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MOLECULAR ACTION OF CLASS I ANTIARRHYTHMIC DRUGS AND CLINICAL IMPLICATIONS VALERIA KECSKEMETI Department of Pharmacology, Semmelweis University of Medicine, Budapest Nagyvarad ter 4, P .O . Box 370, 1446 Hungary Received in final form 7 January 1991
SUMMARY This report briefly reviews the advance in our knowledge of cellular electrophysiological effects of membrane stabilizer antiarrhythmic drugs (sodium channel blockers) including some new ones . The class I drugs block cardiac sodium channels and differ in the kinetics of the interaction with sodium channels and in the actions on the repolarization phase . The class I drugs can be subdivided into subclasses (I a,b,c) . This review focuses on the interaction of these drugs with sodium channels and the molecular models of their action . The interaction of class I drugs with the sodium channel receptor is influenced by the state of the myocardium (pH, ischaemia) and by other drugs as well . The clinical implications of different actions of sodium channel blockers, alone and in combination, and their proarrhythmic effects are summarized . KEY WORDS : antiarrhythmic drugs, sodium channel blockers, cellular electrophysiology, proarrhythmic effects of antiarrhythmic drugs .
INTRODUCTION During the last 10 years the burst of research activity fuelled by the claim of having the `ideal' antiarrhythmic drug has amplified and extended our knowledge . Key advances have been made in developing new methods for analysing the mode of action of antiarrhythmic drugs (ADs) and assessing the interactions of ADs and settling treatment strategies . The present review is limited to a discussion of sodium channel blockers, focusing on the electrophysiology, and the molecular basis of their antiarrhythmic actions, which might be important for preclinical studies .
CLASSIFICATION OF ANTIARRHYTHMIC DRUGS Among the several classifications of ADs only two are widely accepted . One was suggested by Hoffman and Bigger [1] and classifies ADs into two groups : one 1043-6618/91/060131-12/$03 .00/0
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group slows conduction and decreases the maximum rate of rise of phase 0 depolarization of the action potential (Vmax), while the second group does not modify conduction and Vmax . The second classification proposed by Vaughan Williams [2] is based on the various mechanisms of action of ADs and groups ADs into several classes . The appearance of Ca 2+ channel blockers as ADs extended the original scheme into four categories [3] . This classification seems to be better accepted and appears to be a practical way of grouping clinically useful ADs . Since class I drugs have distinct electrophysiological properties, these drugs have been further subdivided into three subclasses and the original classification was modified [4] . Recently a fourth subclass, Id, has been suggested for transcainide [5], and in the case of alinidine a new, fifth class of antiarrhythmic action has been proposed [6, 7] . ADs are summarized in Table I . The table shows some prototype ADs and the main changes in the action potential (AP) and ionic currents and the main alteration on the electrocardiogram induced by these agents . Although this classification may help the practising physician in rationalizing the prescription of specific drugs, it has often been criticized . The critique has been strengthened by several data showing that non-'primary' ADs (antidepressive drugs, neuroleptics, adenosine, histamine-receptor blockers) might have antiarrhythmic effects [7] . An antihistaminic agent, dimethindene, was found to inhibit fast Na' current and to have electrophysiological properties similar to those of both lignocaine and quinidine [8, 9] . A new antiasthmatic drug, azalestine, was reported to have antiarrhythmic effects, and to inhibit slow Ca" and fast Na' channels [10] . Moreover, dantrolene sodium, a skeletal muscle relaxant, has been found to exert antiarrhythmic activity [11] which can be predicted by its class III and class IV electrophysiological effects [12-14] . The classification is made more difficult by the fact that most agents have more than one action . Such overlapping effects can be observed in the case of beta-adrenoceptor blockers, amiodarone, and some members of class la, Ic . Beta-blockers have additional antiarrhythmic class I properties [6, 15-17] . Moreover, sotalol belongs not only to class II and III, but it has an additional decreasing effect on the time-dependent K+ current [18] too . The new `modified' beta-blocker, propafenone, possesses class I properties and has a slight Ca2+ channel blocking effect (class IV) [19, 20] . Amiodarone, the main representative of class III drugs in appropriate concentration and stimulation frequency, reduces Na+ current, too [21] . It has an antiadrenergic action (class II) [22] and reduces Ca 2+ current (class IV) [23] and K+ current [24] as well . Some class I agents (quinidine, flecainide, ethmozine) were found to inhibit Ca 2+ current [25] .
CLASS I ANTIARRHYTHMIC DRUGS These drugs have the common property of blocking the fast inward Na' current (INa ) in cardiac muscle . Based upon their distinct electrophysiological properties, these agents can be subclassified into smaller more homogeneous groups . The three main subgroups have different actions on clinical electrophysiological parameters . The la agents depress conduction of both sinus and premature beats and prolong refractory periods and repolarization . lb drugs selectively depress
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conduction of premature beats or conduction in ischaemic tissue and shorten the duration of repolarization, without changing refractory periods . The Ic compounds markedly depress the conduction of normal and premature beats and have small effects on repolarization and refractory period . The fundamental bases for subclassification are the interaction of these drugs with the sodium channel, their actions on the repolarization phase of AP in atrial, ventricular and Purkinje fibres and their effects on sinoatrial and ventricular node potentials [26] .
