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Comparative mechanisms of antiarrhythmic agents
Letters. to the Editor
Comparative Mechanisms of Antiarrhythmic Agents Pamintuan, Dreifus and Watanabe in their recent paper1 in this Journal attempted to provide a systematic working classification of antiarrhythmic drugs. How-, ever, they appear to have overlooked several recent electrophysiologic observations which have a bearing on the classification they propose. A few brief comments are therefore pertinent. The authors have classified antiarrhythmic drugs into 2 main categories: 1. Agents that reduce conduction velocity and the maximal rate of rise of cardiac action potential as exemplified by quinidine and procainamide. Experimental and clinical data completely justify this grouping. Nevertheless, the authors’ contention that these drugs reduce the ,resting membrane potential applies only to toxic concentrations of the drugs. In “therapeutic” concentrations neither drug causes a reduction in the resting membrane voltage.2*3 The main electrophysiologic actions of these drugs are explained simply by their ability to inactivate the depolarizing sodium current since they do not alter the extracellular/intracellular sodium ion gradient.* 2. Agents that increase conduction velocity and the maximal rate of rise of cardiac action potential. In this group the authors have placed diphenylhydantoin and bretylium tosylate. The evidence that these compounds do, in fact, significantly increase the maximal rate of rise of cardiac action potential is far from conclusive. Even less conclusive is the evidence for the claim that an increase in the maximal rate of rise constitutes a clinically significant antiarrhythmic action. The accepted therapeutic blood level of diphenylhydantoin lies between 5 and 25 mg/liter.c Sano and associate@ showed that 1 to 10 mg/liter of diphenylhydantoin caused a marked decrease in the maximal rate of rise of cardiac action potential and conduction velocity in canine ventricular fibers. Bigger et al.7 reported an increase in the maximal rate of rise and conduction velocity with diphenylhydantoin in concentrations up to 5 mg/liter. However, they used a low external potassium (3.0 mM) medium. It is well known that hypokalemia can completely nullify the membrane effects of antiarrhythmic drugs.x A comparison of the cardiac electrophysiologic effects of diphenylhydantoin in solutions with normal and low potassium levels by 2 independent groups of investigator&ml’ has clearly demonstrated that the “quinidine-like” actions of the drug are potassium-dependent and that such membrane depressant actions will be completely missed if only low potassium levels in the perfusion media, as in the studies of Bigger and associates,? are employed. Figure 1 illustrates how a grossly misleading conclusion regarding the mode of action of diphenylhydantoin may be reached if the perfusion medium used is defi-
240
cient in potassium. The increase in conduction velocity that diphenylhydantoin produces in vivo therefore cannot be attributed to the direct effects of the drug on cardiac muscle. In the denervated heart diphenylhydantoin regularly produces a decrease in conduction velocity,12-14 suggesting associated autonomic actions of the drug modifying its primarily membrane-depressant effects. From their own work Pamintuan and co-workers1 also reported that bretylium increased conduction velocity and the maximal rate of rise of the cardiac action potential. They further claimed that the drug shortened the duration of the action potential and the effective refractory period. Against this must be placed the detailed observations of Wit and associates,l” who showed that the increase in the maximal rate of rise and conduction velocity produced by bretylium occurred only transiently and in depressed fibers being clearly related to the release of catecholamines. Wit et al. found that the most striking electrophysiologic effect of bretylium
Ventricular
Atrial ImM #mM
0
5
IO
20
40 DPH
Therapeutic Range
Concentration (mgjl)
Figure 1. The effects of variations in the level of potassium in the perfusion media on the effects of diphenylhydantoin (DPH) on the maximal rate of rise (MRD) of cardiac action potential. Each point on the curve represents mean data from 3 experiments. Control is taken as 100 percent. The membrane-depressant effects of diphenylhydantoin in the low potassium solution are reversed or greatly minimized (unpublished data from Singhq.
