Nitrous oxide (medication)

Last updated
Nitrous oxide
Entonox set.png
Entonox CD cylinder and giving set
Clinical data
Trade names Entonox, Nitronox, others
ATC code
Pharmacokinetic data
Onset of action 30 seconds [1]
Duration of action 1 minute [1]
Identifiers
  • Nitrous oxide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
Formula N2O
Molar mass 44.013 g·mol−1
3D model (JSmol)
  • [N-]=[N+]=O
  • InChI=1S/N2O/c1-2-3
  • Key:GQPLMRYTRLFLPF-UHFFFAOYSA-N

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]

Contents

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 lungbrain 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.

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 N
2
O
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 N
2
O
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, N
2
O
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 Adminsitration of nitrous oxide Wellcome L0013787.jpg
Administration of nitrous oxide, 1870

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]

Related Research Articles

General anaesthetics 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 analgesics and should also not be confused with sedatives. 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.

<span class="mw-page-title-main">Nitrous oxide</span> Colourless non-flammable gas

Nitrous oxide, commonly known as laughing gas, nitrous, nitro, or nos, is a chemical compound, an oxide of nitrogen with the formula N
2
O
. At room temperature, it is a colourless non-flammable gas, and has a slightly sweet scent and taste. At elevated temperatures, nitrous oxide is a powerful oxidiser similar to molecular oxygen.

<span class="mw-page-title-main">Anesthesia</span> State of medically-controlled temporary loss of sensation or awareness

Anesthesia or anaesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia, paralysis, amnesia, and unconsciousness. An individual under the effects of anesthetic drugs is referred to as being anesthetized.

<span class="mw-page-title-main">Isoflurane</span> General anaesthetic given via inhalation

Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane. Isoflurane is given via inhalation.

<span class="mw-page-title-main">Sevoflurane</span> Inhalational anaesthetic

Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.

<span class="mw-page-title-main">General anaesthesia</span> Medically induced loss of consciousness

General anaesthesia (UK) or general anesthesia (US) is a method of medically inducing loss of consciousness that renders a patient unarousable even with painful stimuli. This effect is achieved by administering either intravenous or inhalational general anaesthetic medications, which often act in combination with an analgesic and neuromuscular blocking agent. Spontaneous ventilation is often inadequate during the procedure and intervention is often necessary to protect the airway. General anaesthesia is generally performed in an operating theater to allow surgical procedures that would otherwise be intolerably painful for a patient, or in an intensive care unit or emergency department to facilitate endotracheal intubation and mechanical ventilation in critically ill patients. Regardless of whether a patient may prefer to be unconscious or not, certain pain stimuli could result in involuntary responses from the patient that may make an operation extremely difficult. Thus, for many procedures, general anaesthesia is required from a practical perspective.

<span class="mw-page-title-main">Anaesthetic machine</span> Medical device to supply a mix of life-support and anaesthetic gases

An anaesthetic machine or anesthesia machine is a medical device used to generate and mix a fresh gas flow of medical gases and inhalational anaesthetic agents for the purpose of inducing and maintaining anaesthesia.

<span class="mw-page-title-main">Anesthetic</span> Drug that causes anesthesia

An anesthetic or anaesthetic is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two broad classes: general anesthetics, which result in a reversible loss of consciousness, and local anesthetics, which cause a reversible loss of sensation for a limited region of the body without necessarily affecting consciousness.

<span class="mw-page-title-main">Desflurane</span> Chemical compound

Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether) is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia. Like halothane, enflurane, and isoflurane, it is a racemic mixture of (R) and (S) optical isomers (enantiomers). Together with sevoflurane, it is gradually replacing isoflurane for human use, except in economically undeveloped areas, where its high cost precludes its use. It has the most rapid onset and offset of the volatile anesthetic drugs used for general anesthesia due to its low solubility in blood.

<span class="mw-page-title-main">Horace Wells</span> American dentist who pioneered the use of anesthesia (1815–1848)

Horace Wells was an American dentist who pioneered the use of anesthesia in dentistry, specifically the use of nitrous oxide.

