# Inhalational anesthetic

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.

## List of inhalational anaesthetic agents
### Currently-used agents

* Desflurane
* Isoflurane
* Nitrous oxide
* Sevoflurane
* Xenon

### Previously-used agents

Although some of these are still used in clinical practice and in research, the following anaesthetic agents are primarily of historical interest in developed countries:
* Acetylene
* Chloroethane (ethyl chloride)
* Chloroform
* Cryofluorane
* Cyclopropane
* Diethyl ether
* Divinyl ether
* Enflurane
* Ethylene
* Fluroxene
* Halothane (still widely used in the developing world and is on the WHO Model List of Essential Medicines)
* Methoxyflurane (still used currently as an analgesic)
* Methoxypropane
* Trichloroethylene
* Vinyl chloride

### Never-marketed agents

* Aliflurane
* Halopropane
* Norflurane
* Roflurane
* Synthane
* Teflurane

## Volatile anaesthetics

Volatile anaesthetic agents share the property of being liquid at room temperature, but evaporating easily for administration by inhalation. The volatile anesthetics used in the developed world today include: Desflurane, isoflurane and sevoflurane. Other agents widely used in the past include ether, chloroform, enflurane, halothane, methoxyflurane. All of these agents share the property of being quite hydrophobic (i.e., as liquids, they are not freely miscible with water, and as gases they dissolve in oils better than in water).
The ideal volatile anaesthetic agent offers smooth and reliable induction and maintenance of general anaesthesia with minimal effects on non-target organ systems. In addition it is odorless or pleasant to inhale; safe for all ages and in pregnancy; not metabolised; rapid in onset and offset; potent; safe for exposure to operating room staff; and has a long shelf life. It is also cheap to manufacture; easy to transport and store; easy to administer and monitor with standard operating room equipment; stable to light, plastics, metals, rubber and soda lime; and non-flammable and environmentally safe. None of the agents currently in use are ideal, although many have some of the desirable characteristics. For example, sevoflurane is pleasant to inhale and is rapid in onset and offset. It is also safe for all ages. However, it is expensive (approximately 3 to 5 times more expensive than isoflurane), and approximately half as potent as isoflurane.

## Gases

Other gases or vapors which produce general anaesthesia by inhalation include nitrous oxide, carbon dioxide, cyclopropane, and xenon. These are stored in gas cylinders and administered using flowmeters, rather than vaporisers. Cyclopropane is explosive and is no longer used for safety reasons, although otherwise it was found to be an excellent anaesthetic. Xenon is odorless (odourless) and rapid in onset, but is expensive and requires specialized equipment to administer and monitor. Nitrous oxide, even at 80% concentration, does not quite produce surgical level anaesthesia in most people at standard atmospheric pressure, so it must be used as an adjunct anaesthetic, along with other agents.

## Hyperbaric anaesthesia

Under hyperbaric conditions (pressures above normal atmospheric pressure), other gases such as nitrogen, and noble gases such as argon, krypton, and xenon become anaesthetics. When inhaled at high partial pressures (more than about 4 bar, encountered at depths below about 30 metres in scuba diving), nitrogen begins to act as an anaesthetic agent, causing nitrogen narcosis. However, the minimum alveolar concentration (MAC) for nitrogen is not achieved until pressures of about 20 to 30 atm (bar) are attained. Argon is slightly more than twice as anaesthetic as nitrogen per unit of partial pressure (see argox). Xenon however is a usable anaesthetic at 80% concentration and normal atmospheric pressure.

## Endogenous analogous

Endogenous analogs of inhaled anesthetics are compounds that the body produces and that have the properties and similar mode of action of inhaled anesthetics. Among the gases in the human body, carbon dioxide is among the most abundant and produces anesthesia from insects to humans. CO$_2$ anesthesia was first demonstrated to the king of France in the early 1800s by Henry Hill Hickman. Initially CO$_2$ was thought to work through anoxia, but in the early 1900, increased CO$_2$ in the lung showed a dramatic increase oxygenation of the brain disproving the anoxia argument. Prior to the development of modern anesthetics, CO$_2$ was used extensively by psychiatrists in a treatment called carbon dioxide inhalation therapy.

## Neurological theories of action

The full mechanism of action of volatile anaesthetic agents is unknown and has been the subject of intense debate. "Anesthetics have been used for 160 years, and how they work is one of the great mysteries of neuroscience," says anaesthesiologist James Sonner of the University of California, San Francisco. Anaesthesia research "has been for a long time a science of untestable hypotheses," notes Neil L. Harrison of Cornell University.
"Most of the injectable anesthetics appear to act on a single molecular target," says Sonner. "It looks like inhaled anesthetics act on multiple molecular targets. That makes it a more difficult problem to pick apart."
The possibility of anaesthesia by the inert gas argon in particular (even at 10 to 15 bar) suggests that the mechanism of action of volatile anaesthetics is an effect best described by physical chemistry, and not a chemical bonding action. However, the agent may bind to a receptor with a weak interaction. A physical interaction such as swelling of nerve cell membranes from gas solution in the lipid bilayer may be operative. Notably, the gases hydrogen, helium, and neon have not been found to have anaesthetic properties at any pressure. Helium at high pressures produces nervous irritation ("anti-anaesthesia"), suggesting that the anaesthetic mechanism(s) may be operated in reverse by this gas (i.e., nerve membrane compression). Also, some halogenated ethers (such as flurothyl) also possess this "anti-anaesthetic" effect, providing further evidence for this theory.

## History

Paracelsus developed an inhalational anaesthetic in 1540. He used sweet oil of vitriol (prepared by Valerius Cordus and named Aether by Frobenius): used to feed fowl: “it was taken even by chickens and they fall asleep from it for a while but awaken later without harm”. Subsequently, about 40 years later, in 1581, Giambattista Delia Porta demonstrated the use of ether on humans although it was not employed for any type of surgical anesthesia.
In modern medicine, Dr. Horace Wells used nitrous oxide for his own dental extraction in 1844. However his attempt to replicate these results at Massachusetts General Hospital (MGH) resulted in a partial anesthetic and was deemed a failure.
William T.G. Morton is credited with successfully demonstrating surgical anesthesia for the first time on October 16, 1846, at MGH. Following this event, the use of ether and other volatile anesthetics became widespread in Western medicine.
After the experiments and publications by the Scottish obstetrician James Young Simpson in late 1847, chloroform became the first widespread halocarbon anaesthetic. Chloroform is a much stronger and effective anaesthetic than ether, it is non-inflammable and it did not irritate the airways, unlike ether.
First non-gaseous inhalational anaesthetics such as ether and chloroform were inhaled from a handkerchief which the liquid was poured on and allowed to evaporate. Concerns about the dosage of chloroform lead to development of various inhalers.