Microkinetics of Lidocaine and Bupivacaine Transfer across Myelinated Nerve Fibre

Abstract

Background The present study aimed to predict the time to onset and duration of action of two local anesthetics (lidocaine and bupivacaine) based on the experimental dimensions of a typical nerve and experimental octanol/water partition coefficients. Methods We started our compilation of experimental data with a numerical solution of the diffusion equation of transfer of lidocaine and bupivacaine across the axon membrane at the region of the node of Ranvier (axolemma) and across the Schwann cell. By including the coordinate-dependent chemical potential, the difference between the aqueous and lipid environments of the neuron was simulated. In the second step, permeation rates calculated using the diffusion equation were applied to solve a system of four ordinary differential equations. This approach allowed us to simulate the cell environment for longer, enabling us to compare our model to the pharmacokinetic properties (time to onset and duration of action) of local anaesthetics found in the literature. The behaviour of local anaesthetics under physiological conditions and in the case of local acidosis was also simulated. Results We demonstrated that local anaesthetics cross the axolemma on a sub-microsecond time scale. Time to onset, controlled by diffusion from epineurium to an axon with a typical distance of 500 µm, was 167 s and 186 s for lidocaine and bupivacaine, respectively. Calculated half-time, which is a measure of the duration of action, was 41min and 328 min for lidocaine and bupivacaine, respectively. Conclusions Duration of action is controlled by the storage capacity of lipophilic compartments around the axon that are higher for bupivacaine and lower in the case of local acidosis. For the latter case, the literature, including textbooks, provides an incorrect interpretation that protonated species cannot penetrate the membrane.