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P&S Medical Review: Oct 1994, Vol.2, No.1
Treatment of Cardiac Arrhythmias
Brian F. Hoffman, M.D.
Department of Pharmacology, College of Physicians and Surgeons, New York, NY
ABSTRACT:
The pharmacological treatment of many cardiac arrhythmias is unsatisfactory in terms of both efficacy and safety. Some of the reasons for this are described. Even though the electrophysiological mechanisms for different types of arrhythmias have been adequately described, often it is not possible to assign a particular mechanism to the arrhythmia presented by a patient. Improved means to identify mechanisms in patients clearly are needed. Also, we have a reasonably adequate understanding of the mechanisms of action of available antiarrhythmic agents. With respect to the arrhythmogenic potential of both class I and class III drugs probable mechanisms have been identified. This information indicates that the production of new arrhythmias is an anticipated consequence of the primary mechanism of action of both classes of agents. To improve efficacy of available agents the suggestion is made that, for each arrhythmogenic mechanism, a suitable vulnerable parameter be identified and selection of a particular agent be based on the electrophysiological basis for this parameter. To reduce arrhythmogenic potential a suggestion is made that antiarrhythmic drugs acting by new mechanisms are needed.
THE TREATMENT OF CARDIAC ARRHYTHMIAS
Disturbances of cardiac rhythm can be treated by surgical interventions, electronic devices or pharmacological agents. For example, when the path for reentrant excitation is known, as in the cases of a-v nodal tachycardia, anomalous a-v pathways or bundle branch reentry, means are available to ablate part of the reentrant circuit and thus both terminate the arrhythmia and prevent its recurrence. For some arrhythmias such as those resulting from sinus node disease or a-v block implanted pacemakers are safe and effective. Also, electrical cardioversion is used routinely to terminate atrial flutter or fibrillation and, for life- threatening ventricular arrhythmias, implanted cardioverters have been found to be a safe and reliable means to terminate ventricular tachycardia or ventricular fibrillation.
In contrast, the efficacy and safety of pharmacological agents used to prevent or terminate arrhythmias are far from satisfactory. It is true that a wide variety of antiarrhythmic drugs work reasonably well when they are used to prevent premature impulses or self- terminating atrial arrhythmias such as the atrial flutter that commonly follows cardiac surgical procedures 1. However, if one considers arrhythmias that need pharmacological treatment the case is quite different. When employed to prevent sustained ventricular tachycardia the efficacy of commonly used drugs probably ranges from 30 to 40% overall with a lower value for patients in whom ventricular function is severely depressed 2. Also, as shown by the CAST trial 3, even though flecainide and encainide were reasonably effective in preventing premature impulses in patients who had survived myocardial infarction, the mortality of those receiving drug was significantly greater than that of controls. A similar increase in mortality early during drug administration was noted with moricizine. When used in an attempt to terminate persistent atrial flutter or fibrillation, most drugs have shown limited efficacy 4,5; efficacy also is low when drugs are used to prevent paroxysmal atrial fibrillation 5. Perhaps more important, one study has shown that in patients with atrial fibrillation chronic administration of an antiarrhythmic drug increased arrhythmic death by a factor of 2.6 and, in those with congestive heart failure, this increase amounted to 4.7 6.
These disappointing findings for antiarrhythmic drugs may suggest that the development and wider use of non-pharmacologic modes of treatment should be a major research emphasis. In relation to this suggestion, several factors deserve consideration. Advanced non-pharmacologic means of treatment are not widely available and probably will not be generally available for many years. Also, the cost of cardioversion or catheter ablation is high. Finally, as the population ages the incidence of serious arrhythmias increases 5: for atrial fibrillation the incidence reaches at least 5% at 65 and appears to increase as a continuous function of age. The incidence of serious ventricular arrhythmias in patients with coronary artery disease may be decreased by prompt reperfusion but arrhythmias in patients with heart failure still will remain a serious problem.
These considerations suggest that it may be worth while to ask why antiarrhythmic drugs present the problems that are commonly encountered and what, if anything, can be done about them. Some of the answers are complex and some are far from certain but this does not render the inquiry valueless.
MECHANISMS FOR ARRHYTHMIAS
It seems reasonable to assume that if the mechanism responsible for an arrhythmia were known it would be possible either to administer a drug that acted to eliminate this mechanism or, alternatively, to bring about a compensatory antiarrhythmic change in electrophysiological properties. A brief consideration of arrhythmogenic mechanisms thus is in order.
