Ketamine

Ketamine
Ketamine, sold under the brand name Ketalar among others, is a

Ketamine
medication mainly used for starting and maintaining anesthesia.[16]
It induces a trance-like state while providing pain relief, sedation,
and memory loss.[17] Other uses include for chronic pain and for
sedation in intensive care.[18][19] Heart function, breathing, and
airway reflexes generally remain functional during its effects.[17]
Effects typically begin within five minutes when given by injection
with the main effects lasting up to 25 minutes.[20][16]
Common side effects include psychological reactions as the

medication wears off.[21] These reactions may include agitation,
confusion, or hallucinations.[16][21][22] Elevated blood pressure and
muscle tremors are relatively common, whilelow blood pressure and
a decrease in breathing are less so.[16][22] Spasms of the larynx may
rarely occur.[16] Ketamine has been classified as an NMDA receptor
antagonist but its mechanisms are not well understood as of
2017.[23]
Ketamine was discovered in 1962, first tested in humans in 1964,

and was approved for use in the United States in 1970.[20][24]
Shortly after its US approval it was extensively used for surgical
anesthesia in the Vietnam War, due to its safety.[24] It is on the
Clinical data
World Health Organization's List of Essential Medicines, the most
effective and safe medicines needed in a health system.[25] It is Trade names Ketalar, others
available as a generic medication.[16] The wholesale cost in the Synonyms CI-581; CL-369; CM-52372-2[6]
developing world is between US$0.08 and US$0.32 per dose.[26] AHFS/Drugs.com Consumer Drug Information
Ketamine is also used as arecreational drug.[27]
License data US FDA: Ketamine
Pregnancy AU: B3
category
Contents US: C (Risk not ruled out)
Medical uses Addiction Low–moderate[1]

Anesthesia liability
Pain management
Depression
Routes of IV, IM, IT,[2] insufflation, by
administration mouth, sublingual, SC,
Contraindications
epidural,[3] intraosseous,
Side effects
intranasal, topical,
Neurological
Urinary tract
transdermal[4][5]
Liver Drug class NMDA receptor antagonists;
Interactions General anesthetics;
Pharmacology Dissociative hallucinogens;
Pharmacodynamics Analgesics; Antidepressants
Pharmacokinetics ATC code N01AX03 (WHO)
Chemistry
Structure
Legal status
Analogues Legal status AU: S8 (Controlled)
History CA: Schedule I

Medical use
UK: Class B
Nonmedical use
US: Schedule III
Society and culture
Generic names UN: Unscheduled
Brand names
Legal status
Pharmacokinetic data
Recreational use Bioavailability • Intravenous: 100%[4]
Clinics • Intramuscular: 93%[4]
Research • Subcutaneous: high[8]
Veterinary medicine • Epidural: 77%[9]
References • Intranasal: 25–50%[4][10]
• Sublingual: 30%[4]
External links
• Rectal: 30%[11]
• By mouth: 16–24%[9][12]
Medical uses Protein binding 12–47% (low)[10][13][9]