Interaction with sodium channel
Although Aldrich and coworkers [27] gave the reinterpretation of the cardiac Na' channel based on single channel studies with the patch-clamp technique, most of the evidence agrees with the view that the cardiac Na' channel is similar to that in nerve [28] . The cardiac Na' channel may exist in one of three possible states : active or open (conducting Na'), resting, and inactivated . The kinetics of interaction of class I drugs with the cardiac Na' channel can be concluded from the studies of interaction of local anaesthetics with Na' channels in nerve [29, 30] on the one hand and the results obtained from cardiac fibres with the patch-clamp technique [31, 32] on the other . Many workers have relied on the Vmax of cardiac APs as a measure of the Na' current [7, 26] . There are theoretical difficulties (i .e . non-linear relationship between Vmax and IN,, data) with this approach [28, 33-35] but it has provided a number of interesting insights into the mode of action of these drugs . These studies showed that the rate of stimulation modified the degree of depression of Vmax produced by class I drugs . The property of class I drugs is similar to the property of use-dependence (frequency-dependent inhibition of INa) of local anaesthetics in nerve [36] . The rate (frequency)-dependent block of Vmax is a common property of class I drugs and this is dependent on drug concentration . The rate of onset of frequency-dependent depression of Vmax and the rate of recovery from rate-dependent block (RDB) for different class I agents are quite different [26, 37] . It was found that lignocaine (lidocaine), mexiletine and tocainide (lb subclass) had `fast' kinetics (the rate of onset of RDB is quick, the time constant of recovery from RDB is small), encainide, flecainide, lorcainide (Ic drugs) had very slow kinetics (RDB develops slowly, the time constant of recovery is high), while quinidine, procainamide, disopyramide (la group) were intermediate . Finally a fourth subclass has been suggested for transcainide, which exhibits no frequency- and voltage-dependent block [5]. That means that this drug has equal affinity for the three primary states of the Na' channel and does not alter the voltage dependence of the channel . This drug caused a fixed block and thus there is also no recovery from block during diastole . Under normal physiological conditions, in the case of class lb drugs, a large fraction of the Na' channels becomes blocked during AP but this block dissipates quickly during diastole . Thus, conduction of the normal heart beat is not slowed and the QRS duration is not widened . In contrast, class Ic drugs, even at normal heart rate, exert a significant degree of block at end diastole and slow conduction and widen the QRS complex . Class la drugs have intermediate kinetics of block
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development and recovery, and they have intermediate effects on conduction and QRS duration. Many direct data have confirmed that several class I drugs prolonged the reactivation process and slightly modified the activation one [38-40] . These results suggested that class I agents enhance the inactivation of the channel and this effect can be increased at faster rates . Lignocaine can be seen as an inactivated channel blocker, while flecainide may be considered as an open channel blocker [41] . Mexiletine and tocainide also stabilize the Na' channel in its inactivated state [42] . Penticainide, a new disopyramide analogue, binds to open Na' channels and is trapped when the activated channel returns to the resting state [43, 44] . Some properties of penticainide, such as AP duration reduction, mimic the properties of class lb drugs, while the slow recovery kinetic of rate-dependent block is similar to that of class Ic agents . Among the newest ADs, ropitoin, a new diphenylhydantoin derivative, has similar properties to flecainide and reduces the slow Ca t current, too [45] ; RS-87337, a piperazine carboxamidine, has an electrophysiological profile characteristic of both class la and class II compounds [46] ; cibenzoline belongs to class Ic, but it also affects the Ca" channel [47] . Our group reported the electrophysiological characteristics of newly developed compounds, Chinoin-103 and EGYT-2936 [17, 48] . Chinoin-103 (4cyclohexylamino-1-1-naphtholenyloxy-2-butanol maleate) strongly reduced IN, and slightly decreased the slow Ca21 current. The reduction of Vmax was found to be voltage- and use-dependent . Its effect on atrial and ventricular AP duration was similar to that of quinidine [17] . As this compound has beta,-receptor blocking activity, it can be classified as a la and II drug, too . EGYT-2936 (DL-erythroalloerythro-l-phenyl-2-1-methyl-2-phenoxyethyl-amino-propandiol) caused usedependent inhibition of Vmax and INa and a shortening of the duration of ventricular AP [48] . The atrial muscles were less sensitive to the drug . The characteristics of this drug seem to be similar to those of lignocaine .
MODELS FOR THE SODIUM CHANNEL AND ITS INTERACTION WITH ANTIARRHYTHMIC DRUGS Studying the effects of quaternary local anaesthetic agents in nerve, Strichartz proposed a model [30] . The receptor for local anaesthetics lies within the sodium channel and the binding and unbinding of the drugs to the receptor occur when the channels are in an open state . This model was modified by Courtney [36] who demonstrated the altered voltage dependence of drug-associated channels and identified the property of use-dependence of local anaesthetics . Based on these results Hille [49] in nerve and Hondeghem and Katzung in myocardium [50] independently proposed a nearly similar model . The drugs were considered to associate and dissociate from sodium channels in any of the primary states (resting, open and inactivated) . Each sodium channel blocker has a characteristic association (k R ,kA ,kr ) and dissociation (I R ,IA ,I,) rate constant for channels in each of these states, but they have much affinity for active and inactive states . Drugassociated channels do not conduct sodium (blocked) and their voltage dependence of inactivation is shifted in the direction of hyperpolarization . Since
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the rate constant for binding and unbinding depends on the state of the channel, this hypothesis is termed the modulated receptor hypothesis [51 ] . This hypothesis provides an explanation for several facts (i .e . use-dependent block of sodium current) and raises some issues as follows . The reduction of the sodium current by drugs that block open channels is not dependent on AP duration, but drugs that block inactivated channels may have more effect in tissues that have long AP (Purkinje fibres) than in tissues that have shorter AP duration (atria) . Drugs having higher affinity for the inactivated state (lignocaine, amiodarone) may depress abnormal conduction in depolarized tissues (ischaemia) better than blockers of open channels, because depolarization promotes the inactivated state . Clinically useful drugs will block activated channels (e .g . quinidine), inactivated channels (e .g . amiodarone) or both (e .g . lignocaine), but they will usually have a very low affinity for resting channels . A drug that preferentially blocks resting channels would reduce conduction in normally polarized fibres (channels are R state), while modifying less conduction in depolarized tissues (channels are predominantly I state) . Such a drug would be predicted to be arrhythmogenic [52, 53] .
