ISCHEMIA-INDUCED LOSS OR REVERSAL OF THE EFFECTS OF THE CLASS-I ANTIARRHYTHMIC DRUGS ON VULNERABILITY TO FIBRILLATION

1 In the last decade, a number of clinical observations have questione d the efficacy of certain class I antiarrhythmic drugs against ischaem ia-induced ventricular fibrillation. The effects of three drugs of thi s class, disopyramide (Ia), lignocaine (Ib) and flecainide (Ic) on the vulnerability to fibrillation during experimental ischaemia were inve stigated. 2 The study was carried out in anaesthetized, open-chest pig s (n = 8 for each of the drugs, in addition to the control group, n = 6). Vulnerability to fibrillation was evaluated by measuring electrica l fibrillation threshold (EFT) by means of stepwise increased intensit y of wide (100 ms) diastolic impulses applied to the ischaemic tissue at a 180 beats min(-1) rate. Monophasic action potential (MAP) duratio n and conduction time in the ischaemic region were also measured. 3 EF T determinations were performed before and during periods of ischaemia induced by complete occlusion of the left anterior descending coronar y artery near its origin. Ischaemic periods of increasing duration (30 , 60, 90, 120, 150 s) were induced to determine the electrophysiologic al changes, of EFT especially, leading to fibrillation. 4 In the absen ce of ischaemia, all three drugs, administered by intravenous route (1 mg kg(-1) plus 0.04 mg kg(-1) min(-1)) increased EFT to a similar ext ent (from approximately 7 to 10 mA), despite a 25% prolongation of con duction time. 5 During ischaemia, none of the drugs prevented the fall in EFT towards 0 mA, resulting in spontaneous fibrillation. After 30 s of ischaemia, they no longer had any capacity for raising EFT and, a fter 60, 90 and 120 s of ischaemia, the decrease in EFT was exacerbate d. This accelerated reduction in EFT shortened the time to onset of fi brillation (after 120 s of ischaemia, 62.5% of fibrillations with flec ainide instead of 12.5 under control conditions, 75% instead of 25 wit h lignocaine and 50% instead of 25 with disopyramide). The reduction i n MAP duration due to ischaemia was also significantly accelerated (at 60 s, 178 +/- 5 ms instead of 192 +/- 4 with flecainide, 175 +/- 3 ms instead of 194 +/- 5 with lignocaine and 180 +/- 5 ms instead of 196 +/- 3 with disopyramide) and the slowing of conduction was made worse (prolongation of conduction time by 70% instead of 50). 6 In conclusio n, the antifibrillatory properties normally manifested by these drugs are first suppressed, then inverted by ischaemia, depending on oxygen debt varying with severity and duration of ischaemia.