Ketamin

DEA NFLIS-Drug Category -> Depressants and Tranquilizers

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

Pharmaceuticals -> Illicit drugs

Pharmaceuticals

log Kow = 2.18

2.9

2.18

Soluble

White crystals, mp 262-263 °C. Solubility in water: 20 g/100mL. Freely soluble in methanol; soluble in alcohol; sparingly soluble in chloroform /Ketamine hydrochloride/

4.64e-02 g/L

Breast Feeding; Lactation; Milk, Human; Anesthetics, Intravenous; Hypnotics and Sedatives; Anesthetics, Dissociative; Excitatory Amino Acid Antagonists

General anaesthetics and oxygen > Injectable medicines

Pharmaceuticals -> Animal Drugs -> Approved in Taiwan

Pharmaceuticals -> UK Veterinary Medicines Directorate List

92.5ºC

92.5 °C

92.5 °C

Stable under recommended storage conditions. /Ketamine hydrochloride/

VET: Color of solution may vary from colorless to very slightly yellowish and may darken upon prolonged exposure to light. This darkening does not affect potency. Do not use if precipitate appears.

7.5

pKa = 7.5

Warning

H302+H332 (66.7%): Harmful if swallowed or if inhaled [Warning Acute toxicity, oral; acute toxicity, inhalation]

P261, P264, P270, P271, P301+P317, P304+P340, P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 3 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H302: Harmful if swallowed [Warning Acute toxicity, oral]

Status: Active Update: 31-07-2015 https://echa.europa.eu/registration-dossier/-/registered-dossier/11298

Ketamine: Does not have an individual approval but may be used under an appropriate group standard

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Ketamine hydrochloride is included on this list. /Ketamine hydrochloride/

Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Depressants. ... Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a depressant effect on the central nervous system: Ketamine, its salts, isomers, and salts of isomers. DEA Code Number: 7285.

Implanatation or injectable dosage form new animal drugs. Ketamine. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian. ... Conditions of use - (1) Cats ... Indications for use: For restraint or as the sole anesthetic agent in diagnostic or minor, brief surgical procedures that do not require skeletal muscle relaxation. (2) Subhuman primates ... Indications for use: For restraint.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ketamine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ketamine hydrochloride/

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Ketamine hydrochloride is included on this list. /Ketamine hydrochloride/

Incompatible materials: Oxidizing agents. /Ketamine hydrochloride/

Ketamine hydrochloride is maintained at an acidic pH for stability and solubility. If mixed with alkalinizing solutions, instability or precipitation can result.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Ketamine hydrochloride/

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Ketamine hydrochloride/

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2-8 °C. /Ketamine hydrochloride/

Store in a tightly sealed container, protected from light, and at room temperature.

Store at 20 to 25 °C (68 to 77 °F).

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Ketamine hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product. /Ketamine hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. /Ketamine hydrochloride/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Ketamine hydrochloride/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Ketamine hydrochloride/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Ketamine hydrochloride/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Ketamine hydrochloride/

Skin protection: Handle with gloves. /Ketamine hydrochloride/

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Ketamine hydrochloride/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Ketamine hydrochloride/

/The study objective was/ to determine the effects of ketamine-diazepam and ketamine-acepromazine combinations on intraocular pressure (IOP) in rabbits. /This was a/ randomized clinical trial. Sixteen adult New Zealand white rabbits approximately one year old, weighing 2.3 +/- 0.2 kg were used in this study. The animals were randomly divided into two groups of eight each (KA and KD). The pre-treatment IOPs were recorded in both groups (T0). All rabbits in group KA received intramuscular ketamine-acepromazine (ketamine 30 mg/kg + acepromazine 0.5 mg/kg). Ketamine-diazepam (ketamine 30 mg/kg + diazepam 1 mg/kg) was administered intramuscularly in members of group KD. The IOP values were measured at 5 (T(5)), 15 (T(15)), and 20 (T(20)) minutes after drug administration in both treatment groups. Significant increases in IOP values were observed in both treatment groups at T(5,) T(15), and T(20) in comparison to the baseline values. In group KA the mean +/- SD IOP at T(5,) T(15), and T(20) were 37 +/- 13 (p < 0.001), 35 +/- 4 (p < 0.001) and 34 +/- 4 mmHg (p < 0.001). The post-treatment mean +/- sd values in group KD were 23 +/- 8 (p = 0.002), 23 +/- 5 (p < 0.001) and 23 +/- 6 mmHg (p = 0.001) at 5, 15, and 20 minutes respectively. Both ketamine-diazepam and ketamine-acepromazine combinations increased IOP after intramuscular administration in rabbits.