Guarded receptor model
Starmer proposed another model [54, 55] . According to his model the sodium channel receptor has a constant affinity for the drug but the accessibility of the receptor is guarded by the channel gates so that the rate constants for the open and inactivated state are different although the affinity is the same . This hypothesis assumes use-dependent block as the result of transient access to a binding site of constant affinity, controlled by the channel gate conformation . This hypothesis postulates that drug-associated channels have the same voltage dependence as drug-free channels . While the results concerning disopyramide [56, 57] support this model, there are several data which criticize it [21, 58-60] . These latter queried the free and continuous transitions between the channel states [59] and showed that the affintiy of ADs for open and inactivated states is not equal (i .e . bupivacaine, amiodarone have high affinity for the inactivated state without binding to open channels, while quinidine occupies the channel receptor in the activated state) [21, 58, 60] . While the two models consider different factors to be the determinant for the onset and recovery of the drug-induced block of sodium channels, both of these models agree that a channel is blocked completely when drug is bound and that it only conducts when unbound . The recently obtained data with the patch clamp technique also supports this hypothesis [61, 62] .
MODIFICATIONS OF THE INTERACTION OF SODIUM CHANNELS WITH ANTIARRHYTHMIC DRUGS The binding and unbinding of one antiarrhythmic agent to the specific receptor within the sodium channel can be influenced by several molecular factors
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(molecular size, lipophilicity, pH) and by the presence of other drugs which could compete for the receptor [63] .
pH
Many of the clinically useful ADs are weak bases . The fraction of drug molecules that are in the charged and neutral forms will vary with pH . The charged form of ADs is more hydrophilic than the neutral one, which is lipophilic . The cationic species of the drugs using the hydrophilic pathway interact with the channel receptor in the open state and dissociate from the receptor more slowly . Hence, acidosis, as occurs in ischaemic tissue, promotes the cationic drug form, which dissociates more slowly from the receptor [64] . In contrast alkalinization promotes the neutral form of the drug . Competition for the receptor : two different drugs interacting with the sodium channel receptor
The combination of two drugs of different electrophysiological properties can result in synergistic or antagonistic interactions . Synergistic interaction can be considered when the combination of two drugs has more effect than is achieved by either drug alone . Such synergistic interactions have been observed in the combination of quinidine plus lignocaine [65], and in the case of disopyramide plus mexiletine [66] . Synergistic action has been also confirmed clinically . For example, the combination of mexiletine plus quinidine can provide more protection against arrhythmia with fewer side effects [67, 68] . Synergistic interactions will probably be most prevalent when drugs with different kinetics (slow or fast) and belonging to different subclasses are combined . If the combined drugs have similar time constants, the combination is not predicted to be of great benefit (for example, two class Ic drugs) [52] . Antagonist interaction can be reported in the liganocaine-bupivacaine combination [58] . Similar antagonistic interactions have been demonstrated for other drugs [69, 70] . Sometimes the interaction between the same ADs can be changed depending on the stimulation frequency. The electrophysiological interaction between quinidine and mexiletine and mexiletine-ropitoin is antagonistic at frequencies greater than 0 .5 Hz, whereas the interaction is synergistic at slow rates [71] . A special case of drug interactions is the parent and metabolite interaction (e .g . lignocaine and glycylxylidide) [72] . In the case of encainide the metabolite is more potent than the parent compound.
CLINICAL IMPLICATIONS OF SUBCLASSIFICATION The clinical relevance of understanding the differences between class I drugs in terms of their mode and speed of interaction with the sodium channel lies in its ability to explain some of the differences in the electrophysiological properties of these agents already noted by clinicians . Ischaemic myocardium is usually partly depolarized and hence a higher proportion of its sodium channels is in the inactivated state than is normal
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myocardium . Therefore, drugs (lignocaine, amiodarone) which bind mainly to inactivated channels show a selectivity for ischaemic myocardium . Atrial APs are shorter than ventricular ones so that at a given heart rate sodium channels in atrial cells spend a smaller proportion of their time in the inactivated state than do the ventricular cells . Thus Ib drugs will depress atrial fibres less than the ventricular cells at a given heart rate and drug concentration . Differing rates of onset of rate-dependent blockade of sodium channels can explain differences in effects of the drugs on refractory periods . Class lb drugs had very fast onset-offset kinetics, which explains why H-V conduction time and QRS width are unaffected in sinus rhythm, a normal diastole being of sufficient duration to permit unbinding of the drug from most sodium channels . The effective refractory period (ERP) is prolonged because at the beginning of diastole nearly all the channels have drug attached and so are non-conducting . The Ic drugs, in contrast, unbind so slowly from sodium channels that the number of nonconducting channels at the end of diastole is almost the same as at the beginning . Consequently H-V time is lengthened and QRS widened . The difference in offset kinetics (unbinding from the sodium channel) of the class I drugs might explain differential drug effects on the conduction velocity of premature beats ('ectopics') . Thus Ib drugs selectively depress conduction of premature beats and tachycardia . la and Ic drugs don't show such selectivity .
PROARRHYTHMIC EFFECTS Proarrhythmia is the suggestion that an antiarrhythmic agent can worsen preexistent arrhythmias or provoke new ones .