Studies on the mechanisms that can cause arrhythmias began many years ago. For reentrant arrhythmias, those caused by circus movement of the impulse, experiments by Mayer 7, Mines 8 and Garrey 9 demonstrated that circus movement was possible and identified the conditions necessary for circus movement to occur. What was needed was a central obstacle around which the impulse could circulate and for initiation an area of unidirectional conduction block in one limb of the path around this obstacle. Lewis 10 later showed in studies on the in situ canine heart that reentrant excitation was the cause of atrial flutter and partially delineated the circus path during this arrhythmia. He also concluded that for the arrhythmia to persist there must be an appropriate relationship between the speed of conduction of the impulse and the duration of refractoriness of the tissues that constituted the circus path. In other words, in front of the propagating impulse there must always be an excitable gap: a segment that has recovered sufficiently from prior excitation to permit reecxitation. These early studies were the basis for attempts to understand the mechanism by which an antiarrhythmic drug might act. It was assumed that an agent able to prolong refractoriness would terminate reentry by abolishing the excitable gap and causing the impulse to encounter unexcitable tissue whereas one that slowed conduction would tend to perpetuate the circus movement.
Table 1
Arrhythmogenic Mechanisms
Mechanisms for arrhythmias other than reentry were less certain. It was shown that local application of aconitine could cause tachyarrhythmias due to local repetitive impulse generation 11 and also that arrhythmias might result from afterdepolarizations new depolarizations occuring during or after recovery from a normal action potential 12. Nevertheless, the alterations in cardiac electrical properties responsible for repetitive impulse generation or afterdepolarizations were not defined.
Understanding of arrhythmogenic mechanisms was advanced considerably when it became possible to record the transmembrane potentials of cardiac fibers through intracellular microelectrodes 13 and to obtain quantitative data on the electrophysiological properties of heart. It was shown that in most cardiac fibers depolarization and the propagation of the impulse depended on an inward sodium current and that repolarization resulted from a decay of inward currents and an increase in outward potassium current. The inward sodium current inactivated on depolarization and did not again become available for activation until the membrane had repolarized; this was the main basis for refractoriness. In some heart fibers, such as those of the sinus node 14 and a-v node 15 the upstroke of the action potential resulted from an inward calcium current rather than a sodium current. In these and in other specialized fibers spontaneous impulse generation was caused by a slow decrease in transmembrane potential during diastole, the so-called slow diastolic depolarization.
As information on normal electrophysiological properties became available studies were directed towards possible arrhythmogenic abnormalities of cardiac electrophysiology. It was found that under suitable conditions, such as partial depolarization, fibers of the atrium and ventricle, not normally capable of spontaneous impulse generation, would become automatic . This abnormal automaticity (AA) 16 differed from the normal mechanism in terms of its response to overdrive and premature stimulation 17 as well to pharmacological agents. Two different classes of afterdepolarizations were identified and characterized 18. One, early afterdepolarizations (EAD), occurred during phase 3 of the action potential, prevented full repolarization and initiated repetitive responses. The other, delayed afterdepolarizations (DAD) occurred after repolarization had been completed and usually was associated with an abnormality of calcium handling by the fibers. These mechanisms are shown diagrammatically in Figure 1(not available in on-line version). Studies on mechanisms for reentry demonstrated that slow conduction and unidirectional block might result either from depression of the sodium-dependent fast response or replacement of the fast response by a calcium-dependent slow response 19. Also, it was shown that one form of reentrant excitation might be caused by a mechanism called reflection 20,21. In this case sufficient slowing of conduction at one site caused the forward propagating impulse to generate a new impulse that propagated in the reverse direction (Fig. 2). During the same period studies employing mapping techniques the timing of local cardiac activation through the use of multiple electrodes in contact with the myocardium 22, and catheter electrode recordings provided much detailed information on the properties of paths for reentrant excitation.
