Local anesthetics transfer relies on pH differences and affinities toward lipophilic compartments

Abstract

AbstractLocal anesthetics are weak bases and alter their properties in accordance with their protonation state, which depends on the environmental pH. We studied the transport dynamics of several local anesthetics from the extracellular fluid across biological membranes to the axoplasm, in order to understand the effect of pH on their pharmacodynamic properties. By using experimental pKa values and n‐octanol/water partition coefficients, we calculated pH‐dependent distribution coefficients and therewith associated relative populations and free energy profiles between extracellular fluid, membrane, and axoplasm. We estimated the local anesthetic capacity of neural tissue, using a simple 2D model. All values were calculated under physiological conditions and under the effect of local acidosis. Under physiological conditions, local anesthetics were most prevalent in the membrane. Change of free energy for transfer across biological membrane and the difference in relative population between extracellular fluid and axoplasm was dependent only on the difference of pH values between both environments, and not on pKa values. Estimated storage capacities for long‐lasting local anesthetics are higher by a factor of 10 or 100 than for short‐lasting local anesthetics. The membrane does not represent a barrier for local anesthetic diffusion. Local anesthetics move from the compartment with higher pH to the compartment with lower pH, due to favorable solvation free energy of protonated species. The rate of transfer across biological membrane is diffusion‐controlled and is similar for all local anesthetics. Neural tissue has a higher storage capacity for highly lipophilic local anesthetics, which can explain their longer duration of action.