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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/09/11 03:24:59」(JST)
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For the functional group referred to as ketimine, see imine.
| Systematic (IUPAC) name | |
|---|---|
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(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
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| Clinical data | |
| AHFS/Drugs.com | Consumer Drug Information |
| License data |
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| Pregnancy category |
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| Addiction liability |
Low–moderate[1] |
| Routes of administration |
IV, IM, insufflated, oral, topical |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Metabolism | Liver, primarily by CYP3A4[2] |
| Onset of action | < 5min (IM, IV), < 30min (by mouth)[3] |
| Biological half-life | 2.5–3 hours |
| Duration of action | less than one hour[3] |
| Excretion | Kidney (>90%) |
| Identifiers | |
| CAS Number | 6740-88-1 Y |
| ATC code | N01AX03 (WHO) |
| PubChem | CID 3821 |
| IUPHAR/BPS | 4233 |
| DrugBank | DB01221 Y |
| ChemSpider | 3689 Y |
| UNII | 690G0D6V8H Y |
| KEGG | D08098 Y |
| ChEBI | CHEBI:6121 Y |
| ChEMBL | CHEMBL742 Y |
| Chemical data | |
| Formula | C13H16ClNO |
| Molar mass | 237.725 g/mol |
| Chirality | Racemic mixture |
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SMILES
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InChI
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| Physical data | |
| Melting point | 262 °C (504 °F) |
| (verify) | |
Ketamine, sold under the brand name Ketalar among others, is a medication mainly used for starting and maintaining anesthesia.[4] It induces a trance-like state while providing pain relief, sedation, and memory loss.[5] Other uses include for chronic pain and for sedation in intensive care.[6][7] Heart function, breathing, and airway reflexes generally remain functional.[5] Effects typically begin within five minutes when given by injection with the main effects lasting up to 25 minutes.[3][4]
Common side effects include psychological reactions as the medication wears off.[8] These reactions may include agitation, confusion, or hallucinations.[4][8][9] Elevated blood pressure and muscle tremors are relatively common, while low blood pressure and a decrease in breathing is less so.[4][9] Spasms of the larynx may rarely occur.[4] Ketamine has been classified as an NMDA receptor antagonist; it also acts on opioid receptors and monoamine transporters among others.[10]
Ketamine was discovered in 1962.[3] It is on the World Health Organization's List of Essential Medicines, of the most important medications needed in a basic health system.[11] It is available as a generic medication.[4] The wholesale cost in the developing world is between 0.08 and 0.32 USD per dose.[12] Ketamine is also used as a recreational drug.[13]
Contents
- 1 Uses
- 1.1 Medical
- 1.1.1 Anesthesia
- 1.1.2 Pain management
- 1.1.3 Depression
- 1.2 Recreational
- 1.1 Medical
- 2 Side effects
- 2.1 Neurological effects
- 2.2 Urinary tract effects
- 2.3 Liver problems
- 2.4 Interactions
- 3 Pharmacology
- 3.1 Pharmacodynamics
- 3.1.1 Effects in central nervous system
- 3.1.2 Effects in peripheral systems
- 3.2 Pharmacokinetics
- 3.3 Administration
- 3.1 Pharmacodynamics
- 4 Chemistry
- 4.1 Structure
- 5 History
- 5.1 Medical use
- 5.2 Nonmedical use
- 6 Society and culture
- 6.1 Legal status
- 7 Research
- 7.1 Treatment of addiction
- 8 Veterinary medicine
- 9 See also
- 10 References
- 11 External links
Uses
1000mg/10ml vial of ketamine
Medical
Anesthesia
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 painful procedures in emergency departments[5]
- 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,[14] 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 and appears to be safe in this group.[15] A 2011 clinical practice guideline supports the use of ketamine as a dissociative sedative in emergency medicine.[5] It is the drug of choice for people in traumatic shock who are at risk of hypotension.[16] Low blood pressure is harmful in people with severe head injury[17] and ketamine is least likely to cause low blood pressure, often even able to prevent it.[18][19]
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.[20] It is sometimes possible to perform ketamine anesthesia without protective measures to the airways.[citation needed] Ketamine is considered relatively safe because protective airway reflexes are preserved.[21]
Ketamine is used as a bronchodilator in the treatment of severe asthma.[22] However, evidence of clinical benefit is limited.[22][23]
Pain management
Ketamine may be used for postoperative pain management. Low doses of ketamine reduce morphine use and nausea and vomiting after surgery.[24] High quality evidence in acute pain is insufficient to determine if ketamine is useful in this situation.[25]
It may also be used as an intravenous analgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic. 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.[26] Ketamine is an analgesic that is most effective when used alongside a low-dose opioid; because, while it does have analgesic effects by itself, the doses required for adequate pain relief when it is used as the sole analgesic agent are considerably higher and far more likely to produce disorienting side effects.[26] A review article in 2013 concluded, "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".[27]
Low-dose ketamine is sometimes used in the treatment of complex regional pain syndrome (CRPS).[28] A 2013 systematic review found only low-quality evidence to support the use of ketamine for CRPS.[29]
Depression
See also: Rapid-acting antidepressant
