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PubMed1990

High-performance liquid chromatographic determination of the enantiomers of flecainide in human plasma and urine.

A stereospecific high-performance liquid chromatographic method for the determination of (R,S)-flecainide acetate [(R,S)-N-(2-piperidylmethyl)-2,5-bis-(2,2,2-trifluoroethoxy)benzam ide acetate] in human plasma and urine is described. After addition of the internal standard [IS; (R,S)-N-(2-piperidylmethyl)-2,3-bis(2,2,2-trifluoroethoxy)- benzamide hydrochloride], a single-step extraction of alkalinized samples was performed with distilled diethyl ether. The organic layer was evaporated and the drug and IS were derivatized with 1-[(4-nitrophenyl)sulfonyl]-L-propyl chloride at 80 degrees C for 2 h. The diastereomeric derivatives of flecainide and IS were chromatographed on a C18 reversed-phase column with a mobile phase consisting of acetonitrile: water:triethylamine (45:55:0.2) at a flow rate of 1 mL/min. Flecainide diastereomers were separated with a resolution factor of 1.25 and detected by UV spectroscopy at a wavelength of 280 nm. An excellent linearity was observed between the peak area ratios (flecainide derivatives:IS) and plasma concentrations, and the intra- and interday coefficients of variation were always less than 9.8%. The lowest quantifiable concentration was set at 50 ng/mL for each enantiomer (CV of 4.9 and 4.4%), while the lowest limit of detection (signal:noise, 3:1) was on the order of a few nanograms. The assay was used to study the pharmacokinetics of flecainide enantiomers in a patient receiving (R,S)-flecainide therapy. The steady-state plasma time courses for the enantiomers were found to be parallel, but the difference between (R)- and (S)-flecainide concentrations was significant. The urinary excretion data were consistent with the plasma results. The method is suitable for therapeutic monitoring of flecainide enantiomers and for stereoselective pharmacokinetic studies in humans.

Adult↗
PubMed1990

Altered flecainide disposition in healthy volunteers taking quinine.

The pharmacokinetics of flecainide and its two sequential metabolites, both free and conjugated, its pharmacodynamics, and the influence of simultaneously administered quinine, have been studied in 10 healthy subjects. The study comprised two, 48-h open phases at an interval of 1 week. Flecainide acetate 150 mg was given as a 30-min i.v. infusion and quinine sulphate orally 500 mg x 3 over 24 h. Quinine administration did not change the apparent volume of distribution or the renal clearance of flecainide, but it significantly reduced its systemic clearance (9.1 vs 7.6 ml.kg-1.min-1), thus increasing the elimination half-life (9.6 vs 11.5 h). The amount of flecainide transformed to its first, meta-O-dealkylated metabolite (MODF) fell with no change in the renal excretion of the latter, either in its free or conjugated forms. This finding, in association with a fall in amount of the second, meta-O-dealkylated lactam metabolite (MODLF) recovered in its conjugated forms in the urine, suggests that quinine inhibits both the first and the second steps of the sequential metabolism of flecainide. When the subjects received quinine in addition to flecainide, the PR interval in the ECG was slightly more prolonged than with flecainide alone. Due to the study design, an effect of quinine per se and the consequence of increased serum flecainide levels could not be distinguished.

Adult↗
PubMed1993

Electrophysiological effects of flecainide acetate on stretched guinea pig left atrial muscle fibers.

