Antiarrhythmic Drugs: Electrophysiological Actions

Bassett, and A L; Hoffman, Brian F.

doi:10.1146/annurev.pa.11.040171.001043

Cited by 77 publications

(19 citation statements)

References 77 publications

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“…Increases in this ratio correlate with the antiarrhythmic activity of many agents and may reflect changes in membrane responsiveness. [17][18][19] Therapy designed to optimize the VERP/ APD ratio would increase the ventricular effective refractory period (VERP) and shorten the action potential duration (APD). However, quinidine prolongs both APD and to a greater extent VERP, resulting in an overall increase in this ratio.…”

Section: Combination Antiarrhythmic Therapymentioning

confidence: 99%

Mexiletine in the treatment of resistant ventricular arrhythmias: enhancement of efficacy and reduction of dose-related side effects by combination with quinidine.

Duff¹,

Roden²,

Primm³

et al. 1983

Circulation

146

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SUMMARY Mexiletine, an orally active lidocaine congener, was used to treat 21 patients whose ventricular arrhythmias were not responsive to conventional antiarrhythmic therapy (or in whom therapy produced limiting side effects). Seventeen of the 21 patients had ischemic heart disease; five had episodes of ventricular fibrillation, six had recurrent, sustained ventricular tachyeardia requiring cardioversion, and the remainder had episodic nonsustained ventricular tachycardia. As the dosage of mexiletine was gradually increased, only three patients' arrhythmias were controlled without limiting side effects. One patient continued to have episodic ventricular fibrillation during mexiletine therapy and was excluded from the remainder of the study. The other 17 patients had a partial antiarrhythmic response (the mean suppression of ventricular ectopic depolarizations [VEDs] was 62.5 + 25%) and 10 continued to have ventricular tachycardia), but dose-related side effects limited therapy (at a mean dose of 950 + 202 mg/day). These 17 patients had not responded to or did not tolerate quinidine (mean dose of 1042 + 362 mg/day). With the maximum well-tolerated dosage of quinidine, the mean suppression of VEDs was 59 16%. Eleven of 17 patients (64%) continued to have ventricular tachycardia with quinidine, and therapy was limited by side effects (diarrhea) in 11. In the group of 17 patients, the addition of a previously well-tolerated dosage of quinidine (824 + 298 mg) to a well-tolerated but only partially effective dosage of mexiletine (800 + 239 mg) produced a significantly greater antiarrhythmic response. The mean suppression of VEDs during combination therapy increased to 85.9 + 26%. Only one patient continued to have ventricular tachycardia, and limiting side effects occurred in only 12% of the patients. Continuation of quinidine and withdrawal of mexiletine was associated with recurrence of complex ventricular arrhythmias and documented the need for combination treatment in nine patients. Electrocardiographic intervals were measured at baseline, during mexiletine therapy and during combination therapy. The coupling interval of the predominant ectopic beat prolonged (p < 0.05) during mexiletine treatment and further prolonged (p < 0.05) with the addition of quinidine. After withdrawal of mexiletine from the combination treatment in nine patients, the QTc interval significantly prolonged (p < 0.05). Thus, mexiletine limited the quinidine-induced increase in QTc interval. During 18 5.2 months of follow-up, three patients have died, one with intractable congestive heart failure and two related to documented noncompliance to their medical regimen. The addition of quinidine, which prolongs repolarization of the action potential in vitro, enhanced the antiarrhythmic efficacy of mexiletine, which shortens the action potential duration in vitro. We conclude that combinations of drugs with different electrophysiologic properties may provide enhanced antiarrhythmic efficacy.ANTIARRHYTHMIC drugs are widely prescribed to suppress...

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Section: Combination Antiarrhythmic Therapymentioning

confidence: 99%

Mexiletine in the treatment of resistant ventricular arrhythmias: enhancement of efficacy and reduction of dose-related side effects by combination with quinidine.

Duff¹,

Roden²,

Primm³

et al. 1983

Circulation

146

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“…The Lapicque equation is known to describe the strength-duration curve for long Purkinje fibers, 1 ' l s but its calculation depends on the extrapolation of charge threshold to time zero and, as emphasized by Fozzard and Schoenberg, 14 this extrapolation may be in error twofold in either direction. The possibility of large error prevented the use of the Lapicque equation to compare data obtained during the control and drug periods.…”

Section: Strength-duration and Charge-duration Curvesmentioning

confidence: 99%

The effect of procaine amide on components of excitability in long mammalian cardiac Purkinje fibers.

