Stereoselective ketamine effect on cardiac output: a population pharmacokinetic/pharmacodynamic modelling study in healthy volunteers

Abstract

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 Sketamine, its metabolite S-norketamine reduced cardiac excitation in a dose-dependent manner. Clinical trial registration: Dutch Cochrane Center 5359.

The median effective concentration of propofol with different doses of esketamine during gastrointestinal endoscopy in elderly patients: A randomized controlled trial

“…There are two possible reasons why increasing doses of SK with propofol are less likely to produce hypotension: (i) due to the decrease in the TCI concentration of propofol, the dose-dependent depression of propofol on the circulation was alleviated; or (ii) the sympathomimetic properties of esketamine may, at least partially, counter propofol-induced haemodynamic depression. 37,38 It is reported that esketamine nasal spray could cause transient and asymptomatic blood pressure elevations. 37 Kamp et al 38 demonstrated that S-Ketamine increased cardiac output in a dose-dependent manner: 1.68 nmol/mL of the S-ketamine plasma concentration could cause a 25% increase in cardiac output.…”

“…37,38 It is reported that esketamine nasal spray could cause transient and asymptomatic blood pressure elevations. 37 Kamp et al 38 demonstrated that S-Ketamine increased cardiac output in a dose-dependent manner: 1.68 nmol/mL of the S-ketamine plasma concentration could cause a 25% increase in cardiac output.…”

Ketamine Psychedelic and Antinociceptive Effects Are Connected

“…The data used in this analysis are part of a larger data set that was used previously to study the effects of sodium nitroprusside on ketamine-induced adverse effects, 9 and to construct a population pharmacokinetic model of ketamine and its metabolites, 10 as well as a pharmacodynamic model of ketamine-induced changes in cardiac output. 11 In the secondary analysis that is currently planned, we developed a population pharmacokinetic–pharmacodynamic model of ketamine and its metabolite norketamine to describe the relationship between plasma concentrations of S - and R -ketamine (and their metabolites) and pressure pain threshold and the change in external perception as a measure of ketamine psychotropic effect. The study protocol was approved by the Institutional Review Board (Medical Ethics Review Committee Leiden, Den Haag, Delft, Leiden University Medical Center, Leiden, The Netherlands) and registered at the trial register of the Dutch Cochrane Center (www.trialregister.nl) under registration No.…”

Midazolam Attenuates Esketamine-Induced Overactive Behaviors in Mice Before the Sedation, but Not During the Recovery

“…Ketamine can be converted to an active metabolite, norketamine, by CYP3A4 ( 27 ). Norketamine, included Nor-S-ketamine and Nor-R-ketamine can retain anesthetic effects, which can explain the maintenance of the anesthesia at lower blood ketamine concentrations ( 30 , 31 ). Norketamine can also cross the blood–brain barrier and induces psychoactive effects ( 23 , 32 ).…”