View source for General anaesthetic

{{short description|Compound that induces a loss of consciousness}}
{{Hatnote|These drugs are not to be confused with [[sleep medicine]] for [[insomnia]].}}

'''General anaesthetics''' (or '''anesthetics''') are often defined as compounds that induce a loss of consciousness in humans or loss of [[righting reflex]] in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act as [[analgesic]]s and should also not be confused with [[sedative]]s. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompass multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.<ref>{{Cite journal|last=Franks|first=Nicholas P.|date=May 2008|title=General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal|journal=Nature Reviews Neuroscience|language=En|volume=9|issue=5|pages=370–386|doi=10.1038/nrn2372|pmid=18425091|s2cid=14020693|issn=1471-0048}}</ref>

General anesthetics elicit a state of [[General anaesthesia|general anesthesia]]. It remains somewhat controversial regarding how this state should be defined.<ref name=":04">{{Cite journal|last1=Brown|first1=Emery N.|last2=Purdon|first2=Patrick L.|last3=Van Dort|first3=Christa J.|date=2011-06-21|title=General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis|journal=Annual Review of Neuroscience|volume=34|issue=1|pages=601–628|doi=10.1146/annurev-neuro-060909-153200|pmid=21513454|issn=0147-006X|hdl=1721.1/86331|pmc=3390788}}</ref> General anesthetics, however, typically elicit several key reversible effects: immobility, analgesia, [[amnesia]], unconsciousness, and reduced autonomic responsiveness to noxious stimuli.<ref name=":04" /><ref name=":16">{{Cite book|title=Goodman & Gilman's pharmacological basis of therapeutics.|date=2011|publisher=McGraw-Hill|others=Goodman, Louis S. (Louis Sanford), 1906-2000., Brunton, Laurence L., Chabner, Bruce., Knollmann, Björn C.|isbn=9780071624428|edition= 12th|location=New York|oclc=498979404}}</ref><ref name=":25">{{Cite book|last1=Katzung|first1=Bertram G.|title=Basic and clinical pharmacology|last2=Trevor|first2=Anthony J.|date=2014-12-23|others=Katzung, Bertram G., Trevor, Anthony J.|isbn=9780071825054|edition=Thirteenth|location=New York|oclc=875520239}}</ref>

==Mode of administration==
General anaesthetics can be administered either as gases or vapours ([[inhalational anaesthetic]]s), or as injections ([[intravenous]] or even [[Intramuscular injection|intramuscular]]). All of these agents share the property of being quite hydrophobic (i.e., as liquids, they are not freely [[miscible]]—or mixable—in water, and as gases they dissolve in oils better than in water).<ref name=":16" /><ref name=":52">{{Cite book|title=Rang & Dale's pharmacology|last=M.|first=Dale, M.|date=2007|publisher=Churchill Livingstone|others=Rang, H. P., Dale, Maureen M.|isbn=978-0443069116|edition= 6th|location=[Edinburgh]|oclc=76798115}}</ref> It is possible to deliver anaesthesia solely by inhalation or injection, but most commonly the two forms are combined, with an injection given to induce anaesthesia and a gas used to maintain it.<ref name=":52" />

===Inhalation===

[[File:US Navy 030513-N-1577S-001 Lt. Cmdr. Joe Casey, Ship's Anesthetist, trains on anesthetic procedures with Hospital Corpsman 3rd Class Eric Wichman aboard USS Nimitz (CVN 68).jpg|thumb|General anesthetics are frequently administered as volatile liquids or gases.]]
Inhalational anaesthetic substances are either [[Volatility (chemistry)|volatile]] [[liquid]]s or [[gas]]es, and are usually delivered using an [[anaesthesia machine]]. An anaesthesia machine allows composing a mixture of oxygen, anaesthetics and ambient air, delivering it to the patient and monitoring patient and machine parameters. Liquid anaesthetics are vapourised in the machine.<ref name=":52" />

