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PubMed2004

Simultaneous determination of serum flecainide and its metabolites by using high performance liquid chromatography.

Simultaneous determination of serum flecainide and its oxidative metabolites was carried out by using high performance liquid chromatography (HPLC) equipped with conventional octadecylsilyl silica (ODS) column and fluorescence detector. Flecainide and its metabolites, m-O-dealkylated flecainide (MODF) and m-O-dealkylated lactam of flecainide (MODLF) in serum were extracted with ethyl acetate. The recoveries of flecainide, MODF and MODLF were greater than 92, 93, and 60% with the coefficient of variations (CVs) less than 3.2, 5.8, and 5.3%, respectively. The calibration curves were linear at the concentration range of 50-1500 ng/mL for flecainide and 10-500 ng/mL for MODF and MODLF (r > 0.999). The CVs for intra-day assay were 2.7-5.3% for flecainide, 3.0-4.2% for MODF, and 3.7-4.3% for MODLF, respectively. The CVs for inter-day assay were 7.0-8.4% for flecainide, 3.3-6.7% for MODF, and 4.4-7.7% for MODLF, respectively. This assay method can be used for assessing the metabolic ability of flecainide in the patients with tachyarrhythmia.

Adult↗
PubMed2000

Comparison of intravenous flecainide, propafenone, and amiodarone for conversion of acute atrial fibrillation to sinus rhythm.

In a prospective, single-blind trial, we randomized 150 consecutive symptomatic patients with acute (< or = 48 hours' duration) atrial fibrillation to receive intravenous flecainide, propafenone, or amiodarone. Flecainide and propafenone were administered as a bolus dose of 2 mg/kg in 20 minutes. A second bolus dose of 1 mg/kg in 20 minutes was administered if conversion to sinus rhythm was not achieved after 8 hours. Amiodarone was administered as a bolus of 5 mg/kg in 20 minutes followed by a continuous infusion of 50 mg/hour. By the end of a 12-hour observation period, conversion to sinus rhythm was achieved in 45 patients (90%) in the flecainide group, 36 (72%) in the propafenone group, and 32 (64%) in the amiodarone group (p = 0.008 for the overall comparison, p = 0.002 for flecainide vs amiodarone, p = 0.022 for flecainide vs propafenone, and p = 0.39 for propafenone vs amiodarone). When compared with amiodarone, this higher reversion rate with flecainide was present from the first hour of the study period. However, only after administering the second bolus was there a significant difference between flecainide and propafenone. Median time to conversion to sinus rhythm was different among groups (p < 0.001), and it was lower in the flecainide (25 minutes; range 4 to 660) and propafenone (30 minutes; range 10 to 660) groups than in the amiodarone group (333 minutes; range 15 to 710; p < 0.001 for both comparisons). Flecainide, at the doses administered in this study, is more effective than propafenone and amiodarone for conversion of acute atrial fibrillation to sinus rhythm. Propafenone and amiodarone have similar conversion rates, although propafenone was faster in achieving the conversion to sinus rhythm.

Aged↗
PubMed1983

Cardiac electrophysiologic effects of flecainide acetate for paroxysmal reentrant junctional tachycardias.

Intravenous flecainide acetate was administered to 33 patients undergoing routine electrophysiologic study: 18 patients had a direct accessory atrioventricular (AV) pathway and 15 patients had functional longitudinal A-H dissociation (dual A-H pathways). Flecainide was given to 14 patients during sustained AV reentrant tachycardia and to 9 patients during sustained intra-AV nodal reentrant tachycardia. AV reentrant tachycardia was successfully terminated in 12 of 14 patients. Tachycardia termination was due to retrograde accessory pathway block in 11 patients and AV nodal block in 1. During flecainide administration, tachycardia cycle lengths increased (327 +/- 55 to 426 +/- 84 ms) principally because of retrograde conduction delay in the accessory pathway (127 +/- 34 to 197 +/- 67 ms). After flecainide administration, tachycardia reinitiation was not possible in 6 patients. In all 18 patients with accessory AV pathway conduction, flecainide significantly increased both anterograde and retrograde accessory pathway effective refractory periods, with anterograde accessory pathway block in 3 patients and retrograde accessory pathway block in 8. Intra-AV nodal reentrant tachycardia was successfully terminated in 8 of 9 patients. Tachycardia termination was due to retrograde "fast" A-H pathway block in 7 patients and anterograde "slow" A-H pathway block in 1 patient. During flecainide administration, tachycardia cycle lengths increased (326 +/- 50 to 433 +/- 64 ms) due to both anterograde, A-H and H-V (AV 242 +/- 97 to 343 +/- 75 ms), and retrograde, earliest ventricular to earliest atrial (51 +/- 14 to 70 +/- 23 ms) conduction delay. After flecainide administration, reinitiation of intra-AV nodal reentrant tachycardia was not possible in 4 patients. In all 15 patients with dual A-H pathways, flecainide selectively prolonged the retrograde effective refractory period of the fast A-H pathway, having little effect on anterograde fast A-H pathway refractoriness or on anterograde and retrograde slow A-H pathway refractoriness. Anterograde fast A-H pathway block occurred in 1 patient and retrograde fast A-H pathway block occurred in 6 patients. No serious adverse effects were encountered during the study. Flecainide acetate is an effective agent for the acute termination of both orthodromic AV and intra-AV nodal reentrant tachycardias. This antiarrhythmic action appears to be mediated through a predominant effect on either accessory AV pathway or retrograde fast A-H pathway refractoriness.

