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

Abstract

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.

Protonation and orientation: a computational approach to cocaine diffusion through a model membrane

“…Partition coefficients stemming from experiments 30 or reaction field computations 31 can be used in a thermodynamic model to compute the pH-dependent distribution of anesthetics in detail. 32 While we qualitatively discuss pH effects, the main focus of our work is on the transfer dynamics and its time scale. Below, we make use of the potential of mean force computed in this section and the diffusion coefficient parallel to the lipid layer – as estimated below – to address the time scales of transport in the following two sections.…”

Ultrasound-Guided Suprainguinal Fascia Iliaca Block as Part of Anesthesia Management for Lower Extremity Surgeries: A Single-Center Retrospective Cohort Feasibility Study

“…However, high fragility rates may be present in the selected/high-risk patient group who underwent high-volume SIFIB for surgical anesthesia. Additionally, it is known that the intercompartmental transfer of local anesthetic is high in elderly patients [18]. As such, these patients should be accepted as being at high risk for local anesthetic systemic toxicity, and therefore, additional care should be taken by clinicians.…”

Antioxidant activity of lidocaine, bupivacaine, and ropivacaine in aqueous and lipophilic environments: an experimental and computational study

“…Quantum chemical calculations indicated a plausible reaction between the -C-H group at position 2 ( Figure 1 ) of bupivacaine or ropivacaine and peroxyl radical. Therefore, it is suggested that the most likely reaction mechanism with peroxyl radical in water is the HAT mechanism at position 2, similar to certain flavonoids ( Apak et al, 2013 ) The pKa values of bupivacaine and ropivacaine are 8.21 and 8.16, respectively ( Kavčič et al, 2021b ). Compared to lidocaine, there is a higher proportion of protonated form of the molecule present at the same pH value in the environment.…”

“…The lipophilic compartment model suggests that the intramembrane concentration of lidocaine could be 42 times higher than the extracellular concentration due to its high degree of lipid solubility in its neutral form ( Kavčič et al, 2021b ). Please note that the lipid solubility of bupivacaine and ropivacaine is even higher.…”