The
American
Journal
of
CARDIOLOGY
LETTERS
was the increase in the duration of the action potential associated with the prolongation of the refractory period. In some preliminary experiments we have made similar observations. The prolongation of the action potential duration and, hence, of the absolute refractory period thus provides a reasonable basis for the observed antiarrhythmic action of the drug. In short, therefore, the evidence in the literature does not justify the claim that the antiarrhythmic actions of diphenylhydantoin and bretylium can be ascribed to an increase in the maximal rate of rise or “membrane responsiveness” and conduction velocity. It would appear that the fundamental action of diphenylhydantoin on the cardiac membrane is a depressant action but this is modified in vivo by the extracardiac effects of the drug. The main effect of bretylium appears to be to prolong the duration of the action potential, and drugs that do this have already been shown to have antiarrhythmic actions.lB B. N. SINGH, MB, BMedSc., Oxford, England
DPhil,
MRCP, MRACP
References 1. Pamlntuan JC, Dreifus LS, Watanabe Y: Comparative mechanisms of antiarrrythmic agents. Amer J Cardiol 26:512-519, 1970 2. Vaughan Williams EM: The mode of action of quinidine on isolated rabbit atria interpreted from intracellular records. Brit J Pharmacol 13:276-287, 1958 3. Szekeres L, Vaughan Williams EM: Antifibrillatory action. J Physiol (London) 160~470-482, 1961 4. Goodford PJ, Vaughan Williams EM: Intracellular Na and K concentrations of rabbit atria in relation to the action of quinidine. J Physiol 160:483-493, 1962 5. Bigger JT, Schmidt DH, Kutt H: Relationship between plasma level of diphenylhydantoin sodium and its cardiac anti-arrhythmic effects. Circulation 38:363374, 1968 Mode of action of new anti6. Sano Y, Suzuki F, Sato S. et al: arrhythmic agents. Jap Heart J 9:161-168. 1968 7. Bigger JT, Bassett AL, Hoffman BF: Electrophysiological effects of diphenylhydantoin on canine Purkinje fibers. Circ Res 22:221236, 1968 8. Watanabe Y, Dreifus LS, Likoff W: Electrophysiologic antagonism and synergism of potassium and antiarrhythmic agents. Amer J Cardiol 12:702-710, 1963 9. Jensen RA, Katzung BG: Electrophysiological actions of diphenylhydantoin on rabbit atria. Circ Res 24:17-27. 1970 Actions of Certain 10. Singh BN: A Study of the Pharmacological Drugs and Hormones with Particular Reference to Cardiac Muscle. Doctor of philosophy thesis, Oxford University, 1971 11. Singh BN: An explanation for the discrepancy in the reported cardiac electraphysiological actions of diphenylhydantoin and lidocaine. Brit J Pharmacol 41:385-386P. 1971 12. Rosati RA. Alexander JA, Schaal SF, et ak Influence of diphenylhydantoin on electrophysiological properties of the canine heart. Circ Res 21:757-765. 1967 on 13. Sasynluk, BI, Dresel~ PE: The effect of diphenylhydantoin conduction in isolated, blood-profused hearts. J Pharmacol Exp Ther 161:191-196, 1968 on canine 14. Russel JM, Harvey SC: Effects of diphenylhydantoin atria and A-V conducting system. Arch Int Pharmacodyn 182:21% 231, 1969 Electrophysiological effects of 15. Wit AL, Steiner C. Damato AN: bretylium tosylate on single fibers of the canine specialized conducting system and ventricle. J Pharmacol Exp Ther 173:344-356, 1970 16. Singh BN, Vaughan Williams EM: The effects of amiodarone, a new anti-angina1 drug, on isolated cardiac muscle. Brit J Pharmacol 39:657-667, 1970
Reply We appreciate Dr. Singh’s comments on our paper.l The first point he raises is related to the concentration-dependence of drug action. We agree that one of the major effects of quinidine is to reduce the maximal rate of depolarization, especially at “toxic” levels of the drug. In our earlier paper,2 which was quoted by Singh, we demonstrated a reduction in the maximal
VOLUME
28. AUGUST
1971
TO THE
EDITOR
rate of depolarization without a “significant” change in the membrane resting potential, although the latter showed a “tendency” to decrease. It was unfortunate that a more detailed qualifying statement was not also made in our recent paper regarding the concentrationdependence of quinidine action. However, our main aim in this discussion on quinidine was to identify the fact that when an agent decreased the membrane resting potential, in addition to the shifting of membrane responsiveness curve to the right, the ,resultant decrease in the maximal rate of depolarization would be far more marked than in the presence of either factor alone. Secondly, Singh raises the question of whether diphenylhydantoin and bretylium tosylate would increase or decrease the maximal rate of depolarization. In classifying diphenylhydantoin as an