Determinants and mechanisms of flecainide-induced promotion of ventricular tachycardia in anesthetized dogs.
Journal - Circulation (UNITED STATES )
BACKGROUND: Class IC antiarrhythmic agents such as flecainide are known to have potentially significant ventricular proarrhythmic actions, but the underlying mechanisms are incompletely understood. While some studies have reported proarrhythmia in both healthy dogs and dogs that previously have had a myocardial infarction (MI), there are no published, controlled studies comparing proarrhythmia in healthy dogs vs in dogs with MI. In addition, the concentration dependence of proarrhythmia is unknown and the electrophysiological changes associated with proarrhythmia are not well established. METHODS: We administered successive loading and maintenance infusions of flecainide until ventricular tachyarrhythmia or death occurred in 13 healthy dogs and 19 dogs with 72-hour-old MIs (MI dogs). Ventricular proarrhythmia, defined as reproducible ventricular tachycardia absent under control conditions and occurring in the presence of flecainide, was observed in 4 of 13 healthy dogs (31%) and 15 of 19 MI dogs (79%, P = .02), and drug-induced spontaneous ventricular tachycardia occurred in 8 of 19 MI dogs but in no healthy dogs (P = .007). Activation data at the time of proarrhythmia were available for 11 MI dogs and provided evidence for reentry in 9, with a complete epicardial reentry circuit identified in 4 dogs and a partial circuit in 5. While flecainide slowed ventricular conduction in both the longitudinal and transverse directions, there were no significant differences between overall drug-induced conduction changes in MI dogs compared with healthy dogs. However, in 7 MI dogs for whom activation data were available during ventricular pacing at concentrations comparable to those causing proarrhythmia, flecainide induced a new arc of block in 6 of 7, whereas an arc of block was never observed in the absence of proarrhythmia. Conduction block was induced transverse to fiber orientation in a rate-dependent fashion and was caused by a regionally-specific effect of the drug. No differences were noted between refractory periods proximal and distal to the site of block. CONCLUSIONS: Prior MI strongly predisposes dogs to flecainide proarrhythmia, which occurs in the majority of such dogs in a concentration-related way. In most cases, activation data suggest that anisotropic reentry around a localized arc of rate-dependent transverse conduction block underlies proarrhythmia. These results provide insights into the conditions and mechanisms underlying the ability of flecainide to promote the occurrence of ventricular tachycardia.
|ISSN : ||0009-7322|
|Mesh Heading : ||Animals Cardiac Pacing, Artificial Dogs Dose-Response Relationship, Drug Electrocardiography Flecainide Heart Block Heart Conduction System Myocardial Infarction Refractory Period, Electrophysiological Tachycardia, Ventricular administration & dosage chemically induced physiopathology physiopathology physiopathology drug effects physiopathology|
|Mesh Heading Relevant : ||toxicity drug effects chemically induced|
Modulation of flecainide's cardiac sodium channel blocking actions by extracellular sodium: a possible cellular mechanism for the action of sodium salts in flecainide cardiotoxicity.
Journal - The Journal of pharmacology and experimental therapeutics (UNITED STATES )
Sodium salts reverse the clinical cardiotoxicity of class 1c antiarrhythmic agents, but the underlying mechanisms are unknown. We studied the modulation of flecainide's action by changes in extracellular sodium concentration ([Na+]e) produced by isotonic substitution of choline for sodium. Increasing [Na+]e by 25 mM attenuated the depressant effects of 3.2 microM flecainide of Vmax in canine cardiac Purkinje fibers, whereas decreasing [Na+]e enhanced drug action. The voltage dependence of Vmax was shifted by flecainide (activation potential for 50% decrease in Vmax, V50: -77.4 +/- 3.5 mV at 3.2 microM flecainide) compared to control (V50: -73.7 +/- 2.8 mV, mean +/- S.D., P < .05). Increasing [Na+]e in the presence of flecainide returned V50 toward control (-75.8 +/- 3.1 mV, P < .05 vs. flecainide at normal [Na+]e). Increased [Na+]e shifted the flecainide concentration-response curve to the right (EC50 19.0 microM) compared to normal (EC50 14.6 microM) and low (EC50 10.8 microM) [Na+]e. [Na+]e modulated the concentration-dependent displacement by flecainide of [3H]batrachotoxin-A-benzoate, with increased [Na+]e shifting the binding curve to the right and decreased [Na+]e shifting it to the left compared to normal [Na+]e. There was a strong linear correlation (r = 0.99) between flecainide's EC50 for Vmax depression and its IC50 for [3H]batrachotoxin-A-benzoate displacement at various [Na+]e. We conclude that [Na+]e modulates flecainide's interaction with the sodium channel. Sodium's ability to displace blocking drug from the sodium channel may underlie the efficacy of sodium salts in treating flecainide toxicity, and could play a similar role in antagonizing cardiotoxicity of other class 1 compounds.
|ISSN : ||0022-3565|
|Mesh Heading : ||Action Potentials Animals Batrachotoxins Choline Dogs Dose-Response Relationship, Drug Flecainide Heart Sodium Sodium Channels drug effects metabolism pharmacology physiology|
|Mesh Heading Relevant : ||toxicity drug effects pharmacology drug effects|
Kinetics of use-dependent ventricular conduction slowing by antiarrhythmic drugs in humans.
Journal - Circulation (UNITED STATES )
BACKGROUND. Rate-dependent conduction slowing by class I antiarrhythmic agents has clinically important consequences. Class I drugs are known to produce use-dependent sodium channel blockade. If rate-dependent conduction slowing by class I agents is due to sodium channel blocking actions, the kinetics of conduction slowing should be similar to those of depression of sodium current indexes in vitro. The purpose of the present investigation was to study the onset time course of ventricular conduction slowing caused by a variety of class I agents in humans. METHODS AND RESULTS. Twenty-seven patients undergoing electrophysiological evaluation for antiarrhythmic therapy were studied. Changes in QRS duration at initiation of ventricular pacing at cycle lengths of 400 and 500 msec were used to evaluate the kinetics of drug action. Mean time constants for each drug were similar to values for Vmax depression reported in vitro studies: flecainide, 24.9 +/- 11.6 beats in eight patients (versus 34.5 beats reported for Vmax block); propafenone, 17.8 +/- 6.9 beats in five patients (versus 8.4-20.8 beats); quinidine, 7.0 +/- 2.4 beats in six patients (versus 5.6-6.2 beats); and amiodarone, 3.6 +/- 2.0 beats for eight patients (versus 3.0 beats). Time constants were significantly different among the various drugs tested (p = 0.0002 at a cycle length of 400 msec; p = 0.002 at 500 msec), and there was a strong correlation (r = 0.89, p less than 0.0001) between values obtained at a cycle length of 400 msec and those at a cycle length of 500 msec. No rate-dependent changes in QRS duration were seen at onset of ventricular pacing among eight age- and disease-matched control patients not taking class I antiarrhythmic drugs, including three patients subsequently showing such changes during type I antiarrhythmic drug therapy. CONCLUSIONS. We conclude that class I agents produce use-dependent QRS prolongation in humans with characteristic kinetics for each agent that are similar to the kinetics of Vmax depression in vitro. These results suggest that rate-dependent ventricular conduction slowing by antiarrhythmic drugs in humans is due to use-dependent sodium channel blockade.
|ISSN : ||0009-7322|
|Mesh Heading : ||Anti-Arrhythmia Agents Cardiac Pacing, Artificial Electrocardiography Heart Conduction System Heart Rate Humans Kinetics Time Factors Ventricular Function|
|Mesh Heading Relevant : ||pharmacology drug effects drug effects|