General anaesthetic

A general anaesthetic (or anesthetic, see spelling differences) is a drug that has the ability to bring about a reversible loss of consciousness. Anesthesiologists administer these drugs to induce or maintain general anaesthesia to facilitate surgery. Some of these drugs are also used in lower dosages for pain management. The biological mechanism(s) of the action of general anaesthetics are not well understood.

Mode of administration
Drugs given to induce or maintain general anaesthesia can be either as gases or vapours (inhalational anaesthetics), or as injections (intravenous anaesthetics or even intramuscular). 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.

Inhalation
Inhalational anaesthetic substances are either volatile liquids or gases, 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 vapourized in the machine. 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).

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 anaesthetics 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.

Injection
Injectable anaesthetics are used for the induction and maintenance of a state of unconsciousness. Anaesthetists prefer to use intravenous injections, as they are faster, generally less painful and more reliable than intramuscular or subcutaneous injections. Among the most widely used drugs are:


 * Propofol
 * Etomidate
 * Barbiturates such as methohexital and thiopentone/thiopental
 * Benzodiazepines such as midazolam
 * Ketamine is used in the UK as "field anaesthesia", for instance at a 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 anesthetics where conditions allow their use. It is more frequently used in the operative setting in the US.

It should be noted that Benzodiazepines are strictly sedatives and are used in combinations with other general anaesthetics

Method of action
General anaesthetics are often defined as compounds that induce a reversible loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include the lack of awareness to a 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 encompasses multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and on-going research.

Lipid theory
It was postulated by Overton and Meyer that general anaesthetics exert their action by acting on the plasma membrane. This was supported by evidence that the potency of the drug has a direct, positive correlation with the lipid solubility of the blood. The mechanism of action was proposed to be increased fluidity of the membrane. The interpretation of the Overton and Meyer finding has been challenged and discredited.

Ion channels
General anaesthetics exert their action by the activation of inhibitory central nervous system (CNS) receptors, and the inactivation of CNS excitatory receptors. The relative roles of different receptors is still under much debate, but evidence has emerged for some targets being involved with particular anaesthetics.

Multiple anaesthetics have been found to affect the inhibitory GABAA receptor, including propofol, thiopental and isoflurane. However, xenon and nitrous oxide are thought to have no effect here. Glycine receptors have been suggested as putative target for at least the analgesic effect of inhalational anaesthetics.

2-pore-domain potassium channels, with the subfamilies TREK and TASK, have recently emerged as a potential target. These channels regulate membrane excitability, and halothane has been found to reduce neuronal firing by hyperpolarizing neurons by a current similar to TASK. Knockout mouse models have provided support for TREK-1. NMDA receptors, HCN channels and some sodium channels.

Induction
Induction is a term that refers to the first stage of anaesthesia, Stage 1, prior to reaching a depth suitable for surgery i.e. Stage 3. The speed of induction depends on the time taken for the drug to reach an effective concentration in the brain. Different compounds partition to different compartments of the body, such as fatty tissue, at different rates. Hence, different compounds have different rates of induction. Intravenous anesthetics like Thiopental have been used for induction and it is common for aneasthesia to be maintained by inhalational anesthetics such as Isoflurane. Propofol is now the most widely used intravenous general anesethetic.

Elimination
Volatile anaesthetics are eliminated in the terminal phase via the lungs. A low blood:gas partition coefficient is therefore necessary for quick removal of the anaesthetic. When the oil:water coefficient is high, there will be little anaesthetic in the blood, so elimination will be slow, giving a prolonged hangover effect.

Intravenous and intramuscular drugs are eliminated by metabolic pathways in the liver. It is not uncommon to produce toxic metabolites (e.g. chloroform).