing with an AVnodal blocking agent should be considered with asodium channel blocker in patients with AF andintact AV nodes.

Similarly, digitalis may promote the develop-ment of AF by shortening atrial effective refractoryperiod. In addition, digitalis toxicity may resultin the development of DAD-mediated paroxysmalatrial tachycardia.

Ventricular Proarrhythmias

They can generally be divided into two cat-egories based on mechanisms and electrocardio-graph (ECG) features: monomorphic ventriculartachycardia and TdP.

Class Ic drugs have the highest propensity tocause monomorphic ventricular tachycardia thatmay degenerate to ventricular fibrillation, leadingto increased mortality in patients with coronaryartery disease and left ventricular systolic dys-function.10–12 Myocardial ischemia seems to playa pivotal role in the genesis of proarrhythmia withclass Ic drugs.

TdP occurs under conditions of QT intervalprolongation.6,13 A typical example is “quinidinesyncope” in patients who have taken quinidinefor the treatment of AF and experienced recurrentsyncope or cardiac arrest as a result of QT pro-longation and TdP. The incidence of TdP associ-ated with the use of class Ia and III antiarrhythmicdrugs that prolongs QT varies among individualagents. Interestingly, amiodarone, a commonlyused class III antiarrhythmic drug, significantlyprolongs the QT interval but rarely causes TdP.

Marked QT prolongation and resultant TdPare more likely to occur in patients with reduced

repolarization reserve.14

Clinical diseases orconditions that are associated with reducedrepolarization reserve include congenital long QTsyndrome, bradycardia, female gender, ventric-ular hypertrophy, electrolyte disturbances, suchas hypokalemia and hypomagnesemia, and co-administration of other QT prolonging agents.14

Antiarrhythmic Drug Classification

The antiarrhythmic drug classification sys-tem most often employed was originally put forth

by Vaughan-Williams and modified by Harrison.




SHU, ET AL.

Table I.

Vaughan-Williams Classification of Antiarrhythmic Drugs

Class Action Drugs

I Sodium channel blockadeIa Moderate phase 0 depression and conduction slowing, Disopyramide, quinidine, procainamide,

prolonging of action potential durationIb Minimal effect on phase 0 upstroke Lidocaine, mexiletine, tocainide

No change or shortening of action potential durationIc Marked phase 0 depression and conduction slowing, Flecainide, propafenone, moricizine

little effect on repolarizationII β-adrenergic blockers Propanolol, metoprolol, pindolol, atenolol,

esmolol, acebutolol, carvedilol, betaxolol,

besoprolol, nadolol, timololIII Prolonging repolarization d,l -Sotalol, dofetilide, amiodarone, dronedarone,

bretylium, ibutilide, azimilideIV Calcium channel blockers Verapamil, diltiazem

This classification is relatively simple and useful.It assumes that each antiarrhythmic drug has aprominent electrophysiologic effect and has a pri-mary therapeutic application (Table I). Althoughit has a number of important drawbacks, thisVaughan-Williams classification schema has beenused as conversational shorthand to facilitate ex-change of information about the electrophysio-logic properties of antiarrhythmic drugs.

The antiarrhythmic drugs confer protectionagainst cardiac arrhythmia by either affecting au-

tomaticity/triggered activity or by prolonging ac-tion potential/effective refractory period. Selec-tion of effective but safe antiarrhythmic drug ispatient specific and in-depth knowledge of patientco-morbid cardiovascular conditions and pharma-cokinetic and electrophysiologic properties of thedrug is mandatory before employing antiarrhyth-mic drug therapy. The electrophysiological effectsand important pharmacokinetics of some typicaland clinically useful antiarrhythmic drugs in eachclass are briefly discussed.