Ketamine has been tested in treatment-resistant bipolar disorder, major depressive disorder, and people in a suicidal crisis in emergency rooms.[30] Benefit is often of a short duration.[31] The quality of the evidence supporting benefit is generally low.[31]
The drug is given by a single intravenous infusion at doses less than those used in anesthesia, and preliminary data indicate it produces a rapid (within 2 hours) and relatively sustained (about 1–2 weeks long) reduction in symptoms in some people.[32] Initial studies have resulted in interest due to its rapid onset,[33] and because it appears to work by blocking NMDA receptors for glutamate, a different mechanism from most modern antidepressants that operate on other targets.[31][34]
Recreational
Main article: Recreational use of ketamine
Ketamine poured onto glass and left to dry
Ketamine use as a recreational drug has been implicated in deaths globally, with more than 90 deaths in England and Wales in the years of 2005-2013.[35] They include accidental poisonings, drownings, traffic accidents, and suicides.[35] The majority of deaths were among young people.[36] This has led to increased regulation (e.g., upgrading ketamine from a Class C to a Class B banned substance in the U.K.).[37]
Unlike the other well-known dissociatives phencyclidine (PCP) and dextromethorphan (DXM), ketamine is very short-acting. It takes effect within about 10 minutes,[38] while its hallucinogenic effects last 60 minutes when insufflated or injected and up to two hours when ingested orally.[39]
At anaesthetic doses, under-dosaged from a medical point of view, 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.[40] At sufficiently high doses, users may experience what is called the "K-hole", a state of extreme dissociation with visual and auditory hallucinations.[41] 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.[42] Both Moore and Turner died prematurely (due to hypothermia and drowning respectively) during presumed unsupervised ketamine use.[43]
Side effects
Ketamine is generally safe for those critically ill, when administered by trained medical professionals.[44] Even in these cases, there are known side effects that include one or more of the following:[45]
- Cardiovascular: abnormal heart rhythms, slow heart rate or fast heart rate, high blood pressure or low blood pressure
- Central nervous system: Ketamine is traditionally avoided in people with or at risk of intracranial hypertension (ICP) due to concerns about ketamine causing increased intracranial pressure. It does not increase ICP more than opioids.[46]
- Dermatologic: Transient erythema, transient morbilliform rash
- Gastrointestinal: Anorexia, nausea, increased salivation, vomiting
- Local: Pain or exanthema of the injection site
- Neuromuscular and skeletal: Increased skeletal muscle tone (tonic-clonic movements)
- Ocular: Double vision, increased intraocular pressure, nystagmus, tunnel vision
- Respiratory: Airway obstruction, apnea, increased bronchial secretions, respiratory depression, laryngospasm
- Other: Anaphylaxis, dependence, emergence reaction
In 10-20% of patients at anesthetic doses experience adverse reactions that occur during emergence from anesthesia, reactions that can manifest as seriously as hallucinations and delirium.[8] These reactions may be less common in some patients subpopulations, and when administered intramuscularly, and 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, alongside a lower dose of ketamine.[8] Patients who experience severe reactions may require treatment with a small dose of a short- or ultrashort-acting barbiturate.[45]
Tonic-clonic movements are reported at higher anesthetic doses in greater than 10% of patients.[47]
Neurological effects
In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes in two small areas of the rat brain. However, the rat brain has significant differences in metabolism from the human brain, therefore such changes may not occur in humans.[48]
The first large-scale, longitudinal study of ketamine users found 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.[49]
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 noncell-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.[50][51]
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.[52] 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.[52] A study conducted on rhesus monkeys found a 24-hour intravenous infusion of ketamine caused signs of brain damage in five-day-old but not 35-day-old animals.[53] Some neonatal experts do not recommend the use of ketamine as an anesthetic agent in human neonates because of the potential adverse effects 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.[54]
The acute effects of ketamine cause cognitive impairment, including reductions in vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.[55]
Urinary tract effects
A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from ketamine recreational use.[56] 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.[56][57] 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.[58]
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 g/day reported symptoms of the lower urinary tract.[56] Urinary tract symptoms appear to be most common in daily ketamine users who have used the drug recreationally for an extended period of time.[57] These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.[57]
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.[56] 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.[56]
Liver problems
In case reports of three patients treated with esketamine 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.[59]
Interactions
Other drugs which increase blood pressure may interact with ketamine in having an additive effect on blood pressure including: stimulants, SNRI antidepressants, and MAOIs. Increase blood pressure and heart rate, palpitations, and arrhythmias may be potential effects.