Many compounds have been used for inhalation anaesthesia, but only a few are still in widespread use. [[Desflurane]], [[isoflurane]] and [[sevoflurane]] are the most widely used [[volatile anaesthetic]]s today. They are often combined with [[nitrous oxide]]. Older, less popular volatile anaesthetics include [[halothane]], [[enflurane]], and [[methoxyflurane]]. Researchers are also actively exploring the use of [[xenon]] as an anaesthetic.<ref name=":52" />

===Injection===

Injectable anaesthetics are used for the induction and maintenance of a state of unconsciousness. Anaesthetists prefer to use [[intravenous injection]]s, as they are faster, generally less painful and more reliable than [[Intramuscular injection|intramuscular]] or [[subcutaneous injection]]s. Among the most widely used drugs are:
* [[Propofol]]
* [[Etomidate]]
* [[Barbiturate]]s such as [[methohexital]] and [[thiopentone]]/[[thiopental]]
* [[Benzodiazepine]]s such as [[midazolam]]
* [[Ketamine]] is used in the UK as "field anaesthesia", for instance in road traffic incidents or similar situations where an operation must be conducted at the scene or when there is not enough time to move to an operating room, while preferring other anaesthetics where conditions allow their use. It is more frequently used in the operative setting in the US.<ref name=":52" />
Benzodiazepines are sedatives and are used in combinations with other general anaesthetics.<ref name=":04" /><ref name=":52" />

==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" />

== Stages of anesthesia ==
During administration of an anesthetic, the receiver goes through different stages of behavior ultimately leading to [[unconsciousness]]. This process is accelerated with intravenous anesthetics, so much so that it is negligible to consider during their use. The four stages of anesthesia are described using Guedel's signs, signifying the depth of anesthesia. These stages describe effects of anesthesia mainly on cognition, muscular activity, and respiration.<ref name=":25" />

=== Stage I: Analgesia ===
The receiver of the anesthesia primarily feels [[Analgesic|analgesia]] followed by amnesia and a sense of confusion moving into the next stage.<ref name=":25" />

=== Stage II: Excitement ===
Stage II is often characterized by the receiver being delirious and confused, with severe amnesia. Irregularities in the patterns of respiration are common at this stage of anesthesia. Nausea and vomiting are also indicators of Stage II anesthesia. Struggling and panic can sometimes occur as a result of delirium.<ref name=":25" />

=== Stage III: Surgical Anesthesia ===
Normal breathing resumes at the beginnings of Stage III. Nearing the end of the stage, breathing ceases completely. Indicators for stage III anesthesia include loss of the eyelash reflex as well as regular breathing. Depth of stage III anesthesia can often be gauged by eye movement and pupil size.<ref name=":25" />

=== Stage IV: Medullary Depression ===
No respiration occurs in stage IV. This is shortly followed by circulatory failure and depression of the [[vasomotor center]]s. Death is common at this stage of anesthesia if no breathing and circulatory support is available.<ref name=":25" />

== Physiological side effects ==
Aside from the clinically advantageous effects of general anesthetics, there are a number of other physiological consequences mediated by this class of drug. Notably, a reduction in blood pressure can be facilitated by a variety of mechanisms, including reduced cardiac contractility and dilation of the vasculature. This drop in blood pressure may activate a reflexive increase in heart rate, due to a [[Baroreceptor reflex|baroreceptor-mediated feedback mechanism]]. Some anesthetics, however, disrupt this reflex.<ref name=":16" /><ref name=":25" />

