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Despite the close correlation between lipid solubility and anesthetic potency, deviations from this correlation do exist. For example, enflurane and isoflurane are structural isomers (see Fig. 4-1 ) having approximately the same oil-gas partition coefficient, but the anesthetic requirement for enflurane is 45% to 90% greater than that for isoflurane (see Table 4-2 ). These differences in anesthetic requirements for agents having similar oil-gas partition coefficients suggest that the potency of an agent depends on factors other than lipid solubility.
Several of the commonly used inhaled anesthetics (see Fig. 4-1A ) exist as mixtures of two stereoisomers, which are nonsuperimposable compounds that are mirror images of each other, having identical physicochemical properties except for the direction in which they rotate polarized light. For isoflurane stereoisomers in rats, the (+) isomer is 17% to 53% more potent than the (-) isomer.[92] The differential effects of the inhaled anesthetic stereoisomers are relatively modest.
Another apparent exception to the Meyer-Overton rule is the ability of certain lipid-soluble compounds to produce convulsions. Complete halogenation or full halogenation of the end-methyl groups of alkanes and ethers tends to decrease the anesthetic potencies of these agents and to enhance convulsant activity.[93] Flurothyl (CF3 CH2 OCH2 CF3 ) produces convulsions at concentrations an order of magnitude less than those predicted to be anesthetic by the Meyer-Overton rule.[94] Although loss of the righting reflex in the mouse at very high flurothyl concentrations implies an anesthetic effect, 3% to 4% atm flurothyl only marginally decreases the isoflurane MAC in dogs.[94]
Compound 485 (see Fig. 4-1C ) possesses completely halogenated end-methyl groups and is a structural isomer of enflurane and isoflurane. It has occasionally produced convulsions in dogs at concentrations near 6% atm.[95] As an isomer of enflurane and isoflurane, it was predicted to have similar potency and solubility characteristics; however, its MAC was found to be 12.5% atm. This high MAC value was balanced by an approximately fourfold lower oil-gas partition coefficient (see Table 4-2 ).[95]
Convulsant halogenated ethers have different physical properties from the anesthetic halogenated ethers and have different effects on synaptic transmission. In dissociated rat brain neurons, halothane and enflurane enhance the response to GABA, whereas flurothyl decreases the GABA response (see Fig. 4-7 ).[49] In contrast to the enhancement of agonist-induced responses at GABAA receptors by anesthetic ethers, flurothyl acts as a noncompetitive antagonist and decreases current flow through GABAA receptors.[96]
There has been a long-standing impression that the highly lipid-soluble
paraffin hydrocarbon n-decane was nonanesthetic in
animals, even though less soluble paraffin homologs such as n-pentane
caused anesthesia. This decrease in anesthetic potency in the higher members of
a homologous series is known as the cutoff effect.
[97]
However, detailed reexamination of this issue
has revealed the cutoff for n-alkanes may be explained
by limited delivery of the larger alkanes because of decreasing volatility. Although
decane does not anesthetize rats when given alone at its saturated vapor pressure,
anesthetic properties are demonstrated by an ability to decrease the requirement
for isoflurane.[98]
A "true" cutoff exists for
the perfluoroalkanes.[99]
Perfluoromethane (CF4
)
produces anesthesia in rats (MAC 
60 atm), but perfluoroethane (CF3
CF3
)
and longer-chain perfluorinated derivatives are nonanesthetic despite being soluble
in hydrophobic solvents and in tissues.[99]
In addition to the nonanesthetic perfluoroalkane gases previously discussed, certain volatile polyhalogenated agents that are even more lipid soluble but lack anesthetic properties have also been discovered.[100] [101] [102] Examples of such nonanesthetics are seen in Figure 4-10 . These nonanesthetics do not produce anesthesia when administered alone, even when administered at partial
Figure 4-10
Examples of nonanesthetics (i.e., nonimmobilizers).
Although these compounds have oil-gas partition coefficients (43.5 for 1,2-dichlorohexafluorocyclobutane;
25 for 2,3-dichlorooctafluorobutane; 10.8 for 1-chloro-1,2,2,2-tetrafluoroethyl chlorodifluoromethyl
ether) similar to those of conventional anesthetics (see Table
4-2
), they completely lack anesthetic properties as determined by minimum
alveolar concentration (MAC) measurements.[100]
[102]
These nonanesthetics are not inert. They quickly reach the brain, produce excitable behavior, and typically cause convulsions when administered at high enough partial pressures.[100] [101] [102] [103] Because MAC is used as the end point to define a nonanesthetic, it is more appropriate to call these compounds nonimmobilizers than nonanesthetics. Although these nonimmobilizers fail to produce immobility in response to a noxious stimulus, they do impair learning and memory and cause amnesia.[31] [104]
The nonimmobilizers may be helpful in identifying anesthetic sites and mechanisms of action.[105] Physiologic or biochemical and biophysical changes produced by conventional anesthetics in a model system thought to be important for the anesthetic state (as measured by MAC) should not be produced by the nonimmobilizers.
The suggestion of a possible nonhydrophobic anesthetic site of action is not new. For example, Pauling[106] suggested that anesthesia might be caused by the ability of anesthetics to precipitate the formation of hydrates. These hydrates are cagelike structures of water molecules surrounding a central anesthetic molecule, and it was speculated that hydrate microcrystals could alter the transmission of electrical charge through a neuron.[106] However, a unitary hydrate theory of anesthesia seems unlikely because there is a poor correlation between the ability of anesthetics to form hydrates and their anesthetic potency.
Another hypothesis is that certain inhaled anesthetics act by disrupting hydrogen bonds.[107] This cannot be a unitary hypothesis because compounds such as xenon and argon are anesthetics but do not form hydrogen bonds. One suggestion is that general anesthetic target sites have, in addition to an overall hydrophobicity, a polar component that is a relatively poor hydrogen bond donor but that accepts a hydrogen bond about as well as water. [107] If hydrogen bonds are important in anesthesia, substitution of hydrogen for deuterium atoms in anesthetic molecules might alter the hydrogen bonding capabilities of a compound and change its anesthetic potency. However, the identical anesthetic potencies of halothane and deuterated halothane [108] do not support this prediction.
Although the Meyer-Overton rule postulates that anesthesia occurs when a sufficient number of anesthetic molecules dissolve at a certain site, it does not explain why anesthesia results. One suggestion, called the critical volume hypothesis, is that anesthesia occurs when the absorption of anesthetic molecules expands the volume of a hydrophobic region beyond a critical amount. Such an expansion may produce anesthesia by obstructing ion channels or by altering the electrical properties of neurons.
A prediction of the volume expansion hypothesis is that anesthetizing partial pressures of inhaled agents should produce a consistent volume expansion in a model hydrophobic system. Anesthetizing doses of inhaled agents cause hydrophobic solvents to undergo a significant increase in volume.[109] The hypothesis also predicts that anesthesia should be reversed by compressing the volume of the expanded hydrophobic region, and high pressures do reverse many effects of anesthetics in vivo.[14] However, the influence of body temperature on anesthetic requirement (see Fig. 4-3 ), a nonlinear pressure antagonism for certain anesthetics, and the fact that not all lipid-soluble compounds are anesthetics are findings that are difficult to reconcile with the critical volume hypothesis. Although the critical volume hypothesis is a useful model for estimating the interactions between pressure and inhaled anesthetics, it probably is an oversimplified view of the way in which anesthetics act.
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