The Class I Antiarrhythmic Drugs

According to the original schema, drugs thathave an effect on sodium channels were placed inclass I. Later, it was recognized that the relativepotency of all of these drugs varied, and that somehad additional electrophysiological effects differ-entiating them from others (Table I).15 For that rea-son, subclasses a, b, and c were used to designatethese differences. The class Ia agents, includingquinidine, procainimide, and disopyramide, ex-ert an intermediate effect to block the fast sodiumcurrent and prolong the action potential duration

by blocking outward potassium current. The class

Ib agents, including lidocaine, mexiletine, and to-cainide, are the weakest sodium channel blockersthat produce little change on the QRS duration innormal cardiac tissues and have a negligible effecton repolarization. The class Ic drugs, includingflecainide and propafenone, have a more potenteffect on the sodium current leading to depressionof phase 0 of the action potential.15

Since class I drug blocks cardiac fast sodiumcurrent, it prolongs action potential refractory pe-riod in myocardial tissues in which action poten-

tial is dependent on the sodium current, such asatrial myocytes, His-Purkinje system, and ventric-ular myocardium. Therefore, class I drugs are ef-fective in the treatment of arrhythmias via reen-trant mechanism.

Use-dependence is a term describing the ef-fect of an antiarrhythmic drug that is enhancedduring faster heart rates. Class I drugs exhibitmore or less use-dependent effect. In other words,these drugs produce more pronounced blockadeof the sodium channels at faster heart rates. Theclass Ic drugs like flecainide dissociate from thesodium channel in the resting state very slowly,

exhibiting strong use-dependence, and this resultsin pronounced sodium channel blockade duringtachycardia.15 In other words, inhibition of INa

that leads to depression of Vmax of phase 0 isgreater in rapidly depolarizing tissues in whichthe sodium channel is frequently “used.” Thisis thought to be responsible for the increasedefficacy of the class Ic antiarrhythmic in slow-ing and converting tachycardia with minimal ef-fects at normal sinus rates.15 As discussed above,strong use-dependence may be associated withproarrhythmias.





Disopyramide

Disopyramide is a class Ia drug with predomi-nant effects on sodium and potassium channels.15

It increases refractoriness in atrial and ventricu-lar tissue and may suppress abnormal automatic-ity. Since it has marked anticholinergic effects, ithas been used in vagally mediated AF. It should

be cautiously used in patients with severely de-creased left ventricular systolic function becauseof its negative inotropic effect. On the other hand,due to its negative inotropic effects, disopyramidemay reduce left ventricular out-flow gradient andimprove symptoms in patients with obstructivehypertrophic cardiomyopathy.16

Lidocaine

Lidocaine is a short-acting intravenous (IV)class Ib antiarrhythmic agent.15 It blocks sodiumchannels predominantly in their inactivated state

and therefore has more inhibitory effects in par-tially depolarized tissues as occurs in myocardialischemia. Therefore, it is useful in the acute treat-ment of ischemia-induced ventricular arrhyth-mias. Lidocaine has little to no effect on atrial, AVnodal, or accessory pathway tissue; thus it is in-effective in treating supraventricular arrhythmiasincluding AF.

Flecainide

Flecainide is a class Ic drug that slows con-duction in the atria, His-Purkinje system, ven-tricles, and accessory pathways.15 It also pro-longs refractoriness, especially in the atria. Both

actions are use-dependent, i.e., more marked athigher heart rates. This may explain why fle-cainide, like other class Ic drugs, is effectivein terminating AF.17,18 However, flecainide maysometimes convert AF to atrial flutter. Due toits strong use-dependence, it may cause ventric-ular arrhythmias, particularly in patients with is-chemic cardiomyopathy.10

The Class II Antiarrhythmic Drugs

These agents indirectly affect thecardiac ioniccurrents primarily by inhibiting sympathetic ac-tivity through β -adrenergic blockade.15 β-blockers

may prevent shortening of refractoriness at all lev-els in the heart. They also block adrenergic activa-tion of calcium channels, an effect that is responsi-

ble for therapeutic benefits in ischemia-dependentventricular fibrillation.19 β-blockers decrease rest-ing and maximum heart rate during exercises, pro-long sinus node recovery time, and increase PRand atrial-His intervals. In addition, they prolongthe refractoriness of the AV node.15

β-blockers can suppress arrhythmias due toincreased automaticity and triggered activities,and slow the ventricular response during AF.

