Attenuation of antifibrillatory effects of lidocaine by its metabolite, glycylxylidide: application of modulated receptor hypothesis.
Lidocaine, one of the drugs effective in treating ventricular arrhythmias in acute myocardial infarction (AMI), sometimes loses its efficacy after prolonged administration, possibly owing to the counteraction of glycylxylidide, one of the metabolites of lidocaine, through modulation of binding of lidocaine to sodium channels. To determine whether glycylxylidide interferes with the antiarrhythmic action of lidocaine, we compared the antifibrillatory effects of lidocaine, glycylxylidide, and their combination in 14 anesthetized open-chest dogs. Although glycylxylidide alone prolonged intraventricular conduction time (CT) and did not affect ventricular effective refractory period (VERP), it had different effects when added to lidocaine; i.e., it had no effect on intraventricular conduction time but shortened VERP. Although glycylxylidide alone did not change ventricular fibrillation threshold (VFT), the increase in VFT induced by lidocaine was decreased by addition of glycylxylidide, possibly as a result of competition for the same cardiac sodium channels between lidocaine and glycylxylidide with similar onset but different offset kinetics, which may explain, at least in part, the drug-resistance phenomena that ensue from prolonged lidocaine administration.
Yamashita
T
T
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Nozaki
A
A
Usui
M
M
Kuo
T T
TT
Oikawa
N
N
Ajiki
K
K
Murakawa
Y
Y
Sugimoto
T
T
Inoue
H
H
D000818:Animals; D004285:Dogs; D004347:Drug Interactions; D004594:Electrophysiology; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000097:blood / Q000627:therapeutic use*; D014693:Ventricular Fibrillation / Q000188:drug therapy*; D016276:Ventricular Function
D008012:Lidocaine; C001306:glycinexylidide