The electrophysiological effects of flecainide acetate (3 x 10(-6) M) on stretched atrial tissue were investigated using guinea-pig left atrial muscle fibers. Before stretching, the resting membrane potential was not affected by flecainide at 1 Hz, although the overshoot potential (Eov) and the action potential duration at 50% repolarization (APD50) were slightly but significantly decreased by 2 +/- 1 mV and 2 +/- 1 msec, respectively. The effective refractory period (ERP) was increased by 3 +/- 1 msec. The reduction of Vmax was 20.6 +/- 1.2%. The half-maximum potential (Vh) of the relationship between Vmax and the resting potential was shifted to become more negative by flecainide (from -60.6 +/- 2.1 mV to -63.2 +/- 1.7 mV). After 90-120 min of washout with drug-free Tyrode's solution, the tissue was mechanically stretched to 150% of its slack length. Stretching significantly decreased the Vmax by 16.9 +/- 3.1%, along with a slight but significant increase in ERP (3 +/- 1 msec) and shifted Vh to become more negative (from -60.6 +/- 2.1 to -63.1 +/- 1.8 mV). In the presence of flecainide, Vmax further decreased by 20.2 +/- 2.6%, and Vh shifted from -63.1 +/- 1.8 to -65.0 +/- 1.5 mV. Comparison with the control unstretched fibers showed that flecainide significantly decreased Vmax by 34.0 +/- 2.7%, reduced the resting membrane potential by 3 +/- 1 mV, decreased Eov by 4 +/- 1 mV, and shifted Vh from -60.6 +/- 2.1 to -65.0 +/- 1.5 mV, while the APD50 and ERP did not change. In conclusion, the reduction of Vmax in the presence of flecainide was much greater in the stretched atrial muscle fibers than in the unstretched fibers, because the Vmax-resting potential relationship was shifted towards more negative potentials by both flecainide and stretching. These results suggest that flecainide exerts a stronger antiarrhythmic action on stretched atrial muscle fibers than on normal fibers.

Animals↗
PubMed1986

[Hemoperfusion in flecainide poisoning].

A 79-year-old patient, who had received a pacemaker after suffering two posterior myocardial infarctions, was treated with 2 X 100 mg flecainide daily for 9 days for ventricular extrasystoles (Lown IV b). On admission to the hospital the parameters of renal function were within the normal range. Ten days after flecainide treatment was begun a temporary electromechanic decoupling of the pacemaker occurred with reversible asystoly and progressive kidney failure. The flecainide plasma level at that time was 1460 ng/ml. Hemoperfusion for 3 h with activated charcoal removed only 35 mg flecainide in spite of an excellent flecainide clearance (164-180 ml/min). The patient's flecainide plasma level did not decrease sufficiently during the procedure, showing clearly that flecainide levels cannot be lowered fast enough by hemoperfusion to treat a flecainide intoxication.

Aged↗
PubMedDate not supplied

Transplacental pharmacokinetics of flecainide in the gravid baboon and fetus.

The objective of this study was to characterize the transfer of flecainide across the placenta and determine the fetal: maternal ratio of flecainide in the gravid baboon. Flecainide acetate has been especially successful for the treatment of fetal supraventricular tachycardia associated with hydrops fetalis. However, the degree of transplacental transmission remains unknown. In this study, all animals were placed under general anesthesia. Flecainide 2.5 mg/kg was administered intravenously. Percutaneous umbilical blood sampling was performed simultaneously with maternal sampling. Flecainide levels were measured using high-performance liquid chromatography with ultraviolet detection. A total of six gravid baboons were studied at an average gestational age of 132 days. The mean maternal volume of distribution at steady state was 5.1 +/- 1.8 L/kg. The mean combined elimination constant (k(el)) was 0.79 +/- 0.19 hr(-1) [95% confidence interval (CI), 0.64-0.93]. There was a linear relationship between maternal and fetal concentrations, with a ratio of fetal-to-maternal serum levels of 0.49 +/- 0.05 (95% CI, 0.39-0.59). At steady state, fetal flecainide levels are approximately 50% of maternal flecainide levels. Flecainide is rapidly distributed in the mother and fetus following a single intravenous dose with a maternal volume of distribution similar to that reported in normal healthy human adults. Since fetal levels correlate closely with maternal levels, we propose that it is possible to estimate fetal levels by monitoring maternal levels.

Animals↗
PubMed1982

Electrophysiologic effects of flecainide acetate in patients with sinus nodal dysfunction.

