Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy

@article{Peltoniemi2016KetamineAR,
  title={Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy},
  author={Marko Peltoniemi and Nora Hagelberg and Klaus T. Olkkola and Teijo I. Saari},
  journal={Clinical Pharmacokinetics},
  year={2016},
  volume={55},
  pages={1059-1077}
}
Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-d-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more… 
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References

SHOWING 1-10 OF 165 REFERENCES
Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings)
TLDR
Experimentally, ketamine may promote neuronal apoptotic lesions but, in usual clinical practice, it does not induce neurotoxicity, and Cognitive disturbances are frequent in chronic users of ketamine, as well as frontal white matter abnormalities.
Metabolism of ketamine stereoisomers by human liver microsomes.
TLDR
To characterize ketamine racemate and enantiomer metabolism by human liver and to test the hypothesis that differences in hepatic ketamine enantiomers metabolism can account for observed differences in ketamineEnantiomer pharmacokinetics, it is found that S(+) ketamine exhibits a greater clearance and faster anesthetic recovery compared to the racemate.
Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing
TLDR
Simulations suggested that after oral dosing, norketamine AUC at steady state is 16.5 times higher than that of S-ketamine, a feasible alternative to repeated intravenous dosing in the setting of chronic pain.
[The clinical use of S-(+)-ketamine--a determination of its place].
TLDR
Clinical use of S(+)-ketamine administered at one-half of the usual dose is not only associated with a reduction of undesirable adverse effects without altering ketamine's anaesthetic and analgesic potency, but also offers distinctive improvements due to the reduced drug load.
Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity
TLDR
There are large differences between arterial and venous data in the pharmacokinetic parameters that are heavily dependent on distribution processes in low-dose ketamine.
[From the racemate to the eutomer: (S)-ketamine. Renaissance of a substance?].
TLDR
The pharmacokinetic improvements of (S)-ketamine are characterized by a reduced drug load, along with more rapid recovery, which may be the treatment of chronic pain and the assumed neuroprotective action of the substance.
Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man
TLDR
A classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results, and its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.
Rifampicin has a Profound Effect on the Pharmacokinetics of Oral S‐Ketamine and Less on Intravenous S‐Ketamine
TLDR
Rifampicin profoundly reduces the plasma concentrations of ketamine and norketamine after oral administration of S‐ketamine, by inducing mainly its first‐pass metabolism.
Comparative pharmacology of the ketamine isomers. Studies in volunteers.
TLDR
It is concluded that the more potent S(+) isomer of ketamine was associated with a more rapid recovery of psychomotor skills than the currently used racemic mixture.
Interaction of Ketamine and Halothane in Rats
TLDR
It is concluded that ketamine is not a short-acting drug and that concomitant use with halothane would be expected to prolong further the duration of its action on the central nervous system.
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