Interaction of Local Anesthetics with Biomembranes Consisting of Phospholipids and Cholesterol: Mechanistic and Clinical Implications for Anesthetic and Cardiotoxic Effects
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. 1. Introduction Local anesthetics clinically used so far have the common chemical structure that is composed of three portions: the hydrophobic moiety consisting of an aromatic ring, the intermediate chain, and the hydrophilic moiety consisting of an amino terminus. The aromatic residue confers lipid solubility on a drug molecule, whereas the ionizable amino group confers, water solubility. The intermediate portion provides the spatial separation between hydrophobic and hydrophilic end and structurally classifies local anesthetics into amide type and ester type (Figure 1). Figure 1: Representative amide and ester local anesthetics. Because of the presence of substituted amino groups, local anesthetics are referred to as the bases with pKa values ranging from 7.7 to 8.1 at 37°C for the amide type and from 8.4 to 8.9 at 37°C for the ester type [1], so they exist in uncharged and positively charged form. After injected, local anesthetics show an in vivo equilibrium between the uncharged and the charged fraction of molecules. According to the Henderson-Hasselbalch equation, the percentage of uncharged molecules depends
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