|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||Controlled (S8) (AU) Schedule I (CA) CD (UK) Schedule III (US)|
|Routes||IV, IM, Insufflated, oral, topical|
|Metabolism||Hepatic, primarily by CYP3A4|
|Mol. mass||237.725 g/mol|
|Melt. point||262 °C (504 °F)|
|(what is this?)|
Ketamine is a drug with multiple applications used in medical procedures with humans and subsequently adopted for veterinary medicine, mainly for starting and maintaining general anesthesia. Other uses include sedation in intensive care, as a pain killer (particularly in emergency medicine and patients with potentially compromised respiration and/or allergies to opiate and barbiturate analgesics), and as treatment of bronchospasm, and as a treatment for complex regional pain syndrome.
Respiratory function is unchanged with the administration of ketamine, which makes it a valuable anaesthetic. Potential complications include agitation.
Pharmacologically, ketamine is classified as an NMDA receptor antagonist, but it also acts at numerous other sites (including opioid receptors and monoamine transporters). Like other drugs in its class, such as tiletamine and phencyclidine (PCP), it is classified as a dissociative agent. The state it induces is described as a "trancelike cataleptic state of 'sensory isolation' [which] is characterized by potent analgesia, sedation, and amnesia while maintaining cardiovascular stability and preserving spontaneous respirations and protective airway reflexes."
It is on the World Health Organization's List of Essential Medicines, a list of essential medicines that should be available in a health system. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Recreational use has led to high-profile deaths.
- 1 Use
- 2 Side effects
- 3 Pharmacology
- 4 Interactions
- 5 Chemistry
- 6 History
- 7 Society and culture
- 8 Research
- 9 Veterinary medicine
- 10 See also
- 11 References
- 12 External links
Uses as an anaesthetic:
- Anesthesia in children, as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and tracheal intubation;
- Asthmatics or people with chronic obstructive airway disease;
- As a sedative for physically or emotionally painful procedures in emergency departments;
- Emergency surgery in field conditions in war zones;
- To supplement spinal or epidural anesthesia/analgesia using low doses;
Since it suppresses breathing much less than most other available anaesthetics, ketamine is used in medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available.
Ketamine is frequently used in severely injured people. A 2011 clinical practice guideline supports the use of ketamine as a dissociative sedative in emergency medicine. It is the drug of choice for patients in traumatic shock who are at risk of hypotension. Low blood pressure is harmful in people with severe head injury and ketamine is least likely to cause hypotension, often even able to prevent it.
The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. When used at anesthetic doses, it will usually stimulate rather than depress the circulatory system. It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is considered relatively safe because protective airway reflexes are preserved.
Ketamine is also used for postoperative pain management. A 2006 Cochrane Collaboration systematic review found low doses of ketamine reduced morphine consumption and nausea/vomiting after surgery.
It may also be used as an intravenous coanalgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic (pain due to vascular insufficiency or shingles are good examples). It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain. At these doses, the psychotropic side effects are less apparent and well managed with benzodiazepines. Ketamine is a coanalgesic, so is most effective when used alongside a low-dose opioid; while it does have analgesic effects by itself, the higher doses required can cause disorienting side effects. The combination of ketamine with an opioid may be useful for pain caused by cancer, as suggested in animal models. A review article in 2013 concluded that "despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain".
Low-dose ketamine is sometimes used in the treatment of complex regional pain syndrome (CRPS). A 2013 systematic review found only low quality evidence to support the use of ketamine for CRPS. Although low-dose ketamine therapy is established as a generally safe procedure, reported side effects in some patients have included hallucinations, dizziness, lightheadedness and nausea. Therefore, the administration of ketamine to patients with CRPS should only be done by medical personnel that are appropriately licensed and trained if needed to assess potential adverse effects on patients.
Ketamine is also a potent analgesic and can be used in subanesthetic doses to relieve acute pain; however, its psychotropic properties must be taken into account. Patients have reported vivid hallucinations, "going into other worlds" or "seeing God" while anesthetized, and these unwanted psychological side effects have reduced the use of ketamine in human medicine. They can, however, usually be avoided by concomitant administration of a sedative such as a benzodiazepine.
Unlike the other well-known dissociatives PCP and DXM, ketamine is very short-acting. It takes effect within approximately 10 minutes, while its hallucinogenic effects last 60 minutes when insufflated or injected and up to two hours when ingested orally. The total experience lasts no more than a few hours.
At subanesthetic doses, ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world which is known as depersonalization and derealization. At sufficiently high doses, users may experience what is called the "K-hole", a state of extreme dissociation with visual and auditory hallucinations. John C. Lilly, Marcia Moore and D. M. Turner (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with ketamine. Both Moore and Turner died prematurely during presumed unsupervised ketamine use.