They are the drugs of choice in patients withexercise-induced arrhythmias, especially in longQT syndrome.20

Some β -blockers like pindolol and acebutololexhibit intrinsic sympathomimetic activity, i.e.,partial agonist activity. These may be useful in pa-tients who develop significant bradycardia withother β -blockers.

The Class III Antiarrhythmic Drugs

The class III antiarrhythmic drugs are thosethat prolong the action potential duration and,therefore increase the effective refractory period.15

There is a great deal of heterogeneity within thisclass since the drugs may act on one or more of several different ion active during phase III orrepolarization. In addition, several drugs in thisclass have additional electrophysiologic effectsthat complicate their classification. For example,

sotalol has β-adrenergic blocking activity, whileamiodarone appears to have properties of all fourclasses.

The class III antiarrhythmic drugs suppressreentrant arrhythmias, except TdP, in the atriaand ventricles. They are particularly effective inAF, atrial flutter, and monomorphic ventriculartachycardia.15

As opposed to use-dependence observed fordrugs that block the sodium channels, inhibi-tion of IKr is enhanced during bradycardia whenthe channel is “not frequently used,” leading tomore significant action potential prolongation atslow heart rates. The action is called “reverseuse-dependence.” The mechanism is probably re-lated to the dependence of IKr blockade on extra-cellular potassium concentration.21 Reverse use-dependent properties of antiarrhythmic drugs mayreduce their efficacy in tachycardias, and predis-pose to bradycardia-dependent proarrhythmia, forexample, TdP. Amiodarone, ibutilide, and azim-ilide have a fairly homogeneous effect on refrac-toriness across a range of cycle lengths.

Sotalol

Sotalol is a class III agent that blocks IKr andalso a β-blocker that is useful in AF/atrial flutter

and monomorphic ventricular tachycardia.15,22,23

Sotalol should preferably be initiated in-hospitalto monitor for severe bradycardia, atrioventricu-lar block, and QT prolongation. Because sotalolis primarily excreted unchanged in the urine,dose adjustment is needed in patients with renalinsufficiency.

Amiodarone

Although amiodarone is classified as aclass III agent, it has properties of all the fourclasses of Vaughan-Williams classification.15 The




SHU, ET AL.

electrophysiologic effects of intravenous amio-darone differ from oral amiodarone. Oral amio-darone has a delayed onset of action, whichusually takes at least 2–3 days or longer, whileintravenous amiodarone is effective within 1–12 hours.Although amiodarone may cause markedQT prolongation, it rarely leads to TdP.24 This may

be related to several factors: lack of reverse use-dependence; concurrent blockade of sodium andL-type calcium channels; and reduction of disper-sion of repolarization. Amiodarone treatment maylead to slight increase in QRS duration and mayhave a more profound effect on sinus node and AVconduction.15

Amiodarone is a versatile antiarrhythmic drugand suppresses a wide spectrum of atrial and ven-tricular arrhythmias, ranging from simple symp-tomatic premature ventricular contractions to sus-tained ventricular tachycardia and fibrillation.5

Additionally, it is a useful and safe antiarrhyth-mic in patients with congestive heart failure as itdoes not have negative inotropic effect.25

Unfortunately, amiodarone is associated witha high incidence of severe extracardiac side ef-fects including thyroid, pulmonary, liver, skin,ocular, and neurologic toxicities, largely due toiodine in amiodarone molecule.26 This has ledto the development of amiodarone congener drugdronedarone that is free of iodine. Recent clini-cal trials have shown that dronedarone is effectivein reducing the incidence of a first AF recurrencewithout thyroid and pulmonary toxicities.27

DofetilideDofetilide selectively blocks IKr.15 As a con-

sequence, it prolongs the QT interval without anyeffects on PR or QRS interval. It also lengthens therefractory period of atrial and ventricular tissuesas well as the accessory pathway. In general, ithas no effects on conduction velocity, sinus cyclelength, or sinus node recovery. Like other class IIIagents that block IKr, dofetilide exhibits reverseuse-dependence. Dofetilide is metabolized mainly

by the CYP3A4 family. Thus, erythromycin, keto-conazole, verapamil, cimetidine, and certain otherantibiotics may increase serum concentration of

dofetilide.15

Like sotalol, dofetilide is 50% ex-creted through the kidneys and dose adjustment isrequired in patients with renal insufficiency. Dueto the risk of severe QT prolongation and TdP, in-patient initiation of dofetilide therapy and carefulmonitoring of QT interval is mandatory.