Ketamine may increase the effects of other sedatives in a dose dependent manner, including, but not limited to: alcohols,[60] benzodiazepines,[61] opioids,[62] quinazolinones, phenothiazines, anticholinergics and barbiturates.[63]
Pharmacology
Pharmacodynamics
Ketamine acts primarily as an antagonist of the NMDA receptor, and this action accounts for most of its effects.[10] 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.[10]
A study conducted in mice that published in Nature in 2016 found that ketamine's antidepressant activity in mice is not caused by ketamine inhibiting NMDAR, but rather by sustained activation of a different glutamate receptor, the AMPA receptor, by a metabolite, (2R,6R)-hydroxynorketamine.[64][65]
Known actions of ketamine include:
- Non-competitive antagonist of the NMDA receptor (NMDAR)[10][66]
- Negative allosteric modulator of the nACh receptor[10]
- Weak agonist of the μ-opioid and κ-opioid receptors (10- and 20-fold less affinity relative to NMDAR, respectively),[10] and very weak agonist of the δ-opioid receptor[10]
- Agonist of the D2 receptor[67]
- Weak mACh receptor antagonist (10- to 20-fold less affinity relative to NMDAR)[10]
- Inhibitor of the reuptake of serotonin, dopamine, and norepinephrine[10]
- Voltage-gated sodium channel and L-type calcium channel blocker,[10][68] and HCN1 cation channel blocker[69]
- Inhibitor of nitric oxide synthase[10][70]
- σ receptor 1 and 2 agonist (μM affinities).[10][70][71]
- Activation of AMPA receptors[72]
Ketamine appears to inhibit the NMDAR by binding both in the open channel and at an allosteric site.[73] The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively.[74]
The significance of these additional mechanisms in the therapeutic effects of ketamine is poorly understood due to its relatively complex pharmacological profile.
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 hallucinogenic properties.[10] Dopamine reuptake inhibition is likely to underlie the euphoria the drug produces, although an additional involvement of μ-opioid receptor activation cannot be excluded.[10] The mechanisms of action for the possible antidepressant effects of ketamine at lower doses have yet to be elucidated.[75]
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.[47] Inhibition of nitric oxide synthase lowers the production of nitric oxide – a neurotransmitter involved in pain perception, hence further contributing to analgesia.[76] The action of ketamine at sigma and μ-opioid receptors is relatively weak, and evidence is mixed as to whether the latter is of significance to its analgesic effects.[10][77]
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.[47][78]
Effects in peripheral systems
Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:[76]
- 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.[10]
- Respiratory: Catecholamine elevation and stimulation of β2 adrenergic receptors probably causes bronchodilation, although other processes may also be involved. The exact mechanism is not fully understood.
Pharmacokinetics
Ketamine is absorbable by intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities.[76] 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.[79] Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine.[80] 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.[76][81] Bioavailability through the oral route reaches 17–20%; bioavailability through other routes are: 93% intramuscularly, 25–50% intranasally, 30% sublingually, and 30% rectally.[47][79] Peak plasma concentrations are reached within a minute intravenously, 5–15 min intramuscularly, and 30 min orally.[81] Ketamine's duration of action in a clinical setting is 30 min to 2 h intramuscularly and 4–6 h orally.[47]
Plasma concentrations of ketamine are increased by diazepam and other CYP3A4 inhibitors due to inhibition of conversion to norketamine.[47]
Administration
In medical settings, ketamine is usually injected intravenously or intramuscularly.[82]
Ketamine can be started using the oral route, or people may be changed from a subcutaneous infusion once pain is controlled. Bioavailability of oral ketamine hydrochloride is around 20%
- Oral ketamine is easily broken down by bile acids, thus has a low bioavailability (about 20%). Often, 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.[83]
Chemistry
Structure
In chemical structure, ketamine is an arylcyclohexylamine derivative. 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, esketamine (S-ketamine), is also available for medical use under the brand name Ketanest S,[84] while the less active enantiomer, arketamine (R-ketamine), has never been marketed as an enantiopure drug for clinical use.
