Colloids and Surfaces B: Biointerfaces 22 (2001) 3–22ReviewInteractions of some local anesthetics and alcohols withmembranesPetre T. Frangopola,*, Dan Miha˘ilescub,1aDepartment of Chemical Physics, Faculty of Chemistry,‘Babes-Bolyai’Uni6ersity,11, Aranyi Janos Str.,R-3400Cluj-Napoca, RomaniabLaboratory of Biophysics, Faculty of Biology, Bucharest Uni6ersity,91-95, Spl. Independentei, R-76201Bucharest, RomaniaAbstractA review of the results obtained by our group in the last decade regarding the interactions of procaine, lidocaine,dibucaine and tetracaine with membranes is presented in the context of the literature data. The action uponmembranes, in first approximation monomolecular film of stearic acid spread at the air/water interface used as amembrane model, the modification of biomembrane structure and function using diffraction methods, lipid phasetransition, fluidity of lipids and proteins, membrane expansion and platelet aggregation were studied. The thermody-namic knowledge of membrane-alcohol interactions improved by using highly sensitive calorimetric techniques arebriefly reported. One of the main conclusions is that the physical state of a monolayer model membrane was the resultof competitive interactions between film-film and film-substrate interactions. It was taken into account that localanesthetics, such as lidocaine, carbisocaine, mesocaine, showed changes in the bilayer structure, reflected inmacroscopic mechanical properties. This restructuring of the lipid bilayer has a significant influence on the operationof functional subunits, e.g. ionic channels formed by gramicidin. The results support the concept of non-specificinteractions of local anesthetics with lipid bilayers. The theoretical modeling of the interactions of local anesthetics isclosely compared with experimental data. Our new theory of relaxation for these interactions is using a non-archimedean formalism based on a process resulting from superpositions of different component processes which takeplace at different scales of time. © 2001 Elsevier Science B.V. All rights reserved.Keywords:alcohols with membranes; anesthesia mechanism; local anestheticswww.elsevier.nl/locate/colsurfb* Corresponding author. Tel.: +40-1-413-2375. Fax: + 40-1-411-3933..E-mail addresses:[email protected] (P.T. Frangopol), [email protected] (D. Miha˘ilescu).1Present address: Blvd. Timisoara 17 Bloc H-1/Scara C, Apartment 28, Interfon 228, C 773091 Bucharest 66, Romania.0927-7765/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.PII: S0927-7765(01)00153-9P.T. Frangopol, D. Miha˘ilescu/Colloids and Surfaces B:Biointerfaces22 (2001) 3 – 224Contents1. Introduction ............................................ 42. Local anesthetics and interfacial phenomena ......................... 63. Effects of alcohols on membranes................................ 93.1. Model membrane/substrate interactions: ethanol and procaine inter-actions............................................. 93.2. Thermochemistry of alcohol–membrane interactions ................... 103.3. Chain-length dependent effects of alcohols on the purple membrane ofHalobacteria .......................................... 104. Modification by local anesthetics of biomembrane structure and function.......... 114.1. Structural effects of tertiary amine local anesthetics in model and bio-logical membranes ....................................... 114.2. Influence of local anesthetics on mechanical properties of bilayer lipidmembranesandliposomemembrane............................ 124.3. Red blood cell membranes and tertiary amine local anesthetics ............. 134.4. Modification of the ion transport properties of biomembranes by tertiaryamine local anesthetics .................................... 155. Effects of procaine on platelet aggregation ........................... 166. Theoretical modeling of the interactions between local anesthetics and biomem-branes ................................................ 177.Conclusions ............................................. 18Acknowledgements ......................................... 18References .............................................. 181. IntroductionAnesthesia was discovered more than a centuryago but the mechanism of action of anesthetics isstill unknown and subject of intense experimentaland theoretical work. Although it is now wellestablished that anesthesia is brought about by alarge number of chemically different molecularspecies, their exact sites of action and details oftheir interactions with their molecular compo-nents of nerve cells are still subject of considerablecontroversy. Consequently, especially during thelast two decades, a significant amount of interdis-ciplinary scientific research has been devotedworldwide to the task of obtaining a unified pic-ture of anesthesia mechanism. Attempts to solvingthis problem can be ascribed to a variety ofdisciplines, among which chemistry, biophysics,biochemistry, physiology and pharmacology arethe most important. These approaches have pro-duced a remarkable amount of scientific data,including both physico-chemical and pharmaco-logical characteristics of various compounds withanesthetic action as well as information on theirinteractions with different biological and modelsystems. The investigation itself and the collectionand interpretation of information goes beyond thecapacity of any individual investigator or labora-P.T. Frangopol, D. Miha˘ilescu/Colloids and Surfaces B:Biointerfaces22 (2001) 3 – 225tory. Therefore, naturally, appeared the excellentidea of Kenji Ogli to publish a new internationaljournal ‘‘Progress in Anesthetic Mechanism’’ [1]in 1993 and to organize, periodically the Interna-tional Workshop on Anesthetic Mechanisms, thesecond edition, held in 1999. The results achievedthus far have been extensively reviewed [2–11].Numerous models and theories have been putforward for anesthesia, which are based mostly onbiophysical and biochemical data [12– 18]. Thetheories of molecular mechanism of anesthesia:lipid theories, perturbation of physicochemicalproperties of biomembranes, theories involvingthe interaction of anesthetics with water, proteintheory [19] along with the chemicals that couldexert their modulation effect through the lipiddomain on transmembrane protein structure andfunction [20] are particularly well presented.The terms ‘‘local anesthesia’’ or ‘‘regional anes-thesia’’ are