HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst utilized 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 symptoms (Pender1971). Theseagents never ever got in routine medical practice, however phencyclidine (phenylcyclohexylpiperidine, frequently described 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, however was still associated with anesthetic emergence phenomena, such as hallucinations and agitation, albeit of much shorter period. It became commercially available in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is approximately three to four times as potent as the R isomer, probably because 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 reflects its increased potency). Conversely, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a clinical preparation of the S(+) isomer is available insome countries, the most common preparation in clinical use is a racemic mixture of the two isomers.The only other agents with dissociative features still commonly used in clinical practice arenitrous oxide, first used clinically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent used as an antitussive in cough syrups since 1958. Muscimol (a potent GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are also said to be dissociative drugs and have been used in mysticand religious rituals (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
Recently these have been a resurgence of interest in making use of ketamine as an adjuvant agentduring general anesthesia (to help in reducing acute postoperative pain and to help prevent developmentof chronic pain) (Bell et al. 2006). Recent literature suggests a possible role for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually also been utilized as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Mechanisms of ActionThe primary direct molecular mechanism of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) occurs via a noncompetitiveantagonist effect at theN-methyl-D-aspartate (NDMA) receptor. It might likewise act through an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (PET) imaging studies recommend that the system of action does not include binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream results vary and rather questionable. The subjective effects ofketamine appear to be 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 agents (such as sub-anesthetic dosages of ketamine) produce theirneurocognitive and psychotomimetic impacts are partially comprehended. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Research Studies") in healthy topics who were given lowdoses of ketamine has shown that ketamine triggers a network of brain areas, consisting of theprefrontal cortex, striatum, and anterior cingulate cortex. Other studies suggest deactivation of theposterior cingulate region. Remarkably, these impacts scale with the psychogenic results of the agentand are concordant with practical imaging problems observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI Additional hints studies in treatment-resistant major depression indicate thatlow-dose ketamine infusions modified anterior cingulate cortex activity and connection 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 define thedownstream impacts of the drug. In specific, direct displacement research studies with ANIMAL, using11C-labeledN-methyl-ketamine as a ligand, do disappoint clearly concordant patterns with fMRIdata. Further, the role of direct vascular effects of the drug remains uncertain, because there are cleardiscordances in the regional specificity and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by PET 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