European Heart Journal (1992) 13 {Supplement F), 2-13

New insights into the pharmacology of sodium channel blockers J. TAMARGO, C. VALENZUELA AND E. DELPON

Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain

Introduction

Pre-CAST era Sudden cardiac death accounts for an estimated 600 000 deaths yearly in the United States'51. Over 80% of these deaths are due to a ventricular tachyarrhythmia, often preceded by premature ventricular beats (PVBs), that initiates fatal ventricular fibrillation in patients with or without coronary artery disease16"81. In patients with prior myocardial infarction (MI) the presence of critically timed PVBs, especially when they occur in a repetitive form, such as non-sustained ventricular tachycardia, can initiate chaotic disorganization of cardiac electrical activity, resulting in fatal arrhythmias being considered as an independent risk marker of sudden cardiac death'9'10'. Because of the strong association between PVBs and subsequent mortality, it was hypothesized that sudden coronary death results from an electrical accident. For many years, based on this electrical theory, the ADs were defined as compounds able to suppress PVBs and to terminate sustained tachyarrhythmias that can result in morbidity and mortality. Therefore, PVBs were considered in recent years as the villains'11] and the most potent ADs (Ic drugs) were known colloquially as PVB killers. Accordingly, various studies were designed to determine whether Correspondence: J. Tamargo, Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid. Spain. 0195-668X,92,OF0002 + 12 $08.00/0

The inefficacy of class I ADs is not a surprise and their pro-arrhythmic effects were predicted by basic electrophysiologists for many years'19"21'. We believe that one explanation for both inefficacy and pro-arrhythmia was the general perception of cardiac arrhythmias as pure electrical phenomena, ignoring the pathological cardiac substrate supporting the arrhythmogenic mechanisms. Because of the existence of an ischaemic substrate, one would expect that interventions reducing acute myocardial ischaemia (/?-blockers, coronary artery bypass surgery, antiplatelet drugs) would be more effective than class I ADs in the prevention of certain ventricular tachycardias in patients with previous MI. In any case, it is difficult to explain why, whereas the pro-arrhythmic effects of digitalis were recognized over 100 years ago, class I ADs (i.e. quinidine) were used for almost 50 years before clinicians fully recognized their pro-arrhythmic risk. With the shadow of the CAST behind us, it is evident that current cardiac arrhythmia therapy with class I ADs is suboptimal and it is necessary to develop new Na channel blockers for at least three main reasons. First, the arrhythmic population, which truly needs to be treated for supraventricular and ventricular arrhythmias, averages almost 3 million patients in the United States'2'. Second, ADs are likely to remain the mainstay of therapy for the majority of patients with cardiac arrhythmias, © 1992 The European Society of Cardiology

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In the 1970s and 1980s a great number of new antiarrhythmic drugs (ADs) became available for clinical use in an attempt to obtain more selective agents with fewer side effects and higher effectiveness. Most of them were local anaesthetics that inhibit the fast inward sodium current (INl) and they were included as class I drugs'1'. These new class I ADs were considered as better tolerated agents, since in clinical trials only 5-10% of patients stopped these new agents compared to the estimated 2030% who discontinue the conventional drugs (quinidine, lidocaine)12-31. In this review we analysed the pharmacological management of cardiac arrhythmias before the results of the Cardiac Arrhythmia Suppression Trial (CAST)141 were available and, on the basis of the modulated-receptor hypothesis, how the characteristics of the frequency- and voltage-dependent block of Na channels can explain the antiarrhythmic/pro-arrhythmic effects of sodium channel blockers. The further analysis of the diversity of antiarrhythmic actions of Na channel blockers would lead us to formulate some characteristics of the ideal ADs interfering with the fast Na channel.

suppression of potentially lethal PVBs after MI with ADs would reduce sudden arrhythmic death. However, at present there is no study that has demonstrated that suppression of PVBs, even when it provides benefits to the patient by eliminating the symptoms, results in a decrease in mortality in post-MI patients'1213'. Furthermore, in post-myocardial infarction patients, class I ADs do not prevent and may even facilitate sudden death'14'151. In 1989 the CAST study141 reported that patients with asymptomatic ventricular arrhythmias after acute MI receiving encainide and flecainide had a 3-64-fold increase in arrhythmic death/cardiac arrest compared to matched post-infarction patients who were receiving placebo. These findings have prompted the revaluation (metaanalysis) of other trials where the effect of class I ADs was compared with placebo or other active agents. These meta-analyses have der ,nstrated that almost all class I ADs appear to be of little value and may even have the potential for producing late pro-arrhythmic effects (increased arrhythmic death rates) when compared to placebo1'5"181. The enhanced potential for arrhythmic death is a serious shortcoming, particularly when the benefit of AD therapy may be quite minimal, such as in the treatment of symptomatic ventricular arrhythmias in patients without structural heart disease.

Pharmacology of sodium channel blockers

process1251; other factors, like pH, also modulate the rate of reactivation, this process being much slower in acidotic and depolarized tissues than in well-polarized tissues124-26"281.

