1-(2-Chloro-N-methylbenzimidoyl)cyclopentanol, sometimes misleadingly referred to as hydroxylimine hydrochloride, is a chemical compound which is the final intermediate in the synthesis of ketamine, an anaesthetic drug which is also subject to recreational abuse. This chemical intermediate is not active as a drug in its own right, and is legal in most countries, but is readily converted into ketamine by dissolving it in a suitable high-boiling point solvent and heating, with no other chemicals required.[1][2] This has made it subject to illicit trade as a drug precursor, and it has sometimes been seized by law enforcement agencies in significant quantities, leading to it being specifically banned as a controlled drug precursor in some jurisdictions such as Taiwan
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and in pain management.[19] Ketamine is an NMDA receptor antagonist which accounts for most of its psychoactive effects.[20]
At anesthetic doses, ketamine induces a state of dissociative anesthesia, a trance-like state providing pain relief, sedation, and amnesia.[21] Its distinguishing features as an anesthestic are preserved breathing and airway reflexes, stimulated heart function with increased blood pressure, and moderate bronchodilation.[21] At lower, sub-anesthetic doses, it is a promising agent for treatment of pain and treatment-resistant depression.[22] As with many antidepressants, the results of a single administration wane with time.[23]
Ketamine is used as a recreational drug for its hallucinogenic and dissociative effects.[24] When used recreationally, it is found both in crystalline powder and liquid form, and is often referred to by users as "Special K" or simply "K". The long-term effects of repeated use are largely unknown and are an area of active investigation.[25][26][27] Liver and urinary toxicity have been reported among regular users of high doses of ketamine for recreational purposes.[28]
Ketamine was first synthesized in 1962, derived from phencyclidine in pursuit of a safer anesthetic with fewer hallucinogenic effects.[29][30] It was approved for use in the United States in 1970.[19] It has been regularly used in veterinary medicine and was extensively used for surgical anesthesia in the Vietnam War.[31] It is on the World Health Organization's List of Essential Medicines.[32] It is available as a generic medication.[33]
The use of ketamine in anesthesia reflects its characteristics. It is a drug of choice for short-term procedures when muscle relaxation is not required.[34] The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. It suppresses breathing much less than most other available anesthetics.[35] When used at anesthetic doses, ketamine usually stimulates rather than depresses the circulatory system.[36] Protective airway reflexes are preserved,[37] and it is sometimes possible to administer ketamine anesthesia without protective measures to the airways.[34]Psychotomimetic effects limit the acceptance of ketamine; however, lamotrigine[38] and nimodipine[39] decrease psychotomimetic effects and can also be counteracted by benzodiazepines or propofol administration.[40]Ketofol is a combination of ketamine and propofol.
Ketamine is frequently used in severely injured people and appears to be safe in this group.[41] It has been widely used for emergency surgery in field conditions in war zones,[42] for example, during the Vietnam War.[43] A 2011 clinical practice guideline supports the use of ketamine as a sedative in emergency medicine, including during physically painful procedures.[21] It is the drug of choice for people in traumatic shock who are at risk of hypotension.[44] Ketamine is unlikely to lower blood pressure, which is dangerous for people with severe head injury;[45] in fact, it can raise blood pressure, often making it useful in treating such injuries.[46][47]
Ketamine is an option in children as the sole anesthetic for minor procedures or as an induction agent followed by neuromuscular blocker and tracheal intubation.[42] In particular, children with cyanotic heart disease and neuromuscular disorders are good candidates for ketamine anesthesia.[40][48]
Due to the bronchodilating properties of ketamine, it can be used for anesthesia in people with asthma, chronic obstructive airway disease, and with severe reactive airway disease including active bronchospasm.[42][40][49]
Ketamine infusions are used for acute pain treatment in emergency departments and in the perioperative period for individuals with refractory pain. The doses are lower than those used for anesthesia, usually referred to as sub-anesthetic doses. Adjunctive to morphine or on its own, ketamine reduces morphine use, pain level, nausea, and vomiting after surgery. Ketamine is likely to be most beneficial for surgical patients when severe post-operative pain is expected, and for opioid-tolerant patients.[50][51]