Adult↗
PubMed2003

Intravenous flecainide for the treatment of junctional ectopic tachycardia after surgery for congenital heart disease.

BACKGROUND: Junctional ectopic tachycardia (JET) is a life-threatening arrhythmia producing severe hemodynamic dysfunction, which may complicate the postoperative course of surgery for congenital heart disease. Strict care and a fast and effective antiarrhythmic strategy are essential, because mortality largely depends on the duration of the arrhythmia. METHODS: Seven consecutive neonates with postoperative JET without any evidence of myocardial ischemia received intravenous flecainide after conventional therapies proved ineffective. Atrial pacing at the minimal rate for atrioventricular synchrony was followed by a 10-min intravenous infusion of 1.6 mg/kg flecainide, then continuous infusion of 0.4 mg/kg flecainide per hour. Treatment was considered effective based on restoration of sinus rhythm or a JET rate no higher than 170 bpm within 4 hours of flecainide loading. Overall mean flecainide infusion lasted 31.2 hours (range 25 to 53 hours). Side effects were assessed by monitoring plasma flecainide levels, electrocardiogram, arterial pressure, and central venous pressure. RESULTS: Flecainide was effective in all 7 patients after an infusion duration of 3.6 +/- 1.5 hours. Sinus rhythm was restored after 7.2 +/- 9.7 hours. After 4 hours of loading, heart rate fell from 219 +/- 14 to 136 +/- 7 bpm (p < 0.0001), arterial pressure increased from 69 +/- 8 to 93 +/- 10 mm Hg (p < 0.0001), while central venous pressure decreased from 8.0 +/- 1.6 to 5.2 +/- 1.9 mm Hg (p = 0.0007). No side effect or recurrence was noted. CONCLUSIONS: Flecainide can exert a fast antiarrhythmic effect on postoperative JET, and its infusion can be modulated to maintain the concentration within the therapeutic range, thus avoiding toxicity. We propose further consideration of flecainide for treatment of JET in neonates without myocardial ischemia.

Anti-Arrhythmia Agents↗
PubMed1985

Effects of flecainide on the electrophysiologic properties of isolated canine and rabbit myocardial fibers.

The electrophysiologic properties of flecainide, a new potent antiarrhythmic drug, are poorly defined. In this study, they were investigated by standard microelectrode technique in isolated cardiac muscle from rabbit and dog hearts. The concentrations of flecainide used were between 0.1 and 10.0 micrograms/ml. Flecainide produced a concentration-dependent decrease in maximal rate of rise of phase 0 of the action potential (Vmax), action potential amplitude and overshoot potential with an increase in the effective refractory period in ventricular muscle. Vmax was reduced by 52.5% after 1 microgram/ml of flecainide (p less than 0.001) and by 79.8% after 10.0 micrograms/ml (p less than 0.001). The corresponding values for Purkinje fibers were 18.6% (p less than 0.01) and 70.8% (p less than 0.001), respectively, but in these fibers the effective refractory period was shortened at the lower concentration and restored to control value at the higher concentration. The depression of Vmax by flecainide was frequency-dependent. The action potential duration was lengthened by flecainide in ventricular muscle and shortened in Purkinje fibers. At high concentrations (10 micrograms/ml), flecainide depressed slow channel-dependent fibers. Purkinje fiber automaticity induced by isoproterenol was slowed by flecainide. The data indicate that the overall electrophysiologic effects of flecainide in isolated cardiac muscle are complex with a major depressant action on Vmax that may account for its dominant antiarrhythmic effects. It is also possible that the differential effects of the compound on the action potential duration and refractoriness in ventricular muscle and Purkinje fibers contribute to the known arrhythmogenic potential of the drug.