Flecainide acetate (R818) is a new antiarrhythmic agent for oral and intravenous use; it has predominantly class I properties and a long plasma half-life. Electrophysiologic effects were evaluated in 11 patients with sinus nodal dysfunction before administration of flecainide acetate and 15 to 60 minutes after intravenous administration of 1.5 mg/kg body weight of flecainide acetate given over 15 minutes. In 8 of 11 patients with maximal sinus nodal recovery time increased after flecainide acetate. However, the mean maximal sinus nodal recovery time was not statistically significantly increased from 1,929 +/- 184 (mean +/- standard error of the mean [SEM]) to 2,770 +/- 500 ms (p less than 0.10). The corrected sinus nodal recovery time increased from 875 +/- 181 before to 1,727 +/- 507 ms after administration of flecainide acetate (p less than 0.05). The sinus cycle length and sinoatrial conduction time were not significantly changed. Flecainide acetate induced a marked prolongation of the H-V interval (from 41 +/- 3 to 52 +/- 4 mg [p less than 0.01]) as well as a significant increase in the A-H interval, QRS duration, and QT100 interval. The effective and functional refractory periods of the atria increased by 12% (p less than 0.01) and 11% (p less than 0.01), respectively. The atrioventricular (AV) nodal functional refractory period increased significantly by 7% (p less than 0.01), whereas the 9% prolongation of the effective refractory period was not statistically significant. No side effects were observed. It is concluded that flecainide acetate prolongs atrial and ventricular conduction and refractoriness, and thus appears to be a potent antiarrhythmic agent. However, the sinus nodal function is depressed, and thus caution is advised in the use of flecainide acetate in patients with sinus nodal dysfunction.

Adult↗
PubMed1986

Flecainide versus quinidine for conversion of atrial fibrillation to sinus rhythm.

The effectiveness and safety of flecainide and quinidine for conversion of atrial fibrillation (AF) to sinus rhythm were compared. Sixty consecutive patients were treated with either flecainide (up to 2 mg/kg intravenously and then orally) or quinidine (up to 1.2 g orally). There was no statistical difference in age, left atrial size, duration of the arrhythmia and underlying cardiac diseases between the 2 groups. The overall conversion rate to sinus rhythm was 63% (38 patients): AF was converted in 18 patients (60%) treated with quinidine and 20 (67%) with flecainide. If AF lasted less than 10 days, the conversion rate was 86% in the flecainide group and 80% in the quinidine group (difference not significant). When AF lasted more than 10 days the rate was 22% in the flecainide group and 40% in the quinidine group. Adverse effects were more frequent in the quinidine group (27%) (gastrointestinal disturbances) than in the flecainide group (7%) (conduction disturbances), but they were less severe in the quinidine group. Thus, flecainide given intravenously appeared to be as effective as quinidine given orally for conversion of AF of recent onset (within 10 days). However, quinidine should probably remain the preferred drug for conversion of AF of long duration (more than 10 days) to sinus rhythm. Adverse effects occurred less often with flecainide therapy, but they were more severe.

Adolescent↗
PubMed1989

Intravenous flecainide versus verapamil for acute conversion of paroxysmal atrial fibrillation or flutter to sinus rhythm.

In a single-blind randomized study, the efficacy of intravenous flecainide (2 mg/kg/10 minutes) versus verapamil (10 mg/1 minute) was assessed in 40 patients with paroxysmal atrial fibrillation (AF) or atrial flutter (AFI). The treatment was considered successful if sinus rhythm occurred within 1 hour. Of 20 patients receiving flecainide, 14 of 17 (82%) with AF converted to sinus rhythm, but in 3 patients with AFI flecainide failed. All patients treated with verapamil (17 AF, 3 AFI) showed lower ventricular rates after 1 hour; however, only 1 (6%) with AF converted to sinus rhythm and 1 (6%) converted to AFI. Patients who did not convert to sinus rhythm after treatment with verapamil were treated with flecainide and observed for another hour. After the change to flecainide, 9 of 15 patients (60%) with AF still converted. Thus, 23 of 32 patients (72%) with AF and none of 7 with AFI converted to sinus rhythm after treatment with flecainide. Conversion to sinus rhythm was achieved in 19 of 22 patients (86%) when AF lasted less than 24 hours and in 4 of 10 (40%) when the arrhythmia lasted greater than 24 hours. Transient adverse effects were noted in 10 patients (26%) after flecainide. In summary, flecainide is an effective and safe drug for conversion of paroxysmal AF to sinus rhythm, but ineffective for AFI. Verapamil appears to be of no use for conversion of AF or AFI to sinus rhythm.

