Glycine anesthetics

Glycine receptor function is modulated by alcohols and anesthetics [4]. Amino acid residue al(S267) is critical for alcohol potentiation, as mutation to small residues (Gly, Ala) enhance, and mutation to large residues (His, Cys, Tyr) diminish the ethanol effect. Glycine recqrtor modulation by Zn2+ involves structural determinants located within the large N-terminal domain. Additional glycinergic modulators include neuroactive steroids and the anthelmintic, ivermectin, which activates glycine receptors by a novel, strychnine-insensitive mechanism. 

Beckstead MJ, Phelan R, Mihic SJ Antagonism of inhalant and volatile anesthetic enhancement of glycine receptor function. J Biol Chem 276 24959-24964,2001 Beckstead MJ, Phelan R, Trudell JR, et al Anesthetic and ethanol effects on spontaneously opening glycine receptor channels. J Neurochem 82 1343-1351,... 

Intravenous GABAa glycine GABAc Muscle Neuronal 5HT3 AMPA Kainate NMDA Anesthetics nAChR nAChR... 

The indication of interaction with specific amino acid residues in the GABAa and glycine receptors strongly suggests direct anesthetic protein interactions. 

S. Daniels (2003). General anesthetic effects on glycine receptors. In J. Antognini, E. Carstens, D. Raines (Eds.). Neural Mechanisms of Anesthesia. Totowa, New Jersey Humana Press, pp. 333-344. 

Lidocaine (synonyme lignocaine) was introduced as the first amide in 1944 and is the most commonly used LA today. It has a rapid onset of action with intermediate duration and an intermediate toxicity. The maximum tolerated dose with infiltration or injection is 200 mg (500 mg when combined with adrenaline). Lidocaine is dealkylated in the liver to monoethylglycine xylidide and glycine xylidide which retain local anesthetic activity. It is available in a variety of preparations including creams, gels, patches and solutions, often in combination with adrenaline. 

Sites of Alcohol and Volatile Anesthetic Action on Glycine Receptors Ingrid A. Lobo and R. Adron Harris... 

BlievichU. M Zomow M. H Choi K. T Stmat M. A., and ScheBerM. S. (1994) Effects of hypothermia or anesthetics on hippocampal glutamate and glycine concentrations after repeated transient global cerebral ischemia. Anesthesiology 80, 177-186. 

Beckstead, M.J., R. Phelan, and S.J. Mihic. Antagonism of Inhalant and Volatile Anesthetic Enhancement of Glycine Receptor Function. /ourna/ of Biological Chemistry 276 (2001) 24959-24964. 

Benzyl alcohol is oxidized by the liver to benzoic acid, and then conjugated with glycine to form hippuric acid. Metabolic acidosis can be explained by a direct effect of benzoic acid and/or secondary lactic acid production through depression of cellular metabolism. Benzyl alcohol is a weak local anesthetic with disinfectant properties. 

No effective treatment is known. Drugs that counteract the effect of glycine on neuronal cells, such as strychnine, diazepam, and dextromethorphan, could bring mild benefits in milder forms of the condition. Ketamine, an anesthetic blocker of the N-methyl-n-aspartate (NMDA) receptor channel, brought a partial improvement of neurological symptoms and EEG findings m some patients, but their developmental milestones were delayed. 

Lidocaine is dealkylated in the liver by CYPs to mono-ethylglycine xylidide and glycine xylidide, which can be metabolized further to monoethylglycine and xylidide. Both monoethylglycine xylidide and glycine xyhdide retain local anesthetic activity. In humans, about 75% of the xyhdide is excreted in the urine as the further metabohte 4-hydroxy-2, 6-dimethylaniline. 

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