Action Potentials↗
PubMed1989

Flecainide enantiomers: disposition in human subjects and electrophysiologic actions in vitro.

The antiarrhythmic agent flecainide is administered as a racemate. The disposition of the individual enantiomers and their electrophysiologic actions are unknown. We therefore determined through plasma levels of S-(+)-flecainide and R-(-)-flecainide in 13 patients who were receiving long-term oral flecainide therapy. In addition, the effects of the enantiomers on action potential characteristics in canine cardiac Purkinje fibers were assessed. Plasma concentrations of R-(-)flecainide were significantly higher than those of the S-(+)-enantiomer (-/+ ratio, 1.10 +/- 0.13,mean +/- SD; range, 0.89 to 1.32, p less than 0.01), suggesting that the drug undergoes enantioselective disposition. In the in vitro experiments, both enantiomers reduced phase 0 action potential Vmax (an index of the fast inward sodium current) and shortened action potential duration at 50% and 90% repolarization, but no differences between the enantiomers were detected. The time constants for development of Vmax depression were significantly longer for S-(+)-flecainide (13.4 +/- 1.5 seconds) compared with R-(-)-flecainide (8.9 +/- 0.6 seconds, p less than 0.001). Thus, although S-(+)-flecainide and R-(-)-flecainide undergo modest enantioselective disposition, they exert similar electrophysiologic effects. These studies have provided no evidence to indicate that administration of a single enantiomer, rather that the racemic drug, would offer any advantage.

Action Potentials↗
PubMed2001

The effects of flecainide on ATP-sensitive K(+) channels in pig urethral myocytes.

The effects of the antiarrhythmic drug flecainide on levcromakalim-induced hyperpolarization, macroscopic and unitary K(+) currents in pig urethra were investigated using patch-clamp techniques. The effects of flecainide were also examined on currents in inside-out patches of COS7 cells expressing carboxy terminus truncated inwardly rectifying K(+) channel (Kir6.2) subunits (i.e. Kir6.2DeltaC36) which form ATP-sensitive K(+) channels (K(ATP) channels). In current-clamp mode, application of flecainide (> or =100 microM) caused a significant depolarization after the membrane potential had been hyperpolarized by levcromakalim. In voltage-clamp experiments, the levcromakalim-induced outward current was suppressed by 300 microM flecainide in quasi-physiological K(+) conditions (K(i)=51 microM). In contrast, approximately 20% of the levcromakalim-induced inward current still remained even after application of 300 microM flecainide in symmetrical 140 mM K(+) conditions (K(i)=51 microM). In contrast, approximately 20% of the levcromakalim-induced inwar=126 microM). In cell-attached configuration, the channel activity of the levcromakalim-induced K(ATP) channels was reversibly inhibited by flecainide (> or =30 microM) at -50 mV. Their activity was also suppressed by either disopyramide or cibenzoline. Flecainide reversibly inhibited the channel activity of Kir6.2DeltaC36 expressed in COS7 cells using inside-out configuration. Inhibitory effects of flecainide on the levcromakalim-induced currents became more potent when the value of external pH increased, although this slightly reduced the proportion of drug molecules carrying a positive charge. These results suggest that flecainide inhibits channel activity through blocking the pore site of the K(ATP) channel in pig urethra.

Adenosine Triphosphate↗
PubMed2002

Pharmacokinetics and electrocardiographic effects of a new controlled-release form of flecainide acetate: comparison with the standard form and influence of the CYP2D6 polymorphism.

