Talk:Theories of general anaesthetic action

Chirality effect is small

As far as I know, the difference of the anaesthetic potency of chiral molecules is rather small (as far as I remember usually a few 10 percent, at most a factor of 2) and only seen for some chiral anesthetics. So it's by far smaller than usually seen in biologically active chiral molecules (think of thalidomide for example). So the small difference in anaesthetic potenciy of some chiral molecules are by no means a strong indication for a direct interaction between the anaesthetic and protein (by the way, the lipids itself are, despite what the article say, chiral because of the chiral carbon atom of the glycerol backbone). Ralf Schmelter 21:45, 2004 Nov 16 (MET)

Pocket-filling does not explain cutoff effect

The cutoff-effect mentioned, which, according to this article, is 'easily' explained by a hydrophic pocket of a fixed size, is found for many different homologeous series of chemical compounds. For example for 1-alcoholes, a cutoff of about n=12 (n is the number of carbon atoms) is found, while for perflouroalkanes the cutoff is at n=2. Clearly, this is not an evidence for that propoped hydrophobic pocket. Ralf Schmelter 21:45, 2004 Nov 16 (MET)

Lipid-based theories not excluded yet

As far as I can see, there is currently no theory which can accommodate all the various findings about the anaesthetic potency of various chemical compounds (see e.g. the vast amount of data by Eger et.al). The only thing which seems to be clear, is that the in the end the ligand-gated ion channels are the target of the anesthetics. But if they interact directly with these ion channels or the effect is indirect (e.g. as Cantor suggest, that the anesthetics change the lateral pressure profile of the membrane and therefore change the free energe difference between the open and closed state of the ion channel) remains unclear. The main problem for a theory seems to be, to incorporate the findings from such simple 'molecules' as argon to complex halogenated molecules. The theories I know are currently know, are only able to explain some of the findings, while others remained unexplained or are in contradiction to the theory. So I would not rule out the lipid-based theories (apart from the very simple ones). Ralf Schmelter 21:45, 2004 Nov 16 (MET)

Combine this with General anaesthetic ?

Does it really make sense to have this page stand by itself separate from another more comprehensive article like General anaesthetic? It is rather weak out of context. --Oasisbob 10:33, 1 December 2005 (UTC)

I think, due to the continued controversy and number of explanations proposed, this article will be able to stand by itself once it gives a comprehensive view of research on this topic. Tim Vickers (talk) 17:33, 22 April 2009 (UTC)

Still controvercial

In the recent years the lipid theory has recieved some revival. I don't think the issue can be called completely resolved yet. See f.ex: Heimburg T, Jackson A. The thermodynamics of general anesthesia. BIOPHYSICAL JOURNAL v. 92 i. 9 p. 3159-3165. 2007.

130.225.212.4 (talk) 10:29, 26 November 2008 (UTC)Kasper Feld

Theres a discussion of that here at Soliton model, should probably be linked. Bazzargh (talk) 19:20, 14 January 2010 (UTC)

P450s

I can't find any mention in PMID 16430569 of anesthetics being important inhibitors of P450s. What was the source for this statement? Tim Vickers (talk) 17:37, 22 April 2009 (UTC)

That was the sentence left from the previous author and I tried to leave as much as possible from the previous author. Here is the reference however: Frank S. LaBella, Douglas Stein and Gary Queen "Occupation of the cytochrome P450 substrate pocket by diverse compounds at general anesthesia concentrations", European Journal of Pharmacology,Volume 358, Issue 2, 2 October 1998, Pages 177-185, doi:10.1016/S0014-2999(98)00596-2 Anna Kuznetsova (talk) 15:24, 1 May 2009 (UTC)

Style should be encyclopedic

Wikipedia articles should follow a certain "encyclopedic" style, that is easier to recognize than to describe. On a quick reading, this article does not seem to be quite encylopedic: it reads more like a debate on a conference floor, than a cool boring survey of a debate that is happening "out there". Things are being said more than once, extra words and sentences are used to stress a point of view, etc. I tried to help a bit, but more work is needed... --Jorge Stolfi (talk) 19:31, 28 January 2013 (UTC)

The last paragraph of this article is particularly bad in terms of style and non-encyclopedic language. The content does not fit the trends of the article and the grammar and use of English make an already complex topic unreadable to the non-specialist. I am also suspicious, perhaps cynically, of the citation pattern. It does not fit the premise of the content; this is often the case when authors add/promote descriptions of their own research. --IcyEd (talk) 15:58, 9 July 2013 (UTC)

"Outdated lipid hypothesis" demise reported prematurely

I was disappointed that this article seems to be taking the view of one or two pieces of literature that 60 years of the lipid bilayer swelling hypothesis, is wrong. The four reasons for rejecting such a semi-mechanical idea are not really enough to do so:

• The chain-cutoff effect can be explained within conventional lipid bilayer swelling theory, and that is done in this article.
• The fact that temperature effects affect membrane fluidity as much as solubility of anesthetics, only means that the lipid bilayer swelling effect isn't simply a membrane-fluidity effect, but affects ion channels in other ways mechanical ways having to do with with simple thickening of the bilayer.
• The stereoselectivity of a (small minority) of general anesthetics argues only that these particular agents (not all of them) work by a genuine standard "protein receptor" pharmacological means-- but that is fine since hardly anybody believes that ALL general anesthetics work non-selectively on the bilayer (don't throw the baby out here with the bathwater when a few general anesthetics are found to act like drugs, eg. opiates, benzodiazepines).
• The irritability-inducing and seizure-inducing effect of some very hydrophobic compounds like flurothyl reminds us that the lipid bilayer of neurons can be compressed as well as thickened, and that when this is done, the opposite of general anesthesia is achieved. Even the bilayer hypothesis admits that there may be a limit as to how hydrophobic an anesthetic can be, and that limit is one where the bilayer is not expanded but compressed by the agent. This happens under high pressure in the high pressure nervous syndrome with the highly hydrophobic gases helium and neon, and the fact that the high pressure effect, at least, can be reversed with standard gas anesthetics (including just the right amount of high pressure nitrogen narcosis) argues that this, at least, is a semi-mechanical effect. Perhaps it is with florothyl as well (nobody seems to have studied it much).

Finally, the question arises as to how we are to tell a lipid bilayer effect from one a more "pharmacological effect" in which an anesthetic interacts with a hydrophobic domain of a specific protein? To some extent it is difficult to differentiate them, as the bilayer begins to look like a "receptor site" if we aren't too picky about what we regard as a "drug-receptor interaction." However, lack of chemical reactivity of xenon, krypton, nitrogen, and (in particular) argon, coupled with the ability of all these agents to produce deep and profound general anesthesia lacking nothing in quality (given a high enough partial pressure) argues that the mechanism here is quantitative different than a standard ligand-agent chemical bond. The high pressure reversal of most general anesthetics, and the general anesthetic reversal of high pressure nervous syndrome, are two sides of the same coin. Both effects look more physical than one might ascribe to any particular membrane protein like the GABA receptor. They are simply too general, and they work with inert gases like argon as anesthetic and helium as anti-anesthetic. That isn't chemical pharmacology as we know it. SBHarris 00:47, 20 July 2013 (UTC)

That graph though.

Someone has to change it, it either needs units, correct labels or both. It says the OPPOSITE of the meyer-overton hypothesis at the moment... — Preceding unsigned comment added by 185.58.164.44 (talk) 08:20, 15 June 2015 (UTC)

New section about the Orch-OR hypothesis

Hi all, I talked with anesthesiologist Stuart Hameroff about his theory of general anesthesia called Orch-OR. He wrote an addition to this page and asked me to submit it on his behalf. Would there be interest in adding this? — Preceding unsigned comment added by Issac.trotts (talk • contribs) 23:46, 14 September 2019 (UTC)

The section on microtubules contains pseuodscientific gibberish. An example of a word salad is this part of sentence:

scale-invariant, multi-level hierarchy which extends upward by resonant interference to slower frequencies seen in EEG.

The writer has no whatsoever understanding of what the jargon words mean, that is why I have inserted a few Wikilinks. Danko Georgiev (talk) 10:37, 31 August 2022 (UTC)

I have moved the whole speculative section on Microtubule quantum vibration theory of anesthetic action to the Orch OR article, which seems to be the more appropriate place for this text. Danko Georgiev (talk) 17:31, 31 August 2022 (UTC)

References

The article on general anaesthetic action was biased and dubious

The structure of the whole article was written by highly biased or uneducated editors. The division of biomolecules into proteins and lipids, is very basic, and appears as if it is taken from a textbook written in 1900. The human proteome contains about 20 000 different proteins, and in modern molecular biology it is common knowledge that different proteins have different functions. Different anesthetics target different types of proteins and cause anesthesia by different mechanisms. The idea that there should be only 1 mechanism of general anesthesia is naive thinking from 1900, but is demonstrably false by 21st century science. Many of the major protein targets of modern anesthetics were not even mentioned in the article main text. Danko Georgiev (talk) 10:47, 31 August 2022 (UTC)

I have now edited the overall story and have mentioned the main action of intravenous anesthetics on GABA_A receptors. The newly inserted sections are brief, but can be expanded by anyone interested to read the large amount of literature on GABA_A receptor involvement in anesthesia. Danko Georgiev (talk) 16:27, 1 September 2022 (UTC)

2/3 of the article are still dedicated to "outdated lipid hypotheses"

I think that the large portion of text on "outdated lipid hypotheses" and then criticizing the "outdated lipid hypotheses" should be reduced in length and possibly moved to the end of the article in a "History section". I am not sure that a person who is searching online for verified information on how anesthetics work would like to read volumes on the debate that took place in 1900s. The modern developments start from 1980s with the cited works of Franks and Lieb in Nature. Danko Georgiev (talk) 13:58, 1 September 2022 (UTC)