What must be emphasized, however, is the variability of conditions that can create the substrate for reentrant excitation. In the case of anomalous a-v pathways and a-v nodal reentry the necessary slow conduction in part of the circus path is provided by the normal properties of the a-v node. In the case of reentrant ventricular tachycardia following infarction slow conduction may result from an alteration in electrophysiological properties, such as replacement of the normal response by a slow response, one in which inward calcium current generates the action potential upstroke, or from the anisotropic properties of the cardiac syncytium and structural alterations in fibers of the circus path 22. Often the slowing of conduction is merely a result of impulse propagation in tissues that have recovered only incompletely from prior excitation. The unidirectional block needed to initiate reentry similarly may have varied causes: it may result from local differences in the duration of refractoriness, from disadvantageous loading of the action current or, in the case of the a-v node, from its normally slow recovery from prior activity. Clearly this sort of variability makes it quite unlikely that any one drug action will be sufficient to prevent all instances of reentry.
With this information in hand it seemed reasonable to attempt to classify cardiac arrhythmias in terms of underlying electrophysiological mechanisms since this might lead to a more rational use of antiarrhythmic drugs. The general classification suggested 23,24 is shown in table 1. It should be noted, however, that until quite recently 25 efforts to assign specific arrhythmogenic mechanisms to the electrocardiographically characterized arrhythmias were generally successful only for various types of reentrant excitation.
It was demonstrated that characteristic extracellular records of sinus node activity could be recorded both from the epicardium and, through catheter electrodes, from the endocardium of the in situ heart 26,27 and thus foci of abnormal automaticity could be identified by similar methods. The method is somewhat difficult to apply and perhaps for this reason has been used infrequently to characterize human arrhythmias. Also, monophasic action potentials can be recorded from the heart though appropriate catheter electrodes 28 and with this method early and delayed afterdepolarizations can be demonstrated. Again, unfortunately, the technique has not been used often in attempts to demonstrate EAD or DAD in the human heart.
Voltage clamp studies on heart fibers and then patch clamp studies on single myocytes or excised patches of cell membrane 29,30 added importantly to understanding the nature and regulation of the ion channels in the heart cell membrane that were responsible for normal and some forms of abnormal electrical activity but this information, and data from studies on membrane processes responsible for ion transport, contributed more to understanding antiarrhythmic drug action that to mechanisms for arrhythmias.
In summary, the electrophysiological mechanisms that can cause different types of arrhythmias are fairly well understood. However, the mechanism causing a particular arrhythmia often is not known. This weakens but does not prohibit attempts at rational selection of antiarrhythmic agents.
ANTIARRHYTHMIC DRUG ACTIONS
If we had an adequate understanding of how antiarrhythmic drugs acted to modify the electrophysiological properties of normal and abnormal cardiac tissues, we probably would be able to predict with reasonable accuracy their effects on arrhythmias resulting from defined mechanisms. Also, an adequate understanding of effects on electrical activity should help identify the mechanisms for undesirable actions on the heart and in particular the production of arrhythmias. As noted above, our understanding of general mechanisms probably is adequate but assignment of a mechanism for a specific arrhythmia may be problematic. Knowledge about the actions of commonly used drugs on normal cardiac
tissues is reasonably adequate. The major deficiency is detailed information on how different abnormalities of cardiac electrical activity caused by disease modify drugs actions.
The development of antiarrhythmic drugs started with an observation by Wenckebach that a patient with both malaria and atrial fibrillation noted an improvement in his heart's rhythm when he took quinine. Frey 31 followed up on this finding, compared cinchonine, quinine and quinidine and concluded that quinidine was most effective. Some years later Mautz noted that procaine exerted actions like those of quinidine on the heart. Procaine, because it was rapidly hydrolysed, was unsuited for systemic administration but in 1951 Mark 32 found that procainamide resembled procaine in its actions and had a sufficiently long duration of action for clinical use. Subsequently, in 1962 lidocaine was introduced for the emergency treatment of arrhythmias. The major effect of these drugs was to block the sodium channel. Subsequently many agents capable of blocking the sodium channel were synthesized and evaluated (table 2). All shared the ability to slow conduction but differed in terms of effects on potassium channels and thus on Q-T interval and refractoriness. These differences were the basis for the familiar classification of members of the group shown in the table. Over the years, many efforts were made to relate effectiveness against different types of arrhythmias to drug class but these generally have been unsuccessful.