Action potential duration (APD) prolongation as a proarrhythmic effect
At concentrations within the therapeutic range, quinidine and disopyramide markedly increased APD and prolonged ERP more effectively than lb drugs. The prolongation of repolarization by Ia drugs is due to their depressing effect on the K+ current [73] . The question arises of whether APD prolongation is taking part in the proarrhythmic effects of ADs . Krikler and Curry [74] reported a new, severe ventricular arrhythmia called 'torsade de pointes', observed in a small percentage of patients on chronic antiarrhythmic therapy . This bizarre form of ventricular tachycardia is often associated with prolongation of the QT interval, increased APD, and oscillatory electrical activity during the plateau . This arrhythmia is seen most frequently with drugs that markedly prolong APD in vitro (la and III class drugs), but has also been observed in some cases of Ic drugs [75, 76] . In a recent study, patients treated with flecainide and encainide had a 2-5-fold increase in mortality compared with patients treated with placebo [77] . The proarrhythmic responses are also often seen with quinidine, disopyramide, amiodarone, sotalol, and lidoflazine [78] . As all ADs could be potentially arrhythmogenic, before the application of a new AD the physician must consider several aspects, including the side effects and
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safety factor of the drug, and must decide whether the new drug is better at treating arrhythmias and has fewer side effects than those currently available .
ACKNOWLEDGEMENTS I thank Miss E . Kisfalusi and Mr J . Balogh for the careful preparation of this manuscript .
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or an inactivated channel blocker. Naunyn-Schmiedeberg's Arch Pharmacol 1989 ; 339 : 403-8 . 42 . Schwarz JR, Grigat G . Tocainide blocks Na currents by accumulation of inactivated Na channels . Eur J Pharmacol 1988 ; 158 : 267-70 . 43 . Gautier P, Guiraudou P, Pezziardi F, Bertrand JP, Gagnol JP . Electrophysiological studies of penticainide (CM 78 57), a new antiarrhythmic agent, in mammalian myocardium . J Cardiovasc Pharmacol 1987 ; 9 : 601-10 . 44 . Carmeliet E . Activation block and trapping of penticainide, a disopyramide analogue, in the Na' channel of rabbit cardiac Purkinje fibers . Circulation Res 1988 ; 63 : 50-60 . 45 . Elizalde A, Sanchez-Chapula J . Effects of the novel antiarrhythmic compound TR 2985 (ropitoin) on action potentials of different mammalian cardiac tissues . NaunynSchmiedeberg's Arch Pharmacol 1988; 337 : 316-22 . 46 . Dumez D, Patmore L, Ferrandon P, Allely M, Armstrong JM . Electrophysiologic, antiarrhythmic and cardioprotective effects of N-(3,5-dichlorophenyl)4-4-hydroxy-2methoxy-phenyl piperazine carboxamidine dihydrochloride (RS-87337) . J Cardiovasc Pharmacol 1989 ; 14 : 184-93 . 47 . Timour Q, Aupeth JF, Lonfona-Moundaneja J, Betrix L, Freysz M, Faucon G . Ventricular and atrial electrophysiological effects of a Ic antiarrhythmic drug, cibenzoline, in the innervated dog heart. Role of sodium and calcium channels . NaunynSchmiedeberg's Arch Pharmacol 1989 ; 340 : 338-5 . 48 . Kecskemeti V . Effect of EGYT 2936, a new antiarrhythmic drug on the transmembrane potentials of mammalian myocardium . Pharmacol Res Commun 1988 ; 20 (Suppl 1) : 73-4 . 49 . Hille B . Local anesthetics : hydrophilic and hydrophobic pathway for the drug receptor reaction . J Gen Physiol 1977 ; 69 : 497-515 . 50 . Hondeghem LM, Katzung BG . Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels . Biochim Biophys Acta 1977 ; 472 : 373-98 . 51 . Hondeghem LM, Katzung BG . Antiarrhythmic agents : the modulated receptor mechanism of actions of sodium channels-blocking drugs . A Rev Pharmacol Toxicol 1984 ; 24 : 387-423 . 52 . Hondeghem LM . Antiarrhythmic agents : modulated receptor applications . Circulation 1987 ;75 :514-20 . 53 . Hondeghem LM . Interaction of class 1 drugs with the cardiac sodium channel . In : Vaughan Williams EM, ed . Antiarrhythmic drugs . Handbook of experimental pharmacology . Berlin : Springer, 1989 : 157-74 . 54 . Starmer CF, Grant AO, Strauss HC . A model of the interaction of local anesthetics with Na channels . Biophys J 1983 ; 41 : 145a . 55 . Starmer CF, Courney KR . Modelling ion channel blockade at guarded binding sites : application to tertiary drugs . Am J Physiol 1986; 251 : H848-56 . 56 . Yeh JZ, Ten Eick RE . Molecular and structural basis of resting and use-dependent block of sodium current defined rising disopyramide analogues . Biophys J 1987 ; 51 : 123-35 . 57 . Gruber G, Carmeliet E . The activation gate of the sodium channel controls blockade and deblockade by disopyramide in rabbit Purkinje fibres . Br J Pharmacol 1989 ; 97 : 41-50. 58 . Clarkson CW, Hondeghem LM . Mechanism for bupivacaine depression of cardiac conduction : fast block of sodium channels during the action potential with slow recovery from block during diastole . Anesthesiology 1985 ; 62 : 369-405 . 59 . Snyders DJ, Hondeghem LM. Drug-associated channels inactivate and reactivate at more negative potentials than drug-free channels . Proc West Pharmacol Soc 1987 ; 30 : 149-51 . 60 . Snyders DJ, Hondeghem LM . Effects of quinidine on the sodium current of guinea pig ventricular myocytes . Circulation Res 1990 ; 66 : 565-79 . 61 . Kohlhardt M, Fichtner H . Block of single cardiac Na' channels by antiarrhythmic drugs : the effect of amiodarone, propafenone and diprofenone . J Memb Biol 1988 ; 102 : 105-19 . 62 . Undrovinas AI, Burnashew NA, Nesterenko VV, et al . Single channels sodium current in