Arnsdorf¹,

Bigger²

1976

Circulation Research

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SUMMARY The microelectrode technique of intracellular constant current application and intracellular transmembrane voltage recording was used to study the effects of procaine amide (PA) on cardiac excitability. We measured the effect of PA in a concentration equivalent to clinically effective antiarrhythmic plasma levels (5 jig/ml), on nonnormalized and normalized strength-duration and charge-duration curves, membrane characteristics, and cable properties in long sheep Purkinje fibers in normal Tyrode's solution with [K + ] o = 4.0 DIM. PA exerted a complex action and influenced passive resistance-capacitance (RC) and active generator properties by decreasing membrane conductance, primarily membrane sodium conductance. Whether PA increased or decreased excitability depended on the relative contribution of the drug-induced alterations in passive and active membrane properties. These findings may explain, in part, the conflicting results of studies on cardiac excitability in the whole animal, as well as the clinical observation that PA may exert both artiarrhythmic and arrhythmogenic effects. The primary mechanism by which PA modifies excitability would seem to differ considerably from that of the structurally similar local anesthetic agent lidocaine.PROCAINE AMIDE is effective in the treatment of both supraventricular and ventricular arrhythmias, and its clinical and electrophysiological effects have been reviewed recently. '"'In the past, cardiac excitability has been assessed primarily in the whole animal, and the index investigated has been the "threshold" current sufficient to elicit a response in studies on either strength-duration requirements or multiple response thresholds. 8 ' 9 Conflicting results appear in the literature, with some studies showing procaine amide (PA) to decrease excitability in a variety of species, 10 " 12 whereas one failed to show any significant effect.13 Although in these studies there are many differences in experimental technique, part of the variability in the results may be attributed to the fact that the "current threshold" is determined by a complex set of passive and active membrane properties.The microelectrode method for intracellular current application and transmembrane voltage recording allows definition of the individual components of excitability which include the resting transmembrane voltage, threshold voltage, membrane conductance, and cable properties.1 *" 18Although the studies have been few, strength-duration and charge-duration curves have been obtained for the isolated Purkinje fiber preparation with this technique and the determinants of excitability analyzed. 14 " 18 In our present investigation we studied excitability by applying this microelectrode technique to long cardiac Purkinje fibers to determine the effects of PA at concentrations equivalent to clinically effective antiarrhythmic plasma levels. Methods EXPERIMENTAL ARRANGEMENTWe used Purkinje fiber preparations obtained from female sheep anesthetized with sodium pentobarbital (30 mg/ kg). "Long" ...

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“…• Most of the clinically effective antiarrhythmic agents that exert a direct effect on the myocardial cell either decrease the maximum rate of rise, (dV/dt) m ax, of the action potential in nonpremature responses or alter the relationship between membrane potential and (dV/dt) max in premature responses arising from incompletely repolarized fibers (1)(2)(3). In the steady state, (dV/dt) max depends on the membrane potential prior to depolarization and decreases as the membrane potential becomes less negative (4).…”

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confidence: 99%

Effect of lidocaine and quinidine on steady-state characteristics and recovery kinetics of (dV/dt)max in guinea pig ventricular myocardium.

Chen¹,

Gettes²,

Katzung³

1975

Circulation Research

209

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We studied the effects of quinidine and lidocaine on the steady-state relationship between membrane potential and the maximum rate of rise of the action potential, (dV/dt) max , and on the recovery kinetics of (dV/dt) max in guinea pig papillary muscles. The steady-state relationships were determined in fibers stimulated at 0.2/sec and depolarized with KC1. Recovery kinetics were determined at various resting membrane potentials by assessing (dV/dt) max in progressively earlier premature action potentials. Lidocaine caused a dose-dependent decrease in (dV/dt) max , shifted the curve defining the steady-state relationship along the voltage axis in the direction of more negative potentials, and slowed the recovery kinetics of (dV/dt) max . Quinidine caused a dosedependent decrease in (dV/dt) max but did not alter the shape of the curves defining either the steady-state relationship or the recovery kinetics of (dV/dt) max . Both drugs depressed membrane responsiveness as determined in premature action potentials originating from incompletely repolarized fibers. Our study indicates that the mechanisms whereby quinidine and lidocaine influence (dV/dt) max are different. It is possible that this difference may underlie some of the differences in the clinical effects of these two drugs.• Most of the clinically effective antiarrhythmic agents that exert a direct effect on the myocardial cell either decrease the maximum rate of rise, (dV/dt) m ax, of the action potential in nonpremature responses or alter the relationship between membrane potential and (dV/dt) max in premature responses arising from incompletely repolarized fibers (1-3). In the steady state, (dV/dt) max depends on the membrane potential prior to depolarization and decreases as the membrane potential becomes less negative (4). It has recently been shown (5, 6) that the recovery of (dV/dt) max after a preceding depolarization is considerably slower in some types of cardiac fibers than earlier works suggested and is also dependent on the membrane potential at the onset of depolarization (6). Because of this factor, (dV/dt) max of premature action potentials arising from incompletely repolarized fibers is slower than predicted by the steady- This study was supported by U. S. Public Health Service Grant HL 13321-04 from the National Heart and Lung Institute.This paper was presented in part at the meeting of the American Heart Association, Atlantic City, New Jersey, November, 1973 20state resting membrane potential-(dV/dt) max relationship. Therefore, antiarrhythmic drugs could induce changes in (dV/dt) max by altering either the steady-state relationship between membrane potential and (dV/dt) max or the recovery characteristics of (dV/dt) max .In 1957, Johnson and McKinnon (7) reported that quinidine causes only a minimal decrease in (dV/dt) max of guinea pig ventricular action potentials when the driving rate is 0.1/sec but leads to a progressive decrease in (dV/dt) max as the driving rate is increased. Heistracher (8) has shown that in quinidine-tr...

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Antiarrhythmic Drugs: Electrophysiological Actions

Cited by 77 publications

References 77 publications

Mexiletine in the treatment of resistant ventricular arrhythmias: enhancement of efficacy and reduction of dose-related side effects by combination with quinidine.

Mexiletine in the treatment of resistant ventricular arrhythmias: enhancement of efficacy and reduction of dose-related side effects by combination with quinidine.

The effect of procaine amide on components of excitability in long mammalian cardiac Purkinje fibers.

Effect of lidocaine and quinidine on steady-state characteristics and recovery kinetics of (dV/dt)max in guinea pig ventricular myocardium.

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