The Class IV Antiarrhythmic Drugs

The nondihydropyridine calcium channel blockers verapamil and diltiazem affect calcium-dependent slow action potentials in the SA andAV nodes. These agents slow diastolic depolar-

ization in both the nodes, therefore slowing thepacemaker rate. They also prolong the refractoryperiod of the AV node, slowing the ventricular rateduring AF.15 Verapamil and diltiazem may causeperipheral vasodilation, which may partially off-set their sinus and AV nodal-slowing effects.

Calcium channel blockers are mainly usedin supraventricular tachycardias and for rate con-trol in AF.15 Verapamil and diltiazem reduce bothresting and exercise heart rate, whereas digoxinmainly reduces heart rate at rest in patients withAF. Verapamil and diltiazem may also effectivelyprevent ventricular tachycardia or fibrillation dueto coronary artery spasm.

Other Antiarrhythmic Drugs

Adenosine

Rapid intravenous injection of adenosine hasnegative dromotropic and chronotropic effectsmainly on the SA and AV nodes. These effectsare mediated via A1 adenosine receptor. The neg-ative dromotropic effects may lead to transientcomplete AV block. Adenosine can produce coro-nary vasodilatation via its effects on A2 receptorsin the vascular smooth muscle cells. Adenosineis quickly cleared by cellular metabolism with anelimination half-life of 10 seconds or less.

Digitalis

Digitalis enhances vagal activity and thusslows sinus node automaticity and prolongs AVnodal conduction and refractoriness.28 Digitalis

inhibits the sarcolemmal Na+-K+-ATPase leadingto an increase in intracellular calcium that maypromote proarrhythmias.15 Co-administration of antacid may reduce absorption of digitalis,whereas verapamil and amiodarone may increaseserum digitalis concentrations. Hypokalemia aug-ments digitalis toxicity, hence serum potassiumconcentration needs to be monitored especiallywhen co-administered with diuretics. Digitalis can

be used to control the ventricular rate in AF or AVnodal reentrant tachycardia. Digitalis is usually ef-fective in controlling ventricular rate in the elderly

but may be ineffective especially in young pa-tients with higher sympathetic tone. Digoxin can

be safely used during pregnancy and lactation.

Management of Common Arrhythmias

The initial step for successful managementof patients with arrhythmias is to correctly di-agnose an arrhythmia and identify its underlyingcardiac diseases. Correct diagnosis of an arrhyth-mia requires an in-depth and integrated knowl-edge in clinical electrophysiology that will beclearly beyond the scope of this review article.Therefore, we will focus on how to choose an





antiarrhythmic drug for each specific arrhythmiain specific clinical conditions.

Atrial Fibrillation

AF is the most common sustained arrhythmiaaffecting more than 2 million people annually inthe USA and has a profound impact on morbid-ity, including increased susceptibility to embolicstroke, tachycardia-induced cardiomyopathy, anda decreased exercise tolerance or worsening con-gestive heart failure.29 Drug therapy is the initialstep in the management of AF and can be dividedin two principal aspects: (1) control of ventricularrate versus rhythm and (2) long term of anticoag-ulation.30,31 The goals of the treatment include:improving survival, reducing stroke, improvingsymptoms, restoring atrial functions, and revers-ing the remodeling process.

Patients with AF are at higher risk of em-

bolic stroke; hence, long-term anticoagulation isone of the important steps in the managementof AF. Most of the current guidelines recom-mend CHADS2 risk stratification scheme that rec-ommends appropriate anticoagulant for a par-ticular patient based on individual risk factors(Table II).32,33 For the low risk patient with AFwith a CHADS2 score of 0 or 1, aspirin 325-mgdaily is sufficient for long-term anticoagulation.For those with a score of 2 or more, anticoagulationwith warfarin (international normalized ratio 2.0–3.0) is recommended unless contraindicated. It isa consensus that all the patients with rheumaticAF should receive anticoagulation with warfarin

unless contraindicated.It still remains a matter of controversy

whether to adopt the strategy of controlling theventricular rate or to maintain sinus rhythm intreatment of patients with AF. Several large clini-cal trials have demonstrated nonsuperiority of ei-ther of the strategies and clinical guidelines rec-ommend that both strategies are acceptable.30,34

However, clinicians should adapt the therapeu-tic strategy tailored to each individual patient. In

Table II.