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rat cardiomyocytes : use-dependent block by ethacizin . J Pharmacol Exp Ther 1989 ; 248 : 1138-45 . 63 . Kolhardt M, Seifert C . Tonic and phasic IN, blockade by antiarrhythmics . Pflug Arch 1983 ;396 :199-207 . 64 . Grant AO, Strauss LJ, Wallace AG, Strauss HC . The influence of pH on the electrophysiological effects of lidocaine in guinea pig ventricular myocardium . Circulation Res 1980 ; 47 : 542-50. 65 . Hondeghem LM, Katzung BG . Test of a model antiarrhythmic drug action : effects of quinidine and lidocaine on myocardial conduction . Circulation 1980 ; 61 : 1217-24 . 66 . Bretthard G, Seipel L, Abendroth RR . Comparison of antiarrhythmic efficacy of disopyramide and mexiletine against stimulus-induced ventricular tachycardia. J Cardiovasc Pharmacol 1981 ; 3 : 1026-37 . 67 . Duff HJ, Roden D, Primm RK, Oates JA, Woosley RR . Mexiletine in the treatment of resistent ventricular arrhythmias : enhancement of efficacy and reduction of dose-related side effects of combination with quinidine . Circulation 1983 ; 67 : 1124-8 . Mexiletine-quinidine combination . Enhanced and 68 . Duff HJ . antiarrhythmic electrophysiologic activity in the dog . J Exp Ther Pharmacol 1989 ; 249 : 616-23 . 69 . Sanchez-Chapula J . Electrophysiological interactions between quinidine-lidocaine and quinidine-phentoin in guinea pig papillary muscle . Naunyn-Schmiedeberg's Arch Pharmaco1 1985 ; 331 : 369-75 . 70 . Kohlhardt M, Seifert C . Properties of V,,,ax block of INSmediated action potentials during combined application of antiarrhythmic drugs in cardiac muscle . NaunynSchmiedeberg's Arch Pharmacol 1985 ; 330 : 235-44 . Electrophysiologic interaction between 71 . Valenzuela C, Sanchez-Chapula J. mexiletine-quinidine and mexiletine-ropitoin in guinea pig papillary muscle . J Cardiovasc Pharmacol 1989 ; 14 : 783-9 . 72 . Bennet PB, Woosley RL, Hondeghem LM . Competition between lidocaine and one of its metabolites, glycylxylidide, for cardiac sodium channels . Circulation 1988 ; 78 : 692-700 . 73 . Nawrath H . Action potential, membrane currents and force of contraction in mammalian heart muscle fibers treated with quinidine . JPharmacol Exp Ther 1981 ; 216 : 176-81 . 74. Krikler DM, Curry PVL . Torsade de pointes, an atypical ventricular tachycardia . Br Heart J 1976; 38 : 117-20 . 75 . Lui HH, Lee G, Dietrich P, Low RI, Mason DT . Flecainide-induced QT prolongation and ventricular tachycardia. Am Heart J 1982 ; 103 : 567-9 . 76 . Stanton MS, Prystowsky SN, Fineberg NS, Miles WM, Zipes DP, Heger J . Arrhythmogenic effects of antiarrhythmic drugs . A study of 506 patients treated for ventricular tachycardia or fibrillation . JACC 1989 ; 14 : 209-15 . 77 . Josephson ME . Antiarrhythmic agents and the danger of proarrhythmic events . Ann Intern Med 1989 ; 111 : 101-3 . 78 . Scheinman MM . Proarrhythmia and primum non nocere . JACC 1989 ; 14 : 216-17 .
Pharmacological Research, Vol. 24, No . 2, 1991
MOLECULAR ACTION OF CLASS I ANTIARRHYTHMIC DRUGS AND CLINICAL IMPLICATIONS VALERIA KECSKEMETI Department of Pharmacology, Semmelweis University of Medicine, Budapest Nagyvarad ter 4, P .O . Box 370, 1446 Hungary Received in final form 7 January 1991
SUMMARY This report briefly reviews the advance in our knowledge of cellular electrophysiological effects of membrane stabilizer antiarrhythmic drugs (sodium channel blockers) including some new ones . The class I drugs block cardiac sodium channels and differ in the kinetics of the interaction with sodium channels and in the actions on the repolarization phase . The class I drugs can be subdivided into subclasses (I a,b,c) . This review focuses on the interaction of these drugs with sodium channels and the molecular models of their action . The interaction of class I drugs with the sodium channel receptor is influenced by the state of the myocardium (pH, ischaemia) and by other drugs as well . The clinical implications of different actions of sodium channel blockers, alone and in combination, and their proarrhythmic effects are summarized . KEY WORDS : antiarrhythmic drugs, sodium channel blockers, cellular electrophysiology, proarrhythmic effects of antiarrhythmic drugs .
INTRODUCTION During the last 10 years the burst of research activity fuelled by the claim of having the `ideal' antiarrhythmic drug has amplified and extended our knowledge . Key advances have been made in developing new methods for analysing the mode of action of antiarrhythmic drugs (ADs) and assessing the interactions of ADs and settling treatment strategies . The present review is limited to a discussion of sodium channel blockers, focusing on the electrophysiology, and the molecular basis of their antiarrhythmic actions, which might be important for preclinical studies .
