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PubMed2000

Effect of selective serotonin reuptake inhibitors on the oxidative metabolism of propafenone: in vitro studies using human liver microsomes.

Propafenone is mainly metabolized by CYP2D6 to form 5-hydroxypropafenone (5-OHP) and to a minor extent by CYP1A2 and CYP3A4 to form N-depropylpropafenone (N-DPP). The in vitro inhibitory effect of selective serotonin reuptake inhibitors (SSRIs) on the formation of both metabolites was studied, using human liver microsomes. The 5-OHP formation from racemic propafenone and from its individual enantiomers followed one-enzyme Michaelis-Menten kinetics. Incubation with the racemate yielded a mean Vmax of 64 pmol x min(-1) x mg(-1) and a mean Km of 0.12 microM (N = 3). Stereoselectivity in Vmax and Km values was observed, with (S)-propafenone displaying higher Km and Vmax values. N-DPP formation from racemic propafenone followed one-enzyme Michaelis-Menten kinetics and yielded a mean Vmax of 403 pmol x min(-1) x mg(-1) and a mean Km of 116 microM (N = 3). No stereoselectivity in propafenone N-dealkylation was observed. The influence of SSRIs and quinidine, a prototypical CYP2D6 inhbitor, on propafenone 5-hydroxylation was investigated. Quinidine was the most potent inhibitor, followed by fluoxetine, norfluoxetine, and paroxetine. Sertraline, desmethylsertraline, and fluvoxamine had only a moderate inhibitory effect, whereas citalopram displayed slight or no inhibition when racemic propafenone was used as substrate. Mean Ki values of quinidine, fluoxetine, norfluoxetine, and paroxetine were 0.13, 0.33, 0.55, and 0.54 microM, respectively (N = 3). Quinidine and paroxetine were also tested as inhibitors using the individual enantiomers, but no stereoselectivity was observed. Among the SSRIs tested, only fluvoxamine substantially inhbited propafenone N-dealkylation with a mean IC50 of 7.0 microM (N = 3). There was a more pronounced inhibitory effect of fluvoxamine on (R)-propafenone than on (S)-propafenone N-dealkylation. In conclusion, these in vitro data suggest that an in vivo interaction between propafenone and the SSRIs, fluoxetine and paroxetine, can be expected, which can lead to clinically relevant beta-blockade and an increased risk of side effects in the central nervous system. An interaction with fluvoxamine may be of importance in poor metabolizers for CYP2D6.

Algorithms↗
PubMed1992

Stereoselective interactions of (R)- and (S)-propafenone with the cardiac sodium channel.

The specific interactions of both (R)- and (S)-propafenone with the cardiac sodium channel were studied with patch clamp techniques in the whole-cell recording mode at reduced extracellular Na+ on guinea pig ventricular cells. Both (R)- and (S)-propafenone (10 microM) shifted the membrane potential required for half-maximal steady-state inactivation (E0.5) of the cardiac sodium channel to considerably more negative membrane potentials [E0.5 = -70.8 +/- 2.9 mV for controls vs. -85 +/- 3.1 mV for (R)-propafenone and -91.9 +/- 1.7 mV for (S)-propafenone]. (S)-Propafenone at a concentration of 10 microM is more effective in shifting the h infinity curve of the cardiac sodium channel. Recovery from inactivation of the cardiac sodium current is prolonged by orders of magnitude by both stereoenantiomeric forms [time constants were estimated to be 38 +/- 15 ms at -90 mV vs. 46.5 +/- 14.3 s for (R)-propafenone and 74.2 +/- 37.9 for (S)-propafenone]. Development of block occurs mainly through the inactivated channel conformation for both (R)- and (S)-propafenone. Development of block of inactivated cardiac sodium channels occurs with time constants of 15.9 +/- 3.9 s for (R)-propafenone and 19.7 +/- 7.3 s for (S)-propafenone at 10 microM. Action potential duration and possible stereoselective interaction with ion transport systems other than sodium channels may influence the block developed by either (R)- or (S)-propafenone at a given concentration and beating frequency indirectly through the membrane potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Disposition of propafenone in a poor metabolizer of CYP2D6 with Gilbert's syndrome.