OBJECTIVES: Our objectives were study the single- and repeated-dose pharmacokinetics and electrocardiographic effects (QRS duration) of a new controlled-release form of flecainide acetate compared with the immediate-release form and to examine the influence of CYP2D6 activity. METHODS: Twenty-four healthy subjects (6 men and 6 women at both dosages) received single and repeated doses of 100 or 200 mg immediate-release and controlled-release flecainide in a randomized crossover design. Electrocardiograms were recorded and flecainide plasma concentrations were measured before administration and up to 96 hours after administration. RESULTS: The controlled-release formulation had sustained-release properties, with a significantly lower maximum concentration (C(max)) and delayed time to reach C(max). Compared with the immediate-release formulation, the relative bioavailability of the controlled-release formulation at steady state was 0.85 +/- 0.17 and 0.89 +/- 0.17 for the 100-mg/day and 200-mg/day doses, respectively. Trough flecainide plasma concentration at steady state was bioequivalent for both formulations. Maximum and minimum QRS increases were not significantly different for either the immediate-release or the controlled-release form of flecainide after administration of both single and repeated doses. Mean QRS duration during a dosing interval at steady state correlated with mean plasma concentration for both forms (pooled data; P <.001). The 95% confidence interval for this regression was 26% narrower for the controlled-release form than for the immediate-release form. Flecainide-induced QRS prolongation and pharmacokinetics were not significantly influenced by CYP2D6 activity. CONCLUSIONS: Flecainide-induced QRS prolongation did not differ between the new controlled-release form and the immediate-release form. Flecainide plasma concentrations associated with the new controlled-release form predicted QRS prolongation with less variability compared with the immediate-release form. The CYP2D6 polymorphism did not appear to influence flecainide disposition kinetics or electrocardiographic effects at steady state.

Adult↗
PubMed1983

A comparison of the antiarrhythmic effects on AV junctional re-entrant tachycardia of oral and intravenous flecainide acetate.

Both the electrophysiological and antiarrhythmic effects of some antiarrhythmic agents may differ markedly depending on their route of administration. Flecainide acetate, a new class 1 agent, was therefore administered both intravenously and orally to 13 patients with recurrent paroxysmal tachycardia to assess whether the acute response to intravenous flecainide accurately predicts the response to oral therapy. Eight patients had atrioventricular re-entrant tachycardia (AVRT) and five patients intra AV nodal re-entrant tachycardia (AVNRT). When administered by either route, flecainide markedly prolonged both the anterograde and retrograde conduction intervals during constant rate pacing and the anterograde and retrograde Wenckebach cycle lengths during incremental pacing. Five of the 13 patients developed complete retrograde block after both routes of administration of the drug. All 13 patients received intravenous flecainide during tachycardia with successful reversion to sinus rhythm in all cases. Tachycardia could be reinitiated in five of the patients with AVRT after intravenous flecainide and in one further patient after oral administration. It was not possible to reinitiate tachycardia in any of the five patients with AVNRT after either intravenous or oral flecainide. The size of the tachycardia initiation windows, by either atrial or ventricular premature stimuli, were significantly reduced by both intravenous and oral flecainide. In those patients in whom tachycardia could be reinitiated, tachycardia cycle length was significantly increased, and to a similar degree, by both routes of administration of the drug. This increase in cycle length was predominantly due to prolongation in retrograde conduction. It is concluded that flecainide acetate is a potent antiarrhythmic agent for use in patients with junctional tachycardia. The intravenous administration of flecainide reliably predicts the subsequent response to oral therapy.

Administration, Oral↗
PubMed1990

Comparison of the cardiac electrophysiological effects of flecainide and hydroquinidine in anesthetized dog: concentration-response relationship.

The concentration-dependent effects of flecainide and hydroquinidine were studied in closed-chest anesthetized dogs. The electrophysiological effects of three doses (i.v. infusions followed by an appropriate perfusion to plateau the plasma levels) of flecainide (1, 2, and 3.9 mg/kg) and hydroquinidine (2, 4, 7.5 mg/kg) were tested. Sinus cycle length, QRS duration, His-Purkinje and AV nodal conduction times, Wenckebach period, atrial, nodal, and ventricular refractory periods, and corrected QT interval were measured before and 30 min after the beginning of each bolus infusion. Both hydroquinidine and flecainide increased the sinus cycle length, and slowed cardiac conduction to different degrees. Hydroquinidine and flecainide prolonged ventricular conduction; flecainide had a greater effect at the His-Purkinje level. Hydroquinidine exhibited only a weak and nonsignificant effect at the AV node, whereas flecainide dramatically prolonged conduction and refractoriness. The two drugs increased AERP equally. The QT interval and ventricular refractoriness were similarly prolonged to the same extent by both drugs (32 and 35% after the third doses of hydroquinidine and flecainide, respectively). The high plasma flecainide levels reached in our study (1.47 and 2.9 micrograms/ml after the second and third doses, respectively) may explain these effects, which are unexpected for a class Ic agent. These results suggest that flecainide could increase the QT interval, like a class Ia drug when its plasma level exceeds the therapeutic range.

