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 agents fromthis group, such as phencyclidine and cyclohexamine hydrochloride, showed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never ever entered regular medical practice, however phencyclidine (phenylcyclohexylpiperidine, typically referred to 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 connected with anesthetic emergence phenomena, such as hallucinations and agitation, albeit of much shorter duration. It ended up being commercially available in1970. There are 2 optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is roughly 3 to 4 times as powerful as the R isomer, probably 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 readily available insome countries, the most typical preparation in medical usage is a racemic mix of the two isomers.The just other agents with dissociative features still typically utilized in scientific practice arenitrous oxide, first used scientifically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent utilized as an antitussive in cough syrups because 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 recent years these have actually been a renewal of interest in making use of ketamine as an adjuvant agentduring basic anesthesia (to help lower acute postoperative discomfort and to assist prevent developmentof persistent pain) (Bell et al. 2006). Recent literature suggests a possible role for ketamine asa treatment for persistent pain (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually likewise been utilized as a design supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Mechanisms of ActionThe primary direct molecular system of action of ketamine (in common with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) happens 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 (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 effects are variable and rather controversial. The subjective results ofketamine seem mediated by increased release of glutamate (Deakin et al. 2008) and likewise byincreased dopamine release moderated by a glutamate-dopamine interaction in the posterior cingulatecortex (Aalto et al. 2005). In spite of its uniqueness in receptor-ligand interactions noted 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 websites at which dissociative representatives (such as sub-anesthetic dosages of ketamine) produce theirneurocognitive and psychotomimetic impacts are partially comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Research Studies") in healthy subjects who were offered lowdoses of ketamine has 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. Surprisingly, these results scale with the psychogenic effects of the agentand are concordant with functional imaging abnormalities observed in clients with schizophrenia( Fletcher et al. 2006). Similar fMRI studies in treatment-resistant major depression suggest thatlow-dose ketamine infusions altered anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). In spite of these information, it stays uncertain whether thesefMRIfindings straight determine the websites of ketamine action or whether they characterize thedownstream results of the drug. In specific, direct displacement research studies with PET, using11C-labeledN-methyl-ketamine as a ligand, do not show plainly concordant patterns with fMRIdata. Even more, the function of direct Additional reading vascular impacts of the drug stays unpredictable, given that there are cleardiscordances in the local specificity and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by ANIMAL in healthy people (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor results in anti-depressant effectsmediated via downstream effects on the mammalian target of rapamycin leading to increasedsynaptogenesis