Prolonged recovery time may occur if barbiturates and/or /CNS depressants/ are used concurrently with ketamine.

Retrospective analysis was conducted of patients with super-refractory status epilepticus (SRSE) who were treated simultaneously with propofol and ketamine. Sixty-seven patients were identified from 2012 to 2015, and outcomes documented were resolution and mortality. The duration of combined ketamine and propofol use ranged from 1 to 28 days (mean - 3.6 days). Infusion rates ranged up to 145 and 175 ug/kg/min. Vasopressors were used in 53 patients (79%), and were given within the first 5 days of the ICU admission in 48 (91%) patients. The overall SRSE resolution rate was 91%, and the overall mortality including patients with anoxic brain injury was 39%. Of the 13 patients with SRSE as a result of anoxic brain injury, SRSE was controlled in 5 (56%). The primary determinant of mortality was family withdrawing care related to the presence of severe medical/neurological diseases.

The non-competitive N-methyl-D-aspartate receptor antagonist ketamine leads to transient psychosis-like symptoms and impairments in oculomotor performance in healthy volunteers. This study examined whether the adverse effects of ketamine on oculomotor performance can be reversed by the atypical antipsychotic risperidone. In this randomized double-blind, placebo-controlled study, 72 healthy participants performed smooth pursuit eye movements (SPEM), prosaccades (PS) and antisaccades (AS) while being randomly assigned to one of four drug groups (intravenous 100 ng/mL ketamine, 2 mg oral risperidone, 100 ng/mL ketamine plus 2 mg oral risperidone, placebo). Drug administration did not lead to harmful adverse events. Ketamine increased saccadic frequency and decreased velocity gain of SPEM (all P < 0.01) but had no significant effects on PS or AS (all P > or = 0.07). An effect of risperidone was observed for amplitude gain and peak velocity of PS and AS, indicating hypometric gain and slower velocities compared with placebo (both P < or = 0.04). No ketamine by risperidone interactions were found (all P > or = 0.26). The results confirm that the administration of ketamine produces oculomotor performance deficits similar in part to those seen in schizophrenia. The atypical antipsychotic risperidone did not reverse ketamine-induced deteriorations. These findings do not support the cognitive enhancing potential of risperidone on oculomotor biomarkers in this model system of schizophrenia and point towards the importance of developing alternative performance-enhancing compounds to optimize pharmacological treatment of schizophrenia.

For more Interactions (Complete) data for Ketamine (17 total), please visit the HSDB record page.

Short term use of ketamine for anesthesia has been associated with rare instances of serum enzyme elevations, but not with clinically apparent liver injury. With chronic or intermittent use, however, unusual biliary and hepatic complications have been described. In a manner similar to its effects on the urinary tract, ketamine can also cause abnormalities in the biliary system with dilation and irregularity of the intra- and extra-hepatic bile ducts. Patients typically developed right upper quadrant pain and tenderness associated with elevations in serum alkaline phosphatase and aminotransferase levels, with minimal or no increase in bilirubin (Case 1). Biliary imaging may reveal dilation and irregularity of the intra- and extra-hepatic bile ducts with fusiform dilation of the common bile duct suggestive of choledochal cysts. Liver biopsy demonstrates changes suggestive of chronic liver obstruction or sclerosing cholangitis. Discontinuation of ketamine is usually followed by slow improvement and the abnormalities found on biliary imaging may no longer be demonstrable several months later.

