Ketamina

Efectos

Mecanismo de acción

Ketamine interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors, monoaminergic receptors, muscarinic receptors and voltage-sensitive Ca channels. Unlike other general anesthetic agents, ketamine does not interact with GABA receptors. Long-term ketamine abuse is known to affect the lower urinary tract and produce cystitis symptoms. However, the pathophysiology and causative mechanism of changes in bladder function remain unclear. The present study aimed to investigate the existence of ketamine-induced cystitis in a rat model and characterize the underlying mechanisms. Rats were assigned to blank control, normal saline (NS), low-dose ketamine (LK, 5 mg/kg), and high-dose ketamine (HK, 50 mg/kg) groups. The two experimental groups received ketamine hydrochloride daily for 16 weeks. All rats were housed individually for urinary frequency and urine volume assessment. Urinary biomarkers were measured at different time points. Rat bladders were removed for histopathology, immunohistochemistry and western blot analysis. Ketamine-treated rats had higher urinary frequency compared to NS-treated rats at Week 16. Urinary levels of nitric oxide and antiproliferative factor were increased in ketamine-treated rats within the first 30 h after administration. After long-term ketamine administration, urinary levels of glycoprotein GP51 and potassium were decreased in HK and LK groups compared to the NS group. Ketamine-treated rats showed thickened bladder epithelial layer, increased expression of inducible nitric oxide synthase and occludin, and decreased expression of zonula occludens-1 in the bladder wall. Ketamine, or its urinary metabolites, disrupted bladder epithelial cell proliferation, resulting in defective bladder epithelial barrier. The subsequent leakage of urinary potassium causes a stress response in the bladder and provokes cystitis. Recreational ketamine abuse has been associated with the emergence of a new bladder pain syndrome

Vida media

The reported half-life in preclinical studies for ketamine is 186 min. ... The pharmacokinetics and distribution of ketamine and its biotransformation products in dogs were studied after extradural administration of ketamine at L4-5. ... The elimination half-life values of the parent drug for both biological fluids were similar (4.3 (2.96) hr and 4.6 (3.31) hr for plasma and CSF, respectively). ... The half-life is 2.5 hours in adults and 1 to 2 hours in children. beta phase half-life: 3 hours /From table/ ... After intravenous administration, ketamine concentration has an initial slope (alpha phase) lasting approximately 45 minutes with a half-life of 10 to 15 minutes. This first phase clinically corresponds to the anesthetic effect of the drug. The anesthetic action is terminated by a combination of redistribution from the CNS to slower equilibrating peripheral tissues and by hepatic biotransformation to metabolite I. This metabolite is approximately 1/3 as active as ketamine in reducing halothane requirements (MAC) in rats. The subsequent half-life of ketamine (beta phase) is 2.5 hours.

Toxicidad

IDENTIFICATION AND USE: Ketamine is a cyclohexanone derivative used as an anesthetic agent in human and veterinary procedures. Ketamine hydrochloride injection, USP is indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. HUMAN STUDIES: Ketamine is a unique anesthetic because it has both hypnotic and analgesic effects and also possible hallucinogenic side effects. The lack of cardiopulmonary depression makes the drug a popular choice for anesthesia in the prehospital setting. In recent years ketamine has been found to have anti-hyperalgesic and opioid-sparing effects, opening new ways to manage postoperative and chronic pain states. Ketamine has been used as a drug of abuse. Ketamine produces a variety of symptoms including, but not limited to, anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations and psychotic episodes. Dependence and tolerance to ketamine are possible after prolonged administration. A withdrawal syndrome with psychotic features has been described after discontinuing long-term ketamine use. Frequent recreational ketamine users have been found to have impaired memory 3 days after their last dose, compared to infrequent users. Flashbacks have also been reported. Frequent use results in tolerance and the need to increase the dose to maintain similar effects. Respiratory depression may occur with overdose or a very rapid rate of ketamine administration, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to the administration of analeptics. ANIMAL STUDIES: Administration of ketamine hydrochloride altered the blood count of rhesus monkeys when compared to physical restraint for venipuncture. The alterations were decreases in white blood cell count, total plasma proteins and hematocrit. The decrease in white blood cell count was mainly due to a decrease in lymphocytes with a lesser decrease in

Farmacología

Ketamine is a rapidly-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression. The anesthetic state produced by ketamine has been termed as "dissociative anesthesia" in that it appears to selectively interrupt association pathways of the brain before producing sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient brain centers and pathways (reticular-activating and limbic systems). Ketamine potentiates descending inhibitory serotonergic pathways and may exert antidepressant effects. These effects are seen at concentrations ten times lower than the concentration needed for anesthetic purposes. The effect of ketamine can be described as analgesic by preventing central sensitization in dorsal horn neurons as well as by inhibiting nitric oxide synthesis. Ketamine may present cardiovascular changes and bronchodilation. Compounds capable of relieving pain without the loss of CONSCIOUSNESS. Intravenous anesthetics that induce a state of sedation, immobility, amnesia, and marked analgesia. Subjects may experience a strong sense of dissociation from the environment. The condition produced is similar to NEUROLEPTANALGESIA, but is brought about by the administration of a single drug. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed) Drugs that bind to but do not activate excitatory amino acid receptors, thereby blocking the actions of agonists. 690G0D6V8H