Pharmacological Reviews, Vol 24, 583-655, Copyright © 1972 by the American Society for Pharmacology and Experimental Therapeutics

The Membrane Actions of Anesthetics and Tranquilizers

¹ Pharmacology Department, University of Toronto, Toronto, Canada

A diagrammatic summary of the membrane actions of anesthetics and tran-quilizers is shown in figure 15. According to the definition of an anesthetic as a drug which directly blocks the membrane action potential, without appreciably affecting the resting potential, a wide variety of lipid-soluble compounds may be considered as anesthetics. Under conditions of general anesthesia the membrane concentration of an anesthetic is 0.003 moles/kg dry membrane, the anesthetic occupying a volume of 0.02% in the membrane phase. Under conditions of local anesthesia the membrane concentration is 0.04 moles/kg membrane, with an occupying volume of 0.3% in the membrane. The partitioning into the membrane is about 1/10 that of olive oil and about that of octanol. These figures hold for many nerve-blocking drugs, and in order to explain differences in the in vivo action of these drugs, other factors must be considered, such as anesthetic sensitization etc. The biomembranes expand or swell about 10 times more than the anesthetic volume of occupation in the membrane, 0.4% expansion occuring under conditions of general anesthesia, and 2 to 3% expansion occuring under conditions of local anesthesia. Although the anesthetics electrically stabilize the membrane, they fluidize and disorder the components within the membrane, probably including membrane water. As a consequence of membrane expansion, membrane-associated enzymes and proteins can be either stimulated or inhibited. The pathways for facilitated fluxes of solutes across membranes are invariably depressed, presumably because of the conformation changes brought about by the membrane-expanding anesthetics; the Na⁺-conductance channel of the action potential appears to be one of these facilitated pathways. The anesthetic amines displace membrane-bound Ca⁺⁺ and generally depress passive fluxes of cations. The neutral anesthetics generally increase membrane-bound Ca⁺⁺ and generally increase the passive fluxes. The membrane fluidization may explain the enhanced neurosecretion of membrane-bound materials, by a mechanism of membrane-membrane fusion.

Note:

I thank Margaret Wong, Marsha Foster, Stanley Moy Yen and Allan Staiman for their assistance in preparing this review. The author's work was supported by the Ontario Mental Health Foundation, the Addiction Research Foundation of Ontario, and the Medical Research Council of Canada (MT-2951). I thank Dr. L. Spero and Dr. H. Schneider (N.R.C., Ottawa) for the use of their unpublished data.

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