HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst used in clinical practice in the 1950s. Early experience with representatives fromthis group, such as phencyclidine and cyclohexamine hydrochloride, showed an unacceptably highincidence of inadequate anesthesia, convulsions, and psychotic symptoms (Pender1971). Theseagents never entered regular scientific practice, but phencyclidine (phenylcyclohexylpiperidine, typically described as PCP or" angel dust") has remained 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 related to anesthetic introduction phenomena, such as hallucinations and agitation, albeit of shorter period. It ended up being commercially offered in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is approximately 3 to 4 times as powerful as the R isomer, probably due to the fact that of itshigher affinity to the phencyclidine binding sites on NMDA receptors (see subsequent text). The S(+) enantiomer may have more psychotomimetic properties (although it is not clear whether thissimply shows its increased effectiveness). Alternatively, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a medical preparation of the S(+) isomer is available insome nations, the most typical preparation in medical use is a racemic mix of the two isomers.The only other representatives with dissociative features still commonly utilized in medical practice arenitrous oxide, first utilized scientifically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent 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
Recently these have been a renewal of interest in making use of ketamine as an adjuvant agentduring general anesthesia (to assist decrease intense postoperative pain and to assist prevent developmentof persistent pain) (Bell et al. 2006). Current literature suggests a possible function for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually 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 common with other dissociativeagents such as laughing gas, phencyclidine, and dextromethorphan) happens by means of a noncompetitiveantagonist effect at theN-methyl-D-aspartate (NDMA) receptor. It might also act through an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (FAMILY PET) imaging studies recommend that the system 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 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). In spite of its uniqueness in receptor-ligand interactions noted earlier, ketamine might cause indirect inhibitory impacts on GABA-ergic interneurons, resulting ina disinhibiting effect, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The websites at which dissociative representatives (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic impacts are partly comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Studies") in healthy subjects who were provided lowdoses of ketamine has actually revealed that ketamine activates a network of brain regions, consisting of theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies recommend deactivation of theposterior cingulate region. Interestingly, these effects scale with the psychogenic results of the agentand are concordant with functional imaging abnormalities observed in clients with schizophrenia( Fletcher et al. 2006). Comparable fMRI research studies in treatment-resistant major depression indicate thatlow-dose ketamine infusions modified anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). In spite of these information, it remains uncertain whether thesefMRIfindings straight determine the websites of ketamine action or whether they identify thedownstream results of the drug. In specific, direct displacement research studies with FAMILY 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 uncertain, given that there are cleardiscordances in the regional uniqueness and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and 2-FDCK bestellen 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