Adult↗
PubMed1992

Acute pharmacologic conversion of atrial fibrillation and flutter: the role of flecainide, propafenone, and verapamil.

Efficacy and safety of intravenous flecainide (2 mg/kg body weight in 10 minutes), verapamil (10 mg in 1 minute), and propafenone (2 mg/kg body weight in 10 minutes) were investigated in 90 consecutive patients with atrial fibrillation (AF) or flutter (AFL). In the first 40 patients, flecainide and verapamil were evaluated; in the second 50 patients, flecainide and propafenone were compared, both in a single-blind randomized study design. The primary end point was sinus rhythm occurring within 1 hour after start of infusion. Sinus rhythm was attained in 32 of 37 patients (86%) with AF treated with flecainide and in 11 of 20 patients (55%) with AF treated with propafenone. In recent onset AF (less than or equal to 24 hours) conversion rates were 24 of 25 patients (96%) in the flecainide group and 8 of 14 patients (57%) in the propafenone group (p less than 0.05). Conversion of AFL occurred in only 1 of 8 patients (13%) in the flecainide-treated patients and in 2 of 5 patients (40%) treated with propafenone (difference not significant). Verapamil was almost ineffective, since only 1 of 20 patients (5%) responded within 1 hour. Time to conversion was 21 +/- 17 minutes in the flecainide group and 16 +/- 10 minutes in the propafenone group. QRS widening occurred in flecainide-treated patients (83 +/- 15 to 99 +/- 20 msec; p less than 0.001), but not after propafenone (83 +/- 11 to 86 +/- 12 msec). Significantly higher plasma levels were found in patients with conversion within 1 hour using propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Fibrillation↗
PubMed1992

Effectiveness of loading oral flecainide for converting recent-onset atrial fibrillation to sinus rhythm in patients without organic heart disease or with only systemic hypertension.

Sixty-two patients with recent-onset (less than or equal to 1 week) atrial fibrillation (New York Heart Association functional class 1 and 2) were randomized in a single-blind study to 1 of the following treatment groups: (1) flecainide (300 mg) as a single oral loading dose; or (2) amiodarone (5 mg/kg) as an intravenous bolus, followed by 1.8 g/day; or (3) placebo for the first 8 hours. Twenty-four-hour Holter recording was performed, and conversion to sinus rhythm at 3, 8, 12 and 24 hours was considered as the criterion of efficacy. Conversion to sinus rhythm was achieved within 8 hours (placebo-controlled period) in 20 of 22 patients (91%) treated with flecainide, 7 of 19 (37%) treated with amiodarone (p less than 0.001 vs flecainide), and 10 of 21 (48%) treated with placebo (p less than 0.01 vs flecainide). Resumption of sinus rhythm within 24 hours occurred in 21 of 22 patients (95%) with flecainide and in 17 of 19 (89%) with amiodarone (p = not significant). Mean conversion times were shorter for flecainide (190 +/- 147 minutes) than for amiodarone (705 +/- 418; p less than 0.001). No major side effects occurred. At Holter monitoring, a pause of 9.3 seconds was observed in 1 asymptomatic patient treated with flecainide. Phases of atrial flutter with a ventricular rate less than or equal to 150 beats/min were detected before sinus conversion in 1 patient receiving placebo and in 2 receiving flecainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Effects of flecainide on the rate dependence of atrial refractoriness, atrial repolarization and atrioventricular node conduction in anesthetized dogs.

