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Nitrous oxide,dinitrogen oxide or dinitrogen monoxide, is a chemical compound with chemical formula N2O. Under room conditions, it is a colorless non-flammable gas, with a pleasant, slightly sweet odor. It is used in surgery and dentistry for its anaesthetic and analgesic effects, where it is commonly known as laughing gas due to the euphoric effects of inhaling it. It is also used as a means to significantly increase power output of internal combustion engines found in automobiles, as the gas is introduced into the intake manifold it acts as an oxidizer which allows more fuel to be burned. Nitrous oxide is present in the atmosphere where it acts as a powerful greenhouse gas.
The structure of the nitrous oxide molecule is a linear chain of a nitrogen atom bound to a second nitrogen atom, which in turn is bound to an oxygen atom. Nitrous oxide is a resonance hybrid of N=N+-O- and -N=N+=O.
Nitrous oxide, N2O, should not be confused with the other oxides of nitrogen such as nitric oxide NO and nitrogen dioxide NO2.
Nitrous oxide is isoelectronic with carbon dioxide. It can be prepared by heating ammonium nitrate in the laboratory and can be used to produce nitrites by mixing it with boiling alkali metals, and to oxidize organic compounds at high temperatures.
The gas was first synthesized by English chemist and natural philosopher Joseph Priestley in 1775 , who called it phlogisticated nitrous air (see phlogiston). Priestley describes the preparation of "nitrous air diminished" by heating iron filings dampened with nitric acid in Experiments and Observations on Different Kinds of Air, (1775). Priestley was delighted with his discovery: "I have now discovered an air five or six times as good as common air... nothing I ever did has surprised me more, or is more satisfactory."  Humphry Davy in the 1790s tested the gas on himself and some of his friends, including the poets Samuel Taylor Coleridge and Robert Southey. They soon realised that nitrous oxide considerably dulled the sensation of pain, even if the inhaler were still semi-conscious. And so it came into use as an anaesthetic, particularly by dentists, who do not typically have access to the services of an anesthesiologist and who may benefit from a patient who can respond to verbal commands.
N2O is commonly made by heating ammonium nitrate. This method was developed by the French chemist Claude Louis Berthollet in 1785 and has been widely used ever since. Unfortunately, the method poses a potential explosion risk from overheating ammonium nitrate.
- NH4NO3(aq) → N2O(g) + 2H2O(l), ΔH = −36.8 kJ
The addition of various phosphates favors formation of a purer gas. This reaction occurs between 170 - 240°C, temperatures where ammonium nitrate is a moderately sensitive explosive and a very powerful oxidizer (perhaps on the order of fuming nitric acid). At temperatures much above 240 °C the exothermic reaction may run away, perhaps up to the point of detonation. The mixture must be cooled to avoid such a disaster. In practice, the reaction involves a series of tedious adjustments to control the temperature to within a narrow range, which it will not naturally tend to stay in. Professionals have destroyed whole neighborhoods by losing control of such commercial processes. Examples include the Ohio Chemical debacle in Montreal, 1966 and the Air Products & Chemicals, Inc. disaster in Delaware City, Delaware, 1977.
The direct oxidation of ammonia may someday rival the ammonium nitrate pyrolysis synthesis of nitrous oxide mentioned above. This capital-intensive process, which originates in Japan, uses a manganese dioxide-bismuth oxide catalyst. (Suwa et al. 1961; Showa Denka Ltd.)
- 2NH3 + 2O2 → N2O + 3H2O
Higher oxides of nitrogen are formed as impurities. Note that uncatalyzed ammonia oxidation (i.e. combustion or explosion) goes primarily to N2 and H2O. The Ostwald process oxidizes ammonia to nitric oxide (NO), using platinum; this is the beginning of the modern synthesis of nitric acid from ammonia (see above).
Nitrous oxide can be made by heating a solution of sulfamic acid and nitric acid. A lot of gas was made this way in Bulgaria (Brozadzhiew & Rettos, 1975).
- HNO3 + NH2SO3H → N2O + H2SO4 + H2O
There is no explosive hazard in this reaction if the mixing rate is controlled. However, as usual, toxic higher oxides of nitrogen form.
Colorless solutions of hydroxylammonium chloride and sodium nitrite can also be used to produce N2O:
- NH3OH+Cl− + NaNO2 → N2O + NaCl + H2O
If the nitrite is added to the hydroxylamine solution, the gas produced is pure enough for inhalation, and the only remaining byproduct is salt water. However, if the hydroxylamine solution is added to the nitrite solution (nitrite is in excess), then toxic higher oxides of nitrogen form are produced.
Nitrous oxide chemical structure
|ATC code |
|Molecular weight||44.0128 g/mol|
|Legal status||Anasthetic use allowed, Recreational use often illegal|
|Routes of administration||Inhalation|
In the 1800s, nitrous oxide was used by dentists and surgeons for its mild analgesic properties. Today, nitrous oxide is used in dental procedures to provide inhalation sedation and reduce patient anxiety. In small doses in a medical or dental setting, nitrous oxide is very safe, because the nitrous oxide is mixed with a sufficient amount of oxygen using a regulator valve. However, extended, heavy use of inhaled nitrous oxide has been associated with Olney's Lesions in rats, though it is not necessarily possible to extrapolate it to humans.