TERRESTRIAL FATE: Based on a classification scheme(1), a reported log Koc value of 3.062(2), indicates that ketamine is expected to have low mobility in soil(SRC). The pKa of ketamine is 7.5(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the cation from moist soil is not expected because cations do not volatilize(SRC). Volatilization of neutral ketamine from moist soil surfaces is not expected(SRC) given an estimated Henry's Law constant of 1.4X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Ketamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.2X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Ketamine was found to be highly stable to degradation in two studies in sewage with <10% transformation at pH 7.5 at 20 °C(6) suggesting that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), a reported log Koc value of 3.062(2), indicates that ketamine is expected to adsorb to suspended solids and sediment(SRC). A pKa of 7.5(3) indicates ketamine will exist partially in the cation form at pH values of 5 to 9 and, therefore, volatilization of the cation from water surfaces is not expected(SRC). Volatilization from water surfaces of the neutral ketamine is not expected(4) based upon an estimated Henry's Law constant of 1.4X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). Ketamine is not expected to undergo hydrolysis in the environment due to the lacks of functional groups that hydrolyze under environmental conditions(4). According to a classification scheme(6), an estimated BCF of 13(SRC), from its log Kow of 2.18(7) and a regression-derived equation(5), suggests the potential for bioconcentration in aquatic organisms is low. Ketamine was found to be highly stable to degradation in two studies in sewage with <10% transformation at pH 7.5 at 20 °C(1). Ketamine was found to be highly stable to degradation in two studies in sewage with <10% transformation at pH 7.5 at 20 °C(8) suggesting that biodegradation is not an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ketamine, which has an estimated vapor pressure of 5.2X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase ketamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 5 hours(SRC), calculated from its rate constant of 7.7X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase ketamine may be removed from the air by wet or dry deposition(SRC). Ketamine contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The most common adverse drug reactions associated with ketamine are nausea, vomiting, dizziness, diplopia, drowsiness, dysphoria, and confusion. Reports of the emergence phenomenon exist for approximately 6% to 12% of patients. The common adverse drug reactions of ketamine are listed below.

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 potential hallucinogenic side effects. 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 saving effects, opening to new ways of managing post-operative 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. Ketamine dependence and tolerance are possible following prolonged administration. A withdrawal syndrome with psychotic features has been described following discontinuation of long-term ketamine use. Frequent recreational users of ketamine have been found to have impaired memory 3 days after their last dose, compared with infrequent users. Flashbacks have also been reported. Frequent use result in tolerance and the need to increase the dose in order to maintain similar effects. Respiratory depression may occur with overdosage or too rapid a rate of administration of ketamine, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to administration of analeptics. ANIMAL STUDIES: Ketamine hydrochloride administration altered the hemogram of rhesus monkeys when compared to physical restraint for venipuncture. The alterations were decreases in the leukocyte count, total plasma proteins, and hematocrit. The decrease in the leukocyte count was due primarily to a decrease in lymphocytes with a smaller decrease in neutrophils. Ketamine decreased locomotor activity and increased cell death in the prefrontal cortex of monkeys with 6 months of ketamine treatment when compared with the control monkeys. Such decreases were not found in the 1-month ketamine-treated group. Pre- or post-training systemic administration of ketamine (0.3, 1 and 3 mg/kg ip) in a dose-dependent manner disrupted rats performance in spatial and non-spatial recognition memory tests, suggesting that ketamine affected pre- and post-training memory components. Intraperitoneal injections of ketamine 75 mg/kg in rats of both sexes (age 1-16 weeks) revealed a significant relationship between increased age and decreased duration of sleeping time for both sexes during the first 3 weeks of age. This decrease in sleeping time seemed to be associated with the increased production of the cyclohexanone oxidation metabolite of ketamine. After 3 weeks of age there was a greater sleeping time in the female rat than the male and this seemed to be associated with a greater ability of the male to produce the cyclohexanone oxidation metabolite. In rats, ketamine, or its urinary metabolites, disrupted the proliferation of bladder epithelial cells, resulting in defected bladder epithelial barrier. A single 24-hr episode of ketamine anesthesia, occurring during a sensitive period of brain development, resulted in very long-lasting deficits in brain function in rhesus monkeys. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains. A subanesthetic dose of ketamine increased exploratory locomotion in one strain of mice, but decreased it in another strain of mice. Therefore, hereditary factors may play an important role in ketamine-induced responses. Epidural ketamine injection was associated with caudal anti-nociception, sedation and ataxia in the dromedary camels. Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

