Drugs

, Volume 34, Issue 6, pp 617–647 | Cite as

Propafenone

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use in the Treatment of Arrhythmias
  • Dean W. G. Harron
  • Rex N. Brogden
Drug Evaluation

Summary

Synopsis

Propafenone1 is a Class I antiarrhythmic agent with weak β-adrenoceptor antagonist activity which can be given both intravenously and orally. Dosage must be individualised because of dose-dependent pharmacokinetics, a wide range of clinically effective plasma concentrations (64 to 3271 µg/L) after comparable doses, the presence of an active metabolite (5-hydroxy-propafenone) and genetically determined metabolic oxidation. In non-comparative studies propafenone 450 and 900 mg/day orally significantly suppressed premature ventricular complexes and couplets in 96% and 75% of patients, respectively, and abolished ventricular tachycardia in 75% of patients. Efficacy was confirmed in placebo-controlled studies in which propafenone 300 to 900mg daily suppressed premature ventricular complexes (> 80%) in 77% of patients; 87% of patients had significant reductions in couplets and abolition of ventricular tachycardia. In patients with ventricular arrhythmias refractory to other antiarrhythmic agents, propafenone 450 to 1200 mg/day suppressed arrhythmias in 63% of patients (in long term therapy 66%). Electrically induced arrhythmias were prevented by intravenously administered propafenone in 12 to 23% of patients. However, long term oral therapy was effective in 77% of patients selected using programmed electrical stimulation. Propafenone was also effective in suppressing atrial and AV nodal/junctional re-entrant tachycardias and Wolff-Parkinson-White tachycardias involving accessory pathways. A limited number of comparisons with other antiarrhythmic drugs indicate that the antiarrhythmic efficacy of propafenone is superior or similar to that of quinidine, disopyramide and tocainide, and comparable to that of lignocaine (lidocaine), flecainide and metoprolol against ventricular arrhythmias and a smaller number of atrial arrhythmias.

Cardiovascular side effects indicate a proarrhythmic effect similar to that with other Class I drugs, occasional precipitation of congestive heart failure and conduction abnormalities; the latter two occur more often in patients with underlying ventricular dysfunction. Non-cardiovascular side effects (neurological, gastrointestinal) are well tolerated and generally resolve with continued therapy or dosage reduction. Thus, propafenone is an effective antiarrhythmic agent, and is a useful addition to currently available drugs, although further studies will be required to determine clearly its place in therapy compared with more established antiarrhythmic drugs.

Pharmacodynamic Studies

In isolated tissues propafenone caused a dose-dependent decrease in the maximum rate of depolarisation and in the overshoot of the action potential; His-Purkinje (H-V) conduction is slowed and QRS widened in sinus rhythm, indicating Class Ic antiarrhythmic activity. Propafenone also exhibits weak β-adrenoceptor antagonist activity and to a lesser extent Class III and IV activity. In intact animals, the 5-hydroxy metabolite of propafenone (more potent antiarrhythmic) caused more marked prolongation of conduction time than the parent drug. In healthy volunteers, PR interval increased significantly with a small change in QRS duration. In patients with ventricular arrhythmias, propafenone consistently increased the atrioventricular nodal conduction time (A-H) and H-V intervals, the effective refractory period in atria and ventricles, the PR interval (16 to 28%) and the QRS duration (18 to 23%). No effect was seen on sinus cycle length. In patients with underlying conduction abnormalities, conduction slowing with propafenone was more marked indicating that it should be used with caution in patients with sinus node dysfunction. In patients with Wolff-Parkinson-White (WPW) syndrome, propafenone reduces conduction and increases refractoriness in the accessory pathway. Mean arterial pressure and heart rate were unchanged in patients, although intracardiac pressures were slightly increased resulting in depression of cardiac index; pulmonary and systemic vascular resistances were increased. In patients with impaired left ventricular function (ejection fraction less than 50%), a significant reduction in ejection fraction occurred, while in those with ejection fraction greater than 50% no change occurred.

Pharmacokinetic Studies

Propafenone can be administered both intravenously and orally. The pharmacokinetic properties of propafenone differ in extensive and poor metabolisers (defined by their ability to metabolise debrisoquine). It is well absorbed with peak plasma concentration occurring at 2 to 3 hours after administration. In extensive metabolisers a dose-dependent increase in peak plasma concentration and area under the curve occurs with increasing dose [10-fold increase in peak plasma concentration occurred with a 3-fold (300 to 900 mg/day) increase in oral dose]. Steady-state plasma concentrations on 900 mg/day ranged from 482 to 1812 µg/L (mean 1008 µg/L). Bioavailability for the 150mg tablets was 4.8% and for the 300mg tablet 12% indicating extensive presystemic metabolism. The pharmacokinetics following intravenous administration are best represented by a 2-compartment model. Mean plasma elimination half-life following intravenous administration is 2.8 hours in healthy volunteers, 5 hours in patients and 16.8 hours in poor metabolisers (depends on oxidative status). In poor metabolisers, however, plasma concentrations rose proportionally with dose and half-life is about 17 hours. During long term oral administration half-life was 6.2 hours in extensive metabolisers although there was large intersubject variability and values ranged from 2.4 to 11.8 hours. Mean total body clearance was 0.68 L/h/kg. Volume of distribution is 1.1 L/kg in healthy volunteers and 3.6 L/kg in patients. Protein binding ranges from 77 to 89%; propafenone binding to α1-acid glycoprotein is more marked than that with lignocaine, verapamil and propranolol.