-
Skeletal formula of (R)-ketamine -
Ball-and-stick model of (R)-ketamine -
Skeletal formula of (S)-ketamine -
Ball-and-stick model of (S)-ketamine
The optical rotation of a given enantiomer of ketamine can vary between its salts and free base form. The free base form of (S)‑ketamine exhibits dextrorotation and is therefore labelled (S)‑(+)‑ketamine. However, its hydrochloride salt shows levorotation and is thus labelled (S)‑(−)‑ketamine hydrochloride. The difference originates from the conformation of the cyclohexanone ring. In both the free base and the hydrochloride, the cyclohexanone ring adopts a chair conformation, but the orientation of the substituents varies. In the free base, the o-chlorophenyl group adopts an equatorial position and the methylamino group adopts an axial position.[85] In the hydrochloride salt, the positions are reversed, with the o-chlorophenyl group axial and the methylamino group equatorial.[86] Not all salts of ketamine show different optical rotation to the free base: (S)-ketamine (R,R)-tartrate is levorotatory, like (S)‑ketamine.[87]
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(S)-(−)-ketamine -
(S)-(+)-ketamine hydrochloride -
(S)-(−)-ketamine in the crystal structure of the free base -
(S)-(+)-ketamine in the crystal structure of the hydrochloride
History
Medical use
Ketamine vials
Ketamine was first synthesized in 1962 by Calvin L. Stevens, a professor of Chemistry in Wayne State University and a Parke Davis consultant conducting research on alpha-hydroxyimine rearrangements.[88] After promising preclinical research in animals, ketamine was introduced to testing in human prisoners in 1964.[89][90] These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over phencyclidine (PCP) as a dissociative anesthetic.[91] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.[92]
Nonmedical use
Main article: Recreational use of ketamine
See the foregoing discussion and citations regarding the increasing stringency of governmental regulation that has resulted from a number of deaths of youth and young adults by overdose, accident, and suicide in which nonmedical/recreational ketamine use is implicated (in the Recreational use section, above).
Nonmedical use of ketamine began on the West Coast of the United States in the early 1970s.[92] 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.[93] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.[94] 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;[95] in addition, there are reports of ketamine being sold as "ecstasy".[96] The use of ketamine as part of a "postclubbing experience" has also been documented.[97] Ketamine's rise in the dance culture was rapid in Hong Kong by the end of the 1990s.[95] 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.[89] Much of the current ketamine diverted for nonmedical use originates in China and India.[89]
In addition to its ability to cause confusion and amnesia, ketamine can leave users vulnerable to date rape (i.e., because of the associated confusion and amnesia).[38][92]
Society and culture
Legal status
Ketamine is a "core" medicine in the World Health Organization's Essential Drugs List, a list of minimum medical needs for a basic healthcare system.[98]
The increase in illicit use prompted ketamine's placement in Schedule III of the United States Controlled Substance Act in August 1999.[99]
In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[80][100] On 10 December 2013 the UK Advisory Council on the Misuse of Drugs (ACMD) recommended that the government reclassify ketamine to become a Class B drug,[101] 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".[102][103]
The UK Minister of State for Crime Prevention, Norman Baker, responding to the ACMD's advice, said the issue of its recheduling for medical and veterinary use would be addressed "separately to allow for a period of consultation."[102]
In Australia Ketamine is listed as a schedule 8 controlled drug under the Poisons Standard (October 2015).[104] A schedule 8 drug is outlined in the Poisons Act 1964 as "Substances which should be available for use but require restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence." [105]
In Canada, ketamine is classified as a Schedule I narcotic, since 2005.[106]
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.[107][108] By 2002, ketamine was classified as class III in Taiwan; given the recent rise in prevalence in East Asia, however, rescheduling into class I or II is being considered.[80][109]
In December 2013, the government of India, in response to rising recreational use and the use of ketamine as a date rape drug, has added it to Schedule X of the Drug and Cosmetics Act requiring a special license for sale and maintenance of records of all sales for two years.[110][111]
Ketamine is legally marketed in many countries worldwide, under many brand names.[112]
Research
Treatment of addiction
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.[113][114] Krupitsky and Kolp summarized their work to date in 2007.[115]
Veterinary medicine
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.[116] 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.[citation needed] It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.
See also
- Pharmacy and Pharmacology portal
- 3-HO-PCP
- 3-MeO-PCE
- 3-MeO-PCP
- 4-MeO-PCP
- 4-Chlorokynurenine
- Apimostinel (NRX-1074)
- Dextromethorphan
- Dizocilpine (MK-801)
- Lanicemine
- Memantine
- Methoxetamine
- Nitrous oxide
- Rapastinel (GLYX-13)
- Tiletamine
References
- ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 374–375. ISBN 9780071481274.
