A range of very different compounds are used in medicine as anaesthetics. They don't seem to have much in common chemically but they all seem to keep people asleep while medics are doing nasty things to them.

Inhaled anaesthetics include a variety of fluorocarbon gases such as halothane and sevoflurane plus barbiturates like thiopental, oddballs like propofol and even xenon:

anaesthetic structures

What do these heterogeneous compounds have in common and how do they work?

  • $\begingroup$ Comments are not for extended discussion; this conversation has been moved to chat. $\endgroup$ – Faded Giant Nov 21 '17 at 18:01

This answer is a general answer, based on some research.

The mechanisms behind anaesthetics is not entirely understood, according to the article Mechanisms of Anesthesia: Towards Integrating Network, Cellular, and Molecular Level Modeling (Arhem et al. 2003), primarily due to, as you alluded to in your question, the fact that anaesthetics come from a very diverse group of chemicals.

In the fragmentary data presented in the article, the conclusions the authors made were that

general anesthetics modulate the activity of ion channels, the main targets being GABAA and NMDA channels and possibly voltage-gated and background channels, thereby directly or indirectly hyperpolarizing neurons in thalamocortical loops, and thereby disrupting coherent oscillatory activity in the cortex. In our view, it does not seem unreasonable that the ultimate target is NMDA channels.

There is also a suggestion that the unconsciousness that results is in a way like sleep, an adaptive response to the chemical input.

Interesting perspectives are provided in the article Why anesthetic mechanism research has failed, and what to do about it (Hammeroff), where the author suggests, research is needed in investigating anaesthetic mechanisms by

Look closely at the quantum nature of anesthetic binding by van der Waals London forces.

In terms of local anaesthetics, the slides included in the presentation Local Anesthetics: Overview state that the mechanism here is due to

Ionized form of weak base blocks $\ce{Na^+}$ channels by binding to an internal sequence involved in channel inactivation

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One of the perhaps most important theory of anaesthesia is that:

Most anaesthetics enhance the activity of inhibitory GABAa receptors and other cys-loop ligand-gated ion channels. Other important effects are the activation of a subfamily of potassium channels (the two-pore domain K+ channels) and inhibition of excitatory NMDA receptors

Almost all anaesthetics (with the exceptions of cyclopropane, ketamine and xenon) potentiate the action of GABA at GABAa receptors (1)

At the cellular level, the effects of anaesthetics are to enhance tonic inhibition (through enhancing the actions of GABA), reduce excitation (opening K+ channels) and to inhibit excitatory synaptic transmission (by depressing transmitter release and inhibiting ligand-gated ion channels).(2)

  • There is some controversy about whether or not xenon potentiates GABAa responses but at present the weight of evidence suggests it does not.
  • Ketamine is believed to act by blocking activation of the NMDA receptor. (NMDA receptors are also an important site of action for anaesthetics such as nitrous oxide, xenon )

$\ce{GABA}$ receptors are ligand-gated Cl− channels made up of five subunits (generally comprising two α, two β and one γ or δ subunit).

Anaesthetics can bind to hydrophobic pockets within different GABAa receptor subunits.

Specific mutations of the amino acid sequence of the α subunit inhibit the actions of volatile anaesthetics but not those of intravenous anaesthetics, whereas mutations of the β subunit inhibit both volatile and intravenous anaesthetics.

This suggest that volatile anaesthetics may bind at the interface between α and β subunits (analogous to benzodiazepines that bind at the interface between α and γ/δ subunits:

enter image description here

Putative anaesthetic binding sites on GABAa receptor subunits. [A] A model of the α1 subunit of the GABAa receptor with a molecule of isoflurane shown sitting in a putative binding site. The transmembrane α-helices (TM) are numbered 1–4. [B] A model of the β2 subunit of the GABAa receptor with a molecule of propofol shown sitting in the putative binding site. (Adapted from Hemmings HC et al. 2005 Trends Pharmacol Sci 26, 503–510.)


  • Olsen, R.W., Li, G.D., 2011.GABAa receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation. Can. J. Anaesth. 58, 206–215.

  • Schüttler, J., Schwilden, H., 2008. Modern anesthetics. Handb. Exp. Pharmacol. 182.

  • Rang and Dale’s Pharmacology 8th ed H P Rang et al

  • Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th Edition

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It's been suggested by Thomas Heimburg's group in Denmark (perhaps others) that anesthetics work by a common depression of the gel/fluid transition temperature in nervous membranes.

Some virtues of this view include its consistency with the action of anesthetics being proportional to their partition in lipid (Meyer-Overton rule... and notice this rule involves the same puzzle you raise, namely why this apparent diversity shares some property). Another virtue of the view is its explanation of the pressure-reversal of anesthesia in a quantitative manner.

My (admittedly superficial) understanding is Heimberg's group (and perhaps others) is using this as one main bit of ammo against the familiar Hodgkin/Huxley neural model. In the paper linked, they suggest it is not necessarily inconsistent with a molecular mechanism (of anesthesia), though of course the problem you raise happens to be the motivation for their thermo' picture. Maybe the two cannot be consistent, but that is not the author's statement (if anything it is due to my ignorance). I would be interested to see more comments. Good question!

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