Chemistry:Nitrous oxide (medication)

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Short description: Gas used as anesthetic and for pain relief
Nitrous oxide
Entonox set.png
Entonox CD cylinder and giving set
Clinical data
Trade namesEntonox, Nitronox, others
ATC code
Pharmacokinetic data
Onset of action30 seconds[1]
Duration of action1 minute[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
FormulaN2O
Molar mass44.013 g·mol−1
3D model (JSmol)

Nitrous oxide is an inhaled gas used as a pain medication and together with other medications for anesthesia.[2] Common uses include during childbirth, following trauma, and as part of end-of-life care.[2] Onset of effect is typically within half a minute, and the effect lasts for about a minute.[1]

There are few side effects, other than vomiting, with short-term use.[1][2] With long-term use anemia or numbness may occur.[2] It should always be given with at least 21% oxygen.[2] It is not recommended in people with a bowel obstruction or pneumothorax.[2] Use in the early part of pregnancy is not recommended.[1] It is possible to continue breastfeeding following use.[3]

Nitrous oxide was discovered between 1772 and 1793 and used for anesthesia in 1844.[4] It is on the World Health Organization's List of Essential Medicines.[5] It often comes as a 50/50 mixture with oxygen.[1] Devices with a demand valve are available for self-administration.[6] The setup and maintenance is relatively expensive for developing countries.[7][8]

Medical uses

Nitrous oxide (N2O) is itself active (does not require any changes in the body to become active), and so has an onset in roughly the lung–brain circulation time. This gives it a peak action 30 seconds after the start of administration;[1] Entonox should thus be used accordingly, i.e. inhalation should start 30 seconds before a contraction becomes painful in labour. It is removed from the body unchanged via the lungs, and does not accumulate under normal conditions, explaining the rapid offset of around 60 seconds.[1] It is effective in managing pain during labor and delivery.[9]

Nitrous oxide is more soluble than oxygen and nitrogen, so will tend to diffuse into any air spaces within the body. This makes it dangerous to use in patients with pneumothorax or those who have recently been scuba diving, and there are cautions over its use with any bowel obstruction.

Its analgesic effect is strong (equivalent to 15 mg of subcutaneous route morphine[1])[10][11] and characterised by rapid onset and offset, i.e. it is very fast-acting and wears off very quickly.[citation needed]

When used in combination with other anesthetics gases, nitrous oxide causes a dose dependent increased respiratory rate and decreased tidal volumes, the net effect is a lower minute ventilation. Like volatile anesthetics, it increases cerebral blood flow and intracranial pressure. However, contrary to volatile anesthetics, it leads to an increase in cerebral metabolic rate of oxygen.[12][13]

Contraindications

N2O should not be used in patients with bowel obstruction, pneumothorax, or middle ear or sinus disease,[1] or has had a recent intraocular injection of gas[14] and should also not be used on any patient who has been scuba diving within the preceding 24 hours[15] or in violently disturbed psychiatric patients.[16] There are also clinical cautions in place for the first two trimesters of pregnancy and in patients with decreased levels of consciousness.[1]

Composition

The gas is a mixture of half nitrous oxide (N2O) and half oxygen (O2).[1][16] The ability to combine N2O and oxygen at high pressure while remaining in the gaseous form is caused by the Poynting effect (after John Henry Poynting, an English physicist).[1]

The Poynting effect involves the dissolution of gaseous O2 when bubbled through liquid N2O, with vaporisation of the liquid to form a gaseous O2/N2O mixture.[1]

Inhalation of pure N2O over a continued period would deprive the patient of oxygen,[17] but the 50% oxygen content prevents this from occurring. The two gases will separate at low temperatures (<4 °C), which would permit administration of hypoxic mixtures. Therefore, it is not given from a cold cylinder without being shaken (usually by cylinder inversion) to remix the gases.

  • Distinct blue and white cap of an Entonox cylinder

  • Typical Schrader valve attachment, making the gas usable only with demand based giving sets

Administration

The gas is self-administered through a demand valve, using a mouthpiece, bite block or face mask.[16] Self-administration of Entonox is safe because if enough is inhaled to start to induce anaesthesia, the patient becomes unable to hold the valve, and so will drop it and soon exhale the residual gas. This means that unlike other anaesthetic gases, it does not require the presence of an anaesthetist for administration. The 50% oxygen in Entonox ensures the person will have sufficient oxygen in their alveoli and conducting airways for a short period of apnea to be safe.[citation needed]

Mechanism of action

The pharmacological mechanism of action of N2O in medicine is not fully known. However, it has been shown to directly modulate a broad range of ligand-gated ion channels, and this likely plays a major role in many of its effects. It moderately blocks NMDAR and β2-subunit-containing nACh channels, weakly inhibits AMPA, kainate, GABAC and 5-HT3 receptors, and slightly potentiates GABAA and glycine receptors.[18][19] It also has been shown to activate two-pore-domain K+ channels.[20] While N2O affects quite a few ion channels, its anesthetic, hallucinogenic and euphoriant effects are likely caused predominantly, or fully, via inhibition of NMDA receptor-mediated currents.[18][21] In addition to its effects on ion channels, N2O may act to imitate nitric oxide (NO) in the central nervous system, and this may be related to its analgesic and anxiolytic properties.[21] Nitrous oxide is 30 to 40 times more soluble than nitrogen.

