Local anesthetics are one of the most widely used drug classes in clinical practice. Like many other biological molecules, their properties are altered depending on their protonation status, which is dependent on the pH of the environment. We studied the transport energetics of seven local anesthetics from the extracellular fluid across the biological membrane to the axoplasm in order to understand the effect of pH value on their efficacy and other pharmaco-dynamic roperties. In this we applied three different methods of solvent reaction field in conjunction with quantum chemical calculations to reproduce experimental values of n-octanol/water partition coefficients for both neutral and protonated forms. Only the SMD method of Cramer and Truhlar was able to reproduce experimental partition coefficient values. The results are discussed in terms of the function of local anesthetics under physiological conditions and in the case of local acidosis.

Local 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.

Introduction: Local anesthetics are widely recognized pharmaceutical compounds with various clinical effects. Recent research indicates that they positively impact the antioxidant system and they may function as free radical scavengers. We hypothesize that their scavenging activity is influenced by the lipophilicity of the environment.Methods: We assessed the free radical scavenging capacity of three local anesthetics (lidocaine, bupivacaine, and ropivacaine) using ABTS, DPPH, and FRAP antioxidant assays. We also employed quantum chemistry methods to find the most probable reaction mechanism. The experiments were conducted in an aqueous environment simulating extracellular fluid or cytosol, and in a lipophilic environment (n-octanol) simulating cellular membranes or myelin sheets.Results: All local anesthetics demonstrated ABTS˙+ radical scavenging activity, with lidocaine being the most effective. Compared to Vitamin C, lidocaine exhibited a 200-fold higher half-maximal inhibitory concentration. The most thermodynamically favorable and only possible reaction mechanism involved hydrogen atom transfer between the free radical and the -C-H vicinal to the carbonyl group. We found that the antioxidant activity of all tested local anesthetics was negligible in lipophilic environments, which was further confirmed by quantum chemical calculations.Conclusion: Local anesthetics exhibit modest free radical scavenging activity in aqueous environments, with lidocaine demonstrating the highest activity. However, their antioxidant activity in lipophilic environments, such as cellular membranes, myelin sheets, and adipose tissue, appears to be negligible. Our results thus show that free radical scavenging activity is influenced by the lipophilicity of the environment.

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.