Anesthesia↗
PubMed1993

Effects of flecainide on defibrillation threshold in pigs.

Flecainide has been reported to decrease defibrillation efficacy in pentobarbital-anesthetized dogs. Conversely, flecainide did not alter defibrillation energy requirements in halothane-anesthetized pigs. We wished to determine whether these discrepancies were related to defibrillation technique, interaction with the anesthetic regimen, or animal species. The effects of three doses of flecainide on defibrillation threshold (DFT) were determined using single- and sequential-pulse shocks in halothane-anesthetized open-chest pigs. Triplicate DFTs were obtained before and after three doses of flecainide (n = 34) or saline (n = 13) infusion. Similarly, the effects of the highest dose of flecainide were determined using barbiturate-anesthetized animals (n = 10). Flecainide did not alter DFT at any dose with either the single-pulse shock (control 17.7 +/- 2.1 J, highest dose of flecainide 19.1 +/- 3.2 J, p = NS) or sequential-pulse shock (control 9.2 +/- 1.0 J, highest dose of flecainide 8.4 +/- 1.4 J, p = NS) when halothane anesthesia was used. Similar results were obtained using barbiturate anesthesia either with sequential (control 8.7 +/- 0.9 vs. 8.2 +/- 0.6 J, p = NS) or single shocks (control 13.2 +/- 0.8 vs. 13.7 +/- 1.0 J, p = NS). Flecainide did not alter DFT in our model, regardless of defibrillation technique or anesthetic regimen.

Animals↗
PubMed2005

A single residue in the S6 transmembrane domain governs the differential flecainide sensitivity of voltage-gated potassium channels.

Flecainide has been used to differentiate Kv4.2-based transient-outward K(+)-currents (flecainide-sensitive) from Kv1.4-based (flecainide-insensitive). We found that flecainide also inhibits ultrarapid delayed rectifier (I(Kur)) currents in Xenopus laevis oocytes carried by Kv3.1 subunits (IC(50), 28.3 +/- 1.3 microM) more strongly than Kv1.5 currents corresponding to human I(Kur) (IC(50), 237.1 +/- 6.2 microM). The present study examined molecular motifs underlying differential flecainide sensitivity. An initial chimeric approach pointed to a role for S6 and/or carboxyl-terminal sites in Kv3.1/Kv1.5 sensitivity differences. We then looked for homologous amino acid residues of the two sensitive subunits (Kv4.2 and Kv3.1) different from homologous residues for insensitive subunits (Kv1.4 and Kv1.5). Three candidate sites were identified: two in the S5-S6 linker and one in the S6 segment. Mutation of the proximal S5-S6 linker site failed to alter flecainide sensitivity. Mutation at the more distal site in Kv1.5 (V481L) modestly increased sensitivity, but the reciprocal Kv3.1 mutation (L401V) had no effect. S6 mutants caused marked changes: flecainide sensitivity decreased approximately 8-fold for Kv3.1 L422I (IC(50), 213 +/- 9 microM) and increased approximately 7-fold for Kv1.5 I502L (IC(50), 35.6 +/- 1.9 microM). Corresponding mutations reversed flecainide sensitivity of Kv1.4 and Kv4.2; L392I decreased Kv4.2 sensitivity by approximately 17-fold (IC(50) of 37.4 +/- 6.9 to 628 +/- 36 microM); I547L increased Kv1.4 sensitivity by approximately 15-fold (IC(50) of 706 +/- 37 to 40.9 +/- 7.3 microM). Our observations indicate that the flecainide sensitivity differences among these four voltage-gated K(+)-channels are determined by whether an isoleucine or a leucine is present at a specific amino acid location.

Amino Acid Sequence↗
PubMed2000

Safe and efficacious dosage of flecainide acetate for treating equine atrial fibrillation.