Some clarification of antiarrhythmic action was provided through studies on transmembrane potentials 33. It was found that the degree of block of sodium channels was dependent on the transmembrane resting potential, increasing as membrane potential decreased, and that drug-blocked channels recovered more slowly than unblocked channels during and after repolarization. This latter effect accounted in part for the prolongation of refractoriness caused by class IA and IC agents. It also was noted that for most class I drugs the intensity of sodium channel block increased as heart rate increased, i.e. the drugs showed use-dependence 34,35. The degree of channel block and the resulting slowing of conduction thus would increase during a tachycardia. This phenomenon resulted from the balance between the kinetics of association with and dissociation from sodium channels. Finally, largely through the use of patch clamp methods to study single sarcolemmal channels, it was shown that the local anesthetic antiarrhythmic drugs were in no way specific for sodium channels. Many blocked one or more potassium channels and many blocked calcium channels as well. These findings made it quite difficult to relate antiarrhythmic efficacy to an effect on any particular membrane ionic current.
Over the years the clinician has used many of the wide spectrum of class I drugs with varying degrees of success to treat a variety of arrhythmias. In general it was found that some disturbances of rhythm responded to a variety of agents: in general these were arrhythmias like premature ventricular contractions or non-sustained ventricular tachycardia that probably posed no significant risk to the patient. Other arrhythmias were less susceptible to treatment and for some there appeared to be no consistent relationship between the proposed arrhythmogenic mechanism and efficacy of a particular agent. This clearly was the case for ventricular tachycardia caused by reentry 22. For many such cases it was found necessary to induce the arrhythmia by stimulation and test one agent after another before it was possible to select a drug that prevented induction. Also, it was not clear that suppression of initiating events necessarily modified long-term outcomes. This problem was addressed directly in the CAST trial 3 which employed flecainide, encainide and moricizine to prevent premature impulses or non-sustained ventricular tachycardia in post-infarct patients. The outcome was disappointing in that adequate suppression was associated with an increase in mortality, most likely due to a lethal arrhythmia. With moricizine the deaths occurred early during drug administration but with flecainide and encainide the unexpected deaths were independent of duration of treatment. This suggests a dependence on an intercurrent event such as a new ischemic episode.
The possible reasons for the unpredictable efficacy and arrhythmogenic effects deserve evaluation. Figure 3 shows a scheme commonly used to explain reentrant excitation. In this scheme the impulse travels to a branch point in the cardiac syncytium. Distal to this point propagation in one branch fails while in the other it continues. This enables the impulse to return to the blocked segment. Here, if conduction has been slow enough and if the block is unidirectional, the impulse can reexcite fibers proximal to the area of block and establish a reentrant rhythm. A similar phenomenon can occur in an unbranched segment of the myocardium or conducting system 20,22,36. In this case it is implied that the anisotropic properties, the poor lateral coupling between fibers through infrequent gap junctions, are sufficient to protect a sufficient length of the slow-conducting segment from excitation to allow it to recover of some degree of excitability.
If it is correct that the unidirectional block may have a variety of mechanisms it is not surprising that block of fast channels will not always bring about the desired outcome. In some cases, as suggested by the diagram, the drug converts uni- to bidirectional block and thus prevents reentry. However, it is possible that by depressing the fast inward current the drug may substitute a slow response for a depressed fast response in the depressed segment. This change probably would cause added slowing of the reentering impulse and stabilize the reentrant circuit. Alternately, as suggested by Allessie's studies on reentry around an area of functional block 37, a delay in the recovery of excitability caused by the sodium channel blocker can merely drive the circulating impulse into a circuit with a longer length. Finally, it may not be possible to convert uni- to bidirectional block with drug concentrations that do not cause excessive impairment of conduction throughout the heart.
Consideration of the possible mechanisms of action of class I agents also suggests that drugs with this primary mode of action always will have the potential to induce new arrhythmias. Figure 3 attempts to indicate why this is so. It assumes that in a heart in which there is one preexisting reentrant circuit, one that causes premature impulses and can cause reentrant tachycardia, there likely are other areas containing latent reentrant circuits. In each of them there is an area of depressed and slow conduction but no block. In the presence of drug, however, some event such as transient local ischemia, causes partial depolarization of the fibers in part of the latent circuit. This induces unidirectional block and establishes a new reentrant pathway. The general rule seems clear. Normally the cardiac impulse has a large safety factor for conduction. The normal propagating impulse not only delivers enough depolarizing current to activate normal, fully repolarized fibers, it also can excite partially refractory fibers as soon during repolarization as they can develop an active response 38. A drug that decreases the safety factor for propagation and acts more strongly on partially depolarized fibers than on normal fibers will inevitably cause local differences in responsiveness and predispose to local block and reentrant excitation.
