Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings)

Abstract

For more than 50 years, ketamine has proven to be a safe anesthetic drug with potent analgesic properties. The active enantiomer is S(+)-ketamine. Ketamine is mostly metabolized in norketamine, an active metabolite. During "dissociative anesthesia", sensory inputs may reach cortical receiving areas, but fail to be perceived in some association areas. Ketamine also enhances the descending inhibiting serotoninergic pathway and exerts antidepressive effects. Analgesic effects persist for plasma concentrations ten times lower than hypnotic concentrations. Activation of the (N-Methyl-D-Aspartate [NMDA]) receptor plays a fundamental role in long-term potentiation but also in hyperalgesia and opioid-induced hyperalgesia. The antagonism of NMDA receptor is responsible for ketamine's more specific properties. Ketamine decreases the "wind up" phenomenon, and the antagonism is more important if the NMDA channel has been previously opened by the glutamate binding ("use dependence"). Experimentally, ketamine may promote neuronal apoptotic lesions but, in usual clinical practice, it does not induce neurotoxicity. The consequences of high doses, repeatedly administered, are not known. Cognitive disturbances are frequent in chronic users of ketamine, as well as frontal white matter abnormalities. Animal studies suggest that neurodegeneration is a potential long-term risk of anesthetics in neonatal and young pediatric patients.

Figure 1

Metabolism. Ketamine is metabolized mainly to norketamine (80%), itself secondarily transformed into hydroxy‐norketamine (15%), mainly 6‐hydroxy‐norketamine. Accessory pathway passes directly through the transformation of ketamine in hydroxy‐ketamine (5%).

Figure 2

Structure of the four subunits of the NMDA receptor. NTD, N‐terminal domain, ABD, agonist‐binding domain. The M2 segment faces the cytoplasm and would be the receptor ion channel.

Figure 3

The NMDA receptor is anchored in the membrane (sky blue) by the PSD‐95 protein, linked to the Src tyrosine kinase. The four sub‐units (2 NR1 and 2 NR2) form an NMDA receptor channel selective for the cathions, which is shown open in (A). (A) The binding site of glutamate (red polyhedron), selectively activated by NMDA, is in ABD clam shaped NR2 subunit. The site for glycine (dark blue polyhedron), which acts as a co‐agonist of glutamate, is located in the ABD area of the NR1 subunit. We do not know exactly where polyamines (magenta cylinder) bind, but certainly in close connection with one or the other clam‐form fields in NR2 unit. Zinc ion (green spheres) binds to the NTD domain of NR2 subunit. Protons (red sphere) are an essential regulator mechanism that promotes closed state of the channel. The site of the proton detector is unknown, but it is assumed that it is ane area near ABD domain. Protein phosphatase type I (PP1) and cAMP‐dependent protein kinase (PKA) are attached to the NR1 subunit by an anchor protein named Yotiao. (B) When the membrane is not depolarized, even when agonists occupy ABD sites, the channel is blocked by Mg²⁺ ion (sky blue sphere). The binding site of magnesium is near the intracellular part of the receptor. (C) In contrast, a membrane depolarization (phospholipids represented in yellow) causes the departure of the Mg²⁺ ion (voltage‐dependent block) and allows a massive influx of calcium (white spheres), if the two coagonists occupy their binding site. (D) The molecule of ketamine or other derivatives of phencyclidine inactivate the receptor by binding to the intraductal PCP site (green slot), which partially covers the magnesium binding site.