UNLABELLED: Flecainide is effective against certain supraventricular arrhythmias (atrial fibrillation and atrioventricular [AV] node reentrant tachycardia), but its mechanisms of action are unknown. Previous in vitro work suggests that flecainide attenuates rate-dependent action potential duration shortening, producing tachycardia-dependent prolongation of the refractory period. This study was designed to assess whether similar changes occur in vivo and whether the effects of flecainide on AV node conduction depend on heart rate and on direction of propagation (anterograde vs. retrograde). The effects of flecainide at three clinically relevant concentrations were assessed in open chest, morphine-chloralose-anesthetized dogs. Flecainide increased atrial refractory period in a concentration- and rate-related fashion (e.g., dose 3 increased the atrial effective refractory period by 9 +/- 4% at a cycle length of 1,000 ms but by 36 +/- 5% and 55 +/- 10% at a basic cycle length of 400 and 300 ms, respectively; p less than 0.001 for each). Flecainide attenuated the action potential duration accommodation (measured by monophasic action potentials) to heart rate, causing tachycardia-dependent action potential duration prolongation and accounting for most of the rate-dependent atrial effective refractory period changes. Flecainide increased Wenckebach cycle length, but the concentration-response curve was much steeper in the retrograde (slope 41 +/- 7 ms/mumol.liter-1) than in the anterograde direction (17 +/- 4 ms/mumol.liter-1; p less than 0.01), indicating more potent effects on retrograde conduction. The depressant action of the drug on the AV node was also rate dependent, with an effect on the AH interval at a basic cycle length of 400 ms that averaged 1.8, 1.5 and 2 times that at a basic cycle length of 1,000 ms for doses 1 (p less than 0.05), 2 (p less than 0.01) and 3 (p less than 0.001), respectively. CONCLUSIONS: 1) Flecainide suppresses atrial action potential duration accommodation to heart rate changes in vivo, leading to rate-dependent atrial effective refractory period prolongation, which may be important in suppressing atrial fibrillation. 2) The drug has frequency- and direction-dependent effects on AV node conduction, which may lead to selective antiarrhythmic actions during AV node reentry.

Action Potentials↗
PubMed1997

Flecainide overdose: is cardiopulmonary support the treatment?

Flecainide toxicity can impair cardiac function and precipitate circulatory collapse, which in turn depresses clearance and redistribution of flecainide. Treatment directed at improving cardiac function is often ineffective in the presence of persistently increased flecainide levels. We report a novel approach to severe flecainide overdose using peripheral cardiopulmonary bypass support (CBS) to maintain perfusion of the liver, thereby allowing clearance of the drug. CBS was initiated to resuscitate a young woman who had ingested flecainide in a suicide attempt. The patient had an agonal rhythm, no effective blood pressure, and a flecainide level of 5.4 micrograms/mL (therapeutic range, .2 to 1.0 microgram/mL). During 10 hours of CBS, the flecainide level decreased to 1.4 micrograms/mL, a half-life of 6 hours. Effective cardiac rhythm and blood pressure returned. CBS successfully supported this patient until the flecainide level decreased as a result of redistribution and normal clearance mechanisms. Unfortunately, because of severe neurologic damage sustained at the time of overdose, the patient died 4 days after admission.

Adult↗
PubMed2003

Liquid chromatographic determination of unbound flecainide in therapeutic drug monitoring.

An assay method was developed for determining unbound flecainide in serum by reversed phase-high performance liquid chromatography (HPLC). Serum water including unbound flecainide was separated by ultrafiltration of the serum sample and subjected to C(18)-cartridge extraction followed by HPLC analysis. The recovery of flecainide from serum water was greater than 93%. The coefficient variations for intra- and inter-day assay of flecainide were smaller than 2.4 and 3.7%, respectively. We applied the method to determining unbound flecainide in serum samples collected from 20 patients receiving oral flecainide (150-300 mg/day) for tachyarrhythmia. Total and unbound concentrations for serum flecainide were 403.5+/-200.8 ng/ml and 180.2+/-95.0 ng/ml, respectively. Linear relationship was observed between total and unbound concentrations (r=0.978, P<0.0001). Percent unbound (44.3+/-5.7%) determined in the present study agreed with the reported values. The percentage unbound tended to increase in the samples with lower alpha(1)-acid glycoprotein (<60 mg/dl). The assay method can be applied to routine determination of unbound flecainide in therapeutic drug monitoring.

