Esketamina

Esketamina
Identificadores
Número CAS	33643-46-8
PubChem	182137
DrugBank	DB01221
ChemSpider	158414
UNII	50LFG02TXD
KEGG	D07283
ChEBI	60799
ChEMBL	395091
Datos químicos
Fórmula	C13H16NClO
InChI InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3/t13-/m0/s1 Key: YQEZLKZALYSWHR-ZDUSSCGKSA-N
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La esketamina, también conocida como (S)-ketamina o S(+)-ketamina, es una droga alucinógena disociativa utilizada como anestésico general. Es el enantiómero S (+) de la ketamina,^[1]​^[2]​ y empleado también como antidepresivo para el tratamiento de depresión. Se comercializa bajo las marcas Spravato (para la depresión), Ketanest (para anestesia), entre otras.^[3]​^[1]​^[4]​^[5]​ Como enantiómero activo de la ketamina produce antagonismo del receptor NMDA en la que es más potente que la ketamina racémica.^[6]​

La eskatamina se usa específicamente como terapia para la depresión resistente al tratamiento (por sus siglas en inglés, TRD) y para el trastorno depresivo mayor (MDD) con ideación o con comportamiento suicida concomitante.^[3]​^[7]​ Su efectividad para la depresión es modesta y similar a la de otros antidepresivos.^[8]​^[3]​ La esketamina no se usa por infusión intravenosa para anestesia, ya que solo está aprobada por la FDA estadounidense para la depresión en forma de aerosol intranasal (el compuesto principal, la ketamina, se administra con mayor frecuencia por vía intravenosa) y bajo supervisión médica directa como aerosol nasal.^[3]​^[1]​

Algunos efectos adversos de la esketamina incluyen disociación, mareos, sedación, náuseas, vómitos, vértigo, entumecimiento, ansiedad, letargo, aumento de la presión arterial y sensación de embriaguez.^[3]​ Con menos frecuencia la esketamina puede causar trastornos de vejiga.^[3]​^[9]​ La esketamina actúa principalmente como antagonista del receptor de N-metil-D-aspartato (NMDA), pero también tiene otras acciones mediadas por otros tipos de receptores de membrana.^[1]​^[2]​

En forma de ketamina racémica, la esketamina se sintetizó por primera vez en 1962 y se introdujo para uso médico como anestésico en 1970.^[10]​ Como enantiómero puro, la esketamina se introdujo para uso médico como anestésico en 1997 y como antidepresivo en 2019.^[1]​^[3]​ Se utiliza como anestésico en la Unión Europea y como antidepresivo en Estados Unidos y Canadá.^[11]​^[12]​ Debido al uso indebido e ilegal como alucinógeno disociativo, la esketamina es una sustancia controlada.^[10]​^[3]​