The major metabolites are conjugates of 5-hydroxy-propafenone and N-depropylpropafenone. Less than 1% of propafenone is excreted unchanged in urine. The 5-hydroxy metabolite has been reported to have greater antiarrhythmic efficacy than propafenone in extensive metabolisers, but since it achieves concentration in plasma about one-fifth those of the parent drug, its therapeutic role is not clear. Lower doses of propafenone are required in elderly patients. Under steady-state conditions the plasma concentration of propafenone that suppressed premature ventricular contractions by over 70% has ranged between 42 and 1700 µg/L in different studies. Thus, there is a need for individualised dosage.

Therapeutic Trials

Propafenone administered orally and intravenously has been evaluated for suppression of premature ventricular complexes, couplets and ventricular tachycardia in non-comparative and a limited number of double-blind comparative trials. Results in non-comparative studies indicate that propafenone 450 to 900 mg/day significantly suppressed premature ventricular complexes in 96% of patients and couplets in 75% of patients; ventricular tachycardia was abolished in virtually 100% of patients. Dose-dependent suppression of ventricular arrhythmias over the range of 450 to 900mg daily occurred in one study, and during a 12-month follow-up the frequency of arrhythmias decreased by over 80% in 10 of 13 patients. In placebo-controlled, crossover studies, the frequency of premature ventricular complexes was reduced by over 80% in 77% of patients, with 87% of patients having significant reductions in couplets and abolition of ventricular tachycardia. If the patients were ‘selected’ on the basis of their response to an initial screening with intravenous or oral propafenone, generally such patients were well controlled with significant suppression of arrhythmias. In patients with drug refractory ventricular arrhythmias propafenone 450 to 1200 mg/day was effective in suppressing arrhythmias in 63% of patients. In long term follow-ups (12 to 16 months), effective control was maintained in 66% of patients. In long term studies in patients selected on the basis of the ability to prevent arrhythmias induced by using programmed electrical stimulation, 77% of patients were either symptom-free or had no arrhythmias. Propafenone administered intravenously and orally was effective in about 50 to 70% of small numbers of patients with atrial tachycardias, AV nodal/junction re-entrant tachycardias and WPW tachycardias involving accessory pathways; during long term follow-up with propafenone 85% of patients were improved or asymptomatic.

Comparisons with other antiarrhythmic agents demonstrated that propafenone was superior or comparable in efficacy to quinidine and disopyramide and comparable to lignocaine, tocainide, mexiletine, flecainide and metoprolol in suppressing ventricular and a small number of supraventricular arrhythmias. The combination of propafenone and a β-adrenoceptor antagonist significantly improved efficacy relative to either drug alone in ventricular arrhythmias.

Side Effects

Cardiovascular side effects associated with propafenone include proarrhythmic effects in about 12% of patients as well as less frequent instances of sudden death, bundle branch block, AV block and induction of congestive heart failure. Conduction abnormalities and congestive heart failure with propafenone occur more often in patients with underlying dysfunction. Non-cardiovascular side effects (neurological and gastrointestinal mainly) are usually well tolerated and often resolve with continued therapy or dosage reduction. Such effects include dizziness, visual disturbances, metallic taste, nausea and constipation, and less commonly abnormal liver function tests, leucopenia and rash. Overall, only a small proportion (< 3%) of patients discontinued studies due to side effects.

Interactions

As propafenone can cause conduction abnormalities and may have negative inotropic effects in patients with underlying ventricular dysfunction, care must be taken when administering other cardioactive drugs with similar properties. The extensive metabolism, high protein binding and dose-dependent kinetics of propafenone suggest its potential for drug interactions. Interactions that have been reported include inhibition of debrisoquine metabolism by propafenone and an increase in plasma digoxin concentration not associated with digitalis toxicity. A possible interaction between propafenone and digoxin in patients receiving low dose diuretic therapy was suggested. Whole body potassium and magnesium depletion may have existed, thus possibly contributing to proarrhythmic events. β-Adrenoceptor antagonists combined with propafenone increased antiarrhythmic efficacy.

Dosage and Administration

Propafenone dosage should be adjusted to each patient’s needs. Selection of patients on the basis of the response to an initial oral or intravenous dose of propafenone and/or based on the ability of propafenone to prevent arrhythmias induced by programmed electrical stimulation prior to long term therapy improves the response rate. Care must be taken in patients with already compromised left ventricular function or conduction dysfunction as propafenone may potentiate these. In both ventricular and supraventricular arrhythmias intravenous administration of 1 to 2.5 mg/kg and oral administration of 300 to 900 mg/day (divided dose) is effective.