HH

HH

3

HH

Tonic, frequency- and voltage-dependent block

HH'

HH'

RO

ID

Figure I Representation of modulated receptor hypothesis for antiarrhythmic drug action. Sodium channels are depicted as existing in three states: rested (R), activated-open (A) and inactivated (I). RD, AD and ID represent drug associated states. Binding and unbinding of antiarrhythmic drugs with each state are governed by association (k) and dissociation (1) rate constants. Transitions between states are governed by Hodgkin and Huxley (HH) rate constants which are modified in the presence of drug (HH').

frequency-dependent block (UDB), because this block

even when electrical (automated implantable cardioverter defibrillator, anti-tachycardia pacemakers, ablation) and surgical strategies can replace ADs in selected patients. Third, it is necessary to find better drugs than those presently prescribed, with less limiting side effects and higher therapeutic efficacy. CLASS I ADS

Atrial and ventricular muscle and His-Purkinje system excitability and impulse conduction depend on current flowing through selective ion macromolecular pores known as the voltage-gated Na ion channels'221. Disturbances in Na channel function play a key role in the slow conduction and block responsible for some cardiac arrhythmias. Class I ADs comprise a large number of drugs with disparate chemical structures and electrophysiological and pharmacological properties that share their ability to inhibit I Nl of the cardiac action potential"23-241. During the diastole, at negative membrane potentials, Na channels are closed-rested (R) but available to be open-activated (A) when a depolarizing stimulus reaches threshold. During the upstroke, when the membrane is depolarized, the channels are activated and Na permeability increases (maximum after 1 ms) but it spontaneously decreases during the plateau. Thus, during the plateau the inactivated (I) state predominates. In addition, any condition which tends to depolarize the cardiac cell (ischaemia, hyperkalaemia) will shift the equilibrium of channels to the I state. Inactivated channels (I) are not available for opening without first returning to the resting state during diastole. During the diastolic interval a gradual recovery from inactivation (reactivation) occurs (I-+R. Fig. 1). The rate of recovery from the inactivated state (reactivation) is a time- and voltage-dependent

develops when the channel is used and is not fully removed by the time of the next action potential. During repetitive stimulation Na channels spend more time in activated and inactivated states and as the frequency increases the diastolic time for reactivation is shortened. This leads to a progressive increase of inactivated, nonconducting channels, from which they slowly reprime to the rested state. Therefore, Na channel blockers should produce only minor effects at normal heart rates, but inhibit the INa to a far greater degree during tachycardia. Moreover, in 1955 Weidmann'301 showed that local anaesthetics shifted the availability of Na channels to more negative potentials (voltage-dependent block) in cardiac Purkinje fibres. Similar evidence was obtained with quinidine and lidocaine in guinea pig papillary muscles when the membrane potential was depolarized by increasing K concentrations'251. These results were confirmed in voltage-clamped Purkinje fibres where the 50% blocking concentration of lidocaine varied from >0-3 mM at a membrane potential of —120 mV to 10 UM at a membrane potential of — 50 mV to when inactivation was nearly complete13'1.

Modulated receptor hypothesis

To understand the voltage- and frequency-dependent blockade of Na channels produced by local anaesthetics and ADs in nerve and cardiac muscle, Hille1321 and Hondeghem and Katzung1231 formulated the modulated receptor hypothesis (M RH). The M RH proposes that: (1) ADs bind to a specific site on or near the Na channel. (2) The affinity for and the rates of binding and unbinding to their receptor are modulated by the conformation state of the channel (rested, activated or inactivated). Each state has a characteristic set of association (k) and dissociation

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HH'

Under physiological conditions Na channels are activated and inactivated during each cardiac action potential, but the reactivation is complete in less than 100 ms during diastole, so that Na channel availability is complete at the time of the next regular beat. This explains why, in the absence of drugs, the application of a train of pulses had no effect on the amplitude of the INa. However, in the presence of ADs, two modes of Na channel inhibition can be observed following a train of pulses'27-291. The reduction of INs during thefirstdepolarization after a long rest period at sufficiently negative potentials is referred to as tonic block. ADs produce a small tonic block (usually less than 5% at UM range). In contrast, during repetitive stimulation (i.e. during the tachycardia) the INa falls beat to beat until a new steady state is obtained. This additional reduction in Na permeability produced during repetitive depolarizations in the presence of class I ADs is referred to as use- or

4 J. Tamargo et al.

Table 1 Multiple actions of class I antiarrhythmic drugs IK•

Drug

la: Quinidine Procainamide Disopyramide

Ic.

Relative affinity

A A/I A

4-7 s 2-3 s 2-2 s

I I I

230 ms 470 ms I-4 s

Ic: Propafenone Flecainide Encainide

A/I A I

8-5 s 15-5s 20-3 s

Yes Yes Yes

Yes Yes Yes

No

No

Yes

Yes

Yes

Yes Yes

Yes Yes Yes

Yes

Other actions

a-blocker, anticholinergic ganglionic blocker anticholinergic

a and ^-blocker p"-blocker*

A = activated state; I = inactivated state; t re = time constant for recovery from block; I^ = inward Ca current; IK = delayed rectifier outward K current; !„, = transient K outward current.

(1) rate constants, the ratio of the binding to the unbinding rate constants being a measure of the affinity. At therapeutic concentrations (UM range) they show a much higher affinity for either the activated and/or inactivated channels than for the rested channels (K D R >01 muf27i. (3) Drugassociated channels differ from drug-free channels in that they are not able to conduct Na through them. Drugassociated channels exhibit time- and voltage-dependent transitions between the RD, AD and ID states (Fig. 1) and their voltage-dependence is shifted to more negative potentials and the rate of recovery from inactivation (z^) is slowed (Table 1). Recovery from block is usually considered as a slow diastolic process usually related to the dissociation from closed channel states (RD-»R and ID->I->R). However, it has been described the existence of a faster recovery from block associated to activation, the so-called activation unblocking, which is related to the ID-»RD-»AD->A pathway133'341. This process requires strong hyperpolarizations (ID->RD) and will occur when the block exceeds the activated state equilibrium ([AD]> >[A]). Repetitive pulses may in this way lead to use-dependent unblocking which is also a voltage-dependent process. These characteristics explain why ADs produced a greater inhibition of INa at faster heart rates and in depolarized tissue. Subclassification of class I ADs Because of these important differences among class I ADs, different attempts have been made to subclassify these drugs into more homogeneous subgroups. According to the rates of onset and offset of UDB, class I ADs were subclassified1351 as fast, slow and intermediate kinetics that corresponded to subclasses Ib, Ic and la, respectively, of Harrison's classification'3*1. However, it should be pointed out that this subclassification is by no means absolute, that there are important differences

