Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms
- PMID: 29945898
- PMCID: PMC6020109
- DOI: 10.1124/pr.117.015198
Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms
Erratum in
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Correction to "Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms".Pharmacol Rev. 2018 Oct;70(4):879. doi: 10.1124/pr.116.015198err. Pharmacol Rev. 2018. PMID: 30282701 No abstract available.
Abstract
Ketamine, a racemic mixture consisting of (S)- and (R)-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 N-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.
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
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