CHADS2 Risk Stratification Scheme

Risk Factors Score

C Recent congestive heart failure 1H Hypertension 1A Age ≥ 75 years 1D Diabetes mellitus 1

S2 History of stroke or transient ischemic attack 2

Reproduced with permission from Gage et al.32

general, choice of strategy should be determined by several factors, like paroxysmal versus persis-tent AF, severity and type of symptoms, associ-ated cardiac and other medical conditions, and theage of the patient. In patients with severe symp-toms and in young patients with AF, aggressiveuse of antiarrhythmic drugs should be pursued inorder to maintain the sinus rhythm. In older pa-tients, if symptoms can be controlled with rate-control strategy, it should be preferred. Anticoag-ulation is needed in all the patients as derived

by CHADS2 scores irrespective of what strategy ischosen.30

When the strategy of rate control is chosen, β - blockers and/or calcium channel blockers are thefirst line of drugs with a goal of maintaining theheart rate between 60 and 80 beats/min at rest and

between 90 and 115 beats/min during moderateexercises.30 Digoxin can be added if needed, but it

slows the ventricular response only at rest.When strategy of rhythm control is selected,prophylactic treatment with antiarrhythmic drugsis needed to maintain sinus rhythm. Restorationof sinus rhythm can be achieved by pharmaco-logical or direct current cardioversion. Class Icand III drugs are primarily used for the mainte-nance of sinus rhythm and selection is primarily

based on presence or absence of co-morbidities,like hypertension, left ventricular hypertrophy,coronary artery disease, or congestive heart fail-ure. Selection of appropriate antiarrhythmic drugas recommended by American College of Car-diology/American Heart Association (ACC/AHA)

guideline is shown in Figure 3.30

Atrial Flutter

Atrial flutter is a macro-reentrant arrhyth-mia characterized by flutter waves with a rela-tively higher atrial rate generally between 240 and340 beats/min. Typical/type I/counterclockwiseflutter is characterized by negative sawtooth flut-ter waves and atypical/type II/counterclockwiseflutter is characterized by positive sawtooth flut-ter waves in leads II, III, and aVF and both are

right atrial isthmus-dependent macro-reentrantarrhythmia.35,36

Isthmus-dependent right atrial flutter should be treated by catheter ablation and has almost 90%cure rate.30,35 For acute therapy, direct current car-dioversion or intravenous ibutilide are highly ef-fective.30,36 Long-term antiarrhythmic and antico-agulant therapy for atrial flutter mirrors that of AF.30,36 (see Fig. 3) Class III antiarrhythmic drugslike sotalol or amiodarone, which significantlyprolong impulse wavelength, effectively inhibitatrial flutters.




SHU, ET AL.

Figure 3. Pharmacologic therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation. Within each box, drugs are listed alphabetically and not in order of suggested use. The vertical flow indicates order of preference under each condition. LVH indicates left ventricular hypertrophy. (Reproduced with

permission from Fuster et al 30 and Musco et al.31)

Focal and Multifocal Atrial Tachycardia

Focal atrial tachycardia is a relatively uncom-mon cause of supraventricular tachycardia. It ischaracterized by rapid (130–150 beats/min), rela-tively regular rhythm that originates from a fociin atria most commonly found in pulmonary vein

in the left atrium and crista terminalis in theright atrium.35 On the other hand, multifocal atrialtachycardia (MAT) is characterized by atrial rategreater than 100 beats/min with P waves of atleast three distinct morphologies and is charac-teristically seen in patients with acute pulmonarydisorders who are on theophylline or β-agoniststherapy. Whereas focal atrial tachycardia can becaused by abnormal impulse formation (an in-crease in automaticity or triggered activities) orvia reentrant mechanism, MAT is believed to becaused by the triggered activity.35