Aged↗
PubMed1999

Favorable effects of flecainide in transvenous internal cardioversion of atrial fibrillation.

OBJECTIVES: The aim of the study was to evaluate the effects of intravenous (IV) flecainide on defibrillation energy requirements in patients treated with low-energy internal atrial cardioversion. BACKGROUND: Internal cardioversion of atrial fibrillation is becoming a more widely accepted therapy for acute episode termination and for implantable atrial defibrillators. METHODS: Twenty-four patients with atrial fibrillation (19 persistent, 5 paroxysmal) underwent elective transvenous cardioversion according to a step-up protocol. After successful conversion in a drug-free state, atrial fibrillation was induced by atrial pacing; IV flecainide (2 mg/kg) was administered and a second threshold was determined. In patients in whom cardioversion in a drug-free state failed notwithstanding a 400- to 550-V shock, a threshold determination was attempted after flecainide. RESULTS: Chronic persistent atrial fibrillation was converted in 13/19 (68%) patients at baseline and in 16/19 (84%) patients after flecainide. Paroxysmal atrial fibrillation was successfully cardioverted in all the patients. A favorable effect of flecainide was observed either in chronic persistent atrial fibrillation (13 patients) or in paroxysmal atrial fibrillation (5 patients) with significant reductions in energy requirements for effective defibrillation (persistent atrial fibrillation: 4.42+/-1.37 to 3.50+/-1.51 J, p < 0.005; paroxysmal atrial fibrillation: 1.68+/-0.29 to 0.84+/-0.26 J, p < 0.01). In 14 patients not requiring sedation, the favorable effects of flecainide on defibrillation threshold resulted in a significant reduction in the scores of shock-induced discomfort (3.71+/-0.83 vs. 4.29+/-0.61, p < 0.005). No ventricular proarrhythmia was observed for any shock. CONCLUSIONS: Intravenous flecainide reduces atrial defibrillation threshold in patients treated with low-energy internal atrial cardioversion. This reduction in threshold results in lower shock-induced discomfort. Additionally, flecainide may increase the procedure success rate in patients with chronic persistent atrial fibrillation.

Adult↗
PubMed1998

Effect of flecainide on heart rate variability in subjects without coronary artery disease or congestive heart failure.

Heart rate variability is a noninvasive indicator of autonomic nervous system activity. The role of the autonomic nervous system in the genesis of atrial or ventricular arrhythmias is now well established. Little is known about the effects of flecainide on heart rate variability in patients with normal heart structure, the main population receiving flecainide. This study was designed to evaluate the effects of flecainide on heart rate variability in patients without coronary artery disease or congestive heart failure. Time and frequency domain analysis of heart rate variability on 24-hour electrocardiogram recording were assessed in 40 patients with normal echocardiography and without evidence of coronary artery disease before and after 2 months of oral treatment with flecainide (321 +/- 57 mg/day) prescribed for Wolff Parkinson White syndrome with circus movement tachycardia. Flecainide significantly decreased all parameters of heart rate variability in the time domain (median delta% -10% to -25%) and in the frequency domain (median delta% -27% to -38%), including the markers of vagal activity. There was no correlation between plasma concentrations of flecainide and reduction in heart rate variability. It was concluded that in subjects without coronary artery disease or congestive heart failure, flecainide decreases all the measurements of heart rate variability and this decrease is not related to plasma concentrations of flecainide.

Adolescent↗
PubMed2002

Meta-analysis of flecainide safety in patients with supraventricular arrhythmias.