- Oral ketamine is easily broken down by bile acids and thus has a low bioavailability (~20%). Oftentimes lozenges or "gummies" for sublingual or buccal absorption prepared by a compounding pharmacy are used to combat this issue.
- Some specialists stop the subcutaneous infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.
As part of a cream, gel, or liquid (only available from compounding pharmacies as it is not a branded product, specific formulation and ratios are specified by the prescribing physician) for topical application for nerve pain. Other ingredients found useful by pain specialists and their patients, as well as the compounding pharmacists who make the topical mixtures, include amitriptyline, cyclobenzaprine, clonidine, tramadol, gabapentin, baclofen, and mepivacaine and other longer-acting local anaesthetics (e.g. tetracaine, procaine).
- Cardiovascular: Arrythmias, bradycardia or tachycardia, hyper or hypotension
- Central nervous system: Increased intracranial pressure
- Dermatologic: Transient erythema, transient morbilliform rash
- Gastrointestinal: Anorexia, nausea, increased salivation, vomiting
- Local: Pain or exanthema of the injection site
- Neuromuscular & skeletal: Increased skeletal muscle tone (tonic-clonic movements)
- Ocular: Diplopia, increased intraocular pressure, nystagmus
- Respiratory: Airway obstruction, apnea, increased bronchial secretions, respiratory depression, laryngospasm
- Other: Anaphylaxis, dependence, emergence reaction
Emergence reactions manifest as vivid dreams, hallucinations, and delirium and occur in 10 to 20 percent of patients at anesthetic doses. These reactions are less common in patients less than 15 years old and greater than 65 years old and when administered intramuscularly. Emergence reactions can occur up to 24 hours postoperatively. The chance of this occurring can be reduced by minimizing stimulation to the patient during recovery and pretreating with a benzodiazepine. If given a benzodiazepine, a lower dose of ketamine than normal should be given. Patients who experience severe reactions may require treatment with a small dose of a short or ultra-short acting barbiturate.
As discussed below, current research suggests that acute ketamine exposure does not cause significant neurotoxicity.
Until 10 years ago[when?], ketamine was not administered chronically in a typical clinical setting. Before now[when?], the long-term effects were primarily reported and investigated in recreational ketamine users and in animal models. 
In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes in two small areas of the rat brain, which, however, has significant differences in metabolism from the human brain, so may not occur in humans.
The first large-scale, longitudinal study of ketamine users found that current frequent (averaging 20 days/month) ketamine users, had increased depression and impaired memory by several measures, including verbal, short-term memory and visual memory. Current infrequent (averaging 3.25 days/month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests the infrequent use of ketamine does not cause cognitive deficits, and that any deficits that might occur may be reversible when ketamine use is discontinued. However, abstinent, frequent, and infrequent users all scored higher than controls on a test of delusional symptoms.
Short-term exposure of cultures of GABAergic neurons to ketamine at high concentrations led to a significant loss of differentiated cells in one study, and non-cell-death-inducing concentrations of ketamine (10 μg/ml) may still initiate long-term alterations of dendritic arbor in differentiated neurons. The same study also demonstrated chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal maintenance and development.
More recent studies of ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents. One such study administered daily ketamine doses consistent with typical recreational doses (1 mg/kg IV) to adolescent cynomolgus monkeys for varying periods of time. Decreased locomotor activity and indicators of increased cell death in the prefrontal cortex were detected in monkeys given daily injections for six months, but not those given daily injections for one month. A study conducted on rhesus monkeys found that a 24-hour intravenous infusion of ketamine caused signs of brain damage in 5-day-old but not 35-day-old animals. Some neonatal experts do not recommend the use of ketamine as an anesthetic agent in human neonates because of the potential adverse effects that it may have on the developing brain. These neurodegenerative changes in early development have been seen with other drugs that share the same mechanism of action of NMDA receptor antagonism as ketamine.
The acute effects of ketamine cause cognitive impairment including reduced vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.
Urinary tract effects
A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from ketamine abuse in published literature. Urinary tract symptoms have been collectively referred as "ketamine-induced ulcerative cystitis" or "ketamine-induced vesicopathy", and they include urge incontinence, decreased bladder compliance, decreased bladder volume, detrusor overactivity, and painful haematuria (blood in urine). Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases. The pathogenesis of papillary necrosis has been investigated in mice, and mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence has been suggested as a possible mechanism.
The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use corresponds linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 grams per day reported symptoms of the lower urinary tract. Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug for an extended period of time. These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.