Patients under general anesthesia are at greater risk of developing [[hypothermia]], as the aforementioned [[vasodilation]] increases the heat lost via peripheral blood flow. By and large, these drugs reduce the internal body temperature threshold at which autonomic [[Thermoregulation|thermoregulatory]] mechanisms are triggered in response to cold. (On the other hand, the threshold at which thermoregulatory mechanisms are triggered in response to heat is typically increased.)<ref>{{Cite journal|last1=Bindra|first1=Ashish|last2=Bindu|first2=Barkha|last3=Rath|first3=Girija|date=2017-07-01|title=Temperature management under general anesthesia: Compulsion or option|url=http://www.joacp.org/text.asp?2017/33/3/306/214311|journal=Journal of Anaesthesiology Clinical Pharmacology|language=en|volume=33|issue=3|pages=306–316|doi=10.4103/joacp.joacp_334_16|pmid=29109627|pmc=5672515 |doi-access=free }}</ref>

Anesthetics typically affect respiration. Inhalational anesthetics elicit [[Bronchodilator|bronchodilation]], an increase in respiratory rate, and reduced [[tidal volume]]. The net effect is decreased respiration, which must be managed by healthcare providers, while the patient is under general anesthesia.<ref name=":25" /> The reflexes that function to alleviate airway obstructions are also dampened (e.g. gag and cough). Compounded with a reduction in [[lower esophageal sphincter]] tone, which increases the frequency of regurgitation, patients are especially prone to [[asphyxiation]] while under general anesthesia. Healthcare providers closely monitor individuals under general anesthesia and utilize a number of devices, such as an [[endotracheal tube]], to ensure patient safety.<ref name=":16" />

General anesthetics also affect the [[chemoreceptor trigger zone]] and [[Area postrema|brainstem vomiting center]], eliciting nausea and vomiting following treatment.<ref name=":16" />

==Pharmacokinetics==

=== Intravenous general anesthetics ===

====Induction====

Intravenously delivered general anesthetics are typically small and highly [[Lipophilicity|lipophilic]] molecules. These characteristics facilitate their rapid preferential distribution into the brain and spinal cord, which are both highly vascularized and lipophilic. It is here where the actions of these drugs lead to general anesthesia induction.<ref name=":16" />

====Elimination====
Following distribution into the [[central nervous system]] (CNS), the anesthetic drug then diffuses out of the CNS into the muscles and viscera, followed by [[adipose tissue]]s. In patients given a single injection of drug, this redistribution results in termination of general anesthesia. Therefore, following administration of a single anesthetic [[Bolus (medicine)|bolus]], duration of drug effect is dependent solely upon the redistribution kinetics.<ref name=":16" />

The [[half-life]] of an anesthetic drug following a prolonged infusion, however, depends upon both drug redistribution kinetics, [[drug metabolism]] in the liver, and existing drug concentration in fat. When large quantities of an anesthetic drug have already been dissolved in the body's fat stores, this can slow its redistribution out of the brain and spinal cord, prolonging its CNS effects. For this reason, the half-lives of these infused drugs are said to be [[Context-sensitive half-life|context-dependent]]. Generally, prolonged anesthetic drug infusions result in longer drug half-lives, slowed elimination from the brain and spinal cord, and delayed termination of general anesthesia.<ref name=":16" />

=== Inhalational general anesthetics ===
[[Minimum alveolar concentration|Minimal alveolar concentration]] (MAC) is the concentration of an inhalational anesthetic in the lungs that prevents 50% of patients from responding to surgical incision. This value is used to compare the [[Potency (pharmacology)|potencies]] of various inhalational general anesthetics and impacts the [[Partial pressure|partial-pressure]] of the drug utilized by healthcare providers during general anesthesia induction and/or maintenance.<ref name=":16" /><ref name=":25" />

==== Induction ====
[[File:General Anesthesia WIKI - Figure.tif|thumb|437x437px]]
Induction of anesthesia is facilitated by diffusion of an inhaled anesthetic drug into the brain and spinal cord. Diffusion throughout the body proceeds until the drug's [[partial pressure]] within the various tissues is equivalent to the partial pressure of the drug within the lungs.<ref name=":16" /> Healthcare providers can control the rate of anesthesia induction and final tissue concentrations of the anesthetic by varying the partial pressure of the inspired anesthetic. A higher drug partial pressure in the lungs will drive diffusion more rapidly throughout the body and yield a higher maximum tissue concentration. Respiratory rate and inspiratory volume will also affect the promptness of anesthesia onset, as will the extent of pulmonary blood flow.<ref name=":25" />

