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

Abstract

Summary 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.

A Comparison between the Analgesic - Sedative Effects of Ketamine and Nitrous Oxide in Bones’ Fracture Pain Control: A Randomized Clinical Trial

“…Ketamine is a water-soluble and fat where the property causes a broad distribution of the drug in the body and very quickly passes the blood-brain barrier (7). As in the intravenous injection, Ketamine reaches its receptor in less than a minute (8). This medication, at a lower dose, causes analgesia and sedation, while at a high dose, causes general anesthesia (9).…”

Ketamine-The Confluence of Old and Recent Concepts

“…Incidence of hallucinations is reduced to less than 10% with concurrent use of midazolam [16]. Sub-anesthetic doses of ketamine are associated with impaired attention, memory and judgment, and it is also used as a pharmacological model for acute schizophrenia [17]. Chronic use of ketamine may be associated with neuropsychiatric, urinary tract and hepatic side effects, which may decline its use in chronic non cancer pain and cancer pain.…”

Semimechanistic Population Pharmacokinetic Model to Predict the Drug–Drug Interaction Between S‐ketamine and Ticlopidine in Healthy Human Volunteers

“…The so‐called “opioid crisis”2 emphasizes the need to reduce opioid use and to search for ways to improve multimodal analgesia in pain therapy. Activation of N‐methyl‐D‐aspartate (NMDA) receptors may play a crucial role in the pathogenesis of chronic pain,3 and, therefore, orally administered ketamine, a potent NMDA receptor antagonist, has been used to treat complex chronic pain 4. Orally administered ketamine undergoes extensive first‐pass metabolism, resulting in a bioavailability of ~17% 5.…”