Stereoselective ketamine effect on cardiac output: a population pharmacokinetic/pharmacodynamic modelling study in healthy volunteers.
NONMEM
cardiac output
hydroxynorketamine
ketamine
metabolomics
modeling
norketamine
stereoselectivity
Journal
British journal of anaesthesia
ISSN: 1471-6771
Titre abrégé: Br J Anaesth
Pays: England
ID NLM: 0372541
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
09
11
2020
revised:
03
02
2021
accepted:
25
02
2021
pubmed:
27
4
2021
medline:
22
7
2021
entrez:
26
4
2021
Statut:
ppublish
Résumé
Ketamine has cardiac excitatory side-effects. Currently, data on the effects of ketamine and metabolite concentrations on cardiac output are scarce. We therefore developed a pharmacodynamic model derived from data from a randomised clinical trial. The current study is part of a larger clinical study evaluating the potential mitigating effect of sodium nitroprusside on the psychedelic effects of ketamine. Twenty healthy male subjects received escalating esketamine and racemic ketamine doses in combination with either placebo or sodium nitroprusside on four visits: (i) esketamine and placebo, (ii) esketamine and sodium nitroprusside, (iii) racemic ketamine and placebo, and (iv) racemic ketamine and sodium nitroprusside. During each visit, arterial blood samples were obtained and cardiac output was measured. Nonlinear mixed-effect modelling was used to analyse the cardiac output time-series data. Ketamine metabolites were added to the model in a sequential manner to evaluate the effects of metabolites. A model including an S-ketamine and S-norketamine effect best described the data. Ketamine increased cardiac output, whereas modelling revealed that S-norketamine decreased cardiac output. No significant effects were detected for R-ketamine, metabolites other than S-norketamine, or sodium nitroprusside on cardiac output. S-Ketamine, but not R-ketamine, increased cardiac output in a dose-dependent manner. In contrast to S-ketamine, its metabolite S-norketamine reduced cardiac excitation in a dose-dependent manner. Dutch Cochrane Center 5359.
Sections du résumé
BACKGROUND
Ketamine has cardiac excitatory side-effects. Currently, data on the effects of ketamine and metabolite concentrations on cardiac output are scarce. We therefore developed a pharmacodynamic model derived from data from a randomised clinical trial. The current study is part of a larger clinical study evaluating the potential mitigating effect of sodium nitroprusside on the psychedelic effects of ketamine.
METHODS
Twenty healthy male subjects received escalating esketamine and racemic ketamine doses in combination with either placebo or sodium nitroprusside on four visits: (i) esketamine and placebo, (ii) esketamine and sodium nitroprusside, (iii) racemic ketamine and placebo, and (iv) racemic ketamine and sodium nitroprusside. During each visit, arterial blood samples were obtained and cardiac output was measured. Nonlinear mixed-effect modelling was used to analyse the cardiac output time-series data. Ketamine metabolites were added to the model in a sequential manner to evaluate the effects of metabolites.
RESULTS
A model including an S-ketamine and S-norketamine effect best described the data. Ketamine increased cardiac output, whereas modelling revealed that S-norketamine decreased cardiac output. No significant effects were detected for R-ketamine, metabolites other than S-norketamine, or sodium nitroprusside on cardiac output.
CONCLUSIONS
S-Ketamine, but not R-ketamine, increased cardiac output in a dose-dependent manner. In contrast to S-ketamine, its metabolite S-norketamine reduced cardiac excitation in a dose-dependent manner.
CLINICAL TRIAL REGISTRATION
Dutch Cochrane Center 5359.
Identifiants
pubmed: 33896589
pii: S0007-0912(21)00177-X
doi: 10.1016/j.bja.2021.02.034
pmc: PMC8258972
pii:
doi:
Substances chimiques
Anesthetics, Dissociative
0
Ketamine
690G0D6V8H
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
23-31Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
Declarations of interest The authors declare that they have no conflicts of interest.
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