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References

  1. Aguglia F, Gnecchi M, De Marzio P. Lidocaine, mexiletine and propafenone in the treatment of arrhythmias complicating myocardial infarction: a case report. International Journal of Cardiology 7: 303–306, 1985PubMedGoogle Scholar
  2. Arboix M, Puigdemont A, Moya A, Cinca J. Pharmacokinetic intravenous propafenone in patients with episodes of paroxysmal supraventricular tachycardia. Methods and Findings in Experimental and Clinical Pharmacology 7: 435–438, 1985PubMedGoogle Scholar
  3. Axelson JE, Chan GL-Y, Kirsten EB, Mason WD, Lanman RC, et al. Food increases the bioavailability of propafenone. British Journal of Clinical Pharmacology 23: 735–741, 1987PubMedGoogle Scholar
  4. Baker BJ, Dinh H, Kroskey D, de Soyza NDB, Murphy ML, et al. Effect of propafenone on left ventricular ejection fraction. American Journal of Cardiology 54: 20D–22D, 1984PubMedGoogle Scholar
  5. Baker BJ, Dinh H, Murphy ML, Franciosa JA. Safety of propafenone in digitalised patients with left ventricular dysfunction. Abstract 679. Circulation 72(Suppl. III): 170, 1985Google Scholar
  6. Beck OA, Hochrein H. Kombinierte Anwendung von Propafenon und Lidoflazin bei chronischem Vorhofflimmern un-flattern. Deutsche Medizinische Wochenschrift 105: 1243–1246, 1980PubMedGoogle Scholar
  7. Beck OA, Ihle C, Hochrein H. Kombinierte Anwendung von Propafenon und Propranolol bei extrasystolischen Herzrhythmusstörungen. Deutsche Medizinische Wochenschrift 107: 579–583, 1982PubMedGoogle Scholar
  8. Beck OA, Lehmann HV, Hochrein H. Propafenone and lidoflazine in chronic atrial fibrillation and flutter: a comparative study. Deutsche Medizinische Wochenschrift 103: 1068–1072, 1978PubMedGoogle Scholar
  9. Belz GG, Matthews J, Doering W, Belz G. Digoxin — antiarrhythmias: pharmacodynamic and pharmacokinetic studies with quinidine, propafenone and verapamil. Clinical Pharmacology and Therapeutics 31: 202–203, 1982Google Scholar
  10. Bergemann Von N, Huneke H, Kaumeier HS, Kehrhahn OH. Propafenon und Alkohol: Einfluss dieser Kombination auf das Leistungsverhalten und die subjektive Befindlichkeit bei gesunden Freiwilligen. Arzneimittel-Forschung 33: 1598–1602, 1983PubMedGoogle Scholar
  11. Blanke H, Aschbrenner B, Karsch KR, Kreuzer H. Plasmaspiegel-Wirkungs-Beziehung und Organverteilung von Propafenon. Deutsche Medizinische Wochenschrift 104: 587–591, 1979PubMedGoogle Scholar
  12. Bounhoure JP, Sabot G, Cassagneau B, Calazel J, Dechandol AM. Étude de la propafenone orale dans les arythmies auriculaires rebelles. Annales de Cardiologie et D’Angeiologie 34: 485–488, 1985PubMedGoogle Scholar
  13. Breithardt G, Borggrefe M, Wiebringhaus E, Seipel L. Effect of propafenone in the Wolff-Parkinson-White syndrome: electrophysiologic findings and long-term follow-up. American Journal of Cardiology 54: 29D–39D, 1984PubMedGoogle Scholar
  14. Brode E, Sachse R, Hoffman HD. Untersuchungen zur Analytik von Propafenon mittels interner Analogstandardisierung. Arzneimittel-Forschung 32: 1–6, 1982PubMedGoogle Scholar
  15. Brodsky MA, Allen BJ. Ventricular tachycardia in patients with impaired left ventricular function: the role of propafenone. Clinical Progress in Electrophysiology and Pacing 4: 546–552, 1986Google Scholar
  16. Brodsky MA, Allen BJ, Abate D, Henry WL. Propafenone therapy for ventricular tachycardia in the setting of congestive heart failure. American Heart Journal 110: 794–799, 1985PubMedGoogle Scholar
  17. Brown NL, Worcel M, Zanitato J. β-Adrenoceptor antagonist activity of propafenone in the anaesthetised dog. British Journal of Pharmacology 88: 289P, 1986Google Scholar
  18. Budde T, Beyer M, Breithardt G, Passlick J, Grabensee B. Therapie der schweren Propafenonintoxikation-Eliminationsversuch mittels Hämoperfusion. Zeitschrift für Kardiologie 75: 764–769, 1986PubMedGoogle Scholar
  19. Buss J, Neuss H, Bilgin Y, Schlepper M. Malignant ventricular tachyarrhythmias in association with propafenone treatment. European Heart Journal 6: 424–428, 1985PubMedGoogle Scholar
  20. Cazzola M, Lobefalo G, Rosatti F, Brita G, Delgaudio F, et al. Respiratory effects of propafenone in asthmatic volunteers. Drugs Under Experimental and Clinical Research X(6): 405–411, 1984Google Scholar
  21. Cheriex EC, Krijne R, Brugada P, Heymeriks J, Wellens HJJ. Lack of clinically significant beta-blocking effect of propafenone. European Heart Journal 8: 53, 1987PubMedGoogle Scholar
  22. Chilson DA, Heger JJ, Zipes DP, Browne KF, Prystowsky EN. Electrophysiological effects and clinical efficacy of oral propafenone therapy in patients with ventricular tachycardia. Journal of the American College of Cardiology 5: 1407–1413, 1985PubMedGoogle Scholar