Phencyclidine (PCP or angel dust) and ketamine (also known as special K) are structurally related drugs... their reinforcing properties and risks related to compulsive abuse
- ^ Hijazi, Y; Boulieu, R (July 2002). "Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes". Drug Metabolism and Disposition. 30 (7): 853–8. doi:10.1124/dmd.30.7.853. PMID 12065445.
- ^ a b c d "Ketamine - CESAR". Center for substance abuse research. University of Maryland. Retrieved 26 September 2014.
- ^ a b c d e f "Ketamine Injection". drugs.com. Retrieved 1 December 2014.
- ^ a b c d Green, SM; Roback, MG; Kennedy, RM; Krauss, B (2011). "Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update". Annals of Emergency Medicine. 57 (5): 449–61. doi:10.1016/j.annemergmed.2010.11.030. PMID 21256625.
- ^ Zgaia, AO; Irimie, A; Sandesc, D; Vlad, C; Lisencu, C; Rogobete, A; Achimas-Cadariu, P (2015). "The role of ketamine in the treatment of chronic cancer pain.". Clujul medical (1957). 88 (4): 457–61. doi:10.15386/cjmed-500. PMC 4689236. PMID 26733743.
- ^ Zapantis, A; Leung, S (September 2005). "Tolerance and withdrawal issues with sedation.". Critical care nursing clinics of North America. 17 (3): 211–23. doi:10.1016/j.ccell.2005.04.011. PMID 16115529.
- ^ a b c d Strayer, RJ; Nelson, LS (2008). "Adverse events associated with ketamine for procedural sedation in adults". American Journal of Emergency Medicine. 26 (9): 985–1028. doi:10.1016/j.ajem.2007.12.005. PMID 19091264.
- ^ a b "Ketamine Side Effects". drugs.com. Retrieved 1 December 2014.
- ^ a b c d e f g h i j k l m n o p Kohrs, R; Durieux, ME (November 1998). "Ketamine: Teaching an old drug new tricks". Anesthesia & Analgesia. 87 (5): 1186–93. doi:10.1213/00000539-199811000-00039. PMID 9806706.
- ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ "Ketamine". Retrieved 12 January 2016.
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National Institute of Mental Health director Thomas Insel said, "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."
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- Lilly, John Cunningham (1997). The Scientist: A Metaphysical Autobiography. Berkeley, CA: Ronin. pp. 144–. ISBN 0914171720.
- Kelly, Kit (2001). The Little Book of Ketamine. Ronin. pp. 23, 40–45, 46–51, ibid. ISBN 9781579511210.
- Alltounian, Howard Sunny; Moore, Marcia (1978). Journeys Into the Bright World. Rockport, MA: Para Research. ISBN 9780914918127.
- Palmer, Cynthia; Horowitz, Michael (2000). Sisters of the Extreme: Women Writing on the Drug Experience. Inner Traditions. pp. 254–8, ibid. ISBN 9780892817573.
- Turner, D.M. (1994). The Essential Psychedelic Guide. San Francisco: Panther Press. ISBN 0964263610.
- ^ Jansen, Karl (2001). Ketamine: Dreams and Realities. Multidisciplinary Association for Psychedelic Studies. pp. 50, 89. ISBN 0966001931.
- ^ Cohen, L; Athaide, V; Wickham, ME; Doyle-Waters, MM; Rose, NG; Hohl, CM (January 2015). "The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review.". Annals of Emergency Medicine. 65 (1): 43–51.e2. doi:10.1016/j.annemergmed.2014.06.018. PMID 25064742.
- ^ a b Merck Manual; Drug Information Provided by Lexi-Comp. Last full review/revision May 2014 Ketamine
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- ^ a b Narita, M; Yoshizawa, K; Aoki, K; Takagi, M; et al. (September 2001). "A putative sigma1 receptor antagonist NE-100 attenuates the discriminative stimulus effects of ketamine in rats". Addiction Biology. 6 (4): 373–6. doi:10.1080/13556210020077091. PMID 11900615.
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- ^ "Ketamine Lifts Depression via a Byproduct of its Metabolism: NIH-funded team finds rapid-acting, non-addicting agent in mouse study".
- ^ Orser, BA; Pennefather, PS; MacDonald, JF (1997). "Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors". Anesthesiology. 86 (4): 903–17. doi:10.1097/00000542-199704000-00021. PMID 9105235.
- ^ Hirota, K; Lambert, DG (October 1996). "Ketamine: Its mechanism(s) of action and unusual clinical uses". British Journal of Anaesthesia. 77 (4): 441–4. doi:10.1093/bja/77.4.441. PMID 8942324.
