The first description of anesthetic use was in 1846 when diethyl ether (Figure 1) was used to induce unconsciousness in the operating room setting.1 Despite the widespread and increasing use of anesthetics in human medicine for over 150 years, their mechanisms of action have yet to be clearly elucidated, reflecting: (1) the diverse structures of general anesthetics (Figure 1)3'5; (2) the high, generally millimolar, concentrations of anesthetics used to induce anesthesia1; (3) the lack of anesthetic antagonists; and (4) the complex nature of general anesthesia that involves amnesia, analgesia, unconsciousness, and immobility. Additionally, the proposal in the 1860s by the French physiologist, Claude Bernard, based on studies on the effects of anesthetic agents on plants and animals, that anesthetics like ether and chloroform acted by coagulating 'albuminoid' cell contents, focused attention on a relatively nonspecific interaction of these agents with the cell membrane. Subsequently, the seminal studies of Meyer and Overton in 1895 showed that anesthetic potency was correlated with the oil/gas partition coefficient, the Meyer-Overton rule, that the number of molecules dissolved in the lipid cell membrane and not the type of inhalation agent produces anesthesia, focusing attention on the lipid bilayer as the site of action of general anesthetics. The latter led to the unitary theory of anesthesia, namely that all anesthetics, both general and local, produce their effects by a simple perturbation of the cell membrane. In many respects, the lipid perturbation theory confounded both the search for discrete mechanisms of action for anesthetics and, consequently, the search for improved anesthetic agents. This theory has been extended to the lipophilic intrusion protection organization-integrative design (LIPOID) hypothesis of analgesia8 that postulates that the multiple lipophilic properties of anesthetic molecules contribute to many simultaneous actions that result in anesthesia.

Continuing research6-10 has focused on the interaction of anesthetics with membrane proteins, e.g., ion channels, as a primary mechanism of action. The observation11 that several anesthetics, e.g., isoflurane, etomidate (Figure 2), as well as some steroids, have modest enantioselective effects, while further supporting the concept that specific membrane-binding sites or receptors are responsible for the actions of anesthetics, are at odds with Pfiffer's rule,12 given the low affinities measured to date with general anesthetics. It has also been noted, however, that ''each anaesthetic agent has a unique action, the end result of which is to produce a state of anaesthesia.''7

Inhalation anesthetics include a variety of gases and volatile liquids, e.g., halothane, desflurane, nitrous oxide (Figure 1). These agents have a low safety margin with therapeutic indices in the range of 2-4, and with each inhalation anesthetic having a distinct side-effect profile,1 a finding that reinforced the concept of each anesthetic having a unique mechanism of action.7 Their differing side-effect profiles and evidence for gender- and anatomically specific differences in the actions of general anesthetics additionally confused the logic of a search for a common site of action.

The parenteral general anesthetics, administered by the intravenous route, include barbiturates like thiopental and other agents, including propofol, ketamine, and etomidate (Figure 2), as well as certain opioids, e.g., morphine, fentanyl, alfentanil, sufentanil (Figure 3), that can be used for the maintenance of general anesthesia.

Local anesthetics include cocaine, lidocaine, and bupivacaine (Figure 3), that act by blocking voltage-sensitive sodium channels (VSSCs) or Nav channels.13

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