History

Administration of nitrous oxide, 1870[22]

Pure N2O was first used as a medical analgesic in December 1844, when Horace Wells made the first 12–15 dental operations with the gas in Hartford.[23][24]

Its debut as a generally accepted method, however, came in 1863, when Gardner Quincy Colton introduced it more broadly at all the Colton Dental Association clinics, that he founded in New Haven and New York City .[25]

The first devices used in dentistry to administer the gas consisted of a simple breathing bag made of rubber cloth.[26]

Breathing the pure gas often caused hypoxia (oxygen insufficiency) and sometimes death by asphyxiation. Eventually practitioners became aware of the need to provide at least 21% oxygen content in the gas (the same percentage as in air).[24] In 1911, the anaesthetist Arthur Ernest Guedel first described the use of self-administration of a nitrous oxide and oxygen mix. It was not until 1961 that the first paper was published by Michael Tunstall and others, describing the administration of a pre-mixed 50:50 nitrous oxide and oxygen mix, which led to the commercialisation of the product.[24]

In 1970, Peter Baskett recognised that pre-mixed nitrous oxide and oxygen mix could have an important part to play in the provision of pre-hospital pain relief management, provided by ambulance personnel. Baskett contacted the Chief Ambulance Officer for the Gloucestershire Ambulance Brigade, Alan Withnell, to suggest this idea. This gained traction when Baskett negotiated with the British Oxygen Company, the availability of pre-mixed nitrous oxide and oxygen mix apparatus for training. Regular training sessions began at Frenchay Hospital (Bristol) and a pilot study was run in Gloucestershire (in which ambulances were crewed by a driver and one of the new highly trained ambulance men), the results of this trial were published in 1970.[27]

Today the nitrous oxide is administered in hospitals by a relative analgesia machine, which includes several improvements such as flowmeters and constant-flow regulators, an anaesthetic vaporiser, a medical ventilator, and a scavenger system, and delivers a precisely dosed and breath-actuated flow of nitrous oxide mixed with oxygen.[citation needed]

The machine used in dentistry is much simpler, and is meant to be used by the patient in a fully conscious state. The gas is delivered through a demand-valve inhaler over the nose, which will only release gas when the patient inhales through it.[citation needed]

Society and culture

Nitronox was a registered trademark of the BOC Group between 1966 and 1999,[28] and was reregistered by Hs Tm Inc since 2005[citation needed] It is also colloquially known as "gas and air" in the United Kingdom.[29]

