Interaction of Local Anesthetics with Biomembranes Consisting of Phospholipids and Cholesterol: Mechanistic and Clinical Implications for Anesthetic and Cardiotoxic Effects

Abstract

Despite a long history in medical and dental application, the molecular mechanism and precise site of action are still arguable for local anesthetics. Their effects are considered to be induced by acting on functional proteins, on membrane lipids, or on both. Local anesthetics primarily interact with sodium channels embedded in cell membranes to reduce the excitability of nerve cells and cardiomyocytes or produce a malfunction of the cardiovascular system. However, the membrane protein-interacting theory cannot explain all of the pharmacological and toxicological features of local anesthetics. The administered drug molecules must diffuse through the lipid barriers of nerve sheaths and penetrate into or across the lipid bilayers of cell membranes to reach the acting site on transmembrane proteins. Amphiphilic local anesthetics interact hydrophobically and electrostatically with lipid bilayers and modify their physicochemical property, with the direct inhibition of membrane functions, and with the resultant alteration of the membrane lipid environments surrounding transmembrane proteins and the subsequent protein conformational change, leading to the inhibition of channel functions. We review recent studies on the interaction of local anesthetics with biomembranes consisting of phospholipids and cholesterol. Understanding the membrane interactivity of local anesthetics would provide novel insights into their anesthetic and cardiotoxic effects.

Shedding light on the puzzle of drug-membrane interactions: Experimental techniques and molecular dynamics simulations

“…On the other hand, the therapeutic mechanisms concerning drug interactions with membrane proteins have also been related to the drug location and its effect on the membrane order [242,276]. A good correlation between the biophysical perturbations of membranes and both cell uptake and the therapeutic properties have been proven in several studies [3].…”

Lidocaine‐induced potentiation of thermal damage in skin and carcinoma cells

“…Growth medium was changed every 3 days. Experiments were performed with exponential growing cells with low passage number (4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Local Anesthetics

“…Once the free base has penetrated the cell, it re-equilibrates, and the cation is thought to be the form that then interacts with the receptors to prevent sodium conductance. This explains in part why local anesthetic agents are not as effective in areas of an acute infection where the local tissues are acidic changing the balance between uncharged free base and charged cations in favor of the latter which is less effective in penetrating the cell membrane [ 3 ].…”