Comparative study on the proarrhythmic effects of some antiarrhythmic agents.
BACKGROUND
A main side effect of antiarrhythmic drug therapy is the tendency of these drugs to promote arrhythmia within the therapeutic concentration range, i.e., the proarrhythmic activity of these drugs. However, a model for in vitro assessment, quantification, and comparison of proarrhythmic drug activities was still lacking, and only sparse data were available.


RESULTS
To analyze the arrhythmogenic risk of common antiarrhythmic drugs in a quantitative and comparative manner, isolated perfused rabbit hearts were treated with increasing concentrations of antiarrhythmic drugs corresponding to low, medium, and high therapeutic concentrations. For analysis of the epicardial activation process, an epicardial mapping (256 unipolar leads) was performed. For each electrode, the activation time was determined. From these data, the origins of epicardial activation ("breakthrough points" [BTP]) were determined. At each electrode, an activation vector (VEC) was calculated giving direction and velocity of the local excitation wave. The beat similarity of various heartbeats (under treatment) compared with control was evaluated by determination of the percentage of identical BTPs (deviation < or = 1 mm) and of similar VECs (deviation < or = 5 degrees). BTP and VEC were reduced by all antiarrhythmic agents tested (propafenone = flecainide > quinidine > ajmaline > procainamide > disopyramide > mexiletine = lidocaine > sotalol), indicating a more or less pronounced disturbance of the epicardial activation process. Treatment with propafenone, quinidine, and disopyramide and to a lesser extent sotalol prolonged the activation-recovery interval (ARI). ARI dispersion was greatly enhanced by flecainide and was reduced by sotalol. In addition, it could be shown that propranolol is able to reduce the proarrhythmic action of flecainide. This effect seemed to be due to a reduction of the flecainide-induced increase in ARI dispersion.


CONCLUSIONS
From the results of our study, we propose the following rank order of the arrhythmogenic risk: flecainide > propafenone > quinidine > ajmaline > disopyramide > procainamide > mexiletine, lidocaine > sotalol. Moreover, we conclude that propranolol given additionally may be helpful in reducing the proarrhythmic risk of flecainide.
Dhein
S
S
Institut für Pharmakologie, Universität zu Köln, FRG.
Müller
A
A
Gerwin
R
R
Klaus
W
W
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004594:Electrophysiology; D005424:Flecainide / Q000037:antagonists & inhibitors; D008297:Male; D009994:Osmolar Concentration; D010496:Pericardium / Q000187:drug effects / Q000502:physiology; D011433:Propranolol / Q000494:pharmacology; D011817:Rabbits; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D011433:Propranolol; D005424:Flecainide