Research

Investigational trials show potential for antidepressant applications of N2O, especially for treatment-resistant forms of depression, and it is rapid-acting.[30][31][32][33]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 "Anaesthesia UK : Entonox". 26 January 2009. http://www.frca.co.uk/article.aspx?articleid=100364. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 WHO Model Formulary 2008. World Health Organization. 2009. p. 20. ISBN 9789241547659. 
  3. ↑ "Nitrous Oxide use while Breastfeeding". https://www.drugs.com/breastfeeding/nitrous-oxide.html. 
  4. ↑ (in en) 100 Most Important Chemical Compounds, The: A Reference Guide: A Reference Guide. ABC-CLIO. 2007. p. 198. ISBN 9780313080579. https://books.google.com/books?id=nKtzCgAAQBAJ&pg=PA198. 
  5. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  6. ↑ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 878. ISBN 9780857111562. 
  7. ↑ (in en) Gregory's Pediatric Anesthesia, With Wiley Desktop Edition. John Wiley & Sons. 2012. p. 1148. ISBN 9781444333466. https://books.google.com/books?id=Y43oypp8QHkC&pg=PA1148. 
  8. ↑ WHO model prescribing information : drugs used in anaesthesia. World Health Organization. 1989. ISBN 92-4-140101-X. 
  9. ↑ "Pain management for women in labour: an overview of systematic reviews". The Cochrane Database of Systematic Reviews 2012 (3): CD009234. March 2012. doi:10.1002/14651858.CD009234.pub2. PMID 22419342. 
  10. ↑ "A fixed nitrous oxide/oxygen mixture as an analgesic for patients with postherpetic neuralgia: study protocol for a randomized controlled trial". Trials 22 (1): 29. January 2021. doi:10.1186/s13063-020-04960-5. PMID 33407845. 
  11. ↑ "The levels of nitrous oxide analgesia". British Journal of Anaesthesia 39 (12): 974–982. December 1967. doi:10.1093/bja/39.12.974. PMID 4865545. 
  12. ↑ "Anesthetic Gases". StatPearls. 2022. NBK537013. 
  13. ↑ "Nitrous Oxide". StatPearls. 2022. NBK532922. 
  14. ↑ "Entonox: The essential guide". https://www.boconline.co.uk/wcsstore/UK_BOC_Industrial_Ntl_Store/pdf/downloads/Entonox-essential-guide.pdf. 
  15. ↑ "Oxygen administration in diving accidents". South Pacific Underwater Medicine Society Journal 28 (3 Supplement). 1998. 
  16. ↑ 16.0 16.1 16.2 UK Ambulance Service Clinical Practice Guidelines. Joint Royal Colleges Ambulance Liaison Committee. 2006. ISBN 978-1-84690-060-0. http://www2.warwick.ac.uk/fac/med/research/hsri/emergencycare/prehospitalcare/jrcalcstakeholderwebsite/guidelines/clinical_guidelines_2006.pdf. 
  17. ↑ "Breathing Nitrous Oxide". Nitrous Oxide Supplies. http://www.nitrousoxidesupplies.co.uk/automotive/breathing.phtml. 
  18. ↑ 18.0 18.1 "Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol". Anesthesiology 93 (4): 1095–1101. October 2000. doi:10.1097/00000542-200010000-00034. PMID 11020766. 
  19. ↑ "Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures". The Journal of Neuroscience 18 (23): 9716–9726. December 1998. doi:10.1523/JNEUROSCI.18-23-09716.1998. PMID 9822732. 
  20. ↑ "Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane". Molecular Pharmacology 65 (2): 443–452. February 2004. doi:10.1124/mol.65.2.443. PMID 14742687. 
  21. ↑ 21.0 21.1 "Advances in understanding the actions of nitrous oxide". Anesthesia Progress 54 (1): 9–18. 2007. doi:10.2344/0003-3006(2007)54[9:AIUTAO2.0.CO;2]. PMID 17352529. 
  22. ↑ "Manual of the discovery, manufacture, and administration of nitrous oxide, or laughing gas in its relations to dental or minor surgical operations, and particularly for the painless extraction of teeth". Philadelphia : S.S. White. 1870. https://archive.org/details/manualofdiscover1870thom. 
  23. ↑ "The Discoverer of Anæsthesia: Dr. Horace Wells of Hartford". The Yale Journal of Biology and Medicine 5 (5): 421–430. May 1933. PMID 21433572. PMC 2606479. http://ukpmc.ac.uk/picrender.cgi?artid=1703729&blobtype=pdf. 
  24. ↑ 24.0 24.1 24.2 "History of Entonox". BOC Gases. http://www.entonox.co.uk/en/discover_enotonox/story_and_heritage/index.shtml. 
  25. ↑ "Part 1: Legacy of the past, chapter 8: systematic medicine". Drug Discovery –A History. John Wiley and Sons. 2005. pp. 74–87. ISBN 978-0-471-89980-8. https://books.google.com/books?id=mYQxRY9umjcC. Retrieved 21 April 2010. 
  26. ↑ "Technical Development of Gas Anesthesia". Anesthesiology 2 (4): 398–409. 1941. doi:10.1097/00000542-194107000-00004. 
  27. ↑ "Use of Entonox in the ambulance service". British Medical Journal 2 (5700): 41–43. April 1970. doi:10.1136/bmj.2.5700.41. PMID 5440577. 
  28. ↑ "NITRONOX Trademark Information". trademarkia. http://www.trademarkia.com/nitronox-73134512.html. 
  29. ↑ "Entonox (gas and air)". Baby Centre. http://www.babycentre.co.uk/pregnancy/labourandbirth/painrelief/entonox/. 
  30. ↑ "Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial". Biological Psychiatry 78 (1): 10–18. July 2015. doi:10.1016/j.biopsych.2014.11.016. PMID 25577164. 
  31. ↑ "Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression". The American Journal of Psychiatry 172 (10): 950–966. October 2015. doi:10.1176/appi.ajp.2015.15040465. PMID 26423481. 
  32. ↑ "A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression". Science Translational Medicine 13 (597): eabe1376. June 2021. doi:10.1126/scitranslmed.abe1376. PMID 34108247. 
  33. ↑ "'Laughing Gas' May Help Tough-to-Treat Depression" (in en). 2021-06-10. https://www.webmd.com/depression/news/20210610/laughing-gas-may-help-tough-to-treat-depression. 

Further reading

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