Gilbert's syndrome, a genetic deficiency in bilirubin UDP-glucuronosyltransferase (UGT1A1), may dispose to increased toxicity of propafenone in poor metabolizers (PMs) of cytochrome P4502D6 because glucuronidation of propafenone is the major metabolic pathway for drug elimination in PMs. A patient with Gilbert's syndrome who is also PM participated in an interaction study with propafenone and rifampicin along with five otherwise healthy PMs. Using stable isotope techniques, the pharmacokinetics of single doses of 140 mg propafenone i.v. (unlabelled) and 300 mg propafenone p.o. (labelled) were compared between the index patient and the five healthy controls. Propafenone did not accumulate in the plasma of the index patient either before or during induction: AUC(0-infinity) of propafenone in the index patient was within the 95% confidence interval of controls; AUC(0-infinity) of propafenone glucuronide and amount of urinary excretion of propafenone glucuronide in the patient were within or even greater than the 95% confidence intervals of controls. Therefore, individuals with Gilbert's syndrome who also have a PM phenotype appear to be at no higher risk for toxicity of propafenone than otherwise healthy PMs. An indirect conclusion from these in vivo data might be that propafenone is not a substrate of the UGT1A1 isoform.

Adult↗
PubMed1987

Drug interaction between propafenone and metoprolol.

1 The steady-state plasma concentrations of metoprolol and propafenone were determined in patients being treated with one of these drugs alone and during combined treatment with both drugs. In addition, single dose studies with metoprolol, propafenone and the combination of both drugs were performed in healthy volunteers to determine the pharmacokinetics and the time course of beta-adrenoceptor blocking activity. 2 In four patients being treated with metoprolol first and subsequently with propafenone in addition steady-state levels of metoprolol increased two to five fold with simultaneous treatment with propafenone. 3 In four patients being treated with the drug combination first and thereafter with propafenone alone no changes in the steady-state levels of propafenone were observed between both treatment periods. 4 Adverse effects of the drug combination were observed in two patients (one patient experienced severe nightmares and the other left ventricular failure). 5 When single oral doses of metoprolol (50 mg) and propafenone (150 mg) and the combination of both were administered to healthy subjects, an approximately two-fold decrease of the oral clearance of metoprolol was seen when propafenone was given in addition. No conclusive changes in the pharmacokinetics of propafenone could be detected in the presence of metoprolol. 6 Duration of beta-adrenoceptor blocking activity of a single dose of metoprolol in healthy volunteers as measured by reduction of exercise-induced tachycardia increased when propafenone was given in addition. 7 The dose of metoprolol should be reduced when propafenone is given in addition.

Adult↗
PubMed1994

Voltage- and time-dependent inhibitory effects on rat aortic and porcine coronary artery contraction induced by propafenone and quinidine.

