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18 Farmacoterapia de Las Arritmias

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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., P H .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 tomorbidityandmortality.Pharmacologicaltherapystillremainsthemajorapproachinmanagementofpa-tientswithnearlyeveryformofcardiacarrhythmia.Effectiveandsafemanagementofcardiacarrhythmiaswith 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-dentonitsmechanicalpropertiesbutalsorequiresproper 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:jshu2005@126.comReceived 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-inducedproarrhythmiascanbedividedintwoma-jor categories: abnormal impulse formation (i.e.,enhanced automaticity and triggered activities)and reentry (Fig. 1). 1 Some arrhythmias may src-inate via one mechanism and are then maintainedvia other. For example, torsades de points (TdP)is precipitated by early afterdepolarization (EAD)-inducedtriggeredactivityandthenmaintainedviareentry. 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 C  2009, The Authors. Journal compilation  C  2009 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 srcinate 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-atrialnode(SA)ortheatrio-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,andHis-Purkinjefibers,possesstheabilitytogenerate spontaneous action potentials under nor-malconditions—so-calledpacemakercells.Undernormal 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.Abnormalautomaticity,whichisduetoeitherenhanced 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 srcinating principallydue to enhanced automaticity include focal atrialtachycardias, 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 I Ca , l  reactivation. 1,3,4 EADs classicallysrcinate from M cells or endocardial cells in set-ting of disproportional action potential prolonga-tion due to drugs that block I Kr ; however, it can be seen in the setting of altered electrolytes, hy-poxia,acidosis,increasedcatecholamines,andun-der conditions of ventricular hypertrophy or heartfailure. 5,6 Such EADs not only increase the disper-sionofrepolarizationbutcanpropagateandgener-ate new action potential in nearby cells manifest-ingasanR-on-TectopicthatiscapableofinitiatingTdP (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 calciumfromthesarcoplasmicreticulumunderconditions 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 butaccelerateorprecipitatethearrhythmiadriven 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 Theelectricalcycleofcardiomyocyteconsistsof two phases: depolarization and repolarizationand this cycle is initiated by an impulse srcinat-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,thecardiaccellsarerefractorytonewelectricalex-citation.Hence,thefirstelectricalimpulsediesoutafter 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-creasedautomaticityleadstohigherrateofspontaneous firing than normal (dashed lines). (B) Delayed afterde- polarization(dashedlines)arespontaneousoscillationsof membrane after completion of repolarization. Whenitreachesthethresholdpotential(solidredline),itiniti-ates spontaneous action potential. (C) Early afterdepo-larization (dashed line) is spontaneous membrane os-cillation during phase 3 of repolarization. Upper cell (dashedline)thatfailstocompleterepolarizationduetoEADs, causes thelowercell(solidline)tofirerepeatedly generatingextrabeats.(D)Reentrygeneratingextrabeat betweentissueplanesIandII.Asshowninfigure,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 blackline).ActionpotentialCcantravelbacktoplane2,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 ) 1456 November 2009  PACE, Vol. 32  MANAGEMENT OF CARDIAC ARRHYTHMIA 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-tionblockispresent,andthisunidirectionalblockis 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-icantlylessthanthepathlengthsothataspatialex-citablegapispresentbetweenthecrestandthetailof the reentrant wavefront for the maintenance of circusmovement.Therefore,slowconductionlikemyocardial 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-volvementofanatomicobstaclesandiscommonlyassociated with the presence of enhanced disper-sion of repolarization. It should be emphasizedthatthefirstelectricalimpulsethatentersthereen-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 byfunctional 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-tricularfibrillation(VF),andpolymorphicventric-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 suppressarrhythmias 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,theycancauseatrialflutter,oftenwithslowerrates(approximately 200 beats/min). This is classicallyseeninpatientswithAFtreatedwithclassIcdrugslike 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-mentofAFbyshorteningatrialeffectiverefractoryperiod. 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 reducedrepolarization 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 srcinally put forth by Vaughan-Williams and modified by Harrison. PACE,Vol.32  November 2009 1457
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