Ketamine is especially useful in the pre-hospital setting due to its effectiveness and low risk of respiratory depression.[52] Ketamine has similar efficacy to opioids in a hospital emergency department setting for the management of acute pain and the control of procedural pain.[53] It may also prevent opioid-induced hyperalgesia[54][55] and postanesthetic shivering.[56]
For chronic pain, ketamine is used as an intravenous analgesic, mainly if the pain is neuropathic.[30] It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain.[57] In multiple clinical trials, ketamine infusions delivered short-term pain relief in neuropathic pain diagnoses, pain after a traumatic spine injury, fibromyalgia, and complex regional pain syndrome (CRPS).[30] However, the 2018 consensus guidelines on chronic pain concluded that, overall, there is only weak evidence in favor of ketamine use in spinal injury pain, moderate evidence in favor of ketamine for CRPS, and weak or no evidence for ketamine in mixed neuropathic pain, fibromyalgia, and cancer pain. In particular, only for CRPS, there is evidence of medium to longer-term pain relief.[30]
Ketamine is a rapid-acting antidepressant,[19] but its effect is transient.[58] Intravenous ketamine infusion in treatment-resistant depression may result in improved mood within 4 hours reaching the peak at 24 hours.[22][25] A single dose of intravenous ketamine has been shown to result in a response rate greater than 60% as early as 4.5 hours after the dose (with a sustained effect after 24 hours) and greater than 40% after 7 days.[59] Although only a few pilot studies have sought to determine the optimal dose, increasing evidence suggests that 0.5 mg/kg dose injected over 40 minutes gives an optimal outcome.[60] The antidepressant effect of ketamine is diminished at 7 days, and most people relapse within 10 days. However, for a significant minority, the improvement may last 30 days or more.[25][26][59][61]
One of the main challenges with ketamine treatment can be the length of time that the antidepressant effects last after finishing a course of treatment. A possible option may be maintenance therapy with ketamine, which usually runs twice a week to once in two weeks.[25][26][27] Ketamine may decrease suicidal thoughts for up to three days after the injection.[62]
An enantiomer of ketamine – esketamine commercially sold as Spravato – was approved as an antidepressant by the European Medicines Agency in 2019.[63] Esketamine was approved as a nasal spray for treatment-resistant depression in the United States[64] and elsewhere in 2019 (see Esketamine and Depression). The Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends esketamine as a third-line treatment for depression.[26]
A Cochrane review of randomized controlled trials in adults with unipolar major depressive disorder,[19] found that when compared with placebo, people treated with either ketamine or esketamine experienced reduction or remission of symptoms lasting 1 to 7 days.[65] There were 18.7% (4.1 to 40.4%) more people reporting some benefit and 9.6% (0.2 to 39.4%) more who achieved remission within 24 hours of ketamine treatment. Among people receiving esketamine, 2.1% (2.5 to 24.4%) encountered some relief at 24 hours, and 10.3% (4.5 to 18.2%) had few or no symptoms. These effects did not persist beyond one week, although a higher dropout rate in some studies means that the benefit duration remains unclear.[65]
Ketamine may partially improve depressive symptoms[19] among people with bipolar depression at 24 hours after treatment, but not three or more days.[66] Potentially, ten more people with bipolar depression per 1000 may experience brief improvement, but not the cessation of symptoms, one day following treatment. These estimates are based on limited available research.[66]
In February 2022, the US Food and Drug Administration issued an alert to healthcare professionals concerning compounded nasal spray products containing ketamine intended to treat depression.[67]
Ketamine is used to treat status epilepticus[68] that has not responded to standard treatments, but only case studies and no randomized controlled trials support its use.[69][70]
Ketamine has been suggested as a possible therapy for children with severe acute asthma who do not respond to standard treatment.[71] This is due to its bronchodilator effects.[71] A 2012 Cochrane review found there were minimal adverse effects reported, but the limited studies showed no significant benefit.[71]
AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.