between members of the same subgroup, and that drugs may belong to the same or different subgroups as the circumstances change" J 7 l Class Ib drugs (e.g. lidocaine) bind very rapidly to the inactivated state of the Na channel and a steady-state level ofUDBcanbe achieved in less thanfiveaction potentials. They unbind quickly during repolarization (rre < 0-5 s) and therefore, at normal heart rates, the rapid offset kinetics permits the almost complete recovery from block by the time of the next action potential, provided that the resting potential is normal127'28'351. This explains why at normal heart rates these ADs exert minimal effect on conduction velocity and produce no change in QRS duration, but they can selectively depress conduction and prolong the QRS duration at faster heart rates (during tachycardia) or when ventricular conduction is previously depressed (ischaemia, conduction system disease, marked hyperkalaemia). Because with class Ib drugs UDB can be achieved in a few action potentials, if the firing is suddenly increased they would suppress selectively early premature beats and highfrequency arrhythmias at concentrations at which they have little effect on the normal sinus rhythm127-28'33'38"401. However, they are less effective than class la and Ic ADs against slower tachycardias or late PVBs. Class la drugs (e.g. quinidine) interact with the Na channel rather slowly, so that it takes about 5-20 action potentials before a steady-state level of UDB can be reached. These drugs exhibit affinity for the activated state, and their recovery from blocks appears rather slow (r re > 1 < 5 s^27-28-351. Thus, while they can produce some slow conduction and prolong the QRS duration even at normal heart rates, these effects became more marked at increasing heart rates. Class Ic drugs (e.g. flecainide, propafenone) bind very slowly with the Na channel receptor (more than 20 beats) and unbind very slowly (r r e >8s) so that considerable drug is associated with the channel when the next action

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Ib: Lidocaine Mexiletine Amiodarone

Yes

••

Pharmacology of sodium channel blockers 5

Activated, inactivated and rested blockers

There are important clinical implications depending on the affinity of class I ADs for a particular state of the Na channel. In general, it has been proposed that class la and Ic ADs exhibit a high affinity for the activated state, while class Ib drugs exhibit a higher affinity for the inactivated state of the channel1271. However, many of the clinically useful ADs are mixed activated and inactivated blockers'411. Activated channel blockers exhibit a marked increase of block with each action potential upstroke but little further block is observed after the closure of the channel134'41'421. In single channel studies, open channel blockers like propafenone, quinidine and disopyramide decrease single channel mean open time143"451. These ADs might be much less effective in depolarized tissues where the inactivated state predominates, but more effective in tissues firing at high rates with short action potentials (e.g. atrial flutter). Because Na channels are open for a few ms during each action potential, steady-state INa block would be achieved after a certain number of beats. The inhibition of I Nl produced by these drugs is independent of APD, being in contrast to inactivated channel blockers effective in both atrial and ventricular tachyarrhythmias. With the inactivated channel blockers (lidocaine) the degree of block increases in proportion to the time the membrane is depolarized. Thus, inactivated sodium channel blockers produce a continuous increase in block throughout the plateau until steady-state is reached'46^81. Therefore, their effectiveness will be greater: (a) In depolarized tissues (ischaemia, hyperkalaemia) than in normally polarized tissues, since depolarization induces a change from rested to inactivated state of the channel during the diastole, (b) Because the inactivated state

occupies most of the APD they will be more effective in tissues with long action potentials (ventricular muscle and Purkinje fibres) than with shorter action potentials (atrial muscle) and also under circumstances which lengthen the APD (i.e. combination with class III ADs). They will subsequently be more effective in treating ventricular rather than supraventricular tachyarrhythmias. (c) At higher heart rates, because tissues spend more time in the depolarized state and there is less time to recover from block between beats. Rested state blockers can exert important proarrhythmic effects, since they will inhibit the I Nl and slow conduction more in normally polarized tissues, where channels are predominantly in the rested state, than in depolarized cardiac tissues where most of the channels are in the inactivated state. Diversity of antiarrtiythmic drug action CHARGED VS NEUTRAL DRUG FORM

Most ADs are weak bases (pka between 7 and 10), and therefore, the proportion of charged-hydrophilic and uncharged-lipophilic moieties will vary with pH. The charged form of a class I AD will preferentially access the Na channel receptor through a hydrophilic pathway*32'. This pathway allows the access of hydrophilic forms to the receptor from the intracellular aqueous phase only when the channel is activated-open, and thus, they show a pronounced UDB12'1. Uncharged molecules can readily pass through the lipid bilayer of the cell membrane and interact with the inactivated-closed channel by lateral diffusion through the lipid layer, so their access is not strongly affected by the channel state. As a consequence, the access of the charged, but not that of the uncharged form of an AD, to its receptor site in the Na channel is a voltage-dependent process. Membrane depolarization, acidosis and hyperkalaemia favour the interaction of the charged form with its receptor and lengthen the rre. Therefore, in ischaemic tissues, where the acidosis increases the charged moiety, these effects may result in a greater sodium channel block than in non-ischaemic tissue. On the other hand, alkalinization and hyperpolarization of the membrane potential increase the uncharged form and shorten the rre, which may explain the clinical effectiveness of alkalosis-inducing salts in the treatment of cardiotoxicity induced by class I ADs128'. STEREOCHEMICAL INFLUENCES

Many of the class I ADs have a point of molecular asymmetry and exist as a racemic mixture of two optically active stereoisomers. This is important because: (1) the enzymes may metabolize stereoisomers at different rates. Thus, the ratio of enantiomers in plasma changes with time and is extremely variable within the population. Interestingly, in the cases of both tocainide and mexiletine the (R)-enantiomer is the more potent inhibitor of the INl> but it is cleared more rapidly so that the plasma concentration of the (S)- form is much greater14*"501. Even when the clinical relevance of the stereoselective disposition of tocainide and mexiletine is unknown, these differences

