General anesthetics potency

C. North andD.S. Cafiso. Contrasting membrane localization and behavior of halogenated cyclobutanes that follow or violate the meyer-overton hypothesis of general anesthetic potency. Biophys. J., 72 (1997) 1754-1761. 

Although most anesthetics are achiral or are adininistered as racemic mixture, the anesthetic actions are stereoselective. This property can define a specific, rather than a nonspecific, site of action. Stereoselectivity is observed for such barbiturates as thiopental, pentobarbital, and secobarbital. The (3)-enantiomer is modestly more potent (56,57). Additionally, the volatile anesthetic isoflurane also shows stereoselectivity. The (3)-enantiomer is the more active (58). Further evidence that proteins might serve as appropriate targets for general anesthetics come from observations that anesthetics inhibit the activity of the enzyme luciferase. The potencies parallel the anesthetic activities closely (59,60). 

General anesthetics are usually small solutes with relatively simple molecular structure. As overviewed before, Meyer and Overton have proposed that the potency of general anesthetics correlates with their solubility in organic solvents (the Meyer-Overton theory) almost a century ago. On the other hand, local anesthetics widely used are positively charged amphiphiles in solution and reversibly block the nerve conduction. We expect that the partition of both general and local anesthetics into lipid bilayer membranes plays a key role in controlling the anesthetic potency. Bilayer interfaces are crucial for the delivery of the anesthetics. 

Halothane, isoflurane, and enflurane have similar depressant effects on the EEG up to doses of 1-1.5 MAC. At higher doses, the cerebral irritant effects of enflurane may lead to development of a spike-and-wave pattern and mild generalized muscle twitching (ie, myoclonic activity). However, this seizure-like activity has not been found to have any adverse clinical consequences. Seizure-like EEG activity has also been described after sevoflurane, but not desflurane. Although nitrous oxide has a much lower anesthetic potency than the volatile agents, it does possess both analgesic and amnesic properties when used alone or in combination with other agents as part of a balanced anesthesia technique. 

Nonreceptor-Mediated Drug Action. At least one important class of drugs, the general anesthetics, has been assumed not to owe its therapeutic activities to a specific receptor process. Anesthetic potency shows an excellent linear correlation with partition coefficient and this has been extrapolated to a definition of action at a lipid site. The phospholipids of cell membranes, particularly nerve cells, have been considered as principal targets for general anesthetic action. It has been hypothesized... 

General anesthetics are soluble in lipids. Only a few are soluble in water. Furthermore, there is a well known correlation between anesthetic potency and lipid solubility. It is the Meyer-Overton rule that has been known for 80 years to researchers in anesthesia.. This relationship was thoroughly studied and reexamined in recent years (See ). In its most modem form the lipid solubility or oil/water partition coefTicient is plotted against the so-called righting reflex taken for a measure of anesthetic potency. It is log 1/p where p is the effective anesthetic pressure in atmospheres required to suppress the righting reflex of mice in half of the experimental animals On this relationship arc based the unitary hypothesis and the hydrophobic site theory which state that all general anesthetics act by the same mechanism at the same molecular or sub-cellular sites of the membrane and that the sites are hydrophobic. 

Subsequently an extensive infrared spectroscopic study was undertaken in order to ascertain if this hydrogen bond perturbing ability of fluorocarbon anesthetics is of general occurence and if it can be at least qualitatively related to their anesthetic potency. (Di Paolo and Sandorfy, Most of this work was done at low temperatures. It was found that the phenomenon is quite general. 

That the lipid solubility versus anesthetic potency relationship is not above criticism has been intimated for a number of years by a number of authors. Summaries of the relevant facts and comments are found in the reviews of Halsey and Kaufman . It is only since 1974, however, that the possible importance of polar interactions has become a target of intense discussions. General anesthetics have widely different chemical structures and it has never been possible to classify them on chemical grounds. Xenon, nitrous oxide, ethylene, cyclopropane, ether, chloroform, C Fg, SFg, CFj—CHClj, CFj-CHClBr (halothane), CHjOCF.CHCf, (methoxyflurane) can all exert anesthetic action. (This aspect will be discussed in more detail in the next section). Looking at the formulas of these different molecules it is hard to believe that they all associate with the same site and with the same type of forces. A series of observations have been made in recent years that substantiate this scepticism. 

Ketamine is used as a sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. It is best suited for short procedures, but it can be used with additional doses for longer procedures. It is also used for the induction of anesthesia prior to the administration of other general anesthetics and to supplement low-potency agents, such as nitrous oxide. 

A) Anesthetic potency is quantitated by the minimum alveolar concentration (MAC) that causes 50% of subjects to fail to respond to a standardized painful stimulus General anesthesia is associated with increased blood pressure and total peripheral resistance... 

Most local anesthetic agents consist of a lipophilic group (eg, an aromatic ring) connected by an intermediate chain via an ester or amide to an ionizable group (eg, a tertiary amine) (Table 26-1). In addition to the general physical properties of the molecules, specific stereochemical configurations are associated with differences in the potency of stereoisomers (eg, levobupivacaine, ropivacaine). Because ester links are more prone to hydrolysis than amide links, esters usually have a shorter duration of action. 

Research during World War II produced many new fluorinated compounds and, in the early 1950s, a concerted effort was made to find among them nonflammable volatile compounds suitable for general anesthesia. Of hundreds tested, most, with notable exceptions, were found unsuitable for a variety of reasons, for example, toxicity or low potency. Examples of clinically promising halogenated anesthetics are discussed briefly in this section252. 

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