Management of these symptoms primarily involves ketamine cessation, for which compliance is low. Other treatments have been used, including antibiotics, NSAIDs, steroids, anticholinergics, and cystodistension. Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some patients, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulfate, or both. Further follow-up is required to fully assess the efficacy of these treatments.
Case reports of hepatotoxicity in chronic pain management
In case reports of three patients treated with (S)-(+)-ketamine for relief of chronic pain, liver enzyme abnormalities occurred following repeat treatment with ketamine infusions, with the liver enzyme values returning below the upper reference limit of normal range on cessation of the drug. The result suggests liver enzymes must be monitored during such treatment.
Ketamine acts primarily as an antagonist of the NMDA receptor (NMDAR), and this action accounts for most of its effects. However, the complete pharmacology of ketamine is more complex, and it is known to directly interact with a variety of other sites to varying degrees. Known actions of ketamine include the following:
- Non-competitive antagonist of the NMDA receptor (NMDAR)
- Very weak positive allosteric modulator of the GABAA receptor (at concentrations above those used clinically)
- Negative allosteric modulator of the nACh receptor
- Weak agonist of the μ-opioid and κ-opioid receptors (10- to 20-fold less affinity relative to NMDAR), and very weak agonist of the δ-opioid receptor
- Agonist of the sigma receptor and D2 receptor
- Weak mACh receptor antagonist (10- to 20-fold less affinity relative to NMDAR)
- Inhibitor of the reuptake of serotonin, dopamine, and norepinephrine
- Voltage-gated sodium channel and L-type calcium channel blocker, and HCN1 cation channel blocker
- Inhibitor of nitric oxide synthase
Ketamine appears to inhibit the NMDAR by binding both in the open channel and at an allosteric site. The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively.
Effects in central nervous system
NMDAR antagonism is responsible for the anesthetic, amnesic, dissociative, and hallucinogenic effects of ketamine, although activation of κ-opioid receptors and possibly sigma and mACh receptors may also contribute to its psychotomimetic properties. Dopamine reuptake inhibition is likely to underlie the euphoria the drug produces, although an additional involvement of μ-opioid receptor activation cannot be excluded. NMDAR antagonism is responsible for the rapid antidepressant effects of ketamine at lower doses.
NMDAR antagonism 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. Inhibition of nitric oxide synthase lowers the production of nitric oxide – a neurotransmitter involved in pain perception – hence further contributing to analgesia. The action of ketamine at sigma and μ-opioid receptors is relatively weak, and there is mixed evidence as to whether the latter is of significance to its analgesic effects.
Ketamine also interacts with a host of other targets to cause analgesia. In particular, it blocks voltage-dependent calcium channels and sodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it inhibits the reuptake of serotonin and norepinephrine, which are involved in descending antinociceptive pathways.
Effects in peripheral systems
- Cardiovascular: Ketamine inhibits the reuptake of catecholamines, stimulating the sympathetic nervous system, resulting in cardiovascular symptoms.
- Gastrointestinal: Serotonin reuptake inhibition is thought to underlie nausea and vomiting.
- Respiratory: Catecholamine elevation and stimulation of β2 adrenergic receptors causes bronchodilation.
Ketamine is absorbable via intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities. When administered orally, it undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) isoenzymes into norketamine (through N-demethylation) and finally dehydronorketamine. Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into 5-hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine. As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent anesthetically, and plasma levels of this metabolite are three times higher than ketamine following oral administration. Bioavailability through the oral route reaches 17–20%; bioavailability through other routes are as follows: 93% intramuscularly, 25–50% intranasally, 30% sublingually, and 30% rectally. Peak plasma concentrations are reached within a minute intravenously, 5–15 min intramuscularly, and 30 min orally. Ketamine's duration of action in a clinical setting is 30 min to 2 h intramuscularly and 4–6 h orally.
Other drugs which increase blood pressure may interact with ketamine in having an additive effect on blood pressure including: stimulants, SNRI anti-depressants, MAOIs. Increase blood pressure, increased heart rate, palpitations and arrhythmias may be potential effects. Ketamine alone additionally increases intracranial pressure (ICP)
Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in their enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.
Ketamine is synthesized from 2-chlorobenzonitrile, which reacts with the cyclopentylmagnesium bromide to give (2-chlorophenyl)(cyclopentyl)methanone. The next step is bromination using bromine to the corresponding bromoketone, which upon reaction with an aqueous solution of methylamine forms the methylimino derivative. During this reaction, a simultaneous hydrolysis of the tertiary bromine atom occurs. On heating the reaction product in decalin, a ring-expansion rearrangement occurs, forming ketamine.
Ketamine was first synthesized in 1962 by Calvin Stevens, a Parke Davis consultant conducting research on alpha-hydroxyimine rearrangements. After promising preclinical research in animals, ketamine was introduced to testing in human prisoners in 1964. These investigations demonstrated that ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over PCP as a dissociative anesthetic. Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.