CLASSIFICATION OF ANTIARRHYTHMIC DRUGS Among the several classifications of ADs only two are widely accepted . One was suggested by Hoffman and Bigger [1] and classifies ADs into two groups : one 1043-6618/91/060131-12/$03 .00/0
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group slows conduction and decreases the maximum rate of rise of phase 0 depolarization of the action potential (Vmax), while the second group does not modify conduction and Vmax . The second classification proposed by Vaughan Williams [2] is based on the various mechanisms of action of ADs and groups ADs into several classes . The appearance of Ca 2+ channel blockers as ADs extended the original scheme into four categories [3] . This classification seems to be better accepted and appears to be a practical way of grouping clinically useful ADs . Since class I drugs have distinct electrophysiological properties, these drugs have been further subdivided into three subclasses and the original classification was modified [4] . Recently a fourth subclass, Id, has been suggested for transcainide [5], and in the case of alinidine a new, fifth class of antiarrhythmic action has been proposed [6, 7] . ADs are summarized in Table I . The table shows some prototype ADs and the main changes in the action potential (AP) and ionic currents and the main alteration on the electrocardiogram induced by these agents . Although this classification may help the practising physician in rationalizing the prescription of specific drugs, it has often been criticized . The critique has been strengthened by several data showing that non-'primary' ADs (antidepressive drugs, neuroleptics, adenosine, histamine-receptor blockers) might have antiarrhythmic effects [7] . An antihistaminic agent, dimethindene, was found to inhibit fast Na' current and to have electrophysiological properties similar to those of both lignocaine and quinidine [8, 9] . A new antiasthmatic drug, azalestine, was reported to have antiarrhythmic effects, and to inhibit slow Ca" and fast Na' channels [10] . Moreover, dantrolene sodium, a skeletal muscle relaxant, has been found to exert antiarrhythmic activity [11] which can be predicted by its class III and class IV electrophysiological effects [12-14] . The classification is made more difficult by the fact that most agents have more than one action . Such overlapping effects can be observed in the case of beta-adrenoceptor blockers, amiodarone, and some members of class la, Ic . Beta-blockers have additional antiarrhythmic class I properties [6, 15-17] . Moreover, sotalol belongs not only to class II and III, but it has an additional decreasing effect on the time-dependent K+ current [18] too . The new `modified' beta-blocker, propafenone, possesses class I properties and has a slight Ca2+ channel blocking effect (class IV) [19, 20] . Amiodarone, the main representative of class III drugs in appropriate concentration and stimulation frequency, reduces Na+ current, too [21] . It has an antiadrenergic action (class II) [22] and reduces Ca 2+ current (class IV) [23] and K+ current [24] as well . Some class I agents (quinidine, flecainide, ethmozine) were found to inhibit Ca 2+ current [25] .
CLASS I ANTIARRHYTHMIC DRUGS These drugs have the common property of blocking the fast inward Na' current (INa ) in cardiac muscle . Based upon their distinct electrophysiological properties, these agents can be subclassified into smaller more homogeneous groups . The three main subgroups have different actions on clinical electrophysiological parameters . The la agents depress conduction of both sinus and premature beats and prolong refractory periods and repolarization . lb drugs selectively depress
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conduction of premature beats or conduction in ischaemic tissue and shorten the duration of repolarization, without changing refractory periods . The Ic compounds markedly depress the conduction of normal and premature beats and have small effects on repolarization and refractory period . The fundamental bases for subclassification are the interaction of these drugs with the sodium channel, their actions on the repolarization phase of AP in atrial, ventricular and Purkinje fibres and their effects on sinoatrial and ventricular node potentials [26] .
Interaction with sodium channel
Although Aldrich and coworkers [27] gave the reinterpretation of the cardiac Na' channel based on single channel studies with the patch-clamp technique, most of the evidence agrees with the view that the cardiac Na' channel is similar to that in nerve [28] . The cardiac Na' channel may exist in one of three possible states : active or open (conducting Na'), resting, and inactivated . The kinetics of interaction of class I drugs with the cardiac Na' channel can be concluded from the studies of interaction of local anaesthetics with Na' channels in nerve [29, 30] on the one hand and the results obtained from cardiac fibres with the patch-clamp technique [31, 32] on the other . Many workers have relied on the Vmax of cardiac APs as a measure of the Na' current [7, 26] . There are theoretical difficulties (i .e . non-linear relationship between Vmax and IN,, data) with this approach [28, 33-35] but it has provided a number of interesting insights into the mode of action of these drugs . These studies showed that the rate of stimulation modified the degree of depression of Vmax produced by class I drugs . The property of class I drugs is similar to the property of use-dependence (frequency-dependent inhibition of INa) of local anaesthetics in nerve [36] . The rate (frequency)-dependent block of Vmax is a common property of class I drugs and this is dependent on drug concentration . The rate of onset of frequency-dependent depression of Vmax and the rate of recovery from rate-dependent block (RDB) for different class I agents are quite different [26, 37] . It was found that lignocaine (lidocaine), mexiletine and tocainide (lb subclass) had `fast' kinetics (the rate of onset of RDB is quick, the time constant of recovery from RDB is small), encainide, flecainide, lorcainide (Ic drugs) had very slow kinetics (RDB develops slowly, the time constant of recovery is high), while quinidine, procainamide, disopyramide (la group) were intermediate . Finally a fourth subclass has been suggested for transcainide, which exhibits no frequency- and voltage-dependent block [5]. That means that this drug has equal affinity for the three primary states of the Na' channel and does not alter the voltage dependence of the channel . This drug caused a fixed block and thus there is also no recovery from block during diastole . Under normal physiological conditions, in the case of class lb drugs, a large fraction of the Na' channels becomes blocked during AP but this block dissipates quickly during diastole . Thus, conduction of the normal heart beat is not slowed and the QRS duration is not widened . In contrast, class Ic drugs, even at normal heart rate, exert a significant degree of block at end diastole and slow conduction and widen the QRS complex . Class la drugs have intermediate kinetics of block