To determine a safe and efficacious dose of flecainide acetate for treating equine atrial fibrillation (Af), the safe dosage level was determined by injecting 1, 2, or 3 mg/kg i.v. of 1% flecainide acetate solution at a rate of 0.2 mg/kg/min to five clinically healthy horses. Clinical signs and the ECG were monitored (HR, PR, QRS, and QT intervals) and blood was taken to measure the plasma flecainide concentration pre- and post-administration. No abnormal signs were observed in the 1- or 2-mg/kg groups, while agitation was observed in three of five horses in the 3-mg/kg group. The QRS, and QT intervals for the 3-mg/kg group increased significantly. The peak plasma flecainide concentrations were 1.316 +/- 358 (SD) ng/ml, 1,904 +/- 314 ng/ml, and 2,251 +/- 387 ng/ml for the 1-, 2-, and 3-mg/kg groups, respectively. To evaluate the efficacy of flecainide, Af was induced by right atrial pacing in six clinically healthy horses, and 1% flecainide acetate solution was then administered until they converted to sinus rhythm. All horses with induced Af converted. For the conversion, a total dose of 1.40 +/- 0.63 mg/kg flecainide was required, the duration of administration was 7.00 +/- 3.15 min and plasma flecainide concentration at conversion was 1,303 +/- 566 ng/ml. In conclusion, flecainide acetate is a safe and effective antiarrhythmic agent for equine Af, and the clinically effective dosage is 1 to 2 mg/kg.

Animals↗
PubMed2004

Use of intravenous flecainide in horses with naturally-occurring atrial fibrillation.

REASONS FOR PERFORMING STUDY: It has been reported that i.v. flecainide has a high efficacy for the treatment of experimentally-induced acute atrial fibrillation (AF) in horses and that its use is associated with minimal toxic side effects. OBJECTIVES: The objectives were to study the efficacy of i.v. flecainide as a treatment for atrial fibrillation in horses with naturally-occurring AF. METHODS: Ten horses with naturally-occurring AF were treated with 2 mg/kg bwt flecainide i.v. at a rate of 0.2 mg/kg bwt/min. In 3 horses, the infusion was continued at 0.05-0.10 mg/kg bwt/min until a total dose of 3.0 mg/kg bwt had been administered. Heart rate, QRS duration and average interval between fibrillation waves were measured before, during and following flecainide infusion. If conversion to normal sinus rhythm was not achieved, horses were treated with quinidine sulphate per os at a dose of 22 mg/kg bwt given every 2 h. RESULTS: None of the horses with chronic AF (n = 9) converted to sinus rhythm with flecainide i.v. The only horse treated successfully had acute AF of 12 days' duration. The QRS duration and fibrillation cycle length increased significantly (P = 0.006 and 0.002, respectively) during and following flecainide infusion. Heart rate did not increase significantly over time however, 3 horses developed heart rates in excess of 100 beats/min. Two horses developed a potentially dangerous ventricular dysrhythmia during the first 15 mins of treatment. Quinidine sulphate given per os restored sinus rhythm in 8 out of 9 horses, with minimal adverse effects. CONCLUSIONS: Although flecainide might be efficacious in cases of acute AF, it was not possible to restore sinus rhythm in horses with naturally-occurring chronic AF at the dosages used in this study. In 2 horses, 2.0 mg/kg bwt flecainide was associated with potentially dangerous dysrhythmias. POTENTIAL CLINICAL RELEVANCE: Intravenous administration of 2 mg/kg bwt flecainide is unlikely to convert chronic AF in horses and could induce dangerous dysrhythmias.

Acute Disease↗
PubMed2004

Effects of flecainide on atrial and ventricular refractoriness in rabbits in vitro and in vivo.

This study compared the in vitro versus in vivo effects of flecainide on effective refractory period (ERP) in atrial and ventricular tissue in rabbits. Flecainide (a class 1c agent) was chosen, on the basis of its known pharmacological profile and antiarrhythmic actions, to provide a reference compound for investigating models that suitably predict the clinical effects of antiarrhythmics. The rabbit models used were those previously described by Lowe et al. (2002) and Leung et al. (2003). ERP was measured as the shortest S1-S2 interval that elicited a second contraction (in vitro) or electrogram (in vivo). Flecainide (1-10 microM) in vitro produced a concentration-dependent increase in ERP. The greatest drug-induced change from pre-drug values in vitro occurred with the highest concentration in atria and ventricles at 4 Hz. The change was 30+/-4 msec (33+/-7%) in atria versus 53+/-8 msec (46+/-10%) in ventricles. In vivo, flecainide (1 - 4 micromol/kg) dose-dependently increased atrial ERP at 2 and 6 Hz. The biggest change was 28+/-17 msec (29+/-16%). However, there was no effect at 4 Hz. In the ventricles, a dose-related increase in ERP was only seen at 4 Hz (26+/-6 msec). Flecainide showed no frequency dependence of action on ERP in any preparation. Flecainide produced adverse effects both in vitro and in vivo. A concentration and frequency-dependent negative inotropic effect was seen in vitro, and dose-related hypotension in vivo. The highest dose (8 micromol/kg i.v.) of flecainide was lethal. Flecainide produced the expected electrophysiological and toxicity profile, both in vitro and in vivo. Despite such findings, the drug is used to terminate and prevent atrial arrhythmias clinically. In conclusion our rabbit models for determining ERP may not be useful in predicting the clinical usefulness of a drug like flecainide.