Ketamine is potentially fatal in alcohol-intoxicated patients. It has been used recreationally as a drug of abuse. The street name for ketamine is "K" or "Special K." Illicit use of ketamine includes snorting or inhalation, and it is ingestable in food or drinks. The recreational use of ketamine can lead to toxicity. Ketamine overdose induces varying dose-dependent symptoms, notably altering consciousness and manifesting as sedation, impaired mental status, mydriasis, and hemodynamic compromise. Accidental ingestion up to 10 times higher than the standard induction dose of ketamine has been reported. Overdose of ketamine did not result in systemic effects such as hemodynamic or central nervous system perturbations, except for prolonged awakening.

Ketamine has several clinically useful properties, including analgesia and less cardiorespiratory depressant effects than other anaesthetic agents, it also causes some stimulation of the cardiocascular system. Ketamine has been reported to produce general as well as local anaesthesia. It interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors, monoaminergic receptors, muscarinic receptors and voltage sensitive Ca ion channels. Unlike other general anaesthetic agents, ketamine does not interact with GABA receptors.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of November 16, 2017: http://actor.epa.gov/dashboard/]

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for ketamine hydrochloride is available.[Available from, as of August 24, 2017: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

Raw wastewater samples collected 2008-2014 from sewage treatment plants in 17 Italian cities contained ketamine as follows(1):[Table#3905]

Ketamine was detected in 2 of 7 wastewater treatment plant influent samples at 16 and <5 ng/L; samples were collected from different regions of the US on unreported dates(1). Wastewater treatment plant influent and effluent concentrations of ketamine have been reported as 52-235 and 83-130 ng/L, respectively, in the UK(2). Ketamine was detected at 8033-138,000 and 4300-39,333 ng/L in influent and effluent wastewater treatment plant samples collected from Nanwan, respectively, and at respective concentrations of 44,333-92,667 and <2.5-9867 ng/L from a wastewater treatment plant in Kenting, Taiwan; samples were collected from Oct 2010 to Aug 2011(3). The mean concentration of ketamine in influent samples collected in 2015 from wastewater treatment plants in Beijing, China was reported as 6.63 ng/L(4). The mean wastewater effluent concentration of ketamine was <0.93 and 4.1 ng/L in samples collected Jan and June 2015, respectively from a treatment plant in southwest England(5). Based on studies, ketamine removal is about 23.4% in wastewater treatment plants(6).

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Ketamine hydrochloride is included on this list. /Ketamine hydrochloride/

Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Depressants. ... Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a depressant effect on the central nervous system: Ketamine, its salts, isomers, and salts of isomers. DEA Code Number: 7285.

Implanatation or injectable dosage form new animal drugs. Ketamine. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian. ... Conditions of use - (1) Cats ... Indications for use: For restraint or as the sole anesthetic agent in diagnostic or minor, brief surgical procedures that do not require skeletal muscle relaxation. (2) Subhuman primates ... Indications for use: For restraint.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ketamine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ketamine hydrochloride/

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Ketamine hydrochloride is included on this list. /Ketamine hydrochloride/

N01AX03

N - Nervous system

QN - Nervous system

N01AX03

Ketamine is a rapid-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 somesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems). Ketamine enhances descending inhibiting serotoninergic pathways and can exert antidepressive effects. These effects are seen in concentrations ten times lower than the needed concentration for anesthetic proposes. The effect of ketamine can be described as analgesic by the prevention of central sensitization in dorsal horn neurons as well as by the inhibition on the synthesis of nitric oxide. Ketamine can present cardiovascular changes and bronchodilatation.

