MOLECULAR AND PHYSICOCHEMICAL ASPECTS OF LOCAL ANESTHETIC-MEMBRANE INTERACTION

Local anesthesia is achieved by the binding of anesthetic molecules to the sodium channel, a membrane protein responsible for the transport of the extracellular sodium to the cytosol. Loca!anesthetics (LA) bind to the sodium channel inhibiting sodium transport and, as a consequen ce, the action potential responsible for the nervous impulse. Most LA are relatively hydrophobic ionizable amines that undergo partitioning into lipid. Both activity and toxicity correlate positively with LA hy drophobicity. Effects of LA on the structural and dynamical properties of the membrane lipid region may be responsible for some of the toxic effects caused by these molecules. The present review focuses on rese arch done on the interaction between both the charged and uncharged fo rms of LA and lipid systems - bilayers and micelles. LA have been foun d to alter phospholipid gel to liquid crystal phase transition tempera ture (T-c), to affect bilayer permeability, to influence molecular pac king, and to inhibit the bilayer to hexagonal phase transition. Anesth etics in micellized form disrupt bilayers giving rise to lipid-LA mixe d micelle-like aggregates. The question of LA location in the bilayer is also addressed. Special emphasis is placed on work focusing on the quantitative analysis of drug binding, as well as on the effects of bi nding on physicochemical properties of the LA, such as extent of ioniz ation (pK shifts) and rates of chemical reactions. The understanding o f these phenomena has contributed to the development of less toxic lip osomal formulations capable of prolonging the duration of anesthesia.