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potential occurs127'28'35-38"401. Therefore, class Ic ADs would slow conduction and prolong the QRS even at normal heart rates. Since slow conduction may facilitate or aggravate reentrant arrhythmias these ADs would be expected to be more pro-arrhythmogenic than class la and Ib ADs'211. This poor discrimination between sinus rhythm and tachycardia is a pro-arrhythmic effect that may explain in part the adverse results of the CAST study141. Differences in the onset kinetics of UDB may also explain the differential effects of class I ADs on atrial and ventricular effective refractory periods (ERP)1''361. The ERP is determined by interpolating premature extrastimuli at various coupling intervals every 8-10 basic stimuli'35'. Under these conditions the increased refractoriness is determined by the drug's ability to produce an additional inhibition of Na channels in response to a sudden increase in heart rate. Class Ib drugs shorten the action potential duration (APD) but prolong the ERP relative to the APD because they produce a rapid depression of Na channels in response to a sudden increase in heart rate. Class Ic and la ADs produce small or moderate increases in the ERP relative to APD, respectively, because their slow onset of block does not allow a rapid additional blocking effect.

6 J. Tamargo et al.

may explain the poor correlation between plasma levels and effectiveness when levels of ADs whose enantiomers differ in potency are measured using a non-stereospecific assay. (2) The enantiomers may differ in their potency to inhibit the INa. In fact, (R)-tocainide is more potent than the (S)-enantiomer for slowing conduction velocity in isolated perfused rabbit hearts'50' and against experimental arrhythmias induced by programmed electrical stimulation[51l Enantiomers can also differ in the characteristics of their onset and offset kinetics of I N , block'52*531. (3) Each enantiomer may exhibit some other properties unrelated to the blockade of INa. Thus, the prolongation of the APD produced by disopyramide is mediated by a stereospecific inhibition of outward repolarizing current by the ^enantiomer1541. Most class I ADs are extensively metabolized, which leads either to their inactivation or to the production of active metabolites that may affect their clinical efficacy. Unfortunately, this pharmacological aspect has received little attention until recent years'571. Three factors need to be considered when assessing the clinical role of metabolites: their intrinsic activity with respect to the parent drug, the extent to which active metabolites can accumulate during chronic treatment, and the possible individual differences in drug metabolism. Some active metabolites can be just as, or even more potent, than the parent compound in the inhibition of the INa or may even exhibit new antiarrhythmic actions. Then the metabolite is primarily responsible for the antiarrhythmic actions of the parent compound. Recently, our group has investigated the effects of the main metabolites of imipramine (class la) and propafenone (class Ic). We found that both desipramine and 5-hydroxypropafenone produced more UDB of the V ^ of the ventricular action potentials than the parent compound'55-561. Moreover, the slow onset and offset kinetics of both metabolites led us to classify them as class Ic drugs. The offset kinetics of imipramine (la) and desipramine (Ic) are compared in Fig. 2. These results clearly indicated that desipramine and 5-hydroxypropafenone may be responsible for most of the cardiodepressant effects previously attributed to imipramine and propafenone, respectively. Another example is O-demethylencainide, which is 10 times more potent than encainide in blocking the Na channels'581. Sometimes the metabolites exhibit electrophysiological properties different from those of the parent drugs. The best examples of this are N-acetylprocainamide (NAPA) and 3-methoxy-O-desmethylencainide (MODE), metabolites of procainamide and encainide, respectively. NAPA is almost devoid of class I actions, unlike MODE, but both metabolites prolong the QT interval and the ERP, i.e. exhibit a class III profile157*59"601. This explains why some cardiac arrhythmias that initially respond to intravenous procainamide (before NAPA accumulates) may fail to respond to oral therapy with NAPA and vice versa. Therefore, differences in the effects of ADs depending on the route of administration indicate the importance of the metabolites. Quinidine metabolites can also explain why

001

Figure 2 Effects of imipramine ( • , 5UM) and desipramine (A, 5 UM) on the recovery kinetics of V ^ . Semilogarithmic plot of the lime course of recovery of V m of the test action potential Ordinate: normalized V ^ values [1 - (Vc_vl/VlJ)^J; V,^,: V m l of the test action potential and V0Mllx, \Bmt of the first action potential of the conditioning train]. Abscissa: time interval (T, s) defined as the interval between 90% repolanzation of the conditioning action potential and the onset of the test action potential. The basic driving rate was 002 Hz. First-order regressions were fitted by the method of least squares. • = imipramine 5UM, rre = 2-4s; A = desipramine 5UM, T =15-8s.

its effects on repolanzation are greater during oral therapy than after intravenous infusion'6'1. Because the active metabolites are closely related structurally to the parent compound, it is possible that both can bind to a common receptor. The metabolite may thus compete for receptor occupance at the Na channel level, altering the efficacy of the parent drug. Under these circumstances, the net effect will depend on the relative concentrations of the two agents, their affinities for the receptor and the kinetics of the reaction'21-621. In the beating heart, Na channel opening precedes inactivation; therefore, activated channel blockers will bind first and may prevent the binding of inactivated blockers, although this antagonistic interaction will also depend on the onset and offset kinetics of the UDB for each AD. This may be the mechanism for reducing toxicity of lidocaine, an inactivated Na blocker, by its metabolite glycylxylidide that blocks primarily activated Na channels'21-621. In patients receiving lidocaine, it is possible that the drug would become less effective after accumulation of significant levels of glycylxylidide by hepatic metabolism of lidocaine162-"1. Another interesting interaction exists between procainamide and NAPA. Because NAPA prolonged the APD it may potentiate the effects of procainamide which exhibits a high affinity for the inactivated state of the channel'27-281. The presence of active metabolites can also explain the lack of correlation between plasma concentrations and

