HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst used in medical practice in the 1950s. Early experience with representatives fromthis group, such as phencyclidine and cyclohexamine hydrochloride, showed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic symptoms (Pender1971). Theseagents never ever got in regular scientific practice, however phencyclidine (phenylcyclohexylpiperidine, commonly referred to as PCP or" angel dust") has actually remained a drug of abuse in many 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 ended up being commercially available 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). Alternatively, R() ketamine might preferentially bind to opioidreceptors (see subsequent text). Although a scientific preparation of the S(+) isomer is available insome countries, the most typical preparation in clinical use is a racemic mixture of the 2 isomers.The only other agents with dissociative functions still commonly used in scientific practice arenitrous oxide, initially used clinically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative utilized as an antitussive in cough syrups considering that 1958. Muscimol (a potent GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are likewise said to be dissociative drugs and have been utilized in mysticand religious routines (seeRitual Uses of Psychedelic 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 making use of ketamine as an adjuvant agentduring basic 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 utilized as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Systems of here ActionThe primary direct molecular system of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) takes place via a noncompetitiveantagonist result at theN-methyl-D-aspartate (NDMA) receptor. It may also act by means of an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (PET) imaging research studies recommend that the mechanism of action does not include binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream results are variable and rather questionable. The subjective results ofketamine appear to be moderated by increased release of glutamate (Deakin et al. 2008) and likewise 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 noted previously, ketamine might cause indirect inhibitory 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 understood. 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 recommend deactivation of theposterior cingulate area. Surprisingly, these effects scale with the psychogenic effects of the agentand are concordant with functional imaging irregularities observed in clients with schizophrenia( Fletcher et al. 2006). Comparable fMRI research studies in treatment-resistant significant anxiety indicate thatlow-dose ketamine infusions altered anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). Regardless of these data, it remains uncertain whether thesefMRIfindings straight recognize the sites of ketamine action or whether they characterize thedownstream results of the drug. In particular, direct displacement studies with PET, using11C-labeledN-methyl-ketamine as a ligand, do disappoint plainly concordant patterns with fMRIdata. Even more, the role of direct vascular impacts of the drug stays unpredictable, considering that there are cleardiscordances in the regional uniqueness and magnitude of modifications in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by ANIMAL in healthy human beings (Langsjo et al. 2004). Recentwork recommends that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated through downstream impacts on the mammalian target of rapamycin resulting in increasedsynaptogenesis