1. Class I antiarrhythmic drugs (e.g. Na+ channel blockers) such as propafenone and quinidine also inhibit voltage-gated Ca2+ and K+ channels. In the present paper the voltage- and time-dependent inhibitory effects of propafenone and quinidine were studied on depolarization-induced vascular contractions and 45Ca2+ uptake in isolated endothelium denuded rat aorta and pig left descending coronary artery. 2. Quinidine and propafenone (10(-7) M -5 x 10(-5) M) produced a concentration-dependent relaxation of the contractions induced by 80 mM KCl. Propafenone was significantly more potent (P < 0.05) than quinidine in both rat aorta and pig coronary arteries but both drugs more potent (P < 0.05) in relaxing rat aorta than pig coronary arteries. In rat aortic rings, the relaxant effects of propafenone were unaffected by pretreatment with the Na+ channel blocker, tetrodotoxin. 3. The degree of inhibition produced after prolonged exposure (40 min) to propafenone and quinidine differed as the time of depolarization with 80 mM KCl was increased. Quinidine (3 x 10(-6) M, 10(-5) M and 3 x 10(-5) M) not only produced an inhibition at the very early stage of contraction, but also a time-dependent inhibition was observed. In contrast, propafenone (10(-6) M, 3 x 10(-6) M and 10(-5) M) produced a more marked concentration-dependent early block but only a mild time-dependent inhibition.4. The voltage-dependence of propafenone- and quinidine-induced inhibition, was studied in rat aorta and coronary arteries which had been incubated in 5 or 40mM KCl Ca2+-free solution and then contracted by changing the bath solution to 100 mM KCI and 2 mM CaCl2 solution. The inhibitor effects of quinidine were significantly enhanced (P <0.05) when the preparations were preincubated in 40 mMKCl (depolarizing) solution. In contrast, the effects of propafenone were quite similar in 5 or in 40 mMKCI solution.5. Quinidine, 10-5 M, produced a greater inhibition (P<0.05) of 100 mM KCl-stimulated 45Ca2+ uptake in aortic rings preincubated in depolarizing as compared to normal solution. In contrast, the inhibition produced by 3 x 10-6 M propafenone was similar in aortic rings incubated in 5 or 40 mM KCl solution.6.It is concluded that both quinidine and propafenone inhibited vascular smooth muscle contraction which could be attributed to reduced Ca2+ entry. The voltage- and time-dependent inhibitory effects of quinidine may reflect an increased binding of the drug to Ca2+ channels at depolarized potentials.

Animals↗
PubMed1989

Stereoselective disposition and pharmacologic activity of propafenone enantiomers.

Propafenone is an antiarrhythmic drug that produces a variable degree of beta-blockade in humans and is administered as a racemate. To examine the relative contribution of the individual enantiomers to pharmacologic effects seen during treatment with propafenone, we assessed the steady-state plasma concentrations of (+)-S-propafenone and (-)-R-propafenone in seven patients who were on long-term oral therapy, and we evaluated the electrophysiologic and beta-blocking properties of both enantiomers in vitro. The metabolism of propafenone is known to be polymorphic and to cosegregate with that of debrisoquine-4-hydroxylation. Among five patients with the extensive metabolizer phenotype (EM), the ratio of the area under the plasma concentration-time curve of (+)-S-propafenone to (-)-R-propafenone was 1.73 +/- 0.15 (mean +/- SD). In the other two patients, who had the poor metabolizer phenotype (PM), the concentrations of both enantiomers were elevated but the S/R ratios were similar to those seen in patients with EM. In canine cardiac Purkinje fibers, both enantiomers produced similar frequency-dependent depression of maximum upstroke of phase 0. In contrast, the affinity of the human lymphocyte beta 2-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (Ki, 7.2 +/- 2.9 nM) than for the (-)-R-enantiomer (Ki, 571 +/- 141 nM). We conclude that during long-term oral therapy, propafenone undergoes stereoselective disposition in patients with either EM or PM. beta-Blockade during propafenone therapy is likely related to accumulation of (+)-S-propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2001

Chiral metabolism of propafenone in rat hepatic microsomes treated with two inducers.

