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 agents fromthis group, such as phencyclidine and cyclohexamine hydrochloride, revealed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never ever got in regular medical practice, however phencyclidine (phenylcyclohexylpiperidine, typically described as PCP or" angel dust") has remained a drug of abuse in many societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to cause convulsions, however was still related to anesthetic introduction 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 around three to four times as potent as the R isomer, probably since of itshigher affinity to the phencyclidine binding websites on NMDA receptors (see subsequent text). The S(+) enantiomer might have more psychotomimetic homes (although it is not clear whether thissimply shows its increased strength). On The Other Hand, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a scientific preparation of the S(+) isomer is offered insome countries, the most common preparation in clinical use is a racemic mix of the two isomers.The just other representatives with dissociative features still commonly utilized in scientific practice arenitrous oxide, first utilized medically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent used 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 likewise stated to be dissociative drugs and have been used in mysticand religious rituals (seeRitual Utilizes 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 using ketamine as an adjuvant agentduring general anesthesia (to help in reducing acute postoperative discomfort and to help prevent 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 utilized as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Systems of ActionThe main direct molecular system of action of ketamine (in common with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) happens via a noncompetitiveantagonist result at theN-methyl-D-aspartate (NDMA) receptor. Additional info It may also act via an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (PET) imaging studies recommend that the mechanism of action does not involve binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream results are variable and rather controversial. The subjective effects ofketamine seem moderated by increased release of glutamate (Deakin et al. 2008) and also byincreased dopamine release moderated by a glutamate-dopamine interaction in the posterior cingulatecortex (Aalto et al. 2005). Despite its specificity in receptor-ligand interactions noted previously, ketamine may trigger indirect repressive impacts on GABA-ergic interneurons, resulting ina disinhibiting result, 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 effects are partly understood. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Studies") in healthy subjects who were offered lowdoses of ketamine has actually revealed that ketamine activates 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 results of the agentand are concordant with practical imaging irregularities observed in clients with schizophrenia( Fletcher et al. 2006). Comparable fMRI research 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 directly identify the websites of ketamine action or whether they characterize thedownstream effects of the drug. In specific, direct displacement research 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 uncertain, given that there are cleardiscordances in the local specificity and magnitude of modifications in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by ANIMAL in healthy people (Langsjo et al. 2004). Recentwork recommends that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated via downstream results on the mammalian target of rapamycin resulting in increasedsynaptogenesis