Nitrous oxide is a weak general anesthetic, and so is generally not used alone in general anaesthesia. However, it has a very low short-term toxicity and is an excellent analgesic. In addition, its lower solubility in blood means it has a very rapid onset and offset, so a 50/50 mixture of nitrous oxide and oxygen ("gas and air", supplied under the trade name Entonox) is commonly used for pain relief during childbirth, for dental procedures, and in emergency medicine.
In general anesthesia it is used as a carrier gas in a 2:1 ratio with oxygen for more powerful general anaesthetic agents such as sevoflurane or desflurane. It has a MAC of 105% and a blood:gas partition coefficient of 0.Α46. Less than 0.004% is metabolised in humans.
Since the earliest uses of nitrous oxide for medical or dental purposes, it has also been used recreationally, because it causes euphoria, slight hallucinations and, in some cases, potential aphrodisiac effects. Only a small number of recreational users (such as dental office workers or medical gas technicians) have legal access to pure nitrous oxide canisters that are intended for medical or dental use. Most recreational users obtain nitrous oxide from compressed gas containers which use nitrous oxide as a propellant for whipped cream, from small canisters of nitrous oxide which are intended for use with whipped cream dispensers, or from automotive nitrous systems. Automotive nitrous available to the public has trace amounts of sulphuric compounds added to prevent recreational use. The sulphur additives only act to make the taste and odor of the gas unpleasant, and does not diminish the effects of the gas in any manner (although such sulfur compounds are harmful to the lungs when inhaled).
Users typically inflate a balloon or plastic bag with nitrous oxide and inhale the gas for its effects. While inhaling nitrous oxide, users face the risk of injury or death from anoxia. Nitrous oxide gas inhaled directly from a metal canister or tank, or by the use of a homemade mask over their mouth directly connected to a canister or tank, presents significantly more dangerous effects.
Nitrous oxide can be habit-forming because of its short-lived effect (generally from 1 - 5 minutes in recreational doses) and ease of access. Death can result if it is inhaled in such a way that not enough oxygen is breathed in. While the pure gas is not toxic, long-term use in very large quantities has been associated with dangerous symptoms similar to vitamin B12 deficiency: anemia due to reduced hemopoiesis, neuropathy, tinnitus, and numbness in extremities. Pregnant women should not use nitrous oxide as chronic use is teratogenic and foetotoxic. It should also be noted that long term recreational use may lead to Olney's lesions, a form of brain damage.
Drug users who use nitrous oxide as a euphoria-inducing inhalant drug often obtain nitrous oxide from whipped cream dispensers which use nitrous oxide as a propellant (see above section).It is non-harmful in small doses
Nitrous oxide shares many pharmacological similarities with other inhaled anesthetics, but there are a number of differences.
Like many classical anesthetics, the exact mechanisms of action is still open to some conjecture. It inhibits the NMDA receptor at partial pressures similar to those used in general anaesthesia. The evidence on the effect of N2O on GABA-A currents is mixed, but tends to show a lower potency potentiation. N2O, like other volatile anesthetics, activates twin-pore potassium channels, albeit weakly. These channels are largely responsible for keeping neurons at the resting (unexcited) potential. Unlike many anesthetics, however, N2O does not seem to affect calcium channels.
Unlike most general anesthetics, N2O appears to affect the GABA receptor. In many behavioral tests of anxiety, a low dose of N2O is a successful anxiolytic. This anti-anxiety effect is partially reversed by benzodiazepine receptor antagonists. Mirroring this, animals which have developed tolerance to the anxiolytic effects of benzodiazepines are partially tolerant to nitrous oxide. Indeed, in humans given 30% N2O, benzodiazepine receptor antagonists reduced the subjective reports of feeling “high”, but did not alter psycho-motor performance.
The effects of N2O seem linked to the interaction between the endogenous opioid system and the descending noradrenergic system. When animals are given morphine chronically they develop tolerance to its antinociceptive (pain killing) effects; this also renders the animals tolerant to the antinociceptive effects of N2O. Administration of antibodies which bind and block the activity of some endogenous opioids (not beta-endorphin), also block the antinociceptive effects of N2O. Drugs which inhibit the breakdown of endogenous opioids also potentiate the antinociceptive effects of N2O. Several experiments have shown that opioid receptor antagonists applied directly to the brain block the antinociceptive effects of N2O, but these drugs have no effect when injected into the spinal cord. Conversely, alpha-adrenoreceptor antagonists block the antinociceptive effects of N2O when given directly to the spinal cord, but not when applied directly to the brain. Indeed, alpha2B-adrenoreceptor knockout mice or animals depleted in noradrenaline are nearly completely resistant to the antinociceptive effects of N2O. It seems N2O-induced release of endogenous opioids causes disinhibition of brain stem noradrenergic neurons, which release norepinephrine into the spinal cord and inhibit pain signaling (Maze, M. and M. Fujinaga, 2000). Exactly how N2O causes the release of opioids is still uncertain.