  23. Clémenty J, Coste P, Metzinger M. Étude de l’efficacité et de la tolérance de la propafénone dans le traitement des troubles du rythme cardiaque. Anales de Cardiologie e d’Angeilogie 36: 207–212, 1987Google Scholar
  24. Cointe R, Levys S, Metge M, Vrancea F, Labrunie P, et al. Traitement des tachycardias ventriculaires recidivantes par la propafenone orale. Archives des Maladies du Coeur et des Vaisseaux 78: 59–62, 1985PubMedGoogle Scholar
  25. Connolly SJ, Kates RE, Lebsack CS, Harrison DC, Winkle RA. Clinical pharmacology of propafenone. Circulation 68: 589–596, 1983bPubMedGoogle Scholar
  26. Connolly ST, Kates RE, Lebsack CS, Echt DS, Mason JW, et al. Clinical efficacy and electrophysiology of oral propafenone for ventricular tachycardia. American Journal of Cardiology 52: 1208–1213, 1983aPubMedGoogle Scholar
  27. Connolly SJ, Lebsack C, Winkle RA, Kates RE. Propafenone disposition kinetics in arrhythmia patients. Clinical Pharmacology and Therapeutics 36: 163–168, 1984PubMedGoogle Scholar
  28. Coumel P, Leclercq JF, Assayag P. European experience with the antiarrhythmic efficacy of propafenone for supraventricular and ventricular arrhythmias. American Journal of Cardiology 54: 60D–66D, 1984PubMedGoogle Scholar
  29. de Soyza N, Terry L, Murphy ML, Thompson CH, Doherty JE, et al. Effect of propafenone in patients with stable ventricular arrhythmias. American Heart Journal 108: 285–289, 1984PubMedGoogle Scholar
  30. Dinh H, Murphy ML, Baker BJ, de Soyza N. Propafenone: a new antiarrhythmic for treatment of chronic ventricular arrhythmias. Clinical Progress in Electrophysiology and Pacing 4: 535–545, 1986Google Scholar
  31. Dinh H, Murphy ML, Baker BJ, de Soyza N, Franciosa JA. Efficacy of propafenone compared with quinidine in chronic ventricular arrhythmias. American Journal of Cardiology 55: 1520–1524, 1985PubMedGoogle Scholar
  32. Doherty JU, Harvey L, Waxman HL, Kienze MG, Cassidy DM, et al. Limited role of intravenous propafenone hydrochloride in the treatment of sustained ventricular tachycardia: electrophysiologic effects and results of programmed electrical stimulation. Journal of the American College of Cardiology 4: 378–381, 1984PubMedGoogle Scholar
  33. Dukes ID, Vaughan Williams EM. The multiple modes of action of propafenone. European Heart Journal 5: 115–125, 1984PubMedGoogle Scholar
  34. Farre J, Grande A, Albo PS, Hermandez SH, Rabago P, et al. The anterograde effective refractory period of the accessory pathway as a partial determinant of the response of the bypass tract to antiarrhythmic drugs. Abstract. Journal of the American College of Cardiology 5: P399, 1985Google Scholar
  35. Farre J, Grande A, Hernandez R, Rabago P. Effects of propafenone on accessory pathways and circus movement tachycardias. Abstract. European Heart Journal 5(Suppl. 1): 216, 1984Google Scholar
  36. Fauchier JP, Cosnay P, Rouesnel P, Moquet B, Huguet R, et al. Etude comparative de l’efficacité de la propafénone et de l’amiodarone dans le traitement des extrasystoles ventriculares chroniques. Archives des Maladies du Coeur et des Vaisseaux 79: 1495–1505, 1986PubMedGoogle Scholar
  37. Finzi A, Massari FM, Pagnoni F, Ambrosini F, Runza M, et al. Haemodynamic effects of intravenous amiodarone and propafenone during antiarrhythmic treatment of acute myocardial infarction. Abstract. European Heart Journal 5(Suppl. 1): 283, 1984Google Scholar
  38. Frabetti L, Marchesini B, Capucci A, Cavallini C, Gubelli S, et al. Anti-arrhythmic efficacy of propafenone: evaluation of effective plasma levels following single and multiple doses. European Journal of Clinical Pharmacology 30: 665–671, 1986PubMedGoogle Scholar
  39. Frank R, Tonet JL, Lacroix H, Fortaine G. Electrophysiological effects and efficacy of oral propafenone in Wolff-Parkinson-White Syndrome. Abstract. Circulation 70(II): 442, 1984Google Scholar
  40. Furlanello F, Disertori M, Vergara G, Guarnerio M, Dal Forno P, et al. Clinical evaluation of new antiarrhythmic agents: experiences with propafenone. International Journal of Clinical Pharmacology Research III(2): 101–105, 1983Google Scholar
  41. Fu-Sheng K, Jui-Chin L, Pei-Tsun L, Qing-Lang L, Jang-Thi C. Observations on the anti-arrhythmic effects of Rytmonorm. In Schlepper & Olssen (Eds) Cardiac arrhythmias, pp. 151–158, Springer-Verlag, Berlin, 1983Google Scholar
  42. Garcia-Civera R, Sanjuan R, Morell S, Ferrero JA, Miralles L, et al. Effects of propafenone on induction and maintenance of atrioventricular nodal re-entrant tachycardia. Pace 7: 649–655, 1984PubMedGoogle Scholar
  43. von Gebhardt VA, Schmuderel R, Hilpert P. Vergleichende Untersuchungen von Tocainide und Propafenon zur Behandlung von ventrikulären Arrhythmien. Arzneimittel-Forschung 34: 303–306, 1984PubMedGoogle Scholar
