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, showed an unacceptably highincidence of inadequate anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never went into routine scientific practice, however phencyclidine (phenylcyclohexylpiperidine, frequently described as PCP or" angel dust") has actually remained a drug of abuse in numerous societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to cause convulsions, but was still associated with anesthetic development phenomena, such as hallucinations and agitation, albeit of shorter duration. It ended up being commercially readily available in1970. There are 2 optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is roughly three to four times as potent as the R isomer, most likely due to the fact that of itshigher affinity to the phencyclidine binding websites 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). On The Other Hand, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a clinical preparation of the S(+) isomer is available insome nations, the most common preparation in clinical usage is a racemic mixture of the two isomers.The just other agents with dissociative features still frequently used in clinical practice arenitrous oxide, initially used medically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative used as an antitussive in cough syrups given that 1958. Muscimol (a powerful 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 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 severe postoperative discomfort and to help avoid developmentof chronic discomfort) (Bell et al. 2006). Recent literature recommends a possible function for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually also 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 system of action of ketamine (in common with other dissociativeagents such as laughing gas, phencyclidine, and dextromethorphan) occurs through a noncompetitiveantagonist effect at theN-methyl-D-aspartate (NDMA) receptor. It may likewise act via an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (ANIMAL) imaging research studies suggest that the system of action does not include binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream effects are variable and rather questionable. The subjective effects ofketamine seem 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 may trigger indirect repressive effects on GABA-ergic interneurons, resulting ina disinhibiting impact, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The websites at which dissociative agents (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic impacts are partly comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Research Studies") in healthy topics 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 suggest deactivation of theposterior Additional reading cingulate area. Surprisingly, these effects scale with the psychogenic effects of the agentand are concordant with practical imaging problems observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI studies in treatment-resistant major anxiety show thatlow-dose ketamine infusions transformed anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). Despite these information, it remains unclear 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 show plainly concordant patterns with fMRIdata. Even more, the function of direct vascular results of the drug stays unpredictable, considering that there are cleardiscordances in the regional specificity and magnitude of modifications in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by FAMILY PET in healthy humans (Langsjo et al. 2004). Recentwork recommends that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated via downstream effects on the mammalian target of rapamycin resulting in increasedsynaptogenesis