While normally inert in storage and fairly safe to handle, nitrous oxide can decompose energetically and potentially detonate if initiated under the wrong circumstances. Liquid nitrous oxide acts as a good solvent for many organic compounds; liquid mixtures can form somewhat sensitive explosives. Contamination with fuels has been implicated in a handful of rocketry accidents, where small quantities of nitrous / fuel mixtures detonated, triggering the explosive decomposition of residual nitrous oxide in plumbing.
Nitrous oxide inactivates the cobalamin form of vitamin B12 by oxidation. Symptoms of vitamin B12 deficiency, including sensory neuropathy, myelopathy, and encephalopathy, can occur within days or weeks of exposure to nitrous oxide anesthesia in people with subclinical vitamin B12 deficiency. Symptoms are treated with high doses of vitamin B12, but recovery can be slow and incomplete. People with normal vitamin B12 levels have sufficient vitamin B12 stores to make the effects of nitrous oxide insignificant, unless exposure is repeated and prolonged (nitrous oxide abuse). Vitamin B12 levels should be checked in people with risk factors for vitamin B12 deficiency prior to using nitrous oxide anesthesia.
In the United States, possession of nitrous oxide is legal under federal law and is not subject to DEA purview. It is, however, regulated by the Food and Drug Administration under the Food Drug and Cosmetics Act; prosecution is possible under its "misbranding" clauses, prohibiting the sale or distribution of nitrous oxide for the purpose of human consumption. Many states have laws regulating the possession, sale, and distribution of nitrous oxide; but these are normally limited to either banning distribution to minors, or to setting an upper limit for the amount of nitrous oxide that may be sold without special license, rather than banning possession or distribution completely. In most jurisdictions, like at the federal level, sale or distribution for the purpose of human consumption is illegal.
- J. R. Partington, A Short History of Chemistry, 3rd ed., Dover Publications, Inc., New York, New York, 1989, pp. 110-121.
- Mennerick, S., Jevtovic-Todorovic, V., Todorovic, S.M., Shen, W., Olney, J.W. & Zorumski, C.F. (1998). Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci, 18, 9716-26.
- Gruss, M., Bushell, T.J., Bright, D.P., Lieb, W.R., Mathie, A. & Franks, N.P. (2004). Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol, 65, 443-52.
- Emmanouil, D.E., Johnson, C.H. & Quock, R.M. (1994). Nitrous oxide anxiolytic effect in mice in the elevated plus maze: mediation by benzodiazepine receptors. Psychopharmacology (Berl), 115, 167-72.
- Zacny, J.P., Yajnik, S., Coalson, D., Lichtor, J.L., Apfelbaum, J.L., Rupani, G., Young, C., Thapar, P. & Klafta, J. (1995). Flumazenil may attenuate some subjective effects of nitrous oxide in humans: a preliminary report. Pharmacol Biochem Behav, 51, 815-9.
- Berkowitz, B.A., Finck, A.D., Hynes, M.D. & Ngai, S.H. (1979). Tolerance to nitrous oxide analgesia in rats and mice. Anesthesiology, 51, 309-12.
- Branda, E.M., Ramza, J.T., Cahill, F.J., Tseng, L.F. & Quock, R.M. (2000). Role of brain dynorphin in nitrous oxide antinociception in mice. Pharmacol Biochem Behav, 65, 217-21.
- Guo, T.Z., Davies, M.F., Kingery, W.S., Patterson, A.J., Limbird, L.E. & Maze, M. (1999). Nitrous oxide produces antinociceptive response via alpha2B and/or alpha2C adrenoceptor subtypes in mice. Anesthesiology, 90, 470-6.
- Sawamura, S., Kingery, W.S., Davies, M.F., Agashe, G.S., Clark, J.D., Koblika, B.K., Hashimoto, T. & Maze, M. (2000). Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of [alpha]2B adrenoceptors. J Neurosci, 20, 9242-51.
- Jevtovic-Todorovic V, Beals J, Benshoff N, Olney J (2003). Prolonged exposure to inhalational anesthetic nitrous oxide kills neurons in adult rat brain. Neuroscience 122 (3): 609-16.
- Center for Cognitive Liberty and Ethics: State Laws Concerning Inhalation of Nitrous Oxide
- Beehive.govt.nz - Time's up for sham sales of laughing gas
- SyphonKing.com - Nitrous Oxide Chargers / Whippets
- Paul Crutzen Interview Freeview video of Paul Crutzen Nobel Laureate for his work on decomposition of ozone talking to Harry Kroto Nobel Laureate by the Vega Science Trust.
- National Pollutant Inventory - Oxide of nitrogen fact sheet
- Nitrous Oxide Specs Extremely thorough Nitrous Oxide Facts
- Erowid Nitrous Oxide Vault - Information on the recreational inhalation of Nitrous Oxide
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