  44. Gentzkow GD, Sullivan JY. Extracardiac adverse effects of flecainide. American Journal of Cardiology 53: 101B–105B, 1984PubMedGoogle Scholar
  45. Gillis AM, Kates RE. Influence of protein binding on the myocardial uptake and pharmacodynamics of propafenone. Journal of Cardiovascular Pharmacology 8: 1163–1167, 1986PubMedGoogle Scholar
  46. Gillis AM, Yee Y-G, Kates RE. α1-Acid glycoprotein binding of antiarrhythmic drugs. Abstract. Clinical Research 33: 20A, 1985aGoogle Scholar
  47. Gillis A, Yee Y-G, Kates RE. Binding of antiarrhythmic drugs to purified human α1-acid glycoprotein. Biochemical Pharmacology 34: 4279–4282, 1985bPubMedGoogle Scholar
  48. Guindo J, Rodriguez de la Serna A, Barja J, Oter R, Jane F, et al. Propafenone and a syndrome of the lupus erythematosus type. Annals of Internal Medicine 104: 589, 1986PubMedGoogle Scholar
  49. Gulker H, Heuer H, Frenking B, Bender F. Enhanced anti-arrhythmic efficacy of combined sotalol/flecainide and combined sotalol/propafenone on chronic ventricular arrhythmias. Abstract. Circulation 70(Suppl. II): 444, 1984Google Scholar
  50. Hammill SC, McLaran CJ, Wood DL, Osborn MJ, Gersh BJ et al. Double blind study of intravenous propäfenone for paroxysmal supraventricular reentrant tachycardia. Journal of the American College of Cardiology 9: 1364–1368, 1987PubMedGoogle Scholar
  51. Hammill SC, Sorenson PB, Wood DL, Surgrue DD, Osborn MJ, et al. Propafenone for the treatment of refractory complex ventricular ectopic activity. Mayo Clinic Proceedings 61: 98–103, 1986PubMedGoogle Scholar
  52. Hapke HJ, Prigge E. Zur Pharmakologie von 2′-(2-Hydroxy-3-propyl-amino-propoxy)-3-phenyl-propiophenon-(propafenon, SA79)-hydrochlorid. Arzneimittel-Forschung 26: 1849–1857, 1976PubMedGoogle Scholar
  53. Harapat SR, Kates RE. High performance liquid Chromatographic analysis of propafenone in human plasma samples. Journal of Chromatography 230: 448–453, 1982PubMedGoogle Scholar
  54. Harder DR, Belardinelli L. Effects of propafenone on TEA-induced action potentials in vascular smooth muscle of canine coronary arteries. Experientia 36: 1082–1083, 1980PubMedGoogle Scholar
  55. Harrison DC. Antiarrhythmic drug classification: new science and practical applications. American Journal of Cardiology 56: 185–187, 1985PubMedGoogle Scholar
  56. Hartel G. Efficacy of oral propafenone in chronic ventricular arrhythmias: A placebo controlled cross-over exercise study. European Heart Journal 6: 123–129, 1985PubMedGoogle Scholar
  57. Hege HG, Hollman M, Kavmeier S, Lietz H. The metabolic fate of 3H-labelled propafenone in man. European Journal of Drug Metabolism and Pharmacokinetics 9: 41–55, 1984PubMedGoogle Scholar
  58. Heger JJ, Hubbard J, Zipes DP, Miles WM, Prystowsky EN. Propafenone treatment of recurrent ventricular tachycardia: comparison of continuous electrocardiographic recording and electrophysiologic study in predicting drug efficacy. American Journal of Cardiology 54: 40D–44D, 1984PubMedGoogle Scholar
  59. Higuchi S, Urano C, Kawamura S. Determination of plasma binding of propafenone in rats, dogs, and humans by highly sensitive gas chromatography-mass spectrometry. Journal of Chromatography 341: 305–311, 1985PubMedGoogle Scholar
  60. Hill MR, Götz VP, Harman E, McLeod I, Hendeles L. Evaluation of the asthomogenicity of propafenone, a new antiarrhythmic drug. Chest 90(5): 698–702, 1986PubMedGoogle Scholar
  61. Hirsowitz G, Podrid PJ, Lampert S, Stein J, Lown B. The role of beta-blocking agents as adjuvant therapy to membrane stabilizing drugs in malignant ventricular arrhythmias. American Heart Journal 111: 852–860, 1986PubMedGoogle Scholar
  62. Hodges M, Salerno D, Granrud G. Double-blind placebo-controlled evaluation of propafenone in suppressing ventricular ectopic activity. American Journal of Cardiology 54: 45D–50D, 1984PubMedGoogle Scholar
  63. Hollman M, Brodie E, Hotz D, Kavmeier S, Kehrhahn OH. Investigations on the pharmacokinetics of propafenone in man. Arzneimittel-Forschung 33: 763–770, 1983Google Scholar
  64. Ibba GV, Terrosv P, Franceschino V, Contini GM, Dore L. Effects of propafenone on coronary and systemic haemodynamics. Abstract. European Heart Journal 5(Suppl. 1): 289, 1984Google Scholar
  65. Jack RA. A case of mania secondary to propafenone. Journal of Clinical Psychiatry 46: 104–105, 1985PubMedGoogle Scholar
  66. Kafka W, Petri H, Hall D, Rudolph W. Propafenone and ajmalinbitartrate in patients with dilated cardiomyopathy: anti-arrhythmic effects and relationship to ventricular function. Abstract A745. Proceedings of 8th Asian-Pacific Congress of Cardiology, p. 201, 1983Google Scholar