AIM: To study the influence of inducers of drug metabolism enzyme, beta-naphthoflavone (BNF) and dexamethasone (DEX), on the stereoselective metabolism of propafenone in the rat hepatic microsomes. METHODS: Phase I metabolism of propafenone was studied using the microsomes induced by BNF and DEX and the non-induced microsome was used as the control. The enzymatic kinetics parameters of propafenone enantiomers were calculated by regress analysis of Eadie-Hofstee Plots. Propafenone enantiomer concentrations were assayed by a chiral HPLC. RESULTS: The metabolite of propafenone, N-desalkylpropafenone, was found after incubation of propafenone with the rat hepatic microsomes induced by BNF and DEX. In these two groups, the stereoselectivity favoring R(-) isomer was observed in metabolism at low substrate concentrations of racemic propafenone, but lost the stereoselectivity at high substrate concentrations. However, in control group, no stereoselectivity was observed. The enzyme kinetic parameters were: (1) K(m). CONTROL GROUP: R(-) 83+/-6, S(+) 94+/-7; BNF group: R(-) 105+/-6, S(+)128+/-14; DEX group: R(-) 86+/-11, S(+) 118+/-16; (2)V(max). CONTROL GROUP: R(-) 0.75+/-0.16, S(+) 0.72+/-0.07; BNF group: R(-) 1.04+/-0.15, S(+)1.07+/-14; DEX group: R(-) 0.93+/-0.06, S(+) 1.04+/-0.09; (3)Cl(int). CONTROL GROUP: R(-) 8.9+/-1.1, S(+) 7.6+/-0.7; BNF group: R(-) 9.9+/-0.9, S(+)8.3+/-0.7; DEX group: R(-) 10.9+/-0.8, S(+) 8.9+/-0.9. The enantiomeric differences in K(m) and Cl(int) were both significant, but not in V(max), in BNF and DEX group. Whereas enantiomeric differences in three parameters were all insignificant in control group. Furthermore, K(m) and V(max) were both significantly less than those in BNF or DEX group. In the rat liver microsome induced by DEX, nimodipine (NDP) decreased the stereoselectivity in propafenone metabolism at low substrate concentration. The inhibition of NDP on the metabolism of propafenone was stereoselective with R(-)-isomer being impaired more than S(+)-isomer. The inhibition constant (Ki) of S(+)- and R(-)-propafenone, calculated from Dixon plots, was 15.4 and 8.6 mg x L(-1), respectively. CONCLUSION: CYP1A subfamily(induced by BNF) and CYP3A4 (induced by DEX) have pronounced contribution to propafenone N-desalkylation which exhibited stereoselectivity depending on substrate concentration. The molecular base for this phenomenon is the stereoselectivity in affinity of substrate to the enzyme activity centers instead of at the catalyzing sites.

Animals↗
PubMed1997

Oral propafenone to convert recent-onset atrial fibrillation in patients with and without underlying heart disease. A randomized, controlled trial.

BACKGROUND: The effectiveness of oral propafenone in converting recent-onset atrial fibrillation to sinus rhythm has been established by controlled trials. However, it is not clear whether the effectiveness of propafenone is affected by the presence or absence of underlying heart disease. OBJECTIVES: To investigate the safety and effectiveness of oral propafenone and the role of underlying heart disease. DESIGN: Randomized, single-blind, controlled study. SETTING: 3 teaching hospitals. PATIENTS: 240 hospitalized patients with recent-onset atrial fibrillation. INTERVENTION: Propafenone (one 500-mg oral dose) or placebo. MEASUREMENTS: Conversion rates at 3 and 8 hours. RESULTS: Propafenone was more effective than placebo for converting atrial fibrillation to sinus rhythm at 3 hours: Fifty-four of 119 patients (45%) receiving propafenone and 22 of 121 patients (18%) receiving placebo had conversion (P < 0.001). It was also more effective at 8 hours: Ninety-one of 119 patients (76%) receiving propafenone and 45 of 121 patients (37%) receiving placebo had conversion (P < 0.001). Subgroup analysis showed that among patients without heart disease, 78% of those receiving propafenone and 56% of those receiving placebo converted to sinus rhythm within 8 hours (P = 0.02). In those with hypertension, the rate was 70% for those receiving propafenone and 27% for those receiving placebo (P < 0.001); in patients with structural heart disease, the rate was 81% for those receiving propafenone and 17% for those receiving placebo (P < 0.001). CONCLUSIONS: Oral loading of propafenone was more effective than placebo for conversion to sinus rhythm within 8 hours and had a favorable safety profile. The rate of spontaneous conversion to sinus rhythm was higher in patients without structural heart disease; this finding has important implications for the assessment of drug effectiveness in recent-onset atrial fibrillation.

Administration, Oral↗
PubMed1997

Intravenous Propafenone for Conversion of Atrial Fibrillation or Flutter to Sinus Rhythm: A Randomized, Placebo-controlled, Crossover Study.