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PARENT-METABOLITE INTERACTIONS

Pharmacology of sodium channel blockers 7

relative importance of the different K channels may vary among cardiac tissues and animal species and with factors such as heart rate and ischaemia'67-691. ANTIARRHYTHMIC DRUGS AFFECTING MORE THAN ONE CHANNEL

Subclassification of class I ADs does not imply that all members of the group exhibit the same properties and most ADs would no longer belong exclusively to a single drug class (Table 1). Moreover, cardiac arrhythmias frequently have a multifactorial origin, so it is not a surprise that drugs with multiple actions may be more effective under certain circumstances. Thus, some class la (quinidine, disopyramide16973-751) and 1c ADs (flecainide, encainide169-761) are not only Na channel blockers but also potent K blockers, exhibiting class III actions. Amiodarone is considered to have combined class I, II, III and IV actions'75-77"801 and sotalol combined class II and III actions'811. Propafenone is a class Ic drug, but in addition exhibits /?adrenoceptor blocking properties (class II action) and Ca antagonistic properties (class IV action) and after chronic treatment prolonged the APD in atrial fibres (class III)'82-831. ACTION POTENTIAL DURATION Moreover, ADs may exhibit very different electroThe effects of class I ADs on APD are variable, a shortening being observed with class Ib drugs, while a physiological effects depending on drug concentration, lengthening is observed with class la drugs. The configur- heart rate and cardiac tissue1371. Thus, the class I action of ation of the action potential reflects changes in net mem- propafenone requires lesser concentrations than its class brane current, the repolarization being triggered when the II and III actions'831, while propranolol and calcium net membrane current becomes outward. Therefore, simi- channel blockers can also block sodium channels at lar alterations in repolarization time course can be higher concentrations'84-851. Additionally, the effects of obtained through entirely different ionic mechanisms. class I ADs on APD can also depend on the heart The blockade of a slow component of Na current flowing rate'86"881. In human atrial fibres driven at a cycle length of during the plateau phase arising from the channels that 1000 ms quinidine and flecainide prolonged the APD at normally produce the INo1651 would alter the balance of 95% of repolarization by 33% and 6%, respectively. inward and outward currents during the action potential However, at increasing rates, the prolongation of APDplateau and cause earlier repolarization. A pure class I produced quinidine was markedly reduced, while that AD would be expected to shorten the APD, as indeed induced byflecainideincreased. Thus, at a cycle length of occurred with tetrodotoxin. This drug shortened the APD 300 ms, quinidine and flecainide increased the APD by of ventricular muscle and Purkinjefibres'661,while the pro- 12% and 35%, respectively1881. Furthermore, and because longation of the APD produced by class I ADs results the ionic currents controlling APD vary widely among the from a blockade of K. currents, i.e. they exhibit both class I different cardiac regions and even within the ventricular and III antiarrhythmic actions. Thus, it has been pro- muscle (endocardium vs epicardium'8'1), the effects of posed'671 that the ability of the class I ADs to exert potent class I drugs varies depending on the tissue type studied. effects on K channels ranged from nearly complete select- In Purkinje fibres the plateau Na current is greater than in ivity for Na channels (Ib) through an increasing com- ventricular muscle'66-73' which can explain why class I ADs ponent of K channel block (la), Ic drugs being possibly in shortened the APD in the former tissue while they had no effect or even lengthened the APD in ventricular muscle an intermediate position. fibres'871. The major voltage-dependent currents responsible for repolarization of heart cells are the delayed rectifier K. (IK) Figure 3 shows the differential effects of propafenone and the transient outward (Ilo) K. currents. The 1^ chan- in Purkinje fibres and ventricular muscle. Propafenone nels are fully activated in milliseconds. Then they undergo shortened the APD values in Purkinje fibres, while it slow inactivation and exhibit slow reactivation kinetics'681. lengthened the APD at 90% of repolarization in ventricuSince this current may be the primary repolarizing current lar muscle. As a consequence, at concentrations ^0-5 UM in atrial cells, a class I AD that selectively blocks Il0 (i.e. propafenone effectively diminished the disparity in APD quinidine) may offer some advantage in the treatment between Purkinje fibres and ventricular muscle, while at of supraventricular arrhythmias'691. The IK activates in higher concentrations it increased this disparity, which response to a depolarization only after several hundred results in an increased inhomogeneity of ventricular milliseconds and it does not undergo inactivation during repolarization, and decreased the conduction velocity the normal action potential'701. Recently, two types of in Purkinje fibres (not shown). These data suggest that IK channels have been described (IKj. and IKJ)17''72'- The propafenone may aggravate and/or induce sustained

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antiarrhythmic efficacy of ADs as well as some side effects of the parent compound'571. Thus, the anticholinergic side effects of disopyramide can be attributed to its N-monodealkylated derivative1641. The pharmacogenetics of drug metabolism is a very important aspect since the patient's phenotype can determine the types of antiarrhythmic action responsible for arrhythmia suppression. Patients with rapid acetylator phenotype have greater concentrations of NAPA, while extensive metabolizers of encainide or propafenone have 2-4 times greater concentrations of MODE and 5-hydroxypropafenone than in patients with poor metabolite phenotype*571. In poor metabolizers the half life and the plasma concentrations of propafenone are two to four times greater and the drug exhibits more P-adrenoceptor blocking (class II) activity than in extensive metabolizers1571. In the future, the development of new ADs must therefore include the evaluation of the intrinsic activity of the drugs, their active metabolites and the possible interactions between them.

8 J. Tamargo et al. 400

Table 2 Specific selectivity ratio of selected class I ADs against tachycardia at ISO beats, min'1 (SSRT) and a depolarization to -68mV(SSRD) SSRT

SSRD

Quinidine Procainamide Disopyramide Lidocaine Mexiletine Phenytoin Propafenone Encainide Flecainide Amiodarone

013 012 0-24 4-44 0-28 166 009 014 014 0-27

008 0-03 0-29 1110 0-82 4-27 008 006 004 0-60

12-63

100-00

HIT

0-1

(Reproduced with permission1421.) HIT = Hypothetically ideal therapeutic class I antiarrhythmic drug.

