Editing General anaesthetic (section)

==Mechanism of action==
{{See also|Theories of general anaesthetic action}}
Induction and maintenance of general anesthesia, and the control of the various physiological side effects is typically achieved through a combinatorial drug approach. Individual general anesthetics vary with respect to their specific physiological and cognitive effects. While general anesthesia induction may be facilitated by one general anesthetic, others may be used in parallel or subsequently to achieve and maintain the desired anesthetic state. The drug approach utilized is dependent upon the procedure and the needs of the healthcare providers.<ref name=":04" />

It is postulated that general anaesthetics exert their action by the activation of inhibitory [[central nervous system]] (CNS) receptors, and the inactivation of CNS [[Neurotransmitter#Excitatory and inhibitory|excitatory receptors]]. The relative roles of different receptors is still under debate, but evidence exists for particular targets being involved with certain anaesthetics and drug effects.<ref name=":04" /><ref name=":32">{{Cite journal|last=Franks|first=Nicholas P|date=2006-01-01|title=Molecular targets underlying general anaesthesia|journal=British Journal of Pharmacology|language=en|volume=147|issue=S1|pages=S72–S81|doi=10.1038/sj.bjp.0706441|pmid=16402123|issn=1476-5381|pmc=1760740}}</ref><ref name=":42">{{Cite journal|last1=Steinberg|first1=E. A.|last2=Wafford|first2=K. A.|last3=Brickley|first3=S. G.|last4=Franks|first4=N. P.|last5=Wisden|first5=W.|date=2015-05-01|title=The role of K2P channels in anaesthesia and sleep|journal=Pflügers Archiv: European Journal of Physiology|language=en|volume=467|issue=5|pages=907–916|doi=10.1007/s00424-014-1654-4|pmid=25482669|issn=0031-6768|pmc=4428837}}</ref>

Below are several key targets of general anesthetics that likely mediate their effects:

=== GABA<sub>A</sub> receptor agonists ===
* [[GABAA receptor|GABA<sub>A</sub> receptors]] are chloride channels that [[Hyperpolarization (biology)|hyperpolarize]] neurons and function as inhibitory CNS receptors. General anesthetics that agonize them are typically used to induce a state of sedation and/or unconsciousness. Such drugs include [[propofol]], [[etomidate]], [[isoflurane]], [[benzodiazepine]]s ([[midazolam]], [[lorazepam]], [[diazepam]]), and [[barbiturate]]s ([[sodium thiopental]], [[methohexital]]).<ref name=":04" /><ref name=":16" /><ref name=":25" />

=== NMDA receptor antagonists ===
* [[Ketamine]], an [[NMDA receptor]] antagonist, is used primarily for its analgesic effects and in an [[Off-label use|off-label]] capacity for its anti-depressant effects. This drug, however, also alters arousal and is often used in parallel with other general anesthetics to help maintain a state of general anesthesia. Administration of ketamine alone leads to a dissociative state, in which a patient may experience auditory and visual [[hallucination]]s. Additionally, the perception of pain is dissociated from the perception of noxious stimuli. Ketamine appears to bind preferentially to the NMDA receptors on GABAergic interneurons, which may partially explain its effects.<ref name=":04" /><ref name=":16" /><ref name=":25" />

=== Two-pore potassium channels (K<sub>2P</sub>s) activation ===
* [[Two-pore-domain potassium channel|Two-pore potassium channels (K<sub>2P</sub>s)]] modulate the potassium conductance that contributes to the [[Resting potential|resting membrane potential]] in neurons. Opening of these channels therefore facilitates a [[Hyperpolarization (biology)|hyperpolarizing]] current, which reduces neuronal excitability. K<sub>2P</sub>s have been found to be affected by general anesthetics (esp. halogenated inhalation anesthetics) and are currently under investigation as potential targets. The K<sub>2P</sub> channel family comprises six subfamilies, which includes 15 unique members. 13 of these channels (excluding TWIK-1 and TWIK-2 homomers) are affected by general anesthetics. While it has not been determined that general anesthetics bind directly to these channels, nor is it clear how these drugs affect K<sub>2P</sub> conductance, [[Electrophysiology|electrophysiological]] studies have shown that certain general anesthetics result in K<sub>2P</sub> channel activation. This drug-elicited channel activation has been shown to be dependent upon specific amino-acids within certain K<sub>2P</sub> channels (i.e. TREK-1 and TASK channels). In the case of TREK-1, activation was shown through an anesthetic perturbation to membrane lipid clusters and activation of phospholipase D2; direct binding of anesthetics to purified reconstituted TREK-1 had no effect on conductance.<ref>{{cite journal |last1=Pavel |first1=Mahmud Arif |last2=Petersen |first2=E. Nicholas |last3=Wang |first3=Hao |last4=Lerner |first4=Richard A. |last5=Hansen |first5=Scott B. |title=Studies on the mechanism of general anesthesia |journal=Proceedings of the National Academy of Sciences |date=16 June 2020 |volume=117 |issue=24 |pages=13757–13766 |doi=10.1073/pnas.2004259117|pmid=32467161 |pmc=7306821 |bibcode=2020PNAS..11713757P |doi-access=free }}</ref>  The effects of certain general anesthetics are less pronounced in K<sub>2P</sub> [[Knockout mouse|knock-out mice]], as compared to their [[Wild type|wild-type]] counterparts. Cumulatively, TASK-1, [[KCNK9|TASK-3]], and [[KCNK2|TREK-1]] are particularly well supported as playing a role in the induction of general anesthesia.<ref name=":16" /><ref name=":32" /><ref name=":42" />

=== Others ===
* [[Opioid receptor]] agonists are primarily utilized for their analgesic effects. These drugs, however, can also elicit sedation. This effect is mediated by opioid actions on both opioid and acetylcholine receptors. While these drugs can lead to decreased arousal, they do not elicit a loss of consciousness. For this reason, they are often used in parallel with other general anesthetics to help maintain a state of general anesthesia. Such drugs include [[morphine]], [[fentanyl]], [[hydromorphone]], and [[remifentanil]].<ref name=":04" /><ref name=":25" />
* Administration of the [[Adrenergic receptor|alpha2 adrenergic receptor]] agonist [[dexmedetomidine]] leads to sedation that resembles [[non-REM]] sleep. It is used in parallel with other general anesthetics to help maintain a state of general anesthesia, in an off-label capacity. Notably, patients are easily aroused from this non-REM sleep state.<ref name=":04" /><ref name=":16" /><ref name=":25" />
* [[Dopamine receptor]] antagonists have sedative and [[antiemetic]] properties. Previously, they were used in parallel with opioids to elicit neuroleptic anesthesia ([[catalepsy]], analgesia, and unresponsiveness). They are no longer used in the context, because patients experiencing neuroleptic anesthesia were frequently aware of the medical procedures being performed, but could not move or express emotion. Such drugs include [[haloperidol]] and [[droperidol]].<ref name=":04" />