agent increasing the rate of depolarization, we quoted the work by Bigger et a1.3 since we have not specifically studied the effect of this drug on Purkinje or ventricular fibers. However, our study on the action of diphenylhydantoin on atrioventricular conduction using concentrations similar to those of the clinical setting suggested a similarity to quinidine,4 a finding that obviously contradicts the results of Bigger et al.3 Hence, we are not at all surprised by papers reporting results similar to our findings.5 One additional comment should be made on the effects of diluent and pure diphenylhydantoin. Bigger et aL3 showed that pure diphenylhydantoin shifted the membrane responsiveness curve to the left, whereas the diluent had the opposite effects. Since diphenylhydantoin in clinical use is supplied with diluent, the therapeutic efficacy of this drug is already complicated by the presence of diluent, even before any considerations can be given to the concentration-dependence of its action. Regarding the effects of bretylium tosylate, Singh’s point based on the study of Wit et al6 is well taken, in that the increase in the maximal rate of depolarization caused by bretylium may be seen only in depressed fibers and as a result of catecholamine release. The same argument may also apply to the shortening of the duration of the action potential observed in some preparations. However, the possibility definitely exists that regions with depressed cardiac fibers are the actual sites of abnormal impulse formation and conduction causing arrhythmias. This implies that even a drug effect seen only in depressed tissue cannot be readily disregarded. On the other hand, we are fully aware that the membrane effects of many antiarrhythmic agents are potassium-dependent.2 In addition to the work quoted by Singh, our initial papers identified and specifically stressed this point.7-B It appears that Singh is reporting similar observation on diphenylhydantoin. We might add that our manuscript was accepted for publication in December 1969, when 5 of the 14 references Dr Singh quoted (including 2 of his own) had not been published. It was certainly impossible for us to “overlook these recent observations” unpublished at the time of writing. Finally, Singh’s comments bring into sharp focus the complexity of understanding the possible mechanisms of antiarrhythmic agents. Many authors have long expressed similar views, and the problem is fur-, ther confused by studies using concentrations below
241
Comparative Mechanisms of Antiarrhythmic Agents Pamintuan, Dreifus and Watanabe in their recent paper1 in this Journal attempted to provide a systematic working classification of antiarrhythmic drugs. How-, ever, they appear to have overlooked several recent electrophysiologic observations which have a bearing on the classification they propose. A few brief comments are therefore pertinent. The authors have classified antiarrhythmic drugs into 2 main categories: 1. Agents that reduce conduction velocity and the maximal rate of rise of cardiac action potential as exemplified by quinidine and procainamide. Experimental and clinical data completely justify this grouping. Nevertheless, the authors’ contention that these drugs reduce the ,resting membrane potential applies only to toxic concentrations of the drugs. In “therapeutic” concentrations neither drug causes a reduction in the resting membrane voltage.2*3 The main electrophysiologic actions of these drugs are explained simply by their ability to inactivate the depolarizing sodium current since they do not alter the extracellular/intracellular sodium ion gradient.* 2. Agents that increase conduction velocity and the maximal rate of rise of cardiac action potential. In this group the authors have placed diphenylhydantoin and bretylium tosylate. The evidence that these compounds do, in fact, significantly increase the maximal rate of rise of cardiac action potential is far from conclusive. Even less conclusive is the evidence for the claim that an increase in the maximal rate of rise constitutes a clinically significant antiarrhythmic action. The accepted therapeutic blood level of diphenylhydantoin lies between 5 and 25 mg/liter.c Sano and associate@ showed that 1 to 10 mg/liter of diphenylhydantoin caused a marked decrease in the maximal rate of rise of cardiac action potential and conduction velocity in canine ventricular fibers. Bigger et al.7 reported an increase in the maximal rate of rise and conduction velocity with diphenylhydantoin in concentrations up to 5 mg/liter. However, they used a low external potassium (3.0 mM) medium. It is well known that hypokalemia can completely nullify the membrane effects of antiarrhythmic drugs.x A comparison of the cardiac electrophysiologic effects of diphenylhydantoin in solutions with normal and low potassium levels by 2 independent groups of investigator&ml’ has clearly demonstrated that the “quinidine-like” actions of the drug are potassium-dependent and that such membrane depressant actions will be completely missed if only low potassium levels in the perfusion media, as in the studies of Bigger and associates,? are employed. Figure 1 illustrates how a grossly misleading conclusion regarding the mode of action of diphenylhydantoin may be reached if the perfusion medium used is defi-
