HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst utilized in clinical practice in the 1950s. Early experience with representatives fromthis group, such as phencyclidine and cyclohexamine hydrochloride, revealed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never ever got in regular scientific practice, however phencyclidine (phenylcyclohexylpiperidine, typically referred to as PCP or" angel dust") has actually stayed a drug of abuse in lots of societies. Inclinical screening in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to trigger convulsions, but was still connected with anesthetic introduction phenomena, such as hallucinations and agitation, albeit of much shorter duration. It became commercially offered in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is roughly three to four times as powerful as the R isomer, most likely since of itshigher affinity to the phencyclidine binding sites on NMDA receptors (see subsequent text). The S(+) enantiomer may have more psychotomimetic homes (although it is unclear whether thissimply reflects its increased potency). On The Other Hand, R() ketamine might preferentially bind to opioidreceptors (see subsequent text). Although a medical preparation of the S(+) isomer is readily available insome countries, the most common preparation in scientific usage is a racemic mix of the 2 isomers.The only other representatives with dissociative functions still typically used in scientific practice arenitrous oxide, first used medically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent used as an antitussive in cough syrups given that 1958. Muscimol (a potent GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are also stated to be dissociative drugs and have been utilized in mysticand religious routines (seeRitual Uses of Psychoactive Drugs"). * Email:
nlEncyclopedia of PsychopharmacologyDOI 10.1007/ 978-3-642-27772-6_341-2 #Springer- Verlag Berlin Heidelberg 2014Page 1 of 6
In current years these have been a renewal of interest in using ketamine as an adjuvant agentduring general anesthesia (to help in reducing intense postoperative pain and to assist prevent developmentof persistent pain) (Bell et al. 2006). Current literature recommends a possible role for ketamine asa treatment for persistent pain (Blonk et al. 2010) and anxiety (Mathews and Zarate2013). Ketamine has likewise been used as a design supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Mechanisms of ActionThe main direct molecular mechanism of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) takes place through a noncompetitiveantagonist effect at theN-methyl-D-aspartate (NDMA) receptor. It may likewise act through an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (FAMILY PET) imaging studies recommend that the mechanism of action does not involve binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream results are variable and somewhat questionable. The subjective effects ofketamine seem moderated by increased release of glutamate (Deakin et al. 2008) and also byincreased dopamine release mediated by a glutamate-dopamine interaction in the posterior cingulatecortex (Aalto et al. 2005). Regardless of its specificity in receptor-ligand interactions kept in mind previously, ketamine may cause indirect repressive results on GABA-ergic interneurons, resulting ina disinhibiting effect, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The sites at which dissociative representatives (such as sub-anesthetic dosages of ketamine) produce theirneurocognitive and psychotomimetic effects are partly comprehended. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Studies") in healthy subjects who were provided lowdoses of ketamine has actually revealed that ketamine triggers a network of brain areas, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other studies suggest deactivation of theposterior cingulate region. Remarkably, these results scale with the psychogenic results of the agentand are concordant with functional imaging abnormalities observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI studies in treatment-resistant major anxiety suggest thatlow-dose ketamine infusions transformed anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). Despite these data, it remains uncertain whether thesefMRIfindings directly identify the sites of ketamine action or whether they characterize thedownstream effects of the drug. In particular, direct displacement studies with FAMILY PET, using11C-labeledN-methyl-ketamine as a ligand, do not 2-FDCK bestellen show plainly concordant patterns with fMRIdata. Even more, the function of direct vascular effects of the drug remains uncertain, since there are cleardiscordances in the local uniqueness and magnitude of modifications in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by FAMILY PET in healthy people (Langsjo et al. 2004). Recentwork recommends that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated by means of downstream results on the mammalian target of rapamycin leading to increasedsynaptogenesis