Anesthetic drugs mechanisms

The mechanism of action of inhalational anesthetics is unknown. The diversity of chemical structures (inert gas xenon hydrocarbons halogenated hydrocarbons) possessing anesthetic activity appears to rule out involvement of specific receptors. According to one hypothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excitability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal alveolar concentration (MAC) at which 50% of patients remain immobile following a defined painful stimulus (skin incision). Whereas the poorly lipophilic N2O must be inhaled in high concentrations (>70% of inspired air has to be replaced), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. 

General anesthetic drugs have the ability to reduce the level of consciousness in a dose dependent fashion. The study of the neurobiological mechanisms of action of these drugs may provide insight into the systems that are necessary for the existence of consciousness. It clearly cannot be assumed however, that the systems that underlie the action of these substances are in themselves sufficient for consciousness. Indeed, within a complex neural network, any number of small alterations can disturb the whole. This chapter focuses on what is known about the molecular mechanism of action of drugs that are used clinically for general anesthesia. 

The induction of unconsciousness may be the result of exposure to excessive concentrations of toxic solvents such as carbon tetrachloride or vinyl chloride, as occasionally occurs in industrial situations (solvent narcosis). Also, volatile and nonvolatile anesthetic drugs such as halothane and thiopental, respectively, cause the same physiological effect. The mechanism(s) underlying anesthesia is not fully understood, although various theories have been proposed. Many of these have centered on the correlation between certain physicochemical properties and anesthetic potency. Thus, the oil/water partition coefficient, the ability to reduce surface tension, and the ability to induce the formation of clathrate compounds with water are all correlated with anesthetic potency. It seems that each of these characteristics are all connected to hydrophobicity, and so the site of action may be a hydrophobic region in a membrane or protein. Thus, again, physicochemical properties determine biological activity. 

Halothane is a very widely used anesthetic drug, which may cause hepatic damage in some patients. It seems that there are two types of hepatic damage, however. One is a very rare reaction, idiosyncratic, resulting in serious liver damage with an incidence of about 1 in 35,000. The other form of hepatotoxicity is a mild liver dysfunction, which is more common and occurs in as many as 20% of patients receiving the drug. The two different types probably involve different mechanisms. 

Briefly describe the important aspects of mechanisms underlying the hepatotoxic effects of the anesthetic drug halo thane. 

It has been generally accepted that anesthetics interact with membrane lipids as a primary step of anesthesia. The detailed mechanism of the anesthetic action is, however, still controversial. This is mainly due to the absence of specific information on delivery sites in membranes. The NMR data for the delivery site of drugs in membranes are of great use. 

C NMR. The membrane perturbation by PRC H+ is found to be relatively smaller than DBC H. The ring current effect on the EPC h NMR signal is not substantial at any site. Only significant NMR downfield shift is noticed in the carbonyl site, as shown in Fig. 10. The difference in the perturbation effect between DBC H and PRC H supports the difference in the trapped site in bilayers and that in the anesthetic mechanism between the two drugs. 

---