One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.
Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.
Table from the 2010 ISCD study ranking various drugs (legal and illegal) based on statements by drug-harm experts. Ketamine was found to be the 11th overall most dangerous drug.[72]
At anesthetic doses, 10–20% of adults and 1–2% of children[10] experience adverse psychiatric reactions that occur during emergence from anesthesia, ranging from dreams and dysphoria to hallucinations and emergence delirium.[73] Psychotomimetic effects decrease adding lamotrigine[38] and nimodipine[39] and can be counteracted by pretreatment with a benzodiazepine or propofol.[73][40] Ketamine anesthesia commonly causes tonic-clonic movements (greater than 10% of people) and rarely hypertonia.[14][73] Vomiting can be expected in 5–15% of the patients; pretreatment with propofol mitigates it as well.[10][73]Laryngospasm occurs only rarely with ketamine. Ketamine, generally, stimulates breathing; however, in the first 2–3 minutes of a high-dose rapid intravenous injection, it may cause a transient respiratory depression.[73]
At lower sub-anesthetic doses, psychiatric side effects are prominent. Most people feel strange, spacey, woozy, or a sense of floating, or have visual distortions or numbness. Also very frequent (20–50%) are difficulty speaking, confusion, euphoria, drowsiness, and difficulty concentrating.[citation needed] The symptoms of psychosis such as going into a hole, disappearing, feeling as if melting, experiencing colors, and hallucinations are described by 6–10% of people. Dizziness, blurred vision, dry mouth, hypertension, nausea, increased or decreased body temperature, or feeling flushed are the common (>10%) non-psychiatric side effects. All these adverse effects are most pronounced by the end of the injection, dramatically reduced 40 minutes afterward, and completely disappear within 4 hours after the injection.[74]
Urinary toxicity occurs primarily in people who use large amounts of ketamine routinely, with 20–30% of frequent users having bladder complaints.[30][75] It includes a range of disorders from cystitis to hydronephrosis to kidney failure.[76] The typical symptoms of ketamine-induced cystitis are frequent urination, dysuria, and urinary urgency sometimes accompanied by pain during urination and blood in urine.[77] The damage to the bladder wall has similarities to both interstitial and eosinophilic cystitis. The wall is thickened and the functional bladder capacity is as low as 10–150 mL.[76] Studies indicate that ketamine-induced cystitis is caused by ketamine and its metabolites directly interacting with urothelium, resulting in damage of the epithelial cells of the bladder lining and increased permeability of the urothelial barrier which results in clinical symptoms.[78]
Management of ketamine-induced cystitis involves ketamine cessation as the first step. This is followed by NSAIDs and anticholinergics and, if the response is insufficient, by tramadol. The second line treatments are epithelium-protective agents such as oral pentosan polysulfate or intravesical (intra-bladder) instillation of hyaluronic acid. Intravesical botulinum toxin is also useful.[76]
Liver toxicity of ketamine involves higher doses and repeated administration. In a group of chronic high-dose ketamine users, the frequency of liver injury was reported to be about 10%.[citation needed] There are case reports of increased liver enzymes involving ketamine treatment of chronic pain.[76] Chronic ketamine abuse has also been associated with biliary colic,[79]cachexia, gastrointestinal diseases, hepatobiliary disorder, and acute kidney injury.[80]
Most people who were able to remember their dreams during ketamine anesthesia report near-death experiences (NDEs) when the broadest possible definition of an NDE is used.[81] Ketamine can reproduce features that commonly have been associated with NDEs.[82] A 2019 large-scale study found that written reports of ketamine experiences had a high degree of similarity to written reports of NDEs in comparison to other written reports of drug experiences.[83]
