Membrane anesthesia mechanisms

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. 

Ketamine and also tiletamine are structurally and pharmacologically related to phencyclidine. Its mechanism of action is not well understood. It has been suggested that it blocks the membrane effects of the excitatory neurotransmitter glutamic acid. Ketamine produces dissociative anesthesia, which means that the patient seems to be awake but there are no responses to sensory stimuli. Ketamine, which can be administered IV or IM, has strong analgesic activity. It is especially indicated for interventions of short duration without any need for skeletal... 

Among the earliest proposals to explain the mechanism of action of anesthetics is the concept that they interact physically rather than chemically with lipophilic membrane components to cause neuronal failure. However, this concept proposes that all anesthetics interact in a common way (the unitary theory of anesthesia), and it is being challenged by more recent work demonstrating that specific anesthetics exhibit selective and distinct interactions with neuronal processes and that those interactions are not easily explained by a common physical association with membrane components. Proposals for the production of anesthesia are described next. 

Hydroxyzine hydrochloride Atarax, Vistarit) is the antihistamine with the greatest use in the treatment of anxiety. It is often used to reduce the anxiety that is associated with anesthesia and surgery. It also produces sedation, dries mucous membranes (via an anticholinergic mechanism), and has antiemetic activity. A more extensive discussion of the pharmacology of the Hj-receptor antagonists is found in Chapter 38. 

Mechanism of Action Procaine causes a reversible blockade of nerve conduction by decreasing nerve membrane permeability to sodium. Therapeutic Effect Local anesthesia. 

Both the inhaled and the intravenous anesthetics can depress spontaneous and evoked activity of neurons in many regions of the brain. Older concepts of the mechanism of anesthesia evoked nonspecific interactions of these agents with the lipid matrix of the nerve membrane (the so-called Meyer-Overton principle)—interactions that were thought to lead to secondary changes in ion flux. More recently, evidence has accumulated suggesting that the modification of ion currents by anesthetics results from more direct interactions with specific nerve membrane components. The ionic mechanisms involved for different anesthetics may vary, but at clinically relevant concentrations they appear to involve interactions with members of the ligand-gated ion channel family. 

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. 

The molecular mechanism of local anesthesia, the location of the local anesthetic dibucaine in model membranes, and the interaction of dibucaine with a Na+-channel inactivation gate peptide have been studied in detail by 2H- and 1H-NMR spectroscopy [24]. Model membranes consisted of PC, PS, and PE. Dibucaine was deuterated at H9 and H3 of the butoxy group and at the 3-position of the quinoline ring. 2H-NMR spectra of the multilamellar dispersions of the lipid mixtures were obtained. In addition, spectra of deuterated palmitic acids incorporated into mixtures containing cholesterol were obtained and the order parameter, SCD, for each carbon... 

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. 

Transient and permanent nerve damage can occur after regional anesthesia, particularly neuraxial anesthesia. The mechanism of this nerve damage is unclear. Some studies have shown an indirect effect. However, in crayfish giant axon, lidocaine had a dose- and time-dependent effect on isolated nerve function in vitro (31). At high concentrations lidocaine caused irreversible conduction block and total loss of resting membrane potential. These results in an isolated nerve suggest a direct neurotoxic effect of lidocaine. 

Tang, P., Xu, Y. (2002). From the Cover Large-scale molecular dynamics simulations of general anesthetic effects on the ion channel in the fully hydrated membrane The implication of molecular mechanisms of general anesthesia. Proceedings of the National Academy of Sciences of the United States of America, 99(25), 16035-16040. 

Despite the considerable number of studies of the mechanism of narcosis, the details regarding its molecular basis have proven very elusive, and the theoretical basis for narcosis or anesthesia still represents a subject of considerable debate. Current research is focused on two major theories, disorganization of membrane lipoid constituents (53-54), and binding to one or more enzymes or proteins (55-56). 

The effect of cyclopropane anesthesia on trltlated water flux across the gut Is another attempt to study the Influence of anesthesia on water structureHigh concentrations of cyclopropane produce tissue damage, but no change In water flux across the rat cecum. Moderate concentrations produce minimal tissue damage but some slowing of water flux across the membrane was noted. It Is suggested that this experiment Is consistent with the hydrate theory of anesthesia, but not necessarily a direct proof of this mechanism of operation of the anesthetic. 

R.S. Cantor. The lateral pressure profile in membranes a physical mechanism of general anesthesia. Biochemistry, 36 (1997) 2339-2344. 

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