- ^ Browne, CA; Lucki, I (2013). "Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants". Frontiers in Pharmacology. 4: 161. doi:10.3389/fphar.2013.00161. PMC 3873522. PMID 24409146.
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- ^ Rowland, LM (July 2005). "Subanesthetic ketamine: How it alters physiology and behavior in humans". Aviation, Space, and Environmental Medicine. 76 (Suppl 7): C52–8. PMID 16018330.
- ^ Meller, ST (December 1996). "Ketamine: Relief from chronic pain through actions at the NMDA receptor?". Pain (correspondence). 68 (2–3): 435–6. doi:10.1016/S0304-3959(96)03167-3. PMID 9121834.
- ^ a b Sinner, B; Graf, BM (2008). "Ketamine". In Schüttler, J; Schwilden, H. Modern Anesthetics. Handbook of Experimental Pharmacology. 182. pp. 313–33. ISBN 9783540728139. doi:10.1007/978-3-540-74806-9_15. PMID 18175098.
- ^ a b c Li, JH; Vicknasingam, B; Cheung, YW; Zhou, W; et al. (2011). "To use or not to use: An update on licit and illicit ketamine use". Substance Abuse and Rehabilitation. 2 (1): 11–20. doi:10.2147/SAR.S15458. PMC 3846302. PMID 24474851.
- ^ a b Haas, DA; Harper, DG (1992). "Ketamine: A review of its pharmacologic properties and use in ambulatory anesthesia". Anesthesia Progress. 39 (3): 61–8. PMC 2148758. PMID 1308374.
- ^ Lankenau, SE; Sanders, B; Bloom, JJ; Hathazi, D; et al. (March 2007). "First injection of ketamine among young injection drug users (IDUs) in three U.S. cities". Drug and Alcohol Dependence. 87 (2–3): 183–93. doi:10.1016/j.drugalcdep.2006.08.015. PMC 1852477. PMID 16979848.
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- ^ Krüger, AD (1998). "Current aspects of using ketamine in childhood". Anaesthesiologie und Reanimation (in German). 23 (3): 64–71. PMID 9707751.
- ^ Chankvetadze, Bezhan; Burjanadze, Naira; Breitkreutz, Jörg; Bergander, Klaus; Bergenthal, Dieter; Kataeva, Olga; Fröhlich, Roland; Luftmann, Heinrich; Blaschke, Gottfried (2002). "Mechanistic study on the opposite migration order of the enantiomers of ketamine with α- and β-cyclodextrin in capillary electrophoresis". J. Sep. Sci. 25: 1155–1166. doi:10.1002/1615-9314(20021101)25:15/17<1155::AID-JSSC1155>3.0.CO;2-M.
- ^ Hakey, P.; Ouellette, W.; Zubieta, J.; Korter, T. (2008). "(S)-(+)-Ketamine hydrochloride". Acta Crystallogr. E. 64: o1487. doi:10.1107/S1600536808021053.
- ^ Ratti-Mobery, Enrica; Groth, Per; Aasen, Arne Jørgen (1991). "The Absolute Configuration of Ketamine – A General Anaesthetic. The Crystal Structure of the (R,R)-Tartrate Salt of (−)-(S)-Ketamine". Acta Chem. Scand. 45: 108–110. doi:10.3891/acta.chem.scand.45-0108.
- ^ Clark, Michael R. (2011). Chronic Pain and Addiction. Basel, Zwitzerland: Karger AG. pp. 166–. ISBN 3805597258.
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- ^ Domino, EF (September 2010). "Taming the ketamine tiger". Anesthesiology. 113 (3): 678–84. doi:10.1097/ALN.0b013e3181ed09a2. PMID 20693870.
- ^ Corssen, G; Domino, EF (January–February 1966). "Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581". Anesthesia & Analgesia. 45 (1): 29–40. doi:10.1213/00000539-196601000-00007. PMID 5325977.
- ^ a b c "Ketamine". Center for Substance Abuse Research (CESAR); University of Maryland, College Park. 29 October 2013. Archived from the original on 2013-11-12. Retrieved 27 July 2014.
- ^ History of non-medical use in literature references:
- Alltounian & Moore 1978
- Palmer & Horowitz 2000
- Kelly 2001
- ^ Increased non-medical use references:
- Awuonda, M (13 July 1996). "Swedes alarmed at ketamine misuse". The Lancet. 348 (9020): 122. doi:10.1016/S0140-6736(05)64628-4.
- Curran, HV; Morgan, C (April 2000). "Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later". Addiction. 95 (4): 575–90. doi:10.1046/j.1360-0443.2000.9545759.x. PMID 10829333.