Propafenone

Figure 3 Effects of propafenone on action potential duration measured at 50% and 90% level ofrepolarizationin sheep Purkinje fibres ( • ) and ventricular muscle fibres (O). Ordinate: action potential duration (APD, ms). Abscissa: drug concentration (UM). (Tamargo J. Unpublished observations).

ventricular tachycardia by increasing the likelihood of incessant reentry, i.e. by slowing conduction (class Ic action) and producing a non-uniform recovery of excitability throughout the ventricle. Frequency-dependent changes in APD may also vary among cardiac tissues and animal species. Thus, the use-dependent prolongation of the APD induced by flecainide in human atria is less marked in dog and rabbit atria and barely perceptible in guinea-pig atria1881. All these results clearly suggest that: (a) many Na channel blockers exhibit mixed electrophysiological properties and therefore cannot be included in a specific class, and (b) that their effects would depend on heart rate, cardiac tissue and animal species where they are analysed, and therefore, the subclass allocations may vary depending on different physiopathological conditions.

Clinical applications of the MRH SELECTIVITY AGAINST TACHYCARDIA

Most clinically life-threatening ventricular tachyarrhythmias arise from a disturbance in impulse conduction leading to reentry*901. In principle, reentrant arrhythmias are favoured by slow conduction and brief refractory periods and may be abolished by improving conduction or further depressing conduction in a region showing unidirectional block. Class I ADs depress myocardial conduction to a point at which one-way block becomes bidirectional190-9'1. On the other hand, by slowing conduction through the potential reentrant circuit, they may be of little interest, or even harmful, depending on their effect on cardiac refractoriness. Because the slowing

in conduction is much more likely in patients with preexisting conduction disturbances, class I ADs (particularly Ic) may facilitate reentrant arrhythmias in patients with a history of ventricular fibrillation and/or previous MI. In fact, pro-arrhythmia due to excessive slowing of conduction has been suggested as a possible contributing factor in the increased mortality seen with class Ic ADs in the CAST study14'92931. It has been proposed that class Ic (and sometimes high concentrations of la) ADs produce an incessant monomorphic ventricular tachycardia that is associated with fast heart rates and excessive slowing of conduction'941. Hondeghem'421 computed the ideal selectivity of various class ADs in the abolition of the INa during tachycardia (180 beats. min"') while they do not inhibit the current under normal conditions (cycle length of 800 ms, APD = 300 ms and resting potential of - 8 5 mV). He calculated the specific selectivity ratio against tachycardia (SSRT), i.e. the ratio between the concentration that elicited 10% block under normal circumstances (EDN.O) and 80% block in the arrhythmic condition (ED go), [SSRT = EDNl0/EDT8O]. The results are summarized in Table 2. It was observed that the EDN,0 values increased during the tachycardia, but this increase was small for most class la and Ic ADs and moderate for class Ib drugs. Unfortunately, the A D ^ was larger than the EDN10 for most class Ic and la ADs, resulting in a SSRT against tachycardia of < 1. This indicated that ADs with long tre values (> 1 s) will not discriminate between normal heart rates and tachycardia, and therefore they cannot selectively suppress the tachycardia without also slowing conduction of normal heart beats, an effect which was predicted to be proarrhythmic1211. The best results were obtained with class Ib drugs (lidocaine, diphenylhydantoin) which, because of their short rre values (< 300 ms) may not effectively protect the heart from late PVBs or slow tachycardias. However, the computed SSRT value for an ideal AD against depolarization was three times higher than that of lidocaine1421.

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Drug

7-
A) occurs. Increased inactivation blocking and decreased activation unblocking would result in a selective depression of INa in depolarized tissue by ADs. Because a higher proportion of Na channels are inactivated in the ischaemic myocardium, ADs that bind preferentially to the inactivated state of the Na channel but unbind very rapidly from inactivated channels (class Ib) would be expected to inhibit the I N , more selectively in the ischaemic rather than in normally polarized tissues. However, this effect can be counteracted, at least partially, by the slow recovery from block that occurs in ischaemic-depolarized cells'24'271. In contrast, class la and Ic drugs unbind very slowly even at normal resting potentials, so that concentrations which depress ischaemic tissues are likely to do the same in normally polarized cells'21^281. Very recently a vulnerable window of 6 ms duration occurring near the tail of the action potential has been simulated, during which premature stimulation resulted in non-uniform conduction and unidirectional block'69'971. In the presence of ADs with a rre value of 280 ms and 667 ms, the window was shifted to a point 41 ms and 1250 ms after repolarization, respectively. At the same time, the probability that a randomly timed extrastimulus would produce unidirectional block increased with the rre value of the AD and when Na channel availability was reduced by membrane depolarization1971. The specific selectivity ratios against depolarization (SSRD) have been recently simulated by Hondeghem1421 (resting potential =—68 m V, cycle length = 800 ms, APD = 300 ms). He computed the concentration that elicited 80% block in the arrhythmic condition (ED 1 3 ^ and found (Table 2) that most class I ADs had a low SSR against depolarized tissues (SSR°). These results confirmed that ADs with long rre (la and particularly Ic ADs) cannot discriminate between normal and ischaemic tissues. These findings cast serious doubts about the effectiveness of ADs in suppressing ventricular arrhythmias arising in ischaemic myocardium without also slowing conduction of normal heart beats. The only exception was lidocaine, a