1. ↑ ^{a b c d e} Himmelseher S, Pfenninger E (December 1998). «[The clinical use of S-(+)-ketamine--a determination of its place]». Anästhesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie 33 (12): 764-70. PMID 9893910. doi:10.1055/s-2007-994851. 
2. ↑ ^{a b} Jelen LA, Young AH, Stone JM (February 2021). «Ketamine: A tale of two enantiomers». J Psychopharmacol 35 (2): 109-123. PMC 7859674. PMID 33155503. doi:10.1177/0269881120959644. 
3. ↑ ^{a b c d e f g h} «Spravato- esketamine hydrochloride solution». DailyMed. 6 de agosto de 2020. Consultado el 26 de septiembre de 2020. 
4. ↑ «Text search results for esketamine: Martindale: The Complete Drug Reference». MedicinesComplete. London, UK: Pharmaceutical Press. Archivado desde el original el 20 de agosto de 2017. Consultado el 20 de agosto de 2017. 
5. ↑ «Ketamine Hydrochloride». MedicinesComplete. London, UK: Pharmaceutical Press. 9 de enero de 2017. Consultado el 20 de agosto de 2017. 
6. ↑ Kohrs R, Durieux ME (November 1998). «Ketamine: teaching an old drug new tricks». Anesthesia and Analgesia 87 (5): 1186-1193. PMID 9806706. doi:10.1213/00000539-199811000-00039. 
7. ↑ McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, Brietzke E, Dodd S, Gorwood P, Ho R, Iosifescu DV, Lopez Jaramillo C, Kasper S, Kratiuk K, Lee JG, Lee Y, Lui LM, Mansur RB, Papakostas GI, Subramaniapillai M, Thase M, Vieta E, Young AH, Zarate CA, Stahl S (May 2021). «Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation». Am J Psychiatry 178 (5): 383-399. PMC 9635017. PMID 33726522. doi:10.1176/appi.ajp.2020.20081251. «A legitimate criticism, as it relates to interpreting the effect sizes reported with single or repeat-dose ketamine in TRD, is the possibility that nonspecific effects such as functional unblinding (e.g., by patients experiencing dissociation or euphoric responses) and expectancymayinadvertentlyinflate the efficacy of ketamine (51, 52). [...] Given the absence of an adequately designed head-to-head trial, the relative efficacies of intranasal esketamine and intravenous racemic ketamine are not known (65). [...] A recent meta-analysis comparing intranasal and intravenous ketamine formulations was unable to identify a significant difference between formulations as well as routes of delivery in efficacy at 24 hours, 7 days, and 28 days (17). A separate meta-analysis concluded that intravenous ketamine may be superior in efficacy and have lower dropout rates (66). However, it is difficult to draw definitive conclusions from these analyses given the heterogeneity across component studies.» 
8. ↑ Khan A, Mar KF, Brown WA (June 2021). «Consistently Modest Antidepressant Effects in Clinical Trials: the Role of Regulatory Requirements». Psychopharmacol Bull 51 (3): 79-108. PMC 8374926. PMID 34421147. «Even drugs with novel mechanisms of action such as the esketamine nasal spray show the same effect size and look nearly identical to other antidepressants when evaluated in the regulatory context (42% symptom reduction with placebo, 54% with drug, effect size 0.29). However, it must be taken under consideration that this trial was unique from the others in that it was an adjunctive study of esketamine nasal spray in treatment resistant patients. It is worth noting that two shortterm trials conducted for regulatory approval of esketamine but not included in the label did not reach statistical significance (P = 0.058 and P = 0.088).28 Independent analysis of these esketamine trial data submitted to the FDA show that despite expectations from smallscale preliminary studies, esketamine performs modestly in patients with treatment resistant depression in the context of large, regulatory trials.29 These authors also raised concerns about the potential lack of specificity of drug effects and the risk of side effects demonstrated in these trials. [...] False negatives are well-known risks of small sized studies. However, it is equally important to note that if we do not enroll adequate sample sizes we will continue run the serious risk of getting an inflated false positive resulting in an overestimate of treatment effects that is not replicable (as was the case with many of the earlier regulatory trials, which tended to have small sample sizes).25 This is especially pertinent for early pilot studies of investigational antidepressants (phase I and II trials), which are not always subject to the same regulatory statutes of later stage trials. This phenomenon is illustrated by the dramatic decline of treatment effect sizes seen with esketamine over the course of development (from small pilot studies to large regulatory trials). Although regulatory agencies allow for more lenient methods for exploratory purposes, this method may yield misleading conclusions because these small trials are invariably under-powered. Specifically, these exploratory trials may end up with an erroneously low placebo response and thus a falsely inflated estimate of effect size.46 This possibility is under appreciated by many investigators but should be strongly considered given the persistence of modest effect sizes in regulatory trials of antidepressants.» 
9. ↑ Ng J, Lui LM, Rosenblat JD, Teopiz KM, Lipsitz O, Cha DS, Xiong J, Nasri F, Lee Y, Kratiuk K, Rodrigues NB, Gill H, Subramaniapillai M, Mansur RB, Ho R, Cao B, McIntyre RS (April 2021). «Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment». Psychopharmacology (Berl) 238 (4): 917-926. PMID 33484298. doi:10.1007/s00213-021-05767-1. 
10. ↑ ^{a b} Tyler MW, Yourish HB, Ionescu DF, Haggarty SJ (June 2017). «Classics in Chemical Neuroscience: Ketamine». ACS Chem Neurosci 8 (6): 1122-1134. PMID 28418641. doi:10.1021/acschemneuro.7b00074. 
11. ↑ «Esketamine». Drugs.com. 
12. ↑ Swainson J, McGirr A, Blier P, Brietzke E, Richard-Devantoy S, Ravindran N, Blier J, Beaulieu S, Frey BN, Kennedy SH, McIntyre RS, Milev RV, Parikh SV, Schaffer A, Taylor VH, Tourjman V, van Ameringen M, Yatham LN, Ravindran AV, Lam RW (November 2020). «The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur». Can J Psychiatry 66 (2): 113-125. PMC 7918868. PMID 33174760. doi:10.1177/0706743720970860.