Recent and elegant studies combing the techniques of molecular biology and membrane biophysics are providing detailed information of the site in the sodium channel at which class I agents bind, on the nature of the binding and on electrophysiological consequences of the interaction 39,40. This work soon will permit the design of blockers with a high degree of specificity and with predictable actions. However, other types of studies still will be needed to determine for which arrhythmias block of the sodium channel is going to be both effective and safe.
In contrast to the drugs that slowed conduction by blocking sodium channels the clinician was provided with another type of drug i.e., a class III agent, that acted mainly to delay repolarization and thus prolong refractoriness. One of the first of these, bretylium, was found to terminate ventricular fibrillation of the canine heart 41 and subsequent studies showed that it caused marked prolongation of the action potential and refractoriness. Amiodarone and sotalol also delayed repolarization and prolonged refractoriness 42,43 but the former also blocked sodium and calcium channels and the latter caused ß-adrenergic blockade. The first agent shown to act almost exclusively to delay repolarization and prolong refractoriness was N-acetylprocainamide, a metabolite of procainamide 44. This finding led to the synthesis of a goodly number of the drugs assigned to class III (table 2). Some of these, such as dofetilide were quite selective in causing potassium channel block without modification of sodium or calcium channel function. In relation to the concept introduced by Lewis and emphasized by Allessie 45 these agents should have been ideally suited to terminate reentrant rhythms since they would prolong refractoriness without modifying conduction. This would abolish the excitable gap in the reentrant circuit and block conduction of the circulations impulse.
Unfortunately, all shared an undesirable property: the degree of action potential prolongation increased at slow rates and decreased at rapid rates 46. This property, unfortunately called reverse use dependence, is thought to result from the fact that at least two types of potassium channels contribute to repolarization in most heart fibers. One, IKs, activates slowly and deactivates slowly. Because of its slow deactivation residual current in this channel contributes strongly to action potential abbreviation during a tachycardia and block of the channel thus should prolong the action potential during a rapid rhythm. The other repolarizing potassium channel, IKr, activates rapidly, then inactivates and recovers only slowly from inactivation. Because of these properties current in this channel makes only a minor contribution to repolarization when the cycle length is short. Unfortunately, most selective potassium channel blockers block IKr and not IKs .
As is the case for sodium channels, recent studies on the structure and function of potassium channels are providing important information on the sites at which drug binding causes block of the channel and the functional consequences of such block 47,48. Hopefully, a detailed description of the structure of the binding site will permit the design of selective and specific agents. However, this information will not tell us which potassium channels to block for which arrhythmias or, more important, whether or not such block is the most desirable mode of treatment.
It has been known for many years that quinidine was arrhythmogenic in some patients and was capable of causing lethal arrhythmias. Interestingly, this problem was most severe early during drug administration as recently was noted for moricizine 3. Procainamide was found to have a similar arrhythmogenic potential and subsequently most if not all of the class III agents were found to share the problem. As mentioned above, the mechanism for the arrhythmias caused by class III drugs was demonstrated in early studies on N-acetylprocainamide and sotalol 43,44. These agents demonstrated so-called reverse use dependence and, on sufficient slowing of the heart rate, caused early afterdepolarizations. The afterdepolarizations caused an arrhythmia termed torsades de pointes. The new potassium channel selective blockers have the same effect as do a variety of other classes of drugs that cause potassium channel blockade.
As is the case for the class I drugs, it is important to reevaluate some of the assumptions about the actions of class III agents. In the design of the newer ones potassium channel selectively was sought since this might avoid problems encountered with drugs like quinidine that block both potassium and sodium channels. The desired selectively was achieved. However, this clearly does not imply that during use they will not impair conduction in a reentrant circuit. If the action potential, and thus the effective refractory period, is prolonged the impulse circulating in the reentrant circuit will encounter a shortened excitable gap. As the wavefront encounters incompletely repolarized fibers the sodium current will be attenuated because, with incomplete repolarization, there is only partial recovery of sodium channels from inactivation. Thus, with progressive prolongation of refractoriness due to class III action there can be progressive impairment of conduction and a likelihood of all the problems that this can cause. The conductance of many potassium channels is influenced by the degree of their phosphorylation 49 and thus is dependent on the metabolic state of the fibers. Local differences in the degree of action potential prolongation by class III agents thus can be anticipated and the resulting inhomogeneities of repolarization can be arrhythmogenic. Disease can and does modify the function of sarcolemmal ion channels 50 and the effect of this modification on drug action is largely unknown.