Ketamine interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors, monoaminergic receptors, muscarinic receptors and voltage sensitive Ca ion channels. Unlike other general anaesthetic agents, ketamine does not interact with GABA receptors.

Long-term ketamine abuse is known to affect the lower urinary tract and produce symptoms of cystitis. However, the pathophysiology and causative mechanism of the 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 underlining 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 assessment of urinary frequency and urine volume. Urinary biomarkers were measured at different time points. Rat bladders were excised for histopathology, immunohistochemistry, and western blot analysis. Ketamine-treated rats had increased urinary frequency compared to NS-treated rats at Week 16. Urinary nitric oxide and antiproliferative factor levels were increased in ketamine-treated rats within the first 30 h after administration. After long-term ketamine administration, urinary glycoprotein GP51 and potassium levels were decreased in the 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 the proliferation of bladder epithelial cells, resulting in defected bladder epithelial barrier. Subsequent leakage of urinary potassium causes a stress response in the bladder and provokes cystitis.

Recreational abuse of ketamine has been associated with the emergence of a new bladder pain syndrome, ketamine-induced cystitis, characterized by chronic inflammation and urothelial ulceration. We investigated the direct effects of ketamine on normal human urothelium maintained in organ culture or as finite cell lines in vitro. Exposure of urothelium to ketamine resulted in apoptosis, with cytochrome c release from mitochondria and significant subsequent caspase 9 and 3/7 activation. The anesthetic mode-of-action for ketamine is mediated primarily through N-methyl d-aspartate receptor (NMDAR) antagonism; however, normal (nonimmortalized) human urothelial cells were unresponsive to NMDAR agonists or antagonists, and no expression of NMDAR transcript was detected. Exposure to noncytotoxic concentrations of ketamine (</=1 mmol/L) induced rapid release of ATP, which activated purinergic P2Y receptors and stimulated the inositol trisphosphate receptor to provoke transient release of calcium from the endoplasmic reticulum into the cytosol. Ketamine concentrations >1 mmol/L were cytotoxic and provoked a larger-amplitude increase in cytosolic Ca(2+) concentration that was unresolved. The sustained elevation in cytosolic Ca(2+) concentration was associated with pathological mitochondrial oxygen consumption and ATP deficiency. Damage to the urinary barrier initiates bladder pain and, in ketamine-induced cystitis, loss of urothelium from large areas of the bladder wall is a reported feature. This study offers first evidence for a mechanism of direct toxicity of ketamine to urothelial cells by activating the intrinsic apoptotic pathway.

Several lines of evidence indicate that ketamine has a rapid antidepressant-like effect in rodents and humans, but underlying mechanisms are unclear. In the present study, we investigated the effect of ketamine on serotonin (5-HT) release in the rat prefrontal cortex by in vivo microdialysis. A subcutaneous administration of ketamine (5 and 25 mg/kg) significantly increased the prefrontal 5-HT level in a dose-dependent manner, which was attenuated by local injection of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonists into the dorsal raphe nucleus (DRN). Direct stimulation of AMPARs in the DRN significantly increased prefrontal 5-HT level, while intra-DRN injection of ketamine (36.5 nmol) had no effect. Furthermore, intra-DRN injection of an alpha 4 beta 2-nicotinic acetylcholine receptor (nAChR) antagonist, dihydro-beta-erythroidine (10 nmol), significantly attenuated the subcutaneous ketamine-induced increase in prefrontal 5-HT levels. These results suggest that AMPARs and alpha 4 beta 2-nAChRs in the DRN play a key role in the ketamine-induced 5-HT release in the prefrontal cortex.