Animals↗
PubMed1990

[Effects of oral flecainide treatment of refractory tachyarrhythmias].

Oral flecainide treatment was given to five patients who were refractory to conventional antiarrhythmic agents. The five patients included one with atrioventricular reentrant tachycardia (AVRT), one with non-sustained ventricular tachycardia (nsVT) and three with sustained VT (sVT). Flecainide produced favorable responses in patients of AVRT, nsVT and sVT with arrhythmogenic right ventricular dysplasia (ARVD). In the case of AVRT, flecainide exhibited a preventive effect on tachycardia induced by programmed electrical stimulation (PES). In the case of nsVT, flecainide markedly reduced the number of VPC and abolished the VT on the Holter ECG. In the case of sVT with ARVD, sVT was not induced by PES after the flecainide. Long-term treatment with flecainide on these three cases produced complete prevention of tachycardias. As an adverse effect of flecainide, an aggravation of congestive heart failure was recognized in one case with cardiac sarcoidosis. PQ interval and QRS interval in all the cases were prolonged after flecainide. The results indicate that flecainide is a useful antiarrhythmic agent for tachyarrhythmias refractory to treatment with conventional drugs.

Administration, Oral↗
PubMed1982

Effects of flecainide on contractile force and electrophysiological parameters in cardiac muscle.

The action of N-(2-piperidylmethyl)-2,5-bis-(2,2, 2-trifluoroethoxy)-benzamide acetate (flecainide, Tambocor) on contractile force and electrophysiological parameters was studied in isolated calf ventricular fibres. Increasing flecainide concentrations (2-10 mg/l) induced a progressive decrease of force of contraction. At the highest concentration the peak of contraction was reduced by 50-40% of the control value, accompanied by a similar fall of the maximal rate of the rise of contraction (dP/dtmax). The negative inotropic effect was not significantly different at driving frequencies of 0.2 and 1 Hz. 5 mg/l flecainide reduced the tonic as well as the phasic components in high potassium contractures and induced a reduction of the action potential maximal upstroke velocity (Vmax). The suppression of Vmax was augmented by increasing the stimulation frequency from 0.2 to 1 Hz. This frequency dependence could partially be explained by a flecainide induced delay of Vmax recovery from inactivation. Plateau height and duration of the action potential were not significantly effected. The height and duration of slow potentials in 22 mmol/l K+-Tyrode solution were reduced under 5 mg/l flecainide. This effect was frequency independent, since the recovery of the slow potentials from inactivation was not delayed by flecainide. The results indicate that the new antiarrhythmic drug flecainide possesses two different sites of action, indicated by the different frequency dependence on Vmax and slow potential system under flecainide. The observed negative inotropic effect seems to be induced by the depressing effect of flecainide on the slow potential system.

Action Potentials↗
PubMed2001

Measurement of flecainide in hair as an index of drug exposure.

We report a method for measuring the concentration of flecainide in hair. An animal study, in which flecainide (1, 5, and 10 mg/kg/day) was orally administered for 1, 2, and 3 weeks to pigmented rats, showed that flecainide concentration in rat hairs newly regrown after administration significantly correlated with both the daily dose and the dosing period. The part of hair containing flecainide continued to grow upward, retaining the drug within the hair structure that had been formed at the time of drug exposure. Flecainide was also determined in human scalp hairs collected from patients treated with flecainide. The drug content of white hairs was much less than that black hairs collected from the same rats and subjects, suggesting the determinant effect of hair pigment on flecainide accumulation in hair. These findings suggest that the analysis of flecainide in hair may be useful for assessing exposure to drug qualitatively.

Animals↗