- Gahlinger, PM (1 June 2004). "Club drugs: MDMA, gamma-hydroxybutyrate (GHB), Rohypnol, and ketamine". American Family Physician. 69 (11): 2619–26. PMID 15202696.
- Jansen, KL (6 March 1993). "Non-medical use of ketamine". BMJ. 306 (6878): 601–2. doi:10.1136/bmj.306.6878.601. PMC 1676978. PMID 8461808.
- Joe-Laider & Hunt 2008
- ^ a b Joe-Laidler, K; Hunt, G (1 June 2008). "Sit down to float: The cultural meaning of ketamine use in Hong Kong". Addiction Research & Theory. 16 (3): 259–71. doi:10.1080/16066350801983673. PMC 2744071. PMID 19759834.
- ^ Ketamine sold as "ecstasy" references:
- Tanner-Smith, EE (July 2006). "Pharmacological content of tablets sold as "ecstasy": Results from an online testing service" (PDF). Drug and Alcohol Dependence. 83 (3): 247–54. doi:10.1016/j.drugalcdep.2005.11.016. PMID 16364567.
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- ^ WHO Model List of Essential Medicines (PDF) (18th ed.). World Health Organization. October 2013 [April 2013]. p. 1 [p. 5 of pdf]. Retrieved 22 April 2014.
- ^ Marshall, Donnie R.; (Deputy Administrator); Drug Enforcement Administration; Dept. of Justice (13 July 1999). "Schedules of Controlled Substances: Placement of Ketamine into Schedule III [21 CFR Part 1308. Final Rule 99-17803]" (PDF). Rules and Regulations. Federal Register. 64 (133): 37673–5.
- ^ "Club 'horse' drug to be outlawed". BBC News. 28 December 2005. Archived from the original on 2009-09-03. Retrieved 7 May 2010.
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- ^ Dixon, Hayley (12 February 2014). "Party drug ketamine to be upgraded to Class B". The Daily Telegraph. Retrieved 2 August 2014.
- ^ Poisons Standard October 2015 https://www.comlaw.gov.au/Details/F2015L01534
- ^ Poisons Act 1964 http://www.slp.wa.gov.au/pco/prod/FileStore.nsf/Documents/MRDocument:26063P/$FILE/Poisons%20Act%201964%20-%20%5B09-f0-04%5D.pdf?OpenElement
- ^ Legal status of ketamine in Canada references:
- "Statutes of Canada (S.C.)". Justice Laws Website. Government of Canada. 12 June 2014. Missing or empty
|url=(help);|chapter=ignored (help) - "Order Amending Schedule I to the Controlled Drugs and Substances Act" (PDF). Canada Gazette Part II. 139 (19). 21 September 2005. p. 2130. Retrieved 2 August 2014.
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- ^ Ho Wai-kin, Victor (2011). Criminal Law in Hong Kong. Kluwer Law International. p. 33. ISBN 9789041133069.
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- ^ Deb Roy, Sumitra (30 December 2013). "Govt makes notorious 'date rape' drug ketamine harder to buy or sell". The Times of India. Archived from the original on 2013-12-30.
- ^ Drugs.com International brands of ketamine Page accessed May 14, 2016
- ^ Krupitsky, EM; Grineko, AYa; Berkaliev, TN; Paley, AI; et al. (1992). "The combination of psychedelic and aversive approaches in alcoholism treatment". Alcoholism Treatment Quarterly. 9 (1): 99–105. doi:10.1300/J020V09N01_09.
- ^ Krupitsky, EM; Grinenko, AY (1997). "Ketamine psychedelic therapy (KPT): A review of the results of ten years of research". Journal of Psychoactive Drugs. 29 (2): 165–83. doi:10.1080/02791072.1997.10400185. PMID 9250944.
- ^ Krupitsky, Evgeny; Kolp, Eli. "Ch. 6: Ketamine Psychedelic Psychotherapy". In Winkelman, Michael J.; Roberts, Thomas B. Psychedelic Medicine: New Evidence for Hallucinogens as Treatments. Vol. 2. Westport, CT: Praeger. ISBN 9780275990237.