With respect to the propensity of class III agents to cause early afterdepolarizations and torsades after long diastolic intervals we still cannot provide a completely satisfactory explanation. In general the potassium channel blockers bind to open channels 51. As a consequence one thus might expect a more intense block during rapid rhythms when the channels are open most of the time. Conversely, the development of open channel block during an action potential may be rather slow, as has been shown for IKs and quinidine 52. This might lead, at slow heart rates, to accumulation of block during the long action potential. This would result in further prolongation of the action potential and thus to additional accumulation of block. The net result would be failure of repolarization and initiation of early afterdepolarizations. Alternatives also must be considered. One candidate is a slowly inactivating component of sodium current. This is a current that normally prolongs the action potential. At slow rates, during potassium channel blockade, this current may cause excessive prolongation of repolarization and early afterdepolarizations whereas, at rapid rates, due to its slow recovery from inactivation, it makes only a minimal contribution to action potential duration.
WHERE DO WE GO FROM HERE?
Although the current state of pharmacological treatment of serious arrhythmias is far from ideal the future probably holds some promise. First, there has been a major effort to change the way clinicians select antiarrhythmic drugs 25. The "Gambit" approach requires first that the electrophysiological mechanism for the arrhythmia be identified precisely using the classification described above. It then proposes that for each arrhythmogenic mechanism there are one or more electrophysiological parameters the modification of which is sufficient to terminate the arrhythmia or prevent its induction. Among these is assumes that one is most susceptible to alteration while entailing minimal risk of adverse cardiovascular effects. This is called the vulnerable parameter. The proposition is logical and, when the mechanisms is clearly understood and a suitable agent is available, identification of the vulnerable parameter permits safe and effective treatment. The residual problems are twofold: Arrhythmogenic mechanisms may not be known with certainty and suitable agents may not be available.
Fortunately efforts have begun to identify new classes of antiarrhythmic drugs that act by mechanisms distinct from those of class I and class III. A few examples can be mentioned. Repolarization depends not just on outward current in the so-called delayed rectifier channels but also on outward current provided by the inward rectifier, the channel that maintains the resting potential. Partial blockade of this channel causes significant action potential prolongation and this effect may not be associated with reverse use-dependence. One such agent 53 has been shown to cause dose-dependent delay of repolarization without an associated decrease in resting potential. Studies on the antiarrhythmic effectiveness of this type of blocker are in progress. Also, it is clear that the duration of the action potential depends on the balance between inward and outward currents, repolarization occurring only when net current is outward. Repolarization thus can be delayed and the action potential prolonged by augmenting inward current instead of blocking outward current. A new agent, ibutilide, increases slowly inactivating sodium current and is under evaluation 54. In some animal models of reentrant rhythm it is consistently effective. Whether or not it will be able to prolong refractoriness without inducing early afterdepolarizations at slow rates is uncertain. Nevertheless, it is encouraging that efforts are being made to develop and evaluate drugs with new mechanisms of antiarrhythmic action.
In summary, we know that for many arrhythmias drug treatment is not satisfactory because of uncertain efficacy, risk of creating new arrhythmias or both. To permit progress, the electrophysiologist must provide a better understanding of mechanisms and of changes in drug sensitivity that can result from disease. The clinician, at the same time, must develop means suitable to identify arrhythmogenic mechanisms more consistently and more precisely. These advances, in conjunction with new types of agents that act by new mechanisms, may result in the desired outcomes.
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Studies by the author were supported in part by grants HL-08508 and HL-30557 from the National Heart, Lung and Blood Institute, National Institutes of Health.
Figure2:
.
Class Drug Sodium Calcium Potassium I A Qunidine 2+ 2+ Procainamide 2+ 1+ Disopyramide 2+ 1+ Moricizine 2+ B Lidocaine 1+ Mexilitine 1+ Phenytoin 1+ Tocainide 1+ C Encainide 3-4+ 1+ Flecainide 3-4+ 1+ Propafenone 3-4+ Indecainide 3-4+ III Amiodarone 1+ 1+ 2+ Bretylium 3+ Sotalol 2+ Dofetilide 2+ IV Verapamil 1+ 2+ Diltiazem 2+ Bepridil 1+ 2+ 1+ 
Figure 3
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