Studies of Interaction between Hexamethonium and Lidocaine, alpha-Bungarotoxin or Decamethonium in Vitro

Background: Interactions of neuromuscular blocking agents are antagonistic in a combination of depolarizing and nondepolarizing agents, additive in a combination of relative two compounds or synergistic in a combination of different two nondepolarizing agents. However, the interactions of neuromuscular blocking agents with a different site of action from each other have not been studied clearly. This study was designed to examine the interaction between hexamethonium and lidocaine, α-bungarotoxin or decamethonium with markedly different pre and postsynaptic sites of action. Methods: Square wave, 0.1 Hz supramaximal stimuli or 2 Hz, 0.2 ms train of four (TOF) stimuli, was applied to the rat phrenic nerve-hemidiaphragm preparation, and the twitch height response was recorded mechanomyographically. The cumulative concentration effect and TOF ratio at each point of twitch depression after hexamethonium, lidocaine, α-bungarotoxin or decamethonium given were measured. The EC50 and EC95 of hexamethonium, lidocaine, α-bungarotoxin and decamethonium were calculated using an inhibitory sigmoid E model. In the experiment of each combination of two drugs, three points of the isobole for hexamethonium-lidocaine, hexamethonium-α-bungarotoxin and hexamethonium-decamethonium were established using ratios of 1: 3, 1: 1 and 3: 1 of their EC50. Points on the line of theoretical additivity and 95% canfidence intervals were calculated according to Tallarida et al. TOF ratios were observed at 75, 50 and 25% of the control twitch height value during each combination ratio of their EC50. Results: Significant deviations of points on the isobole from the line of additivity to the left were found at all EC50 ratios of hexamethonium-lidocaine (P<0.05 respectively), that to the right was found at all EC50 ratios of a hexamethonium-α-bungarotoxin and hexamethonium-decamethonium (P<0.05 respectively). The magnitude of TOF fade depended upon the mixed ratios for their EC50. Conclusions: The interaction was found to be synergistic in the combination of hexamethonium-lidocaine, and antagonistic in the combination of hexamethonium-α-bungarotoxin and hexamethonium-decamethonium. (Korean J Anesthesiol 2001; 40: 645~654)