General anaesthetic

A general anesthetican anaesthetic (or anesthetic) that brings aboutreversible lossconsciousness.

Two typesgeneral anesthetic drugsused: inhalation anestheticsintravenous anesthetics (given by injection).

Inhalation anestheticsliquid or gaseous andusually delivered using an anesthesia machine. An anesthesia machine allows composingmixtureoxygen, anestheticsambient air, deliveringtopatientmonitoring patientmachine parameters. Liquid anestheticsvaporized inmachine.

Various compounds have been usedinhalation anesthesia, but onlyfewstilluse. nitrous oxide, isoflurane, desfluranesevofluraneprobably used most widely today.

Injection anestheticsusedinductionmaintenance ofstateunconsciousness. Amongmost widely used substancespropofol, etomidate, barbiturates such as methohexitalthiopental, benzodiazepines such as midazolamdiazepam,ketamine.

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Tablecontents

1 Pharmacologygeneral anesthetic drugs

1.1 Lipid solubility
1.2 Protein binding sites
1.3 The cutoff effect

2 Usessurgery
3 Usesemergency medicine
4 Usesintensive care medicine
5 Usesdiagnostics
6 Related topics

Pharmacologygeneral anesthetic drugs

The sitesactiongeneral anaesthetics have proved difficultfind, becausehave many different structures, ranging from complex steroids toinert monatomic gas xenon. Itclear, however, that general anaesthetics must act uponcentral nervous system by modifyingelectrical activityneurons. A changeelectrical activity must be brought about atmolecular level by modifyingfunctionion channels. This could occur by anaesthetic molecules binding directlyion channels or by their disruptingfunctionmolecules that maintain ion channels.

Many formsion channel have been cloned inpast decade, adding greatlyour knowledgeproteins involvedneuronal excitability. These range from voltage-gated ion channels, such as sodium, potassium,calcium channels, toligand-gated ionotropic ion channel superfamily andG protein-coupled ion channel superfamily. Although researchers generally agree that ion channels areultimate siteactiongeneral anaesthetics, thereconsiderable disagreement aboutmolecular mechanisms. Some hold that anaesthetics disruptactionsion channels indirectly, by modifying physical properties oflipid bilayer. Others believe that anaesthetics act by directly bindingspecific sites on ion channel proteins.

Lipid solubility

Von BibraHarless,1847, werefirstsuggest that anaesthetics may act by dissolving infatty fractionbrain cells. They proposed that anaesthetics dissolveremove fatty constituents from brain cells, changing their activityinducing anaesthesia. The first reportanaesthetic potency being relatedlipid solubility was published by H. H. Meyer1899, entitled "Zur Theorie der Alkoholnarkose". Two years latersimilar theory was published independently by Overton.

MeyerOverton had discoveredmost striking correlation observed betweenphysical propertiesgeneral anaesthetic moleculestheir potency. Meyer comparedpotencymany agents, defined asreciprocal ofmolar concentration requiredinduce anaesthesiatadpoles,their olive oil/water partition coefficient. He foundnearly linear relationship between potency andpartition coefficientmany typesanaesthetic molecules such as alcohols, aldehydes, ketones, ethers,esters. MeyerOverton also found thatanaesthetic concentration requiredinduce anaesthesia50% ofpopulationanimals (the EC₅₀) was independent ofmeans by whichanaesthetic was delivered, i.e.,gas or aqueous phase.

Protein binding sites

Two classesproteinsinactivated by clinical dosesanaesthetic intotal absencelipid. Theseluciferases, whichused by bioluminescent animalsbacteriaproduce light,cytochrome P450, which isgroupheme proteins that hydroxylatediverse groupcompounds, including fatty acids, steroids,xenobiotics such as phenobarbital. These proteins bind general anaesthetics andinhibited withpotency thatapproximately equaltheir potencygeneral anaesthesiaalso proportional toanaesthetic molecule's lipid solubility.

Fromcorrelation between lipid solubilityanaesthetic potency, both MeyerOverton had surmised that anaesthesia occurs whenanaesthetic reachescritical concentrationsome lipid phase withinbody. However, these results on lipid-free proteins show thatcorrelation between lipid solubilitypotencygeneral anaesthetics isnecessary but not sufficient conditioninferringlipid target site; general anaesthetics could equally well be bindinghydrophobic target sites on proteins inbrain.

The cutoff effect

There islimitation toMeyer-Overton correlation. As one ascendshomologous seriesanaesthetics, such asn-alcohols, one would expect fromMeyer-Overton correlation thatalcohols would become increasingly potent ascarbon chain length increases becausealcohols grow more hydrophobic. Insteadbecoming increasingly potent without limit however, at certain chain lengthsadditionjust one methylene group causesmoleculelose its abilityanaesthetise. Forn-alcoholscutoff occurs atcarbon chain lengthabout 13,forn-alkanes atchain lengthbetween 610, depending onspecies.

If general anaesthetics disrupt ion channels by partitioning intoperturbinglipid bilayer, then one would expect that their solubilitylipid bilayers would also displaycutoff effect. However, partitioningalcohols into lipid bilayers does not displaycutofflong-chain alcohols from n-decanoln-pentadecanol. A plotchain length vs.logarithm oflipid bilayer/buffer partition coefficient Klinear, withadditioneach methylene group causingchange inGibbs free energy-3.63 kJ/mol.

The cutoff effecteasily interpreted if target sitesgeneral anaestheticshydrophobic pocketsfixed dimensionsproteins. Asacyl chain grows,anaesthetic fills more ofhydrophobic pocketbindsgreater affinity. Whenmoleculetoo largebe entirely accommodated byhydrophobic pocket,binding affinity no longer increasesincreasing chain length. Whenaqueous solubility ofofmolecule exceeds that ofhydrophobic pocket, cutoff occurs.