The [[partition coefficient]] of a gaseous drug is indicative of its relative solubility in various tissues. This metric is the relative drug concentration between two tissues, when their partial pressures are equal (gas:blood, fat:blood, etc.). Inhalational anesthetics vary widely with respect to their tissue solubilities and partition coefficients.<ref name=":16" /> Anesthetics that are highly soluble require many molecules of drug to raise the partial pressure within a given tissue, as opposed to minimally soluble anesthetics which require relatively few.<ref name=":25" /> Generally, inhalational anesthetics that are minimally soluble reach equilibrium more quickly. Inhalational anesthetics that have a high fat:blood partition coefficient, however, reach equilibrium more slowly, due to the minimal vascularization of fat tissue, which serves as a large, slowly-filling reservoir for the drug.<ref name=":16" />

==== Elimination ====
Inhaled anesthetics are eliminated via expiration, following diffusion into the lungs. This process is dependent largely upon the anesthetic [[Blood–gas partition coefficient|blood:gas partition coefficient]], tissue solubility, blood flow to the lungs, and patient respiratory rate and inspiratory volume.<ref name=":25" /> For gases that have minimal tissue solubility, termination of anesthesia generally occurs as rapidly as the onset of anesthesia. For gases that have high tissue solubility, however, termination of anesthesia is generally [[Context-sensitive half-life|context-dependent]]. As with intravenous anesthetic infusions, prolonged delivery of highly soluble anesthetic gases generally results in longer drug half-lives, slowed elimination from the brain and spinal cord, and delayed termination of anesthesia.<ref name=":16" />

Metabolism of inhaled anesthetics is generally not a major route of drug elimination.<ref name=":25" />

==History==

===Ethanol===
{{main|Alcohols (medicine)}}

While most research focuses on the intoxicating effects of ethanol, it can also produce a general anesthesia.<ref>{{cite journal |last1=Wong |first1=SM |last2=Fong |first2=E |last3=Tauck |first3=DL |last4=Kendig |first4=JJ |title=Ethanol as a general anesthetic: actions in spinal cord. |journal=European Journal of Pharmacology |date=25 June 1997 |volume=329 |issue=2–3 |pages=121–7 |doi=10.1016/S0014-2999(97)89174-1 |pmid=9226403|doi-access=free }}</ref> Since [[Classical antiquity|antiquity]], prior to the development of modern agents, [[Alcohols (medicine)|alcohol]] was used as a general anaesthetic.<ref name="IISaidman2013">{{cite book| vauthors = Eger II EI, Saidman LJ, Westhorpe RN |title=The Wondrous Story of Anesthesia|url=https://books.google.com/books?id=H--3BAAAQBAJ&pg=PA4|date=14 September 2013|publisher=Springer Science & Business Media|isbn=978-1-4614-8441-7 |pages=4– |url-status=live|archive-url= https://web.archive.org/web/20170918190140/https://books.google.com/books?id=H--3BAAAQBAJ&pg=PA4| archive-date=18 September 2017}}</ref>

== See also ==
* [[Local anesthesia|Local anaesthesia]]
* [[Mechanical ventilation]]
* [[Intraoperative awareness]]
* [[History of general anesthesia]]
* [[Endogenous anesthetic]]

==References==
{{Reflist}}

{{Anesthesia}}
{{General anesthetics}}
{{Major drug groups}}
{{Authority control}}

{{DEFAULTSORT:General Anaesthetic}}
[[Category:Anesthesia]]
[[Category:Drugs with unknown mechanisms of action]]