  67. Karagueuzian HS, Fujimoto T, Katoh T, Peter T, McCullen A, et al. Suppression of ventricular arrhythmias by propafenone, a new anti-arrhythmic agent, during acute myocardial infarction in the conscious dog: a comparative study with lidocaine. Circulation 66: 1190–1198, 1982PubMedGoogle Scholar
  68. Karagueuzian HS, Katoh T, McCullen A, Mandel WJ, Peter T. Electrophysiologic and haemodynamic effects of propafenone, a new anti-arrhythmic agent, on anaesthetised, closed chest dog: comparative study with lidocaine. American Heart Journal 107: 418–424, 1984PubMedGoogle Scholar
  69. Kates RE, Lee JT, Yee Y-G. Influence of hepatic dysfunction on the pharmacokinetics of profafenone. Abstract. Circulation 72: (No. 4 pt. 2): 170, 1985aGoogle Scholar
  70. Kates RE, Yee Y-G, Kirsten EB. Interaction between warfarin and propafenone in healthy volunteer subjects. Clinical Pharmacology and Therapeutics, in press, 1987Google Scholar
  71. Kates RE, Yee Y-G, Winkle RA. Metabolite cannulation during chronic propafenone dosing in arrhythmias. Clinical Pharmacology and Therapeutics 37: 610–614, 1985bPubMedGoogle Scholar
  72. Keller K, Meyer-Estorf G, Beck OA, Hochrein H. Correlation between serum concentration and pharmacological effects on atrioventricular conduction time of the anti-arrhythmic drug propafenone. European Journal of Clinical Pharmacology 13: 17–20, 1978PubMedGoogle Scholar
  73. Kennedy HL, Chandra V, Sayther KL, Caralis DG. Effectiveness of increasing hours of continuous ambulatory electrocardiography in detecting maximal ventricular activity: continuous 48 hour study of patients with coronary heart disease and normal subjects. American Journal of Cardiology 42: 925–932, 1978PubMedGoogle Scholar
  74. Kingma S, Brugada P, Paulusseng G, Wellens HJJ. Intravenous and oral propafenone in patients with ventricular tachycardia or fibrillation. Abstract. Circulation 70(II): 55, 1984Google Scholar
  75. Klein R, Huang SK. Combination therapy of propafenone with quinidine or procainamide: enhanced efficacy and reduced side effects. Journal of the American College of Cardiology 5(2): 423, 1985Google Scholar
  76. Klein RC, Huang SK, Marcus FI, Horwitz L, Fenster L, et al. Enhanced antiarrhythmic efficacy of propafenone when used in combination with procainamide or quinidine. American Heart Journal, in press, 1987Google Scholar
  77. Klempt HW, Nayebagha A, Fabry E. Antiarrhythmic efficacy of mexiletine, propafenone and flecainide in ventricular premature beats: a comparative study in patients after myocardial infarction (translation). Zeitschrift für Kardiologie 71: 340–349, 1982PubMedGoogle Scholar
  78. Kohlhardt M. Basic electrophysiological actions of propafenone in heart muscle. In Schlepper & Olsson (Eds) Cardiac arrhythmias, pp. 91–101, Springer-Verlag, Berlin, 1983Google Scholar
  79. Kohlhardt M, Seifert C. Inhibition of Vmax of the action potential by propafenone and its voltage-time and pH-dependence in mammalian ventricular myocardium. Naunyn-Schmiedeberg’s Archives of Pharmacology 315: 55–62, 1980PubMedGoogle Scholar
  80. Konz KH, Berg PA, Seipel L. Cholestase nach anti-arrhythmischer Therapie mit Propafenon. Deutsche Medizinische Wochenschrift 109: 1525–1527, 1984PubMedGoogle Scholar
  81. Korsukewitz J, Wegscheider K, Schmutzler H. Idiopathische ventrikulare Tachyarrhythmien. Deutsche Medizinische Wochenschrift 110: 1103–1107, 1985PubMedGoogle Scholar
  82. Lachnit KS, Rieder L. Die Bedeutung von Herzrhythmusstörungen im Alter und ihre Behandlung mit Propafenon unter Kontrolle des Plasmaspiegels. Zeitschrift für Gerontologie 18: 343–352, 1985PubMedGoogle Scholar
  83. Laimer H, Glogar D, Zilcher H. Therapie lidocain-refraktärer ventrikulärer tachyarrhythmien mit propafenon. Acta Medica Austriaca 5: 140–143, 1981Google Scholar
  84. Larochelle P, Belanger L, Lemire F, Phaneuf D-C, Huot R. Dose response effect of propafenone in patients with ventricular arrhythmias. Current Therapeutic Research 36: 959–969, 1984Google Scholar
  85. Latini R, Marchi S, Riva E, Cavalli A, Cazzaniga MG, et al. Distribution of propafenone and its active metabolite. 5-hydroxypropafenone, in human tissues. American Heart Journal 113: 843–844, 1987PubMedGoogle Scholar
  86. Ledda F, Mentelli L, Manzini S, Amerini S, Mugelli A. Electrophysiological and anti-arrhythmic properties of propafenone in isolated cardiac preparations. Journal of Cardiovascular Pharmacology 3: 1162–1173, 1981PubMedGoogle Scholar
  87. Lee JT, Yee Y-G, Dorian P, Kates RE. Influence of hepatic dysfunction on the pharmacokinetics of propafenone. Journal of Clinical Pharmacology 27: 384–389, 1987PubMedGoogle Scholar
  88. Ludmer PL, McGowan NE, Antman EM, Friedman PL. Efficacy of propafenone in Wolff-Parkinson-White syndrome: Electrophysiologic findings and long-term follow-up. Journal of the American College of Cardiology 9: 1357–1363, 1987PubMedGoogle Scholar