BACKGROUND: Propafenone has been claimed to be effective in converting atrial fibrillation and flutter to sinus rhythm; however, controlled clinical trials have reported variable results, and data about the safety of propafenone in the setting of heart failure are lacking. The aim of the present study was to evaluate the efficacy and safety of intravenous propafenone in converting atrial fibrillation and flutter to sinus rhythm. METHODS: Sixty patients with acute (<72 h) or chronic atrial fibrillation or flutter were included in a randomized, placebo-controlled, conditional cross-over study. Twenty eight patients, of whom 12 were in New York Heart Association class III and IV, had heart failure. Patients received intravenous propafenone (2 mg/kg in 10 minutes) and placebo subsequently at 1 hour intervals if sinus rhythm was not achieved. The patients' rhythms were continuously monitored for 1 hour and a 12-lead electrocardiogram, a 1-minute continuous rhythm strip and vital signs were recorded at baseline and at 15, 30, 45, and 60 minutes after the administration of each drug. RESULTS: Twenty of teh 59 patients (34%) treated with propafenone converted to sinus rhythm, while only 4 of the 50 patients (8%) treated with placebo converted (P <.001). Propafenone was more effective in patients with acute (<72 h) atrial fibrillation (64.5%). The conversion rate with propafenone was not significantly different from placebo in patients with atrial flutter and chronic atrial fibrillation (>72 h). Propafenone significantly decreased (P <.005 vs placebo) mean ventricular rate in nonresponders with a baseline heart rate of more than 100 beats/min. No clinically significant adverse effect occurred. CONCLUSIONS: We conclude that intravenous propafenone treatment is effective for converting acute atrial fibrillation; however, it seems unlikely to be beneficial in atrial flutter and chronic atrial fibrillation. Propafenone decreases ventricular rate in nonresponders, and a single dose of propafenone is relatively safe even in moderate-to-severe heart failure.

Journal Article↗
PubMedDate not supplied

Influence of hepatic dysfunction on the pharmacokinetics of propafenone.

Hepatic metabolism is the primary process of elimination of propafenone. It therefore is important to understand the effect of altered liver function on the disposition and elimination kinetics of this drug. Patients with abnormal liver function probably will require treatment with propafenone for cardiac arrhythmias; an understanding of the relationship between liver function and the pharmacokinetics of propafenone will provide a rational basis for optimal dosage adjustments in these individuals. Our results demonstrate that both systemic clearance and bioavailability of propafenone are sensitive to variability in liver function. The bioavailability of propafenone is inversely related to the clearance of indocyanine green (ICG), whereas a direct relationship exists between systemic clearance of propafenone and ICG clearance. Comparisons of clinical parameters with the propafenone data yielded interesting results. An overall clinical grading of severity of liver disease based on the presence or absence of portal hypertension (i.e., varices and/or splenomegaly), prior encephalopathy, and ascites did not correlate well with propafenone results. However, albumin, total bilirubin, serum glutamic oxaloacetic transaminase (SGOT) concentrations and prothrombin time values correlated strongly with the overall results. No definite relationships with subjects' age; weight; and hemoglobin, alkaline phosphatase, lactic acid dehydrogenose, cholesterol, blood urea nitrogen, or creatinine levels were detected. These results demonstrate that moderate to severe liver disease significantly affects the absorption and disposition of propafenone. In patients with cirrhosis, and presumably other forms of hepatic dysfunction, careful adjustments of propafenone doses are needed to optimize therapy.

Administration, Oral↗
PubMed1991

Serum digoxin levels related to plasma propafenone levels during concomitant treatment.