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development and recovery, and they have intermediate effects on conduction and QRS duration. Many direct data have confirmed that several class I drugs prolonged the reactivation process and slightly modified the activation one [38-40] . These results suggested that class I agents enhance the inactivation of the channel and this effect can be increased at faster rates . Lignocaine can be seen as an inactivated channel blocker, while flecainide may be considered as an open channel blocker [41] . Mexiletine and tocainide also stabilize the Na' channel in its inactivated state [42] . Penticainide, a new disopyramide analogue, binds to open Na' channels and is trapped when the activated channel returns to the resting state [43, 44] . Some properties of penticainide, such as AP duration reduction, mimic the properties of class lb drugs, while the slow recovery kinetic of rate-dependent block is similar to that of class Ic agents . Among the newest ADs, ropitoin, a new diphenylhydantoin derivative, has similar properties to flecainide and reduces the slow Ca t current, too [45] ; RS-87337, a piperazine carboxamidine, has an electrophysiological profile characteristic of both class la and class II compounds [46] ; cibenzoline belongs to class Ic, but it also affects the Ca" channel [47] . Our group reported the electrophysiological characteristics of newly developed compounds, Chinoin-103 and EGYT-2936 [17, 48] . Chinoin-103 (4cyclohexylamino-1-1-naphtholenyloxy-2-butanol maleate) strongly reduced IN, and slightly decreased the slow Ca21 current. The reduction of Vmax was found to be voltage- and use-dependent . Its effect on atrial and ventricular AP duration was similar to that of quinidine [17] . As this compound has beta,-receptor blocking activity, it can be classified as a la and II drug, too . EGYT-2936 (DL-erythroalloerythro-l-phenyl-2-1-methyl-2-phenoxyethyl-amino-propandiol) caused usedependent inhibition of Vmax and INa and a shortening of the duration of ventricular AP [48] . The atrial muscles were less sensitive to the drug . The characteristics of this drug seem to be similar to those of lignocaine .
MODELS FOR THE SODIUM CHANNEL AND ITS INTERACTION WITH ANTIARRHYTHMIC DRUGS Studying the effects of quaternary local anaesthetic agents in nerve, Strichartz proposed a model [30] . The receptor for local anaesthetics lies within the sodium channel and the binding and unbinding of the drugs to the receptor occur when the channels are in an open state . This model was modified by Courtney [36] who demonstrated the altered voltage dependence of drug-associated channels and identified the property of use-dependence of local anaesthetics . Based on these results Hille [49] in nerve and Hondeghem and Katzung in myocardium [50] independently proposed a nearly similar model . The drugs were considered to associate and dissociate from sodium channels in any of the primary states (resting, open and inactivated) . Each sodium channel blocker has a characteristic association (k R ,kA ,kr ) and dissociation (I R ,IA ,I,) rate constant for channels in each of these states, but they have much affinity for active and inactive states . Drugassociated channels do not conduct sodium (blocked) and their voltage dependence of inactivation is shifted in the direction of hyperpolarization . Since
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the rate constant for binding and unbinding depends on the state of the channel, this hypothesis is termed the modulated receptor hypothesis [51 ] . This hypothesis provides an explanation for several facts (i .e . use-dependent block of sodium current) and raises some issues as follows . The reduction of the sodium current by drugs that block open channels is not dependent on AP duration, but drugs that block inactivated channels may have more effect in tissues that have long AP (Purkinje fibres) than in tissues that have shorter AP duration (atria) . Drugs having higher affinity for the inactivated state (lignocaine, amiodarone) may depress abnormal conduction in depolarized tissues (ischaemia) better than blockers of open channels, because depolarization promotes the inactivated state . Clinically useful drugs will block activated channels (e .g . quinidine), inactivated channels (e .g . amiodarone) or both (e .g . lignocaine), but they will usually have a very low affinity for resting channels . A drug that preferentially blocks resting channels would reduce conduction in normally polarized fibres (channels are R state), while modifying less conduction in depolarized tissues (channels are predominantly I state) . Such a drug would be predicted to be arrhythmogenic [52, 53] .
Guarded receptor model
Starmer proposed another model [54, 55] . According to his model the sodium channel receptor has a constant affinity for the drug but the accessibility of the receptor is guarded by the channel gates so that the rate constants for the open and inactivated state are different although the affinity is the same . This hypothesis assumes use-dependent block as the result of transient access to a binding site of constant affinity, controlled by the channel gate conformation . This hypothesis postulates that drug-associated channels have the same voltage dependence as drug-free channels . While the results concerning disopyramide [56, 57] support this model, there are several data which criticize it [21, 58-60] . These latter queried the free and continuous transitions between the channel states [59] and showed that the affintiy of ADs for open and inactivated states is not equal (i .e . bupivacaine, amiodarone have high affinity for the inactivated state without binding to open channels, while quinidine occupies the channel receptor in the activated state) [21, 58, 60] . While the two models consider different factors to be the determinant for the onset and recovery of the drug-induced block of sodium channels, both of these models agree that a channel is blocked completely when drug is bound and that it only conducts when unbound . The recently obtained data with the patch clamp technique also supports this hypothesis [61, 62] .