<span class="mw-page-title-main">Inhalational anesthetic</span> Volatile or gaseous anesthetic compound delivered by inhalation

An inhalational anesthetic is a chemical compound possessing general anesthetic properties that is delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anesthetic vaporiser and an anesthetic delivery system. Agents of significant contemporary clinical interest include volatile anesthetic agents such as isoflurane, sevoflurane and desflurane, as well as certain anesthetic gases such as nitrous oxide and xenon.

<span class="mw-page-title-main">Halogenated ether</span> Subcategory of ether used in anesthesiology

A halogenated ether is a subcategory of a larger group of chemicals known as ethers. An ether is an organic chemical that contains an ether group—an oxygen atom connected to two (substituted) alkyl groups. A good example of an ether is the solvent diethyl ether. What differentiates a halogenated ether from other types of ethers is the substitution (halogenation) of one or more hydrogen atoms with a halogen atom. Halogen atoms include fluorine, chlorine, bromine, and iodine.

<span class="mw-page-title-main">Methoxyflurane</span> Chemical compound

Methoxyflurane, sold under the brand name Penthrox among others, is an inhaled medication primarily used to reduce pain following trauma. It may also be used for short episodes of pain as a result of medical procedures. Onset of pain relief is rapid and of a short duration. Use is only recommended with direct medical supervision.

Dental anesthesia is the application of anesthesia to dentistry. It includes local anesthetics, sedation, and general anesthesia.

The Fink effect, also known as "diffusion anoxia", "diffusion hypoxia", or the "second gas effect", is a factor that influences the pO2 (partial pressure of oxygen) within the pulmonary alveoli. When water-soluble gases such as anesthetic agent N2O (nitrous oxide) are breathed in large quantities they can be dissolved in body fluids rapidly. This leads to a temporary increase in both the concentrations and partial pressures of oxygen and carbon dioxide in the alveoli.

A relative analgesia machine is used by dentists to induce inhalation sedation in their patients. It delivers a mixture of nitrous oxide and oxygen. A relative analgesia machine is simpler than an anaesthetic machine, as it does not feature the additional medical ventilator and anaesthetic vaporiser, which are only needed for administration of general anesthetics. Instead the relative analgesia machine is designed for the light form of anaesthesia with nitrous oxide, where the patient is less sensitive to pain but remains fully conscious.

<span class="mw-page-title-main">History of general anesthesia</span>

Throughout recorded history, attempts at producing a state of general anesthesia can be traced back to the writings of ancient Sumerians, Babylonians, Assyrians, Egyptians, Indians, and Chinese. Despite significant advances in anatomy and surgical technique during the Renaissance, surgery remained a last-resort treatment largely due to the pain associated with it. However, scientific discoveries in the late 18th and early 19th centuries paved the way for the development of modern anesthetic techniques.

<span class="mw-page-title-main">Inhalation sedation</span>

Inhalation sedation is a form of conscious sedation where an inhaled drug should:

  1. Depress the central nervous system (CNS) to an extent that surgeons can operate with minimal physiological and psychological stress to the patient
  2. Modify the patient's state of mind such that communication is maintained and the patient can respond to verbal command
  3. Carry a margin of safety wide enough to render the unintended loss of consciousness and loss of protective reflexes unlikely.
<span class="mw-page-title-main">Peter Baskett</span> Northern Irish physician

Peter John Firth Baskett (1934–2008) was a Northern Irish physician, specializing in anaesthesia. He was responsible for the introduction of paramedics into the United Kingdom, created specialist ambulances for delivering on-scene pain relief to patients, and was the first chairman of the European Resuscitation Council.

Total intravenous anesthesia (TIVA) refers to the intravenous administration of anesthetic agents to induce a temporary loss of sensation or awareness. The first study of TIVA was done in 1872 using chloral hydrate, and the common anesthetic agent propofol was licensed in 1986. TIVA is currently employed in various procedures as an alternative technique of general anesthesia in order to improve post-operative recovery.

References

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Further reading