Comparison of the in vivo electrophysiological and proarrhythmic effects of amiodarone with those of a selective class III drug, sematilide, using a canine chronic atrioventricular block model.

Amiodarone effectively blocks both the sodium and calcium channels and beta-adrenoceptors, in addition to blocking several potassium currents including IKr, IKs, Ito, IK1, IKACh and IKNa. The incidence of clinical torsade de pointes (TdP) associated with amiodarone has been reported to be low and the present study compared the proarrhythmic potential of amiodarone with that of a selective IKr channel blocker, sematilide, using a canine chronic atrioventrucular block model. Amiodarone or sematilide (3 and 30 mg/kg; n=4 for each group) was administered orally without anesthesia under continuous ECG monitoring. Both drugs prolonged the QT interval, although the onset was faster for sematilide. The high dose of sematilide induced TdP in 3 of 4 animals, which caused their death, but neither the low dose of sematilide nor the 2 dosages of amiodarone induced lethal ventricular arrhythmias. These results suggest that IKr channel inhibition by amiodarone with its additional ion channel blocking action may contribute to the prevention of TdP.

Intrapericardial therapeutics: a pharmacodynamic and pharmacokinetic comparison between pericardial and intravenous procainamide delivery.

INTRODUCTION: Procainamide delivery into the pericardial space may produce a greater and more prolonged electrophysiologic effect, particularly in thin superficial atrial tissue, compared with intravenous delivery. METHODS AND RESULTS: Swine were randomized to sequential procainamide doses delivered intravenously (n = 6) or into the pericardial space (n = 7). The cumulative pericardial doses were 0.5, 1.5, and 3.5 mg/kg, and the intravenous doses were 2, 10, and 26 mg/kg. Pericardial procainamide prolonged right atrial effective refractory period from baseline by 22% (P < 0.01) but only at the 3.5 mg/kg cumulative dose. This dose slowed interatrial conduction time by 14% (P < 0.05) and raised atrial fibrillation threshold by 70 mA (P < 0.05). Pericardial procainamide had minimal effect on ventricular electrophysiology. Similar results occurred with a single 2 mg/kg pericardial dose in a closed chest model. Intravenous 10 and 26 mg/kg cumulative doses prolonged atrial effective refractory period from baseline by 24% and 18% (P < 0.01), respectively. The 26 mg/kg cumulative intravenous dose slowed interatrial and atrial-ventricular conduction times by 27% and 17%, respectively (P < 0.05), raised atrial fibrillation threshold, and slowed ventricular conduction time by 29% (P < 0.05). Pericardial procainamide produced pericardial fluid concentrations ranging from 250 to 1,500 microg/mL, but plasma concentrations were <1 microg/mL. Intravenous procainamide doses produced pericardial fluid concentrations similar to plasma trough concentrations 0 to 12 microg/mL. CONCLUSION: The single 2 mg/kg and 3.5 mg/kg cumulative pericardial procainamide doses prolonged atrial refractoriness and raised atrial fibrillation threshold similar to the 26 mg/kg cumulative intravenous dose, but the duration of effect was similar between delivery methods. Pericardial procainamide did not affect global or endocardial ventricular electrophysiology nor was it associated with ventricular proarrhythmia.

Interaction of bisoprolol and procainamide in human cardiac impulse generation and conduction.

Combined treatment of beta-adrenoceptor-blocking agents and class I antiarrhythmic drugs can potentially have profound and deleterious effects on cardiac impulse formation and conduction. We studied the effect of 5 mg of oral bisoprolol daily and 10 mg/kg of procainamide intravenously with programmed electrical stimulation of the heart in 10 patients with postinfarction ventricular tachyarrhythmias. Oral bisoprolol slowed sinus rhythm and atrioventricular nodal conduction; ventricular effective refractory periods were increased significantly after several days of oral bisoprolol treatment. Combined treatment of oral bisoprolol and intravenous procainamide did not produce clinically relevant changes in parameters of cardiac impulse formation and conduction. This study shows that combined use of bisoprolol and a class I antiarrhythmic drug appears to be safe in patients with ventricular tachyarrhythrhythmias late after myocardial infarction.