Flecainide (CAS 54143-55-4) has been associated with increased mortality in patients with ventricular dysfunction and arrhythmias. It is a potent suppressant of supraventricular arrhythmias, but safety data for use in this condition are rare. A meta-analysis was performed including 122 prospective studies on the use of flecainide in patients with supraventricular arrhythmias and no significant signs of ventricular damage. 4811 patients on flecainide were included (mean age 55 +/- 13 years, 60% male). 38 studies were on i.v. Flecainide, 84 on p.o. application, 21 were placebo-controlled, 37 were comparative studies with other antiarrhythmics. The total exposure time was 2015 patient years, with a mean flecainide dose in p.o. studies of 216 +/- 65 mg/day. The total database on flecainide contains the reports of 8 deaths (total mortality 0.166%, mortality rate per 100 patient years 0.397). 3 deaths were non-cardiac deaths (cancer, suicide, urosepsis). Of the cardiac deaths, all but two occurred in patients with coronary heart disease. In controls, there was 1 death. Even for all deaths, this difference was not significant (p = 0.46). Proarrhythmic events were seen in 120 patients on flecainide, and, significantly more frequent, in 88 control patients (p < 0.001). The data clearly show that the use of flecainide in patients with supraventricular arrhythmias is safe and, because of its proven efficacy, advisable. Scrutiny should be exercised to diagnose all patients with structural left ventricular damage.

Adult↗
PubMed2002

Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations.

Na(+) channel blockers such as flecainide have found renewed usefulness in the diagnosis and treatment of two clinical syndromes arising from inherited mutations in SCN5A, the gene encoding the alpha subunit of the cardiac voltage-gated Na(+) channel. The Brugada syndrome (BrS) and the LQT-3 variant of the Long QT syndrome are caused by disease-linked SCN5A mutations that act to change functional and pharmacological properties of the channel. Here we have explored a set of SCN5A mutations linked both to BrS and LQT-3 to determine what disease-modified channel properties underlie distinct responses to the Na(+) channel blocker flecainide. We focused on flecainide block that develops with repetitive channel activity, so-called use-dependent block (UDB). Our results indicate that mutation-induced changes in the voltage-dependence of channel availability (inactivation) may act as determinants of flecainide block. The data further indicate that UDB by flecainide requires channel opening, but is not likely due to open channel block. Rather, flecainide appears to interact with inactivation states that follow depolarization-induced channel opening, and mutation-induced changes in channel inactivation will alter flecainide block independent of the disease to which the mutation is linked. Analysis of flecainide block of mutant channels linked to these rare disorders has provided novel insight into the molecular determinants of drug action.

Anti-Arrhythmia Agents↗
PubMed1989

Efficacy of flecainide in pacing-induced sustained ventricular tachyarrhythmias: correlation to clinical parameters and tachycardia-characteristics.

Seventy-two patients with sustained ventricular tachycardia or syncope of unknown origin underwent electrophysiologic evaluation before and after therapy with flecainide (200-300 mg day-1). In all patients, sustained ventricular tachycardia or ventricular fibrillation was inducible during control electrophysiologic study. During flecainide therapy, sustained ventricular tachycardia (VT) was no longer inducible in 18 patients (25%) whereas in 54 patients, VT was still inducible. In five of the latter patients, VT became more difficult to induce (overall efficacy 32%). The rate of VT decreased from 214 +/- 49 beats min-1 during the control electrophysiologic study to 178 +/- 48 beats min-1 during flecainide (P less than 0.01). The ERP of the right ventricle increased from 251 +/- 27 ms during the control study to 267 +/- 34 ms on flecainide (P less than 0.01). Mean ejection fraction and mean LVEDP did not differ between responders and non-responders, yet the presence of a left ventricular aneurysm correlated with a lack of antiarrhythmic response to flecainide. VT rate as well as VT morphology during the control study discriminated between responders and non-responders; 11% of patients with VT-rate less than or equal to 230 beats min-1 responded to oral flecainide compared with 31% with a VT rate greater than 230 beats min-1 at control. 26% with induced monomorphic VT responded, compared with 100% with induced VF during the control study. 18 of 23 responders were discharged on flecainide. During a mean follow-up of 26 +/- 18 months, two patients experienced a recurrence of VT and in one patient, flecainide had to be discontinued due to side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