- ^ STANDARD OPERATING PROCEDURE NO. 1 ANESTHESIA AND ANALGESIA IN RODENTS, Washington College, 2012, pp. 1–2, retrieved 27 November 2015
External links
| Wikimedia Commons has media related to Ketamine. |
- Ketamine on RxList
- DEA: Ketamine Fact Sheet
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UpToDate Contents
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- 1. 手術室外での小児への迅速導入気管挿管（RSI）：鎮静薬と筋弛緩薬 rapid sequence intubation rsi outside of the operating room in children medications for sedation and paralysis
- 2. ケタミン中毒 ketamine poisoning
- 3. 成人における選択的脊椎手術のための麻酔 anesthesia for elective spine surgery in adults
- 4. 成人における確定診断を得られていない低血圧やショックの評価および初期アプローチ evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock
- 5. 成人における単極性うつ病：重度の難治性（再発性）うつ病のマネージメント unipolar depression in adults management of highly resistant refractory depression
English Journal
- Reliability, convergent and structural validity and cut-off score of the Severity of Dependence Scale for recreational ketamine users.
- Fernández-Calderón F1, Vidal-Giné C2, López-Guerrero J2, Lozano-Rojas ÓM3.
- Addictive behaviors.Addict Behav.2016 Sep;60:1-7. doi: 10.1016/j.addbeh.2016.03.016. Epub 2016 Apr 6.
- BACKGROUND AND AIMS: There is a lack of instruments for measuring ketamine substance use disorders. The aims were (i) to estimate the reliability and provide evidence of validity of the Severity of Dependence Scale (SDS) in a sample of recreational users, and (ii) propose a cut-off point to determin
- PMID 27082261
- Different dosing regimens of repeated ketamine administration have opposite effects on novelty processing in rats.
- Schumacher A1, Sivanandan B1, Tolledo EC1, Woldegabriel J1, Ito R2.
- Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2016 Aug 1;69:1-10. doi: 10.1016/j.pnpbp.2016.03.007. Epub 2016 Apr 8.
- Repeated exposure to sub-anesthetic doses of ketamine in rats has been shown to induce cognitive deficits, as well as behavioral changes akin to the negative symptoms of schizophrenia, giving much face validity to the use of ketamine administration as a pharmacological model of schizophrenia. This s
- PMID 27064663
- Variability in the effect of antidepressants upon Wfs1-deficient mice is dependent on the drugs' mechanism of actions.
- Reimets R1, Raud S2, Loomets M2, Visnapuu T2, Volke V3, Reimets A2, Plaas M2, Vasar E2.
- Behavioural brain research.Behav Brain Res.2016 Jul 15;308:53-63. doi: 10.1016/j.bbr.2016.04.011. Epub 2016 Apr 11.
- There is significant comorbidity between mood disorders and diabetes. Wolfram syndrome-related to deficient WFS1 gene function-causes diabetes and mood disorders in humans. Mice lacking the Wfs1 gene display impaired emotional behaviour and glucose metabolism. Various antidepressant drugs are used f
- PMID 27080063
Japanese Journal
- 麻酔薬ケタラールを用いたイノシシ(イノブタ)の不動化について(2)
- 井原 正昭,井原 一恵
- 清和大学短期大学部紀要 (38), 37-39, 2009
- NAID 40017115027
- 麻酔薬ケタラールを用いたイノシシ(イノブタ)の不動化について
- 井原 正昭,井原 一恵
- 清和大学短期大学部紀要 37, 29-32, 2008
- NAID 110007325007
- <Originals>Phase relationship of the slow wave and the superposing spike wave in cat ketamine EEG burst
- TOKUNO Tatsuya,ASAI Toshiharu,CHIBA Atsushi,CHICHIBU Shiko,SHIMADA Youichi
- Acta medica Kinki University 14(2), 267-273, 1989-12
- … Cats were anesthetized with veterinary ketalar ranging in amounts of 50-110 mg/kg. …
- NAID 110000007081
Related Pictures
★リンクテーブル★
| リンク元 | 「ケタミン」 |
「ケタミン」
分類
-
- 解離性静脈麻酔薬
概念
- 中枢神経に作用して、意識消失、鎮痛作用をもたらす
- 大脳皮質や視床を抑制する(体性知覚抑制)
- 大脳辺縁系・網様体賦活系は活性化(向精神作用)
- そのため、覚醒時に不快な夢や幻覚を伴う
- 呼吸抑制が弱い(小児検査麻酔にも筋肉内注射で使用される)
- 血圧を上昇させることから、ハイリスク患者の麻酔導入や喘息患者の麻酔導入で使用される
- カタレプシ様。目は半開き。→独特の顔貌を呈する
- ○：注射できる(筋肉注射)。呼吸抑制がない。強力な鎮痛作用
- ×：精神症状出現。唾液分泌亢進。血圧↑。心拍↑。肺動脈圧↑。脳内圧↑。
薬理作用
- 催眠作用、鎮痛作用
注意
- 頭蓋内圧が上昇するため、脳外科の手術には推奨されない
相互作用
添付文書
- ケタラール静注用５０ｍｇ／ケタラール静注用２００ｍｇ