Nine patients with supraventricular rhythm disorders were treated during 5-day periods with different oral doses (300, 450, 600, and 900 mg daily) of propafenone concomitantly to long-term digoxin treatment. A poor correlation (r = .398; P less than .05) was obtained when the difference between the mean digoxin serum level (calculated with the Cmin data determined each of the 5 days) observed during a given propafenone dose and the mean digoxin serum level observed before propafenone treatment, was correlated with the dose of propafenone; but an evident correlation (r = .778; P less than .01) was found when the difference in digoxin level was correlated with the plasma propafenone concentration. The propafenone effect of increasing digoxin blood levels was thus concluded to be poorly dose dependent but strongly concentration dependent. The association of propafenone to a long-term digoxin treatment can be considered with a low risk of toxicity when plasma propafenone concentration does not exceed about 1000 ng/mL. Propafenone plasma levels are unpredictable in view of their wide interindividual variation for a given dose, so their measurement is advised to detect high levels and consequently to prevent a rise in digoxin serum concentrations with the possibility of toxicity. In clinical practice, when propafenone concentration determinations are not readily available, digoxin serum levels at least have to be carefully monitored.

Administration, Oral↗
PubMed1989

In vitro protein binding of propafenone in normal and uraemic human sera.

The protein binding of propafenone, a Class I antiarrhythmic agent, was studied in vitro using a selective and sensitive electron-capture detection gas-liquid capillary chromatographic assay method developed in our laboratory. The concentration-dependency of the serum protein binding of propafenone was confirmed in vitro by equilibrium dialysis, using serum obtained from healthy human subjects and patients with chronic renal failure. In normal serum the unbound fraction of propafenone was 0.027 at a propafenone concentration of 0.25 microgram.ml-1, 0.041 within the therapeutic concentration range (0.5-2 micrograms.ml-1), 0.138 at a propafenone concentration of 25 micrograms.ml-1, and 0.187 when the propafenone concentration was increased to 100 micrograms.ml-1. There was no evidence of significant concentration-dependent changes in unbound fraction within the propafenone concentration range of 0.5-1.5 micrograms.ml-1. However, concentration-dependent binding was demonstrated at concentrations greater than 1.5 micrograms.ml-1. A high-affinity, low-capacity binding site (K1 = 6.53 x 10(5) l.mol-1; n1P1 = 1.73 x 10(-4) mol.l-1) and a low-affinity, high-capacity binding site (K2 = 8.77 x 10(3) l.mol-1; n2P2 = 8.57 x 10(-3) mol. x l-1) were identified. In pooled uraemic serum the unbound fraction of propafenone was approximately 50% of that of normal serum throughout the concentration range studied (1-5 micrograms.ml-1). In sera from patients with chronic renal failure the increase in propafenone binding ratio or the decrease in unbound fraction was associated with the increase in alpha 1-acid glycoprotein concentrations, and there was a correlation (r = 0.8302) between alpha 1-acid glycoprotein concentration and the propafenone binding ratio.

Adult↗
PubMed1985

Comparison of propafenone and disopyramide for treatment of chronic ventricular arrhythmias: placebo-controlled, double-blind, randomized crossover study.

In a double blind, placebo-controlled study, the efficacy of propafenone, a new antiarrhythmic drug was compared to that of disopyramide. Sixteen patients with frequent and complex premature ventricular contractions (PVCs) were studied by serial 24-hour ambulatory monitoring, while they were receiving propafenone, 300 mg, and disopyramide, 200 mg, both every 8 hours. A reduction in the mean frequency of PVCs per hour, in comparison to the placebo period, from 574 +/- 535 to 100 +/- 130, was observed after propafenone (p less than 0.005) and from 629 +/- 455 to 231 +/- 280 after disopyramide (p less than 0.008). A greater than 70% reduction in PVCs in comparison to placebo was observed in 11 of 14 after propafenone and 9 of 15 after disopyramide (NS). A greater than or equal to 90% reduction in PVCs was observed in 9 of 16 with propafenone and in 4 of 15 with disopyramide (p less than 0.05). The suppression of complex PVCs (repetitive, polymorphic, or more than 5/min with bigeminism) was observed in 11 of 14 after propafenone and in 9 of 14 after disopyramide. The abolition of nonsustained ventricular tachycardia was observed in 6 of 6 and 3 of 5, respectively, after propafenone and disopyramide (p less than 0.05). A lower incidence of side effects, 4 of 16 vs 8 of 16, was observed during propafenone than during disopyramide treatment. We conclude that propafenone, in a dose of 900 mg daily, is more effective than disopyramide, in a dose of 600 mg daily, in the treatment of frequent and complex PVCs and nonsustained ventricular tachycardias. Propafenone also showed a lower incidence of side effects.

