Anesthetics molecular mechanism

The clinical effects of chloroform toxicity on the central nervous system are well documented. However, the molecular mechanism of action is not well understood. It has been postulated that anesthetics induce their action at a cell-membrane level due to lipid solubility. The lipid-disordering effect of chloroform and other anesthetics on membrane lipids was increased by gangliosides (Harris and Groh 1985), which may explain why the outer leaflet of the lipid bilayer of neuronal membranes, which has a large ganglioside content, is unusually sensitive to anesthetic agents. Anesthetics may affect calcium-dependent potassium conductance in the central nervous system (Caldwell and Harris 1985). The blockage of potassium conductance by chloroform and other anesthetics resulted in depolarization of squid axon (Haydon et al. 1988). 

General anesthetic drugs have the ability to reduce the level of consciousness in a dose dependent fashion. The study of the neurobiological mechanisms of action of these drugs may provide insight into the systems that are necessary for the existence of consciousness. It clearly cannot be assumed however, that the systems that underlie the action of these substances are in themselves sufficient for consciousness. Indeed, within a complex neural network, any number of small alterations can disturb the whole. This chapter focuses on what is known about the molecular mechanism of action of drugs that are used clinically for general anesthesia. 

Hemmings HC et al Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci 2005 26 503. [PMID 16126282]... 

Kubista H, Boehm S (2006) Molecular mechanisms underlying the modulation of exocytotic noradrenaline release via presynaptic receptors. Pharmacol Ther 112 213 12 Lakhlani PP, MacMillan LB, Guo TZ, McCool BA, Lovinger DM, Maze M, Limbird LE (1997) Substitution of a mutant a2A-adrenergic receptor via hit and run gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc Natl Acad Sci USA 94 9950-5... 

The molecular mechanism of local anesthesia, the location of the local anesthetic dibucaine in model membranes, and the interaction of dibucaine with a Na+-channel inactivation gate peptide have been studied in detail by 2H- and 1H-NMR spectroscopy [24]. Model membranes consisted of PC, PS, and PE. Dibucaine was deuterated at H9 and H3 of the butoxy group and at the 3-position of the quinoline ring. 2H-NMR spectra of the multilamellar dispersions of the lipid mixtures were obtained. In addition, spectra of deuterated palmitic acids incorporated into mixtures containing cholesterol were obtained and the order parameter, SCD, for each carbon... 

Mechanism of action. Na -channel blocking antiarrhythmics resemble most local anesthetics in being cationic amphiphilic molecules (p.206 exception phenytoin, p.191). Possible molecular mechanisms of their inhibitory effects are outlined on p.202 in more detail. Their low structural specificity is reflected by a low selectivity toward different cation channels. Besides the Na channel. Carotid 1C channels are also likely to be blocked. Accordingly, cationic amphiphilic antiarrhythmics affect both the depolarization and repolarization phases. Depending on the substance, AP duration can be increased (Class IA), decreased (Class IB), or remain the same (Class IC). Antiarrhythmics representative of these categories include Class IA—quinidine, procainamide, ajmaline, disopyramide Class IB—lidocaine, mexile-tine, tocainide Class IC—flecainide, propafenone. 

The molecular mechanism of action of inhalation anesthetics remains a matter of controversy. The classical view is that narcosis is induced by an unspecific disruption of cell membrane lipids by insertion of the lipophilic anesthetic [95]. Studies of enantiomerically pure analogs of several of the compounds depicted in Scheme 4.42 [96] have, however, revealed clear differences between the effects of enantiomers [97] (Scheme 4.43). There is also a growing body of evidence that the anesthetic effect is at least partly because of specific interaction with proteins [98], for example potassium ion channels and central nicotinic acetylcholine receptors [99]. 

Tang, P., Xu, Y. (2002). From the Cover Large-scale molecular dynamics simulations of general anesthetic effects on the ion channel in the fully hydrated membrane The implication of molecular mechanisms of general anesthesia. Proceedings of the National Academy of Sciences of the United States of America, 99(25), 16035-16040. 

Ueda, I., Kamaya, H., et al. (1976). Molecular mechanism of inhibition of firefly luminescence by local anesthetics. Proceedings... 

Yeh, J.Z. Blockade of sodium channels by stereoisomers of local anesthetics. In Fink, B.R (ed.) Molecular Mechanisms of Anesthesia, pp. 35-44. Raven Press New York. 

Butterworth JF IV, Strichartz GR. Molecular mechanisms of local anesthetics a review. Anesthesiology 1990 72 711-734. 

Harrison NL, Flood P. Molecular mechanisms of general anesthetic action. Sci Med 1998 (May June) 50 18-27. 

Olsen RW. The molecular mechanism of action of general anesthetics structural aspects of interactions with GABAa receptors. Toxicol Lett 1998 100-101 193-201. 

Tinker, J.H. Voices from the past—from ice crystals to fruit flies in the quest for a molecular mechanism of anesthetic action. Anesth. Analg. 1993, 77,1-3. 

The molecular mechanism of action of anesthetics has defied pharmacologists and biochemists for more than five decades. To be sure, it is puzzling that compounds as different from each other as rare gases and chloroform manifest the same biological activity. Most anesthetics are liposoluble, and the effectiveness of an anesthetic correlates with its solubility in lipids. 

S.J. Mihic and R.A. Harris. Molecular mechanisms of anesthetic action on ligand-gated ion channels. Neurotransmissions, XIII (1997) 1-7. 

It has been proposed that local anesthetics pass nerve membrane by neutral species despite the clinical adminsitration of the cationic form. Experimental molecular information is required for a better understanding of the mechanism. Thus the NMR information can be useful to the anesthetic discharging in membranes. 

A mechanism of local anesthetic action in which they serve as sodium channel blockers has been proposed. According to this mechanism, the molecular targets of local anesthetic action are the voltage-requiring sodium channels, which are present in all the neurons. The process of local anesthesia by respective drugs can be schematically represented in the following manner. 

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