Although the incidence of ketamine dependence is unknown, some people who regularly use ketamine develop ketamine dependence. Animal experiments also confirm the risk of misuse.[24] Additionally, the rapid onset of effects following insufflation may increase potential use as a recreational drug. The short duration of effects promotes bingeing. Ketamine tolerance rapidly develops, even with repeated medical use, prompting the use of higher doses. Some daily users reported withdrawal symptoms, primarily anxiety, shaking, sweating, and palpitations, following the attempts to stop.[24] Cognitive deficits as well as increased dissociation and delusion symptoms were observed in frequent recreational users of ketamine.[84]
Ketamine potentiates the sedative effects of propofol[85] and midazolam.[86]Naltrexone potentiates psychotomimetic effects of a low dose of ketamine,[87] while lamotrigine[38] and nimodipine[39] decrease them. Clonidine reduces the increase of salivation, heart rate, and blood pressure during ketamine anesthesia and decreases the incidence of nightmares.[88]
Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine.[89] It appears most conventional antidepressants can be safely combined with ketamine.[89]
Ketamine is a mixture of equal amounts of two enantiomers: esketamine and arketamine. Esketamine is a far more potent NMDA receptor pore blocker than arketamine.[11] Pure blocking of the NMDA receptor is responsible for the anesthetic, analgesic, and psychotomimetic effects of ketamine.[20][90] Blocking of the NMDA receptor results in analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine's actions interfere with pain transmission in the spinal cord.[14]
The mechanism of action of ketamine in alleviating depression is not well understood and is an area of active investigation. Due to the hypothesis that NMDA receptor antagonism underlies the antidepressant effects of ketamine, esketamine was developed as an antidepressant.[11] However, multiple other NMDA receptor antagonists, including memantine, lanicemine, rislenemdaz, rapastinel, and 4-chlorokynurenine, have thus far failed to demonstrate significant effectiveness for depression.[11][91] Furthermore, animal research indicates that arketamine, the enantiomer with a weaker NMDA receptor antagonism, as well as (2R,6R)-hydroxynorketamine, the metabolite with negligible affinity for the NMDA receptor but potent alpha-7 nicotinic receptor antagonist activity, may have antidepressant action.[11][92] This furthers the argument that NMDA receptor antagonism may not be primarily responsible for the antidepressant effects of ketamine.[11][93][91] Acute inhibition of the lateral habenula, a part of the brain responsible for inhibiting the mesolimbic reward pathway and referred to as the "anti-reward center", is another possible mechanism for ketamine's antidepressant effects.[94][95][96]
Possible biochemical mechanisms of ketamine's antidepressant action include direct action on the NMDA receptor and downstream effects on regulators such as BDNF and mTOR.[94] It is not clear whether ketamine alone is sufficient for antidepressant action or its metabolites are also important; the active metabolite of ketamine, hydroxynorketamine, which does not significantly interact with the NMDA receptor but nonetheless indirectly activates AMPA receptors, may also or alternatively be involved in the rapid-onset antidepressant effects of ketamine.[20][94][97] In NMDA receptor antagonism, acute blockade of NMDA receptors in the brain results in an increase in the release of glutamate, which leads to an activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptors), which in turn modulate a variety of downstream signaling pathways to influence neurotransmission in the limbic system and mediate antidepressant effects.[59][94][98] Such downstream actions of the activation of AMPA receptors include upregulation of brain-derived neurotrophic factor (BDNF) and activation of its signaling receptor tropomyosin receptor kinase B (TrkB), activation of the mammalian target of rapamycin (mTOR) pathway, deactivation of glycogen synthase kinase 3 (GSK-3), and inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase
Find quality suppliers and manufacturers of 1-(2-Chloro-N-methylbenzimidoyl)cyclopentanol for price inquiry.where to buy 1-(2-Chloro-N-methylbenzimidoyl)cyclopentanol(6740-87 …
Compute answers using Wolfram's breakthrough technology & knowledgebase, relied on by millions of students & professionals. For math, science, nutrition, history ...
Pharmaceutical secondary standards for application in quality control provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the …
Reviews
There are no reviews yet.