Lidocaine, carbamazepine, and imipramine have partially overlapping binding sites and additive inhibitory effect on neuronal Na⁺ channels

Background: Despite the structural differences, local anesthetics, anticonvulsants, and tricyclic antidepressants exert similar use-dependent actions against voltage-gated Na⁺ channels, which may be contributory to pain control. The authors explore whether these drugs could doubly occupy the channel and exert synergic clinical effect. Methods: The authors performed electrophysiologic recordings and quantitative analyses in mutant and native neuronal Na channels to investigate molecular interactions between different drugs. Results: The authors demonstrate significant interactions between F1764 and W1716, two residues reported for local anesthetic binding, indicating uncertainties to conclude a common drug-binding site by mutation data. Therefore, the authors performed detailed functional studies in native neurons. Quantitative analyses of the inactivation curve shift argue against effective double occupancy of different drugs. For example, the shift of 20.9 ± 1.3 mV in the simultaneous presence of 10 μm imipramine, 100 μm lidocaine, and 100 μm phenytoin is consistent with the one-site (21.5 mV) rather than the two-site (30.5-33.8 mV) or three-site (42.7 mV) predictions. However, there is a deviation from the recovery courses predicted by one site if lidocaine or imipramine coexists with anticonvulsants. Moreover, gating state dependence of macroscopic-binding rates markedly differs between imipramine and carbamazepine. Conclusions: Carbamazepine, lidocaine, and imipramine bind to a common site with the common aromatic motif. External to the aromatic site, there is another weaker and less gating-dependent site for the tertiary amine chain in the latter two drugs. Concomitant clinical use of these drugs, thus, should have at most a simple additive but not a synergistic inhibitory action on Na⁺ currents.