Anesthetics partitioning into membranes

Seelig, A., Allegrini, P. R. and Seelig, J. (1988). Partitioning of local anesthetics into membranes surface charge effects monitored by the phospholipid head-group, Biochim. Biophys. Acta, 939, 267-276. 

Figure 13.6 Applying pressure drives anesthetic molecules into water from lipid bilayer membranes. K is the partition coefficient from water into the bilayer. Source S Kaneshina, H Kamaya, I Ueda, J Coll InterfSci 93, 215-224 (1983).

Solutes partition into lipid bilayers. Robinson Crusoe and his trusty friend Friday are stranded on a desert island and need to conserve their whiskey. Crusoe, an anesthesiologist, realizes that the effect of alcohol, as with other anesthetics, is felt when the alcohol reaches a particular critical concentration, co, in the membranes of neurons. Crusoe and Friday have only a supply of propanol, butanol, and pcntanol, and a table of their free energies of transfer for T = 300 K. 

This conclusion has been confirmed in simulations of several solutes permeating different membranes. Benzene in DMPC at 310 K [9,10], oxygen in DPPC at 350 K [13], and several alkanes and fluoroalkanes in GMO at 310 K [16,19] all tend to accumulate in the middle of the bilayer. In contrast, a series of small, polar, anesthetically relevant molecules in GMO were found to reside mostly in the interfacial region [16,19]. Several examples are shown in Figure 4. The same preference was observed for a clinical anesthetic, halothane, in DPPC [15]. The tendency of structurally diverse, polar solutes to accumulate at the interface was also found in recent NMR studies. Polar anesthetics, such as 1-chloro-1,2,2-trifluorocyclobutane, halothane, isoflurane, enflurane, xenon and ethanol were all found to exhibit a preference for the water-phospholipid bilayer interface [38-42]. In contrast, nonpolar 1,2-dichlorohexafluorobutane partitions into the hydrocarbon core of the membrane [39,41]. 

General anesthetics are usually small solutes with relatively simple molecular structure. As overviewed before, Meyer and Overton have proposed that the potency of general anesthetics correlates with their solubility in organic solvents (the Meyer-Overton theory) almost a century ago. On the other hand, local anesthetics widely used are positively charged amphiphiles in solution and reversibly block the nerve conduction. We expect that the partition of both general and local anesthetics into lipid bilayer membranes plays a key role in controlling the anesthetic potency. Bilayer interfaces are crucial for the delivery of the anesthetics. 

Several general anesthetics (isoflurane, ketamine, thiopental, etomidate) have one or more chiral carbons and thus exist as pairs ot stereoisomers. In many cases one stereoisomer is more potent than the other at providing anesthesia despite little difference in pharmacokinetics (Christensen Lee, 1973 Benthuysen et ak, 1989 Harris et ak, 1992 Dickinson et ak, 1994). The stereoisomers have equal hydrophobic properties and partition equally into the membrane. 

EXAMPLE 13.6 Pressure affects a two-state equilibrium. A common anesthetic drug molecule is halothane (2-bromo-2-chloro-l,l,l-trifluoroethane). Its mode of action is presumed to involve partitioning from water (state A) into lipid bilayer membranes (state B). Figure 13.6 shows how the partitioning equilibrium depends on pressure. Putting values of (p.lnX) = (0,7.84) and (280, 7.6) into Equation (13.48) gives Av = Ubiiayer fwater ... 

Many local anesthetics have significant surface activity and it is tempting to correlate their surface activity to their action. However, one should not forget other important factors such as partitioning of the drug into the nerve membrane (a factor that depends on the pK ) and the distribution of hydrophobic and cationic groups which must be important for the appropriate disruption of nerve membrane function. 

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