240
cient in potassium. The increase in conduction velocity that diphenylhydantoin produces in vivo therefore cannot be attributed to the direct effects of the drug on cardiac muscle. In the denervated heart diphenylhydantoin regularly produces a decrease in conduction velocity,12-14 suggesting associated autonomic actions of the drug modifying its primarily membrane-depressant effects. From their own work Pamintuan and co-workers1 also reported that bretylium increased conduction velocity and the maximal rate of rise of the cardiac action potential. They further claimed that the drug shortened the duration of the action potential and the effective refractory period. Against this must be placed the detailed observations of Wit and associates,l” who showed that the increase in the maximal rate of rise and conduction velocity produced by bretylium occurred only transiently and in depressed fibers being clearly related to the release of catecholamines. Wit et al. found that the most striking electrophysiologic effect of bretylium
Ventricular
Atrial ImM #mM
0
5
IO
20
40 DPH
Therapeutic Range
Concentration (mgjl)
Figure 1. The effects of variations in the level of potassium in the perfusion media on the effects of diphenylhydantoin (DPH) on the maximal rate of rise (MRD) of cardiac action potential. Each point on the curve represents mean data from 3 experiments. Control is taken as 100 percent. The membrane-depressant effects of diphenylhydantoin in the low potassium solution are reversed or greatly minimized (unpublished data from Singhq.
The
American
Journal
of
CARDIOLOGY
LETTERS
was the increase in the duration of the action potential associated with the prolongation of the refractory period. In some preliminary experiments we have made similar observations. The prolongation of the action potential duration and, hence, of the absolute refractory period thus provides a reasonable basis for the observed antiarrhythmic action of the drug. In short, therefore, the evidence in the literature does not justify the claim that the antiarrhythmic actions of diphenylhydantoin and bretylium can be ascribed to an increase in the maximal rate of rise or “membrane responsiveness” and conduction velocity. It would appear that the fundamental action of diphenylhydantoin on the cardiac membrane is a depressant action but this is modified in vivo by the extracardiac effects of the drug. The main effect of bretylium appears to be to prolong the duration of the action potential, and drugs that do this have already been shown to have antiarrhythmic actions.lB B. N. SINGH, MB, BMedSc., Oxford, England
DPhil,
MRCP, MRACP
References 1. Pamlntuan JC, Dreifus LS, Watanabe Y: Comparative mechanisms of antiarrrythmic agents. Amer J Cardiol 26:512-519, 1970 2. Vaughan Williams EM: The mode of action of quinidine on isolated rabbit atria interpreted from intracellular records. Brit J Pharmacol 13:276-287, 1958 3. Szekeres L, Vaughan Williams EM: Antifibrillatory action. J Physiol (London) 160~470-482, 1961 4. Goodford PJ, Vaughan Williams EM: Intracellular Na and K concentrations of rabbit atria in relation to the action of quinidine. J Physiol 160:483-493, 1962 5. Bigger JT, Schmidt DH, Kutt H: Relationship between plasma level of diphenylhydantoin sodium and its cardiac anti-arrhythmic effects. Circulation 38:363374, 1968 Mode of action of new anti6. Sano Y, Suzuki F, Sato S. et al: arrhythmic agents. Jap Heart J 9:161-168. 1968 7. Bigger JT, Bassett AL, Hoffman BF: Electrophysiological effects of diphenylhydantoin on canine Purkinje fibers. Circ Res 22:221236, 1968 8. Watanabe Y, Dreifus LS, Likoff W: Electrophysiologic antagonism and synergism of potassium and antiarrhythmic agents. Amer J Cardiol 12:702-710, 1963 9. Jensen RA, Katzung BG: Electrophysiological actions of diphenylhydantoin on rabbit atria. Circ Res 24:17-27. 