Adult↗
PubMed1993

Usefulness of propafenone for supraventricular arrhythmias in infants and children.

The relation between propafenone dose, serum level, electrocardiographic parameters, antiarrhythmic drug efficacy and adverse effects was studied in 47 children with symptomatic supraventricular arrhythmias aged 1 day to 10.3 years (median 2.2 months) with a mean follow-up of 14.3 months. Propafenone trough serum levels were measured using gas chromatography. Oral propafenone (mean dose 353 mg/m2/day) was effective in 41 of the 47 patients (87.2%). Serum levels did not differ between patients responding and not responding to propafenone (0.45 +/- 0.40 vs 0.36 +/- 0.41 mg/liter). PR interval and QRS complex duration increased more significantly with propafenone dose increments (p < 0.001), than with propafenone serum levels (p < 0.05). At successful treatment PR interval and QRS complex were prolonged by a mean of 19.2 and 20.5% compared with pretreatment status. Five patients exhibited unexpected marked QRS complex prolongation (50 to 200%) despite low propafenone dosage (< 300 mg/m2/day) and level ranging from 0.05 to 1.33 mg/liter. Three patients (6.1%) were suspected of being "poor" metabolizers of propafenone. Mild chronic elevation of serum liver enzymes was observed in 5 patients treated with a larger dose (mean 448 mg/m2/day, p < 0.001). No proarrhythmia was noted on serial Holter monitors. One patient with Wolff-Parkinson-White syndrome and a normal heart had cardiac arrest after aspiration. Serial monitoring of PR interval and QRS complex duration was more useful for proper dosage adjustment than propafenone serum levels. Serum liver enzymes should be closely monitored when using higher propafenone doses. Malignant proarrhythmia could not be excluded in the 1 patient with cardiac arrest.

Administration, Oral↗
PubMed1996

Effects of oral propafenone administration before electrical cardioversion of chronic atrial fibrillation: a placebo-controlled study.

OBJECTIVES: Our aim was to evaluate the benefits and risks of administering propafenone before electrical defibrillation for chronic atrial fibrillation. BACKGROUND: In this context, an antiarrhythmic drug-although potentially useful in preventing early recurrence of arrhythmia-could adversely affect the defibrillation threshold and reduce the cardioversion success rate. METHODS: We randomly assigned 100 patients with chronic atrial fibrillation to oral treatment with either placebo (51 patients) or 750 mg/day of propafenone (49 patients) for 48 h before administration of direct current shock. After successful cardioversion, all patients received propafenone therapy and were followed up for 48 h. RESULTS: Before defibrillation, three patients in the propafenone group (6.1%) had reversion to sinus rhythm and one had sustained ventricular tachycardia. Shock efficacy (82.4% vs. 84.4%) and the cumulative effective energy (395 +/- 258 vs. 421 +/- 236 J) were not different between the placebo and propafenone groups. In the propafenone group, 11 patients had their arrhythmia transformed into atrial flutter and required a lower energy level for arrhythmia conversion than did the other patients with continued atrial fibrillation (245 +/- 197 vs. 493 +/- 215 J, p < 0.01); the latter patients showed a trend (p < 0.10) toward higher energy requirements than that of patients who received placebo. The incidence of asymptomatic bradyarrhythmias was higher in the propafenone group (28.9% vs. 7.1%, p < 0.02), but more patients who received placebo had early recurrence of atrial fibrillation (16.7% vs. 0%, p < 0.02). Two days after cardioversion, more patients given propafenone (73.5% vs. 52.9%, p < 0.05) were discharged from the hospital with sinus rhythm. During the in-hospital stay, propafenone was withdrawn from six patients (6.6%) because of side effects. CONCLUSIONS: Propafenone, given before electrical cardioversion for chronic atrial fibrillation does not affect the mean defibrillation threshold or the rate of successful arrhythmia conversion. It decreases the recurrence of atrial fibrillation early after shock, thus allowing more patients to be discharged from the hospital with sinus rhythm.

