Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.).
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
Pharmacol Rev. 2018 Jul;70(3):621-660. doi: 10.1124/pr.117.015198.
Ketamine, a racemic mixture consisting of ()- and ()-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine's pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of -methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.
氯胺酮，一种由（）-和（）-氯胺酮组成的外消旋混合物，自 1970 年以来一直用于临床。尽管氯胺酮以其分离麻醉特性而闻名，但它也具有镇痛、抗炎和抗抑郁作用。我们提供了这些治疗用途的全面综述，强调了药物剂量、给药途径和这些作用的时间过程。还讨论了与短期或长期暴露以及娱乐性氯胺酮使用相关的分离、精神病样、认知和外周副作用。我们进一步描述了氯胺酮的药代动力学，包括其快速和广泛的代谢为去甲氯胺酮、脱水去甲氯胺酮、羟基氯胺酮和羟基去甲氯胺酮（HNK）代谢物。虽然氯胺酮的麻醉和镇痛特性通常归因于直接氯胺酮诱导的 -甲基-D-天冬氨酸受体抑制，但氯胺酮的其他假定低亲和力药理学靶标包括但不限于 γ-氨基丁酸（GABA）、多巴胺、血清素、西格玛、阿片、胆碱能受体以及电压门控钠和超极化激活环核苷酸门控通道。我们检查了支持这些氯胺酮及其代谢物靶标与药物临床效果相关性的证据。鉴于 HNK 代谢物在临床前研究中具有抗抑郁作用，氯胺酮代谢物可能具有比以前认为的更广泛的临床相关性。总之，氯胺酮及其代谢物的药理学靶标分解将为开发具有氯胺酮理想临床效果但限制不良副作用的新药物疗法提供关键见解。