For clinically important focal atrial tachycar-

dia, catheter ablation is usually a primary therapy.For patients with infrequent episodes, β-blockerslike metoprolol and calcium channel blockers maypacify the atrial foci, leading to abnormal impulseformation, and may be helpful.37 In patients withatrial tachycardia who are refractory to the treat-ment of β-receptor blockers or calcium channel

blockers, class I (Ia and Ic) or class III antiarrhyth-mic drugs can be added. As MAT is caused bythe triggered activity, calcium channel blockerslike verapamil are particularly effective in thisarrhythmia.37

Digitalis therapy may precipitate or exacer- bate the episodes of atrial tachycardia due to in-creased triggered activity. Stopping digoxin orreducing the dose generally circumvents suchproblem.

Reentrant Arrhythmias via AV Nodal DualPathways or AV Accessory Pathways

These arrhythmias include atrioventricularnodal reentrant tachycardia (AVNRT) and atri-oventricular reentrant tachycardia (AVRT). TheWolff-Parkinson-White (WPW) syndrome is a spe-cific form of AVRT in which patients also exhibitventricular preexcitation, i.e., delta wave with ashort PR interval, on ECG during sinus rhythm.

AVNRT is a reentrant arrhythmia via dual(slow/fast AV) nodal pathways and is seen morecommonly in women than men. Termination of a sustained episode of AVNRT can be accom-

plished by a transient AV block induced by va-gal maneuvers such as carotid sinus massage orthe Valsalva maneuver.38 Acutely, AVNRT is usu-ally terminated by rapid intravenous injection of adenosine (6–12-mg IV bolus) if vagal maneuversfail.38 Adenosine has negative dromotropic effectson the AV node that leads to transient completeAV block and, therefore, terminates AVNRT. Abla-tion of the slow AV nodal pathway is the first-linetherapy for AVNRT unless patient has contraindi-cations for the procedure such as pregnancy.38,39

For patients with contraindications or who refuse





Figure 4. Atrial fibrillation in a patient with Wolff-Parkinson-White syndrome. Atrial impulses conducted to the ven-tricles via the accessory pathway, manifesting wide complex of tachycardia on the ECG. (Reproduced with permission

from Blank et al. Circulation 2007 22;115(20):e469–e471.)

the ablation procedure, AV nodal blocking agentslike β-blockers can be used. For female patientsduring pregnancy, β-blockers or digoxin are con-sidered safe to the fetus.

AVRT is a reentrant arrhythmia as well. Themajority of AVRT cases occur with the impulsewavefront conducting anterograde over the AVnode and retrograde over an AV accessory path-way.38 The tachycardia often has a narrow QRScomplex unless there is a baseline bundle branch

block or aberrant conduction during tachycardia.Ablation of the AV accessory pathway is the first-

line therapy for AVRT.38,39

For patients with con-traindications for ablation, β-blockers or calciumchannel blockers are useful.

Physicians should be very cautious when se-lecting antiarrhythmic drug for treatment of AF(seen in association with WPW syndrome).40 Inpatients with WPW syndrome, during an episodeof AF, atrial impulses can bypass the AV node andpropagate to the ventricles directly via accessorypathway, leading to irregular, fast, and wide com-plex tachycardia (Fig. 4). Hemodynamically stablepatients suspected of having this condition should

not receive agents that predominantly block AVconduction such as intravenous calcium chan-nel blockers, β-blocker, or digoxin because theseagents may accelerate the ventricular response toAF via the accessory pathway, leading to ventricu-lar fibrillation.41 Intravenous propafenone, which

blocks cardiac peak sodium current and thereforeinhibits conduction over the accessory pathway,is effective not only in slowing down the ventric-ular responses to AF but also in converting AF to anormal sinus rhythm under such conditions.42

Ventricular Arrhythmias

Ventricular arrhythmias are common in clin-ical practice and range from benign asymp-tomatic premature ventricular contraction to life-threatening ventricular fibrillation.

