Page 39 - CASA Bulletin of Anesthiology 2021, Vol 8, No. 6 (1)

Vol. 8, No. 6, 2021

Pharmacology

Pharmacokinetics
Ketamine is metabolized by the cytochrome p450 enzymes in the liver, primarily CYP2B6
and CYP3A4. The activity of ketamine can therefore be influenced by other medications.
Medications such as macrolides and azoles that inhibit cytochrome can prolong its duration of
action. Alternatively, anti-seizure medications (e.g. phenytoin) often induce cytochrome
enzymes and result in decreasing ketamine’s duration. Metabolites are renally excreted, the
primary one being Norketamine which is 1/3 to 1/5 weaker.
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Pharmacodynamics
Ketamine is active at many sites but the primary target, the NMDA (N-methyl-D-aspartate)
receptor, opioid (mu>kappa>sigma), Dopamine D2, muscarinic acetylcholine, innate repair, and
HCN1 (hyperpolarization-activated cyclic nucleotide-gated channel 1) receptors are also
effected. Ketamine’s action on the HCN1 receptor blocks signal transmission by blocking Na-K
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channels. The innate repair receptor is similar to erythropoietin and beta common receptor which
activates anti-inflammatory and tissue repair pathways. The NMDA receptor is a ligand gated
channel primarily activated by glutamate, but also relies on glycine binding by unguided
diffusion. Blocking the above channels can decrease signal transmission and inflammation.
Central Sensitization

Central sensitization happens when the intensity of pain is out of proportion to tissue damage
due to aberrant pain processing. Blocking NMDA receptors blocks excitatory signals from
damaged peripheral sites from reaching the brain. Thus ketamine can prevent central
sensitization and windup. There are no human studies that confirm quantitative changes in
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sensation in relation to central sensitization. But there is a mice study that shows ketamine works
better in chronic stages of CRPS (when central mechanisms predominate) than in acute stages
(when peripheral mechanisms predominate). In this study mice were given femur fractures. In
the acute stage they had increased limb temperature, edema, and nociceptive sensitization. These
symptoms were not reduced by ketamine (though pain likely was). During the chronic phase of
healing, the mice were given ketamine, resulting in reduced nociceptive sensitization that
persisted beyond completion of the infusion. These mice also had improved motor function at 18
weeks. This supports ketamine’s reduction on central sensitization.
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PTSD
Ketamine blocks excitatory signals in other parts of the brain, including signals to the
hippocampus, amygdala, and prefrontal cortex. These areas of the brain are all intertwined in
traumatic experiences. The hippocampus is involved in memory, the amygdala is a center for
emotion and instinct, and the prefrontal cortex regulates these emotions and impulses associated
with memories. Inhibiting transmission can help inhibit recurrence of a traumatic experience. On
the other hand, it is important to keep in mind that ketamine can cause an exacerbation of PTSD
in the acute setting, especially if a patient received the drug during a traumatic experience which
is common for wounded warriors.
Enantiomers

Both the R (-) and S (+) enantiomers of ketamine are available. The S-enantiomer is now
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