MODIFICATIONS OF THE INTERACTION OF SODIUM CHANNELS WITH ANTIARRHYTHMIC DRUGS The binding and unbinding of one antiarrhythmic agent to the specific receptor within the sodium channel can be influenced by several molecular factors
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(molecular size, lipophilicity, pH) and by the presence of other drugs which could compete for the receptor [63] .
pH
Many of the clinically useful ADs are weak bases . The fraction of drug molecules that are in the charged and neutral forms will vary with pH . The charged form of ADs is more hydrophilic than the neutral one, which is lipophilic . The cationic species of the drugs using the hydrophilic pathway interact with the channel receptor in the open state and dissociate from the receptor more slowly . Hence, acidosis, as occurs in ischaemic tissue, promotes the cationic drug form, which dissociates more slowly from the receptor [64] . In contrast alkalinization promotes the neutral form of the drug . Competition for the receptor : two different drugs interacting with the sodium channel receptor
The combination of two drugs of different electrophysiological properties can result in synergistic or antagonistic interactions . Synergistic interaction can be considered when the combination of two drugs has more effect than is achieved by either drug alone . Such synergistic interactions have been observed in the combination of quinidine plus lignocaine [65], and in the case of disopyramide plus mexiletine [66] . Synergistic action has been also confirmed clinically . For example, the combination of mexiletine plus quinidine can provide more protection against arrhythmia with fewer side effects [67, 68] . Synergistic interactions will probably be most prevalent when drugs with different kinetics (slow or fast) and belonging to different subclasses are combined . If the combined drugs have similar time constants, the combination is not predicted to be of great benefit (for example, two class Ic drugs) [52] . Antagonist interaction can be reported in the liganocaine-bupivacaine combination [58] . Similar antagonistic interactions have been demonstrated for other drugs [69, 70] . Sometimes the interaction between the same ADs can be changed depending on the stimulation frequency. The electrophysiological interaction between quinidine and mexiletine and mexiletine-ropitoin is antagonistic at frequencies greater than 0 .5 Hz, whereas the interaction is synergistic at slow rates [71] . A special case of drug interactions is the parent and metabolite interaction (e .g . lignocaine and glycylxylidide) [72] . In the case of encainide the metabolite is more potent than the parent compound.
CLINICAL IMPLICATIONS OF SUBCLASSIFICATION The clinical relevance of understanding the differences between class I drugs in terms of their mode and speed of interaction with the sodium channel lies in its ability to explain some of the differences in the electrophysiological properties of these agents already noted by clinicians . Ischaemic myocardium is usually partly depolarized and hence a higher proportion of its sodium channels is in the inactivated state than is normal
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myocardium . Therefore, drugs (lignocaine, amiodarone) which bind mainly to inactivated channels show a selectivity for ischaemic myocardium . Atrial APs are shorter than ventricular ones so that at a given heart rate sodium channels in atrial cells spend a smaller proportion of their time in the inactivated state than do the ventricular cells . Thus Ib drugs will depress atrial fibres less than the ventricular cells at a given heart rate and drug concentration . Differing rates of onset of rate-dependent blockade of sodium channels can explain differences in effects of the drugs on refractory periods . Class lb drugs had very fast onset-offset kinetics, which explains why H-V conduction time and QRS width are unaffected in sinus rhythm, a normal diastole being of sufficient duration to permit unbinding of the drug from most sodium channels . The effective refractory period (ERP) is prolonged because at the beginning of diastole nearly all the channels have drug attached and so are non-conducting . The Ic drugs, in contrast, unbind so slowly from sodium channels that the number of nonconducting channels at the end of diastole is almost the same as at the beginning . Consequently H-V time is lengthened and QRS widened . The difference in offset kinetics (unbinding from the sodium channel) of the class I drugs might explain differential drug effects on the conduction velocity of premature beats ('ectopics') . Thus Ib drugs selectively depress conduction of premature beats and tachycardia . la and Ic drugs don't show such selectivity .
PROARRHYTHMIC EFFECTS Proarrhythmia is the suggestion that an antiarrhythmic agent can worsen preexistent arrhythmias or provoke new ones .
Action potential duration (APD) prolongation as a proarrhythmic effect
At concentrations within the therapeutic range, quinidine and disopyramide markedly increased APD and prolonged ERP more effectively than lb drugs. The prolongation of repolarization by Ia drugs is due to their depressing effect on the K+ current [73] . The question arises of whether APD prolongation is taking part in the proarrhythmic effects of ADs . Krikler and Curry [74] reported a new, severe ventricular arrhythmia called 'torsade de pointes', observed in a small percentage of patients on chronic antiarrhythmic therapy . This bizarre form of ventricular tachycardia is often associated with prolongation of the QT interval, increased APD, and oscillatory electrical activity during the plateau . This arrhythmia is seen most frequently with drugs that markedly prolong APD in vitro (la and III class drugs), but has also been observed in some cases of Ic drugs [75, 76] . In a recent study, patients treated with flecainide and encainide had a 2-5-fold increase in mortality compared with patients treated with placebo [77] . The proarrhythmic responses are also often seen with quinidine, disopyramide, amiodarone, sotalol, and lidoflazine [78] . As all ADs could be potentially arrhythmogenic, before the application of a new AD the physician must consider several aspects, including the side effects and
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safety factor of the drug, and must decide whether the new drug is better at treating arrhythmias and has fewer side effects than those currently available .
ACKNOWLEDGEMENTS I thank Miss E . Kisfalusi and Mr J . Balogh for the careful preparation of this manuscript .
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