Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings)

For over 50 years, ketamine has been a safe anesthetic with potent pain-relieving properties. Its active form is S(+)-ketamine, and it is mainly metabolized into norketamine, an active metabolite. During dissociative anesthesia, sensory inputs reach the brain but are not perceived in some association areas. Ketamine also enhances the descending serotonin pathway for pain relief and has antidepressant effects. Pain relief persists at plasma concentrations ten times lower than those needed for hypnosis. By blocking the NMDA receptor, ketamine reduces the wind-up phenomenon and hyperalgesia, including opioid-induced hyperalgesia.

Study at a glance

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.