1970 Actions of Certain 10. Singh BN: A Study of the Pharmacological Drugs and Hormones with Particular Reference to Cardiac Muscle. Doctor of philosophy thesis, Oxford University, 1971 11. Singh BN: An explanation for the discrepancy in the reported cardiac electraphysiological actions of diphenylhydantoin and lidocaine. Brit J Pharmacol 41:385-386P. 1971 12. Rosati RA. Alexander JA, Schaal SF, et ak Influence of diphenylhydantoin on electrophysiological properties of the canine heart. Circ Res 21:757-765. 1967 on 13. Sasynluk, BI, Dresel~ PE: The effect of diphenylhydantoin conduction in isolated, blood-profused hearts. J Pharmacol Exp Ther 161:191-196, 1968 on canine 14. Russel JM, Harvey SC: Effects of diphenylhydantoin atria and A-V conducting system. Arch Int Pharmacodyn 182:21% 231, 1969 Electrophysiological effects of 15. Wit AL, Steiner C. Damato AN: bretylium tosylate on single fibers of the canine specialized conducting system and ventricle. J Pharmacol Exp Ther 173:344-356, 1970 16. Singh BN, Vaughan Williams EM: The effects of amiodarone, a new anti-angina1 drug, on isolated cardiac muscle. Brit J Pharmacol 39:657-667, 1970
Reply We appreciate Dr. Singh’s comments on our paper.l The first point he raises is related to the concentration-dependence of drug action. We agree that one of the major effects of quinidine is to reduce the maximal rate of depolarization, especially at “toxic” levels of the drug. In our earlier paper,2 which was quoted by Singh, we demonstrated a reduction in the maximal
VOLUME
28. AUGUST
1971
TO THE
EDITOR
rate of depolarization without a “significant” change in the membrane resting potential, although the latter showed a “tendency” to decrease. It was unfortunate that a more detailed qualifying statement was not also made in our recent paper regarding the concentrationdependence of quinidine action. However, our main aim in this discussion on quinidine was to identify the fact that when an agent decreased the membrane resting potential, in addition to the shifting of membrane responsiveness curve to the right, the ,resultant decrease in the maximal rate of depolarization would be far more marked than in the presence of either factor alone. Secondly, Singh raises the question of whether diphenylhydantoin and bretylium tosylate would increase or decrease the maximal rate of depolarization. In classifying diphenylhydantoin as an agent increasing the rate of depolarization, we quoted the work by Bigger et a1.3 since we have not specifically studied the effect of this drug on Purkinje or ventricular fibers. However, our study on the action of diphenylhydantoin on atrioventricular conduction using concentrations similar to those of the clinical setting suggested a similarity to quinidine,4 a finding that obviously contradicts the results of Bigger et al.3 Hence, we are not at all surprised by papers reporting results similar to our findings.5 One additional comment should be made on the effects of diluent and pure diphenylhydantoin. Bigger et aL3 showed that pure diphenylhydantoin shifted the membrane responsiveness curve to the left, whereas the diluent had the opposite effects. Since diphenylhydantoin in clinical use is supplied with diluent, the therapeutic efficacy of this drug is already complicated by the presence of diluent, even before any considerations can be given to the concentration-dependence of its action. Regarding the effects of bretylium tosylate, Singh’s point based on the study of Wit et al6 is well taken, in that the increase in the maximal rate of depolarization caused by bretylium may be seen only in depressed fibers and as a result of catecholamine release. The same argument may also apply to the shortening of the duration of the action potential observed in some preparations. However, the possibility definitely exists that regions with depressed cardiac fibers are the actual sites of abnormal impulse formation and conduction causing arrhythmias. This implies that even a drug effect seen only in depressed tissue cannot be readily disregarded. On the other hand, we are fully aware that the membrane effects of many antiarrhythmic agents are potassium-dependent.2 In addition to the work quoted by Singh, our initial papers identified and specifically stressed this point.7-B It appears that Singh is reporting similar observation on diphenylhydantoin. We might add that our manuscript was accepted for publication in December 1969, when 5 of the 14 references Dr Singh quoted (including 2 of his own) had not been published. It was certainly impossible for us to “overlook these recent observations” unpublished at the time of writing. Finally, Singh’s comments bring into sharp focus the complexity of understanding the possible mechanisms of antiarrhythmic agents. Many authors have long expressed similar views, and the problem is fur-, ther confused by studies using concentrations below
241