Non-medical use of ketamine began on the West Coast of the United States in the early 1970s. Early use was documented in underground literature such as The Fabulous Furry Freak Brothers. It was used in psychiatric and other academic research through the 1970s, culminating in 1978 with the publishing of psychonaut John Lilly's The Scientist, and Marcia Moore and Howard Alltounian's Journeys into the Bright World, which documented the unusual phenomenology of ketamine intoxication. The incidence of non-medical ketamine use increased through the end of the century, especially in the context of raves and other parties. However, its emergence as a club drug differs from other club drugs (e.g. MDMA) due to its anesthetic properties (e.g., slurred speech, immobilization) at higher doses; in addition, reports of ketamine being sold as "ecstasy" are common. The use of ketamine as part of a "post-clubbing experience" has also been documented. Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s. Before becoming a federally controlled substance in the United States in 1999, ketamine was available as diverted pharmaceutical preparations and as a pure powder sold in bulk quantities from domestic chemical supply companies. Today much of the ketamine diverted for non-medical use originates in China and India.
Society and culture
In the United Kingdom, it became labeled a Class C drug on 1 January 2006. On 10 December 2013 the UK ACMD recommended that the government reclassify ketamine to become a Class B drug, and on 12 February 2014 the Home Office announced they would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage".
The UK Minister of State for Crime Prevention, Norman Baker, responding to the ACMD's advice said that the issue of its recheduling for medical and veterinary would be addressed "separately to allow for a period of consultation."
In Canada, ketamine is classified as a Schedule I narcotic, as of August 2005. In Hong Kong, as of 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals, for university research purposes, or with a physician's prescription. By 2002, ketamine was classified as schedule III in Taiwan; given the recent rise in prevalence in East Asia, however, rescheduling into schedule I or II is being considered.
In December 2013 the government of India added ketamine to Schedule X of the Drug and Cosmetics Act, adding restrictions on who can buy or sell it.
International brand names
Brand names for ketamine vary internationally:
- Anesject (ID)
- Brevinaze (ZA)
- Calypsol (AE, BB, BG, BH, BM, BS, BZ, CY, CZ, EG, GY, HU, IL, IQ, IR, JM, JO, KW, LB, LY, OM, PK, PL, PR, QA, RU, SA, SR, SY, TH, TT, YE)
- Ivanes (ID)
- Kanox (MY)
- Keiran (VE)
- Ketacor (PH)
- Ketalar (AE, AR, AT, AU, BB, BE, BH, BM, BR, BS, BZ, CH, CY, DK, EG, ES, FI, FR, GB, GR, GY, HK, HN, ID, IE, IL, IN, IQ, IR, IT, JM, JO, KW, LB, LU, LY, MY, NL, NO, OM, PE, PT, QA, SA, SE, SR, SY, TR, TT, TW, US, UY, YE, ZA)
- Ketalin (MX)
- Ketamax (PH)
- Ketamin-S (+) (PY)
- Ketanest (NL, HR, PL, DE, AT)
- Ketashort (CO)
- Ketava (MY)
- Ketazol (PH)
- Ketmin (IN)
- Ketalor (ES)
- Narkamon (DE, PL)
- Paard (BE)
- Soon-Soon (TW)
- Tekam (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE)
- Velonarcon (PL)
Ketamine was referenced in several episodes of the television show House. It was first mentioned in the finale of the second season, "No Reason", and was responsible for temporarily relieving House's leg pain.
Research on the antidepressant effects of ketamine infusions at subanaesthetic doses has consistently shown rapid (4 to 72 hours) responses from single doses, with substantial improvement in mood in the majority of patients and remission in some. However, these effects are often short-lived, and attempts to prolong the antidepressant effect with repeated doses and extended ("maintenance") treatment have resulted in only modest success in two small trials that were reviewed.
NIMH director Thomas Insel remarked, "To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients."
A 2013 two-site randomized controlled clinical trial of ketamine in patients with treatment-resistant depression found that 64% of the patients responded after 24 hours according to the Montgomery–Åsberg Depression Rating Scale compared to 28% responding to midazolam.
Treatment of addiction
The Russian doctor Evgeny Krupitsky has claimed to have encouraging results by using ketamine as part of a treatment for alcohol addiction which combines psychedelic and aversive techniques. Krupitsky and Kolp summarized their work to date in 2007.
In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. It is an important part of the "rodent cocktail" a mixture of drugs used for anesthetizing rodents. Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help prevent pain wind-up. Ketamine is used to manage pain among large animals, though it has less effect on bovines. It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.
- NMDA receptor
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