  89. Mandel WJ, Katoh T, McCullen A, Peter T, Karagueuzian HS. Comparative haemodynamic and electrophysiologic effects of lidocaine and propafenone, a new antiarrhythmic agent, on the intact canine heart. Abstract. Clinical Research 30: 203A, 1982Google Scholar
  90. Mayrhofer EF, Davogg S, Feilhauer GD, Pilecky I, Seisenbacher H, et al. Fallbericht einer schweren, möglicherweise Propafenon-verursachten Granulozytopenie. Wiener Medizinische Wochenschrift 11: 273–275, 1982Google Scholar
  91. McLeod AA, Stiles GL, Shand DG. Demonstration of beta-adrenoceptor blockade by propafenone hydrochloride: clinical pharmacologic and adenylate cyclase activation studies. Journal of Pharmacology and Experimental Therapeutics 228: 461–466, 1984PubMedGoogle Scholar
  92. Morganroth J, Horowitz LN. Flecainide: its pro-arrhythmic effect and expected changes on the surface electrocardiogram. American Journal of Cardiology 53: 89B–94B, 1984PubMedGoogle Scholar
  93. Morganroth J, Michelson EL, Horowitz LN, Josephson ME, Pearlman AS. Limitations of routine long term electrocardiographic monitoring to assess ventricular ectopic frequency. Circulation 58: 408–414, 1978PubMedGoogle Scholar
  94. Muller-Peltzer M, Greger G, Neugebauer G, Hollman M. Beta-blocking and electrophysiological effects of propafenone in volunteers. European Journal of Clinical Pharmacology 25: 831–833, 1983PubMedGoogle Scholar
  95. Musto B, d’Onofrio A, Greco R, Cavallaro C, Musto A, et al. Electrophysiologic effects and clinical efficacy of propafenone in paroxysmal supraventricular tachycardia in infancy. New Trends in Arrhythmias 1(3): 243–246, 1985Google Scholar
  96. Naccarella F, Agarwal JB, Weintrab WS, Helfant RH. Transmural myocardial distribution of 14-C lidocaine and 14-C propafenone in relation to regional blood flow in chronic myocardial infarction. Abstract. Circulation 68: 193, 1983Google Scholar
  97. Naccarella F, Bracchetti D, Palmieri M, Marchesine B, Ambrosioni E. Propafenone for refractory ventricular arrhythmias: correlation with drug plasma levels during long-term treatment. American Journal of Cardiology 54: 1008–1014, 1984PubMedGoogle Scholar
  98. Naccarella F, Bracchetti D, Palmieri M, Cantelli I, Bertaccini P, et al. Comparison of propafenone and disopyramide for treatment of chronic ventricular arrhythmias: placebo-controlled, double-blind randomized cross-over study. American Heart Journal 109: 833–840, 1985PubMedGoogle Scholar
  99. Nathan AW, Bexton RS, Hellestrand KJ, Camm AJ. Fatal ventricular tachycardia in association with propafenone, a new Class Ic antiarrhythmic agent. Postgraduate Medical Journal 60: 155–156, 1984PubMedGoogle Scholar
  100. Peter T, Mandel WJ, Kotah T, McCullen A, Karagueuzian HS. On the mechanism of action of propafenone, a new anti-arrhythmic agent, during acute myocardial infarction in the dog. Abstract. Clinical Research 30: 213a, 1982Google Scholar
  101. Petri H, Kafka W, Rudolph W. Therapie ventrikulärer Arrhythmien mit Propafenon. Herz 10: 44–52, 1985PubMedGoogle Scholar
  102. Podrid PJ, Cytryn R, Lown B. Propafenone: non-invasive evaluation of efficacy. American Journal of Cardiology 54: 53D–59D, 1984PubMedGoogle Scholar
  103. Podrid PJ, Lown B. Propafenone: a new agent for ventricular arrhythmia. Journal of the American College of Cardiology 4: 117–125, 1984PubMedGoogle Scholar
  104. Pfeiffer D, Assmann I, Rostock KJ, Rathgen K, Schirdewan A. Propafenon in der behandlung paroxysmaler tachyarrhythmien. Herz/Kreislauf 19: 32–36, 1987Google Scholar
  105. Probst P. The influence of propafenone on the accessory pathway in WPW syndrome (an acute intravenous study). Circulation 70(11): 439, 1984Google Scholar
  106. Rabkin SW, Rotem CV, Boroomand-Rashti K, Bar-Shlomo B. Propafenone for the treatment of severe ventricular arrhythmias. Canadian Medical Association Journal 131: 601–603, 1984PubMedGoogle Scholar
  107. Rehnquist N, Ericsson CG, Eriksson S, Olsson G, Svensson G. Comparative investigation of the anti-arrhythmic effects of propafenone (Rytmonorm) and lidocaine in patients with ventricular arrhythmias during acute myocardial infarction. Acta Medica Scandinavica 216: 525–530, 1984Google Scholar
  108. Rizos I, Senges J, Jauernig R, Brachmann J. Intra-individual comparison of the anti-arrhythmic effect of quinidine and propafenone: results using serial testing in patients with paroxysmal supraventricular tachycardia. Abstract. European Heart Journal 5(Suppl. 1): 289, 1984Google Scholar
  109. Rudolph W, Petri H, Kajka W, Hall D. Effects of propafenone on the accessory pathway (AP) in patients with WPW syndrome. Abstract. American Journal of Cardiology 43: 430, 1979Google Scholar