10 J. Tamargo eta\.

The ideal antiarrhythmic drug

Before describing the desirable characteristics of class I ADs, it is necessary to answer a simple question: what is an antiarrhythmic drug? Obviously, it is a drug that effectively suppresses or prevents tachyarrhythmias that can result in morbidity or mortality at concentrations at which it should not exert adverse effects on a normal heartbeat. According to the definition, the antiarrhythmic activity of a particular drug will depend upon its pharmacological properties and the mechanisms responsible for the genesis and maintenance of a given arrhythmia. Unfortunately, the precise mechanisms responsible for the genesis and/or maintenance of tachyarrhythmias and of the effects of Na channel blockers are still poorly understood, and the general approach to antiarrhythmic therapy remains empiric for most patients. Finally, the aetiology of cardiac arrhyth-

mias is frequently multifactorial, because it is unlikely that a single drug can be effective against all tachyarrhythmias. One AD could be very effective against a given arrhythmia but could be ineffective, or even deleterious, for others. Reentrant arrhythmias are favoured by slow conduction and brief refractory periods and may be abolished by improving conduction or depressing conduction further in a region showing unidirectional block and/or by lengthening the ERP191'. Suppression of sustained ventricular tachycardia during electrophysiological testing has been associated with a significantly greater prolongation of refractoriness in responders compared with nonresponders'100'. This agrees with the finding that procainamide tends to abolish reentry with a reduced slowing of conduction and a greater prolongation of refractoriness, while a greater slowing of conduction and a lesser increase in refractoriness stabilizes the reentrant circuit and promotes induction of arrhythmia'101'. ADs which selectively increase APD and ERP without slowing conduction (class III ADs) have been claimed to present greater efficacy than class I ADs in preventing or suppressing ventricular tachyarrhythmias evoked by electrical stimulation or those which occur during acute ischaemia'67-69102'. Consequently, in the post-CAST era, class III ADs are receiving renewed interest as a possible alternative therapy1691. However, the blockade of K channels and the prolongation of the APD and ERP induced by most class III ADs is more marked at normal resting potentials and at slow heart rates, while at depolarized potentials or during sustained tachycardia this prolongation is much less marked or even absent, i.e. they exhibit a reverse use-dependent block'88'103'. This explains why class III (and la) drugs are more likely to induce a polymorphic form of ventricular tachycardia, termed torsade de pointes'1041. The cellular basis for this arrhythmia involves the development of early afterdepolarizations1'04'1051. Therefore, the ideal class III drug should produce a minimal effect on APD at normal sinus rhythms, but a relatively fast, homogeneous and progressive prolongation of the APD and ERP during the tachycardia. Such a profile would tend to cause spontaneous conversion of a tachycardia in a few beats (when ERP > cycle length of the tachyarrhythmia) and may be less likely to induce early afterdepolarizationsandtorsades de pointes. Unfortunately no such class III agent has been developed yet. This is the logical consequence of the little information available about the K channels (Ilo, IK r and IKj) that control repolarization in human ventricular cells, the chemical requirements for a use-dependent prolongation of APD in all cardiac tissues (atria and ventricle) and regions (epicardium vs endocardium). As previously described, selectivity against tachycardia and depolarized-ischaemic tissues can be obtained with an inactivated Na channel blocker with fast offset kinetics (rre between 350 ms and 1 s). Therefore, it has been proposed'42-103' that an ideal profile for a drug would consist of UDB of Na channels with fast diastolic recovery from block (class Ib) and a use-dependent prolongation of APD (class III).

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knowledge of the class AD action mechanisms will be crucial for a more rational design of new class I ADs. However, the patch-clamp technique has many important limitations. The most significant is the limited recording bandwidth, since the intrinsic control bandwidth is limited to various hundred Hz and the rapid kinetics and state transitions of protein occur in the MHz range148-621. This explains why a Na channel blocker whose blocking kinetics are much faster than the open time of a channel may cause an apparent decrease in single channel amplitude. Other limitations include: (a) the difficulty in obtaining membrane patches with only one Na channel. The presence of multiple channels in most patches clearly limits information of the open and shut times, (b) The giga-ohm seal may shift the gating parameters of the cardiac Na channels to more negative potentials in a timedependent manner148'. Because single channel transitions are stochastic, studying the channel properties at a particular time or voltage requires voltage steps must be repeated tens of times to acquire an adequate sample size. Thus, if a significant shift occurs over the time frame of the sample acquisition period, the data so obtained are potentially meaningless, (c) Most of the patch-clamp experiments are performed at room temperature (20 °C). Under these conditions the mean open time values of the channel are larger and the recovery from block is extremely slow1341. Furthermore, at low temperatures the proportion of charged and neutral moieties varies in the hydrophobic pathway, which represents the access route for inactivated blockers. Therefore, ADs may act as activated and inactivated Na channel blockers at 37° and as more pure activated blockers at 20 °C. All these technical problems make a straightforward extrapolation as to what may happen at 37 °C almost impossible, (d) Finally, another important problem is the potential extrapolation of data obtained using isolated myocytes to syncitial preparations in vitro or in vivo. In addition, the electrophysiological effects of class I ADs have been studied in healthy preparations rather than in pathological-arrhythmogenic cells, which renders such an extrapolation all the more difficult. •

