How do inhaled anesthetics work? We understand the answer at a pharmacokinetic level. Anesthetics diffuse from the lungs into the blood, and from the blood into neuronal tissue. We understand the answer at a pharmacodynamic level. Anesthetics suppress the body’s response to noxious stimulation. They suppress the brain’s ability to form memories. They suppress consciousness, rendering patients oblivious to surgery. We understand the processes of uptake and distribution. We understand the clinical responses to anesthetic drugs. We can answer the “how” question with sufficient precision to safely use the drugs to induce the remarkable state of general anesthesia.

Despite the vast amount that we do understand, we simply don’t know how inhaled anesthetics work. The above practical explanation of “how they work” doesn’t explain how anesthetics interact with neural tissue to render the patient still (“immobile”) when the surgeon cuts through the flesh. Where, exactly, does that happen? How, exactly, does that happen? By what pharmacological mechanism do inhaled anesthetics induce seemingly magical lack of responsiveness?

As discussed in Chapters 6 and 7, Giles Merkel and I described MAC as the potency of inhaled anesthetic that prevents response to painful stimulus in dogs.¹ Later, Larry Saidman and I described the same concept in humans.² Remarkably, the value of MAC was the same for dogs and humans. Given that we are so much smarter than dogs, why do our brains blink off at the same concentration that renders a dog immobile in response to noxious stimulation? It turns out that it’s not just humans and dogs that can be anesthetized. Nearly all living organisms can be “anesthetized” within a surprisingly narrow concentration range.³,⁴

To understand how anesthetics work, we looked for factors that affected MAC. Of course, this information was clinically important to safe anesthesia. However, identifying factors that affected MAC might also give us insight into how anesthetics work. We found that MAC was an absolute partial pressure, not a fraction of inspired air.⁵ That showed that inhaled anesthetics were acting
as drugs with dose versus response relationships that had nothing to do with the air that the patient was breathing.

One of our most intriguing findings from that time was the correlation of MAC with the lipophilicity of the anesthetic, ie, the ability of anesthetic gas to dissolve in oil.⁶ The question goes back to the observation Meyer⁷ and Overton⁸ described in Chapter 7 that lipophilicity (the ability of an anesthetic to dissolve in oil) was correlated with anesthetic potency over five orders of magnitude (see Figure 7.3). What does this mean? The correlation is too good, the span is too large, to be mere coincidence. John Severinghaus again provided the nidus: did lipophilicity correlate with our measurements of potency using MAC? It did (see Figure 7.2).⁶ Could this tell us something about how anesthetics work?

We found that the MAC of halothane and cyclopropane correlated directly with changes in body temperature.⁹ We noted that “The heat changes (enthalpies) calculated from these data correlated well with enthalpies of absorption of anesthetics to lipoprotein films. In the case of cyclopropane they also correlated well with the enthalpies found for hydrate formation from ice.” Pauling¹⁰ and Miller¹¹ had recently proposed that anesthesia resulted from the formation of hydrates or ice crystals at neuronal surfaces. Our calculations supported their theory, now long discarded and only of historical interest.

Using MAC as our measure of anesthetic potency, we probed for deviations from the correlation of lipophilicity and potency. We only found a few slight exceptions.¹² As Koblin noted, “The product of the anesthetizing partial pressure of an agent and its oil-gas partition coefficient varies less than twofold over a 70,000-fold range of anesthetic partial pressures.”¹³ The exceedingly lipophilic anesthetic thiomethoxyflurane (oil/gas partition coefficient 7230) had a correspondingly small MAC of 0.035% atm.¹⁴ Like the Meyer-Overton “theory,” the correlation of MAC with lipophilicity withstood extreme tests of the correlation.

The precise correlation of lipophilicity and potency, and the constancy of the product of lipophilicity × potency, supported the notion that inhaled anesthetics acted by their presence in lipid. Perhaps this was the lipid deep within the membrane bilayer. It might be lipid within some hydrophobic (water-repelling) portion of a neuronal protein. We were convinced that knowing where to look, the lipophilic regions of neurons, would readily take us to the answer. Most likely there was a simple answer that would, in retrospect, be obvious. All we needed was that “ah ha!” moment when someone would say “couldn’t this all be explained by X?” We would test X, and this hundred-year-old puzzle would be solved.