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

Summary & key facts

Ketamine has been used as a safe anesthetic for more than 50 years and also works well for pain relief. The active form is S(+)-ketamine and it is mainly broken down into an active metabolite called norketamine. Ketamine blocks NMDA receptors in the brain, which helps explain its special effects on pain, perception, and mood. It can cause a dissociative state where sensory input reaches the brain but is not fully perceived. Some lab studies show possible nerve-cell damage, but typical clinical use has not been shown to be neurotoxic; the effects of large or repeated high doses are not known. Chronic users can have cognitive problems and changes in frontal white matter, and animal studies rai

Key facts:

• Ketamine has been used as an anesthetic for more than 50 years and has strong pain-relief (analgesic) properties.
• The active enantiomer of ketamine is S(+)-ketamine.
• Ketamine is mostly metabolized into norketamine, which is itself an active metabolite.
• During “dissociative anesthesia,” sensory signals can reach cortical receiving areas but may fail to be perceived in some association areas.
• Analgesic effects of ketamine persist at plasma concentrations about 10 times lower than the concentrations that cause hypnosis (sleep-like state).
• Ketamine is an antagonist of the NMDA receptor; NMDA activation is involved in long-term potentiation and in increased pain sensitivity (hyperalgesia).
• Ketamine reduces the “wind up” phenomenon (a rising pain response to repeated stimulation), and its NMDA-blocking effect is stronger when the NMDA channel has already been opened by glutamate (called use dependence).
• In experimental studies, ketamine can promote neuronal apoptotic lesions, but in usual clinical practice it has not been shown to cause neurotoxicity; the consequences of high doses given repeatedly are unknown.
• Chronic ketamine users often have cognitive disturbances and frontal white matter abnormalities.
• Animal studies suggest that anesthetics, including ketamine, could pose a potential long-term risk of neurodegeneration in neonatal and young pediatric patients.

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.

Topics

Anesthesia and Neurotoxicity Research Anesthesia and Sedative Agents Treatment of Major Depression

Categories

Developmental Neuroscience Life Sciences Neuroscience

Tags

Analgesic Anesthesia Anesthetic Dissociative Glutamate receptor Hyperalgesia Internal medicine Ketamine Medicine Neuroscience Neurotoxicity NMDA receptor Nociception Opioid Pharmacology Psychology Receptor Toxicity