Pharmacology of sodium channel blockers

Future directions

New information about Na channel function has recently been obtained by the application of the techniques of molecular biology and immunology to study channel function. The channel hasJoeen cloned and sequenced and the use of selective antibodies against specific domains and site-directed mutagenesis should yield new information on receptor structure and enable us to correlate channel structure with function. Therefore, the multidisciplinary approach of molecular electrophysiologists, biologists, immunologists, and pharmaceutical chemists will provide the information that, in turn, will improve the rational design of more specific andeffective drugs, so that therapy cari be more effectively tailoredvto a particular arrhythmia. Basic research into the biochemical links between ischaemia, membrane currents and arrhythmias is also absolutely essential before more specific drugs can be designed. Finally, traditionally unappreciated aspects of ADs, such as stereochemical differences in Na channel blocking activity, the effects of active metabolites and the possible interactions with their parent compound and the effects of the chemical environment at the Na channel receptor (i.e. changes in pH) on the drug-receptor interaction must be reviewed. References [1] Vaughan Williams EM. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin . Pharmacol 1984; 24: 129-47. [2] Ratner SJ. Changing patterns of antiarrhythmic use in the 1990s. Drugs News Perspectives 1990; 3: 295-8. [3] Morganroth-J, Bigger JB Jr, Anderson JL. Treatment ofven. i tricular arrhythmias by United States cardiologists: a survey before the Cardiac Arrhythmia Suppression Trial results were available. Am J Cardiol 1990; 65:40-8. [4] The Cardiac Arrhythmias Suppression Trial (CAST) Investigators. Increased mortality due to encainide andflecainidcin a randomized trial of arrhythmia suppression after myocardial infarction. NEnglJMed 1989; 321:406-12. [5] Segal BL, Iskandrian AS, Kotler MN. Sudden cardiac death. In: Morganroth J, Horowitz LN, eds. Sudden cardiac death. Orlando: Gnine & Stratton 1985: 1-21. [6] CobbLA,WernerJA,TrobaughGB.Suddencardiacdeath. 1. A decade's experience with out-of-hospital resuscitation. Mod Concepts Cardiovasc Dis 1980; 49: 31 -6.

[7] Panidis I, Morganroth J. Sudden cardiac death in hospitabzed patients: cardiac rhythm disturbances detected by ambulatory electrocardiographic monitoring. J Am Coll Cardiol 1983; 2: 798-805. [8], Bayes de Luna A, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989; 117: 151-9. [9] Bigger JT, Fleiss JL, Kleiger R, Miller JP, Roltnizky LM, the Multicenter Post-Infarction Research Group. The' relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation 1984; 69: 250-8. [10] Mukharji J, Rude RE, Poole WK, Gustafson N, Thomas LJ el al. and the MILIS study group. Risk factors for sudden death after acute myocardial infarction: Two year follow-up. Am J Cardiol 1984; 54: 31-5. [11] Scheidt S. Ventricular premature complexes as villians: Still an important part of the problem. J Am Coll Cardiol 1987; 10: • 243-5. [12] May GS, Eberlein KA, Furberg CD, Passamani ER, DeMets DL. Secondary prevention after myocardial infarction: a review of long-term trials. Prog Cardiovasc Dis 1982; 24: 331-52. [13] Furberg CD. The effects of antiarrhythmic drugs on mortality after myocardial infarction. Am J Cardiol 1983; 52: 32C-36C. [14] IMPACT Research Group. International mexiletine and placebo antiarrhythmic coronary trial. 1. Report on arrhythmia and otherfindings.J Am Col Cardiol 1984; 4: 1148-63. [15] Hine L, Larid N, Hewitt P, Chalmers T. Meta-analysis of erhpirical long-term antiarrhythmic therapy after myocardial an-est. JAMA 1989; 262: 3037-40. [16] Anderson JL. Reassessment of benefit-risk ratio and treatment algorithms for antiarThythmic therapy after the Cardiac Arrhythmia Suppression Trial. J Clin Pharmacol 1990; 30: 981-9. [17] Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: A meta-analysis of randomized control trials. Circulation 1990; 82: 1106-16. [18] Morganroth J, Goin JE. Quinidine-related mortality in the short-to-medium-term treatment of ventricular arrhythmias. Circulation 1991; 84: 1977-83. [19] Elharrar V, Gaum WE, Zipes DP. Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs. Am J Cardiol 1977; 39: 544-9. [20] Nattel S, Pedersen DH, Zipes DP. Alterations in regional myocardial distribution and arrhythmogenic effects of aprindine produced by coronary artery occlusion in the dog. Cardiovasc Res 1981; 15:80-5. [21] Hondeghem LM. Antiarrhythrriic agents: modulated receptor applications. Circulation 1987; 75: 514-20. [22] Fozzard HA. Conduction of the action potential. In: Berne RM, ed. Handbook of Physiology, vol. 1, The Heart. Bethesda, Maryland: Williams and Wilkins Co. 1975: 335-6. [23] Hondeghem LM, Katzung BG. Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 1977; 472: 373-98. [24] Grant AO, Starmer CF, Strauss HC. AntiarThythmic drug action: blockade of the inward sodium current. Circ Res 1984; 55:427-39. [25] Chen C-M, Gettes LS, Katzung B. Effect of lidocaine and quinidine on steady-state characteristics and recovery kinetics of (dV/dt)—t in guinea-pig ventricular myocardium. Circ Res 1975; 37: 20-9. [26] Courtney KR. Review: Quantitative structure/activity relations based on use-dependent INa block and repriming kinetics in myocardium. J Mol Cell Cardiol 1987; 19: 318-30. [27] Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol 1984; 24: 387-423.

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Although in the last decade we have improved our understanding of the cellular mechanisms of arrhythmias and of actions of class I ADs, the general approach to therapy remains empiric for most patients. There is still much to learn about the Na channel and the mechanism of action of class ADs. The examination of the blocking mode of drugs at the single channel level may improve our understanding of the interaction between class I ADs and Na channels at the molecular level and provide the physico-chemical properties that allow a particular drug to behave as a selective open or inactivated channel blocker. This approach also provides an opportunity to test models of antiarrhythmic drug action and new insights into current schemes of classifying ADs. Unfortunately at the present time too few drugs have been examined with this technique to begin to formulate any classification scheme.

11

12 J. Tamargo et al.

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Pharmacology of sodium channel blockers 13

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New insights into the pharmacology of sodium channel blockers.

European Heart Journal (1992) 13 {Supplement F), 2-13 New insights into the pharmacology of sodium channel blockers J. TAMARGO, C. VALENZUELA AND E...
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