Despite a long history in medical and dental application, the molecular mechanism and precise site of action are still arguable\r\nfor local anesthetics. Their effects are considered to be induced by acting on functional proteins, on membrane lipids, or on both.\r\nLocal anesthetics primarily interact with sodium channels embedded in cell membranes to reduce the excitability of nerve cells\r\nand cardiomyocytes or produce a malfunction of the cardiovascular system. However, the membrane protein-interacting theory\r\ncannot explain all of the pharmacological and toxicological features of local anesthetics. The administered drug molecules must\r\ndiffuse through the lipid barriers of nerve sheaths and penetrate into or across the lipid bilayers of cellmembranes to reach the acting\r\nsite on transmembrane proteins.Amphiphilic local anesthetics interact hydrophobically and electrostatically with lipid bilayers and\r\nmodify their physicochemical property, with the direct inhibition of membrane functions, and with the resultant alteration of the\r\nmembrane lipid environments surrounding transmembrane proteins and the subsequent protein conformational change, leading to\r\nthe inhibition of channel functions.We review recent studies on the interaction of local anesthetics with biomembranes consisting\r\nof phospholipids and cholesterol. Understanding the membrane interactivity of local anesthetics would provide novel insights into\r\ntheir anesthetic and cardiotoxic effects.
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