  110. Salerno DM, Granrud G, Sharkey P, Asinger R, Hodges M. A controlled trial of propafenone for treatment of frequent and repetitive ventricular premature complexes. American Journal of Cardiology 53: 77–83, 1984PubMedGoogle Scholar
  111. Salerno DM, Hodges M. New therapy focus: propafenone. Cardiovascular Reviews and Reports 6(8): 924–931, 1985Google Scholar
  112. Schamroth L, Myburgh DP, Schamroth CL, Scholtz ME, Pincus DR, et al. Oral propafenone in the suppression of chronic stable ventricular arrhythmias. Chest 87: 448–451, 1985PubMedGoogle Scholar
  113. Schwartz PJ, Vanoli E. An experimental approach to the choice of antiarrhythmic therapy. European Heart Journal 7(Suppl. A): 135–144, 1986PubMedGoogle Scholar
  114. Seipel L, Breithardt G. Propafenone — a new anti-arrhythmic drug. European Heart Journal 1: 309–313, 1980PubMedGoogle Scholar
  115. Seipel L, Breithardt G. Electrophysiological effects of propafenone. Abstract. American Heart Journal 108: 1587, 1984PubMedGoogle Scholar
  116. Shapiro W, Britt W, Lee G, De Maria AN, Low RI, et al. Comparison of two methods of analyzing frequency of ventricular arrhythmias. American Heart Journal 4: 874–880, 1982Google Scholar
  117. Shen EN, Keung E, Huycke E, Dohrmann ML, Nguyen N, et al. Intravenous propafenone for termination of reentrant supraventricular tachycardia. Annals of Internal Medicine 105: 655–661, 1986PubMedGoogle Scholar
  118. Shen EN, Sung RJ, Morady F, Schwartz AB, Scheinman MM, et al. Electrophysiologic and haemodynamic effects of intravenous propafenone in patients with recurrent ventricular tachycardia. Journal of the American College of Cardiology 3: 1291–1297, 1984PubMedGoogle Scholar
  119. Siddoway LA, McAllister CB, Thompson KA, Barbey JT, Wilkinson GR, et al. Inhibition of debrisoquine metabolism by propafenone in man. Abstract. Clinical Research 33: 288A, 1985Google Scholar
  120. Siddoway LA, McAllister CB, Wang T, Bergstrand RH, Roden DM, et al. Polymorphic oxidative metabolism of propafenone in man. Abstract. Circulation 68(Suppl. III): 64, 1983Google Scholar
  121. Siddoway LA, Thompson KA, McAllister CB, Wang T, Wilkinson GR, et al. Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75: 785–791, 1987PubMedGoogle Scholar
  122. Tai J, Shen EN, Svinarich JT, Mickelson J, Harmann ML, et al. Intravenous propafenone — an effective antiarrhythmic agent for arrhythmias associated with Wolff-Parkinson-White syndrome. Circulation 70(II): 443, 1984Google Scholar
  123. Tamargo J, Delgado C. Electrophysiological effects of propafenone on isolated guinea-pig ventricular muscle and sheep Purkinje fibres. European Journal of Pharmacology 118: 331–340, 1985PubMedGoogle Scholar
  124. Torres V, Flowers D, Somberg JC. The arrhythmogenicity of antiarrhythmic agents. American Heart Journal 109(5): 1090–1097, 1985PubMedGoogle Scholar
  125. Von Philipsborn GJ, Gries R, Ketzschmar VB. Anti-arrhythmic and β-sympatholytic effects of the new anti-arrhythmic propafenone and its main metabolites 5-hydroxy-propafenone. Abstract 615. Proceedings of II World Congress on Clinical Pharmacology and Therapeutics (Washington), p. 105, 1983Google Scholar
  126. Von Philipsborn G, Gries J, Hoffman HP, Kreiskott H, Kretschmar R, et al. Pharmacological studies with propafenone and its main metabolite 5-hydroxy-propafenone. Arzneimittel-Forschung 34: 1489–1497, 1984Google Scholar
  127. Wagner F, Kalusche D, Trenk D, Jähnchen E, Roskamm H. Drug interaction between propafenone and metoprolol. Abstract 240. Acta Pharmacologica et Toxicologica 59: 93, 1986Google Scholar
  128. Waleffe A, Mary-Rabine L, de Rijbel R, Soyeur D, Legrand V, et al. Electrophysiological effects of propafenone studied with programmed electrical stimulation of the heart in patients with recurrent paroxysmal supraventricular tachycardia. European Heart Journal 2: 345–352, 1981PubMedGoogle Scholar
  129. Wester HA, Mouselimis N. Einfluss von Antiarrhythmika auf die Myokardfunktion. Deutsche Medizinische Wochenschrift 107: 1262–1266, 1982PubMedGoogle Scholar
  130. Zaza A, Forster M, Danilo P, Sodowick B, Rosen M. Electrophysiological effects of propafenone and its metabolites on canine Purkinje fibers. Federation Proceedings 46: 871, 1987Google Scholar
  131. Zeiler RH, Gough WB, El-Sherif N. Electrophysiological effects of propafenone on canine ischaemic cardiac cells. American Journal of Cardiology 54: 424–429, 1984PubMedGoogle Scholar

Copyright information

© ADIS Press Limited 1987

Authors and Affiliations

  • Dean W. G. Harron
    • 1
    • 2
  • Rex N. Brogden
    • 1
    • 2
  1. 1.Queen’s University of BelfastBelfastNorthern Ireland
  2. 2.ADIS Drug Information ServicesAucklandNew Zealand

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