Coronary artery disease still remains the maincause of VF. Acute management of VF requiresimmediate delivery of unsynchronized direct cur-rent shock. Intravenous administration of amio-darone is the choice for prevention of recurrence.For VF refractory to amiodarone, lidocaine can beadded.43




SHU, ET AL.

Monomorphic ventricular tachycardia moreoften occurs in the setting of healed myocardial in-farction. For patients with ischemic cardiomyopa-thy and depressed left ventricular systolic func-tion (ejection fraction≤ 35%), implantable cardiacdefibrillator (ICD) should be considered in addi-tion to drug therapy.43 β-blockers are the first lineof drugs for VT in the setting of previous myocar-dial infarction. If VT occurs frequently despite thetreatment with a β -blocker, sotalol or amiodaroneis useful.44

TdP occurs under conditions of QT inter-val prolongation. The initial step in the man-agement of patients with TdP as a consequenceof acquired causes is to remove offending fac-tors like QT-prolonging drugs and correction of electrolyte disturbances like hypokalemia. Magne-sium that inhibits EADs should be administeredintravenously regardless of the patient’s serum

magnesium level.43

Diagnosis of congenital longQT syndrome should be considered in patientswith recurrent episodes of TdP with long QT in-terval on ECG. β-blocker still remains first lineof treatment in patients with congenital long QTsyndrome; however, ICD can be used in refractorycases.20,43

Future Perspective

Pharmacologic management of arrhythmias isa large topic covering knowledge in many areas. Inthis section, we only address a couple of interest-ing issues we encounter in our clinical practice.

Clinicians, even including some electrophys-iology fellows, may be confused regarding theelectrophysiological action of class I antiarrhyth-mic drugs. This class of drugs, particularly classIa and Ic, may cause significant conduction de-lay. Conduction delay per se is not antiarrhyth-mic but proarrhythmic. Not many textbooks haveclearly discussed the antiarrhythmic mechanismsof class I drugs. The antiarrhythmic effect of classI drugs is due to their effects of prolonging ef-fective refractive period. Since the class I drugs

block the fast sodium current, they prolong effec-tive refractive period only in those cells whoseexcitation is dependent on the sodium current,

like atrial myocardium, Purkinje fibers, ventric-

ular muscles, and accessory pathways. Some of them like class Ib and Ic can prolong effective re-fractive period in the absence of action potentialprolongation.

AF by far remains the most common cardiacarrhythmia with profound effects on morbidityand mortality. Although ACC/AHA guideline sup-ports the role of rhythm control in pharmacologicmanagement of AF, there seems to be a trend to-ward using rate control strategy for managementof AF in the last few years. This is primarily dueto the limited efficacy and poor safety profile of currently available antiarrhythmic drugs. Drugslike sotalol and dofetilide, when used for treat-ment of AF, require careful monitoring of QT inter-val to avoid proarrhythmic complication. On theother hand, drugs with established cardiac safety,like amiodarone, have been shown to have signif-icant extra-cardiac toxicities. This has led to de-

velopment of atrial-specific pharmacotherapy fortreatment of AF.45,46 One such drug is ranolazine,which is a specific blocker of atrial fast sodiumchannels with favorable electrophysiologic effectson ventricles. Atrial-specific IKr current blockerlike vernakalant and AVE-0118 and IK-ACh cur-rent blocker like NIP-151 represent potential andpromising therapeutic targets.45,46 Although not aprimary approach, adjuvant therapies that blockrennin–angiotensin–aldosterone pathway and re-duce inflammation have also been shown to beeffective in prevention of AF.45

VF is the most common cause of sudden car-diac death and kills about 600,000 individually in

Europe and United States. Improvement in our un-derstanding of ischemia-induced arrhythmia hasopened up potential therapeutic avenue—the K-ATP channel blockade. Drugs like clamikalantthat selectively block sarcolemmal K-ATP chan-nels have shown promising results in preventionof ischemia-associated VF in animal models.46

With advances in our knowledge of cellularmechanisms of various arrhythmias, our ability todevelop specific antiarrhythmic agents and hencetreat specific arrhythmias has improved signifi-cantly. Although currently available antiarrhyth-mic drugs have limited efficacy and safety profile,

emerging pipeline drugs hold a promising future.

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