Ketamine-induced neuroapoptosis has been attributed to diverse stress-related mechanisms. Glycogen synthase kinase-3beta (GSK-3beta) is a multifunctional kinase that is active in neuronal development and linked to neurodegenerative disorders. We hypothesized that ketamine would enhance GSK-3beta-induced neuroapopotosis, and that lithium, an inhibitor of GSK-3beta, would attenuate this response in vivo. Protein levels of cleaved caspase-3, protein kinase B (AKT), GSK-3beta, and cyclin D1 were measured in post-natal day 7 rat pups after 1.5, 3, 4.5, and 6 hr exposure to ketamine. A cohort of rat pups was randomized to a 6 hr exposure to ketamine with and without lithium. Neuroapoptosis was measured by cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining by immunohistochemistry. Protein levels of cleaved caspase-3 and -9 and the total and phosphorylated forms of AKT, GSK-3beta, and cyclin D1 (cell cycle protein) were also measured. Ketamine produced a duration-dependent increase in cleaved caspase-3 and cyclin D1, which corresponded to decreases in phosphorylated AKT and GSK-3beta. Co-administration of lithium with ketamine attenuated this response. Ketamine-induced neuroapoptosis is associated with a temporal decrease in GSK-3beta phosphorylation, and simultaneous administration of lithium mitigated this response. These findings suggest that GSK-3beta is activated during this ketamine-induced neuroapoptosis.

The general anesthetic ketamine is known to be an N-methyl-D-aspartate receptor blocker. Although ketamine also blocks voltage-gated sodium channels in a local anesthetic-like fashion, little information exists on the molecular pharmacology of this interaction. ... The effects of ketamine on sodium channels /was measured/. Wild-type and mutant (F1579A) recombinant rat skeletal muscle sodium channels were expressed in Xenopus oocytes. The F1579A amino acid substitution site is part of the intrapore local anesthetic receptor. The effect of ketamine was measured in oocytes expressing wild-type or mutant sodium channels using two-electrode voltage clamp. Ketamine blocked sodium channels in a local anesthetic-like fashion, exhibiting tonic blockade (concentration for half-maximal inhibition [IC50] = 0.8 mm), phasic blockade (IC50 = 2.3 mm), and leftward shift of the steady-state inactivation; the parameters of these actions were strongly modified by alteration of the intrapore local anesthetic binding site (IC50 = 2.1 mm and IC50 = 10.3 mm for tonic and phasic blockade, respectively). Compared with lidocaine, ketamine showed greater tonic inhibition but less phasic blockade. Ketamine interacts with sodium channels in a local anesthetic-like fashion, including sharing a binding site with commonly used clinical local anesthetics.

The reported half-life in preclinical studies for ketamine is 186 min.

... The pharmacokinetics and distribution of ketamine and its biotransformation products in dogs after extradural administration of ketamine at L4-5 /were studied/. ... 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 live is 2.5 hours in adults and 1 to 2 hours in children.

beta phase half-life: 3 hours /From table/

... Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes. This first phase corresponds clinically 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 about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat. The later half-life of ketamine (beta phase) is 2.5 hours.

For more Biological Half-Life (Complete) data for Ketamine (10 total), please visit the HSDB record page.

Ketamine presents a mainly hepatic metabolism and its major metabolite is norketamine. The biotransformation of ketamine corresponds to N-dealkylation, hydroxylation of the cyclohexone ring, conjugation to glucuronic acid and dehydration of the hydroxylated metabolites for the formation of cyclohexene derivatives.

Ketamine is hepatically metabolized to norketamine, which has reduced CNS activity; norketamine is further metabolized and excreted in urine and bile.

The biotransformation of ketamine includes N-dealkylation (metabolite I), hydroxylation of the cyclohexone ring (metabolites III and IV), conjugation with glucuronic acid and dehydration of the hydroxylated metabolites to form the cyclohexene derivative (metabolite II). Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes. This first phase corresponds clinically 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 about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat. The later half-life of ketamine (beta phase) is 2.5 hours.

The pharmacokinetics of ketamine-HCl in the cat was described by a 2-compartment open model. The n-dealkylated amine metabolite of ketamine-HCl was detected in plasma of all cats and peak levels which were 0.27 to 0.38 times ketamine-HCl level were reached between 5 and 20 min after injection.