Administration, Oral↗
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↗
PubMed2000

Control of paroxysmal atrial fibrillation recurrence using combined administration of propafenone and quinidine.

The frequent recurrence of paroxysmal atrial fibrillation (PAF) despite the use of standard antiarrhythmic agents prompted the use of new therapeutic approaches. There are few data on systematic assessment of PAF control with stepwise dose escalation and the use of a drug combination. Low-dose quinidine may promote the efficacy of propafenone by inhibiting its degradation through the cytochrome P450 pathway (CYP2D6). We prescribed propafenone 300 to 450 mg/day to 60 patients with PAF for 8 weeks, and 62% were symptomatically controlled. The 19 refractory patients were randomized in a double-blinded fashion to receive either a higher dose of propafenone (450 to 675 mg/day) or the standard dose of propafenone with low-dose quinidine 150 mg/day, each for an 8-week study period, and subsequently crossed over to the alternative treatment. The resulting serum propafenone concentrations were 259 +/- 208 and 336 +/- 237 mg/day (p >0.5), respectively. Both treatment arms prolonged the time to the first symptomatic atrial fibrillation (AF) recurrence and the interval between attacks, and AF was controlled in 37% of patients. However, the higher dose of propafenone was associated with gastrointestinal side effects not present with the low-dose quinidine combination. Of the 10 refractory patients, 7 were further controlled with a standard dose of propafenone plus quinidine (600 mg/day). Overall, control of PAF was achieved in 85% of patients at the end of 8 months; adverse effects necessitating withdrawal were observed in 6%, and uncontrolled AF in 5% of patients. There was no difference in the mean AF rate during recurrences in all phases, and ventricular proarrhythmia was not seen. This study documents the role of stepwise antiarrhythmic treatment of PAF. The use of a standard dose of propafenone, followed by low-dose quinidine combination to reduce propafenone degradation, and the combined standard dose of propafenone and quinidine may be used to maximize efficacy and tolerability.

Adolescent↗
PubMed1984

European experience with the antiarrhythmic efficacy of propafenone for supraventricular and ventricular arrhythmias.

Seventy-one patients (mean age 53 years) were treated with oral propafenone, 900 mg/day, for a mean of 6.6 months. A large spectrum of arrhythmias was encountered, and particular attention was paid to their relation with the autonomic nervous system. Drug efficacy was graded from 1 (no effect) to 5 (complete control) according to the clinical result and Holter recording. This method permitted comparisons to be made between propafenone and 3 other antiarrhythmic agents: quinidine, beta-blockers and amiodarone. Among the 32 patients with supraventricular arrhythmias, 9 cases of vagally dependent atrial flutter and fibrillation were less sensitive to propafenone (mean effect 1.4) than to quinidine (mean effect 2.0) or amiodarone (mean effect 2.3). However, 8 cases of adrenergically dependent atrial tachycardia and fibrillation were more sensitive to propafenone (mean effect 4.1) than to beta blockers (3.0) or amiodarone (mean effect 3.5). In 12 cases of miscellaneous atrial arrhythmias the response to propafenone was intermediate. However, 3 patients with resistant junctional tachycardia were improved with propafenone. Among 42 ventricular arrhythmias, 5 patients with extrasystole who were responsive to quinidine (mean effect 3.8) were also improved with propafenone (mean effect 4.6). Propafenone (mean effect 4.1) was much more effective than quinidine (mean effect 2.4) in treating 8 cases of idiopathic benign ventricular tachycardia and even more successful in treating 13 cases of more severe arrhythmias in diseased hearts (propafenone's mean effect 4.1, quinidine's mean effect 1.9 and amiodarone's mean effect 1.9). Propafenone was less effective (mean effect 3.3) than amiodarone (mean effect 4.0) in 4 cases of severe, adrenergically dependent idiopathic ventricular tachycardia (VT).(ABSTRACT TRUNCATED AT 250 WORDS)

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