... The pharmacokinetics and distribution of ketamine and its biotransformation products in dogs after extradural administration of ketamine at L4-5 /were studied/. ... The apparent formation rate constant of norketamine was greater than that of dehydronorketamine. However, the concentrations of the biotransformation products in CSF were smaller than those of the parent drug. These results are similar to the distribution of ketamine and its metabolites in different cerebral structures and tissues. The concentrations decreased in concert with the increase in polarity of the metabolites. A specific distribution for all compounds was observed. Ketamine showed a greater affinity for brainstem, while norketamine and dehydronorketamine were distributed mostly in cerebellum and kidney, respectively.

For more Metabolism/Metabolites (Complete) data for Ketamine (8 total), please visit the HSDB record page.

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KETAMINE

Physiologic Effects [PE] - General Anesthesia

Established Pharmacologic Class [EPC] - General Anesthetic

Ketamine is a General Anesthetic. The physiologic effect of ketamine is by means of General Anesthesia.

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 feeling 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&apos;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.

Ketamine absorption is very rapid and the bioavailability is around 93%. After the first pass metabolism, only 17% of the administered dose is absorbed. It distributes very rapidly and presents a distribution half-life of 1.95 min. The Cmax levels at peak reach 0.75 mcg/ml in plasma and 0.2 mcg/ml in cerebrospinal fluid.

Pharmacokinetic studies have resulted in the recovery of 85-95% of the administered dose in urine mainly in the form of metabolites. Some other routes of elimination of ketamine are bile and feces. When administered intravenously the resultant recovery is distributed by 91% of the administered dose in urine and 3% in feces.

The apparent volume of distribution of the central compartment and at steady-state are 371.3 ml/kg and 4060.3 ml/kg, respectively.

The clearance rate of ketamine is high and of around 95 L/h/70kg.

Ketamine has a large volume of distribution and rapid clearance that make it suitable for continuous infusion without the lengthening in duration of action seen with thiopental. Protein binding is much lower with ketamine than with the other parenteral anesthetics.

The biotransformation of ketamine includes N-dealkylation (metabolite I), hydroxylation of the cyclohexone ring (metabolites III and IV), conjugation with glucuronic acid and dehydration of the hydroxylated metabolites to form the cyclohexene derivative (metabolite II). Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes. This first phase corresponds clinically 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 about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat. The later half-life of ketamine (beta phase) is 2.5 hours.

Ketamine, its salts, isomers, and salts of isomers (DEA Code Number: 7285) is a Schedule III controlled substance.

Schedule III Controlled Substance: (A) The drug or other substance has a potential for abuse less than the drugs or other substances in schedules I and II. (B) The drug or other substance has a currently accepted medical use in treatment in the United States. (C) Abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence.

Analgesics; Anesthetics, Dissociative; Excitatory Amino Acid Antagonists

MEDICATION

MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >250

Preparation: C.L. Stevens, Belgium patent 634208; idem, United States of America patent 3254124 (1963, 1966 both to Parke, Davis).

... Prepared by bromination of o-chlorophenyl cyclopentyl ketone, which is then reacted with methylamine to give the methylimino alcohol. Thermolysis of the imino hydrochloride yields ketamine by ring expansion.

Trade Names. Ketanest (Parke-Davis); Ketaject (Bristol); Ketalar (Parke-Davis; Sankyo); Ketaset (Bristol); Vetalar (Parke-Davis, veterinary anesthetic).

Ketamine is supplied as a mixture of the R+ and S- isomers even though the S- isomer is more potent with fewer side effects. ... Ketamine is ... available as 10, 50, and 100 mg/mL solutions in sodium chloride plus the preservative benzethonium chloride.

Common street names include: Cat Tranquilizer, Cat Valium, Jet K, Kit Kat, Purple, Special K, Special La Coke, Super Acid, Super K, and Vitamin K.

Since the 1970s, ketamine has been marketed in the United States as an injectable, short-acting anesthetic for use in humans and animals. In 1999, ketamine including its salts, isomers and salts of isomers, became a Schedule III non-narcotic substance under the Controlled Substances Act.

Ketamine is produced commercially in a number of countries, including the United States. Most of the ketamine illegally distributed in the United States is diverted or stolen from legitimate sources, particularly veterinary clinics, or smuggled into the United States from Mexico.