Metabolism Liver (N-demethylation):[4][7]
• Major: CYP3A4
Anesthesia • Minor: CYP2B6, CYP2C9
Metabolites • Norketamine
• Dehydronorketamine
• Hydroxynorketamine
• Conjugates[14]
Onset of action • Intravenous: seconds[10]
• Intramuscular: 1–5 min[10][15]
• Subcutaneous: 15–30 min[15]
• Insufflation: 5–10 min[10]
A 1000 mg/10 mL vial of ketamine.
• By mouth: 15–30 min[10][15]
Biological half- • Ketamine: 2.5–3 hours[10][4]
Uses as an anesthetic:[28] life • Norketamine: 12 hours[15]
Anesthesia in children, as the sole anesthetic for minor Duration of • Intramuscular: 0.5–2 hours[15]
procedures or as an induction agent followed bymuscle action
relaxant and tracheal intubation
• Insufflation: 45–60 min[10]
Asthmatics or people with chronic obstructive airway • By mouth: 1–6+ hours[15][10]
disease Excretion • Urine: 91%[4]
As a sedative for physically painful procedures in
• Feces: 1–3%[4]
emergency departments[17]
Emergency surgery in field conditions in war zones Identifiers
To supplement spinal or epidural anesthesia/analgesia IUPAC name
using low doses
(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
Since it suppresses breathing much less than most other available
anesthetics,[29] ketamine is used in medicine as an anesthetic; CAS Number 6740-88-1
however, due to the hallucinations it may cause, it is not typically 1867-66-9 (hydrochloride)
used as a primary anesthetic, although it is the anesthetic of choice 33643-46-8 (esketamine)
when reliable ventilation equipment is not available. 33643-49-1 (arketamine)
PubChem CID 3821
Ketamine is frequently used in severely injured people and appears
to be safe in this group.[30] A 2011 clinical practice guideline IUPHAR/BPS 4233
supports the use of ketamine as a dissociative sedative in emergency
DrugBank DB01221
medicine.[17] It is the drug of choice for people in traumatic shock ChemSpider 3689
who are at risk of hypotension.[31] Low blood pressure is harmful in
UNII 690G0D6V8H
people with severe head injury[32] and ketamine is least likely to
[33][34]
cause low blood pressure, often even able to prevent it. KEGG D08098
The effect of ketamine on the respiratory and circulatory systems is ChEBI CHEBI:6121
different from that of other anesthetics. When used at anesthetic ChEMBL CHEMBL742
doses, it will usually stimulate rather than depress the circulatory
ECHA InfoCard 100.027.095
system.[35] It is sometimes possible to perform ketamine anesthesia
without protective measures to the airways. Ketamine is considered Chemical and physical data
[36]
relatively safe because protective airway reflexes are preserved. Formula C13H16ClNO
Molar mass 237.725 g/mol
Ketamine is used as a bronchodilator in the treatment of severe
asthma.[37] However, evidence of clinical benefit is limited.[37][38] 3D model Interactive image
(JSmol)
Chirality Racemic mixture:[10]
Pain management • Esketamine (S(+)-isomer)
Ketamine may be used for postoperative pain management. Low • Arketamine (R(−)-isomer)
doses of ketamine may reduce morphine use, nausea, and vomiting Melting point 258 to 261 °C (496 to 502 °F)
after surgery.[39][40]
SMILES
CNC1(C2=CC=CC=C2Cl)CCCCC1=O
It may also be used as an intravenous analgesic with opiates to
manage otherwise intractable pain, particularly if this pain is InChI
InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-
neuropathic. It has the added benefit of counteracting spinal
11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3
sensitization or wind-up phenomena experienced with chronic pain. Key:YQEZLKZALYSWHR-UHFFFAOYSA-N
At these doses, the psychotropic side effects are less apparent and
(verify)
well managed with benzodiazepines.[41] 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.[41] A review article in 2013 concluded, "despite limitations in the breadth and depth of data available, there
[42]
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).[43] A 2013 systematic review
[44]
found only low-quality evidence to support the use of ketamine for CRPS.
Depression
Ketamine has been tested as a rapid-acting antidepressant[45] for treatment-resistant depression in bipolar disorder, and major
depressive disorder.[46] Ketamine's antidepressant effect has a short duration of action.[47] Meta-analyses have shown overwhelming
clinical evidence to support the acute efficacy of ketamine in severely unwell populations, but a lack of data on optimal dosing and
the effect of long-term treatment.[47][48] Currently, ketamine is not approved for the treatment of depression, and so this is an off-
label use. As of June 2017, esketamine, the S(+) enantiomer of ketamine, is in phase III clinical trials for intranasal treatment of
depression.[49][50]
Ketamine 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.[51] Initial
studies have resulted in interest due to its rapid onset,[52] and because it appears to work by blocking NMDA receptors for glutamate,
a different mechanism from most modern antidepressants that operate onother targets.[53]
Contraindications
[54][5]
The use of ketamine is cautioned against in cases of:
Conditions worsened by an increase in blood pressure or heart rate, such as angina, stroke, poorly controlled high
blood pressure, etc. as ketamine increases both heart rate and blood pressure.
Psychiatric disorders. Ketamine can cause hallucinations, so it can exacerbate the symptoms of certain psychiatric
disorders.
Raised intracranial pressure (ICP). Ketamine can further increase ICP .
Raised intraocular pressure (IOP). Ketamine can also increase IOP .
Penetrating eye injury. Can increase risk of loss of eye contents, due to increased IOP .
Acute porphyria. Ketamine is considered porphyrinogenic, that is, it may provoke an attack of acute porphyria in
susceptible persons.
Side effects
Ketamine is generally safe for those critically ill, when administered by trained medical professionals.[55] Even in these cases, there
are known side effects that include one or more of the following:[56]
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.[57]
Dermatologic: Transient reddening of the skin, transient measles-like rash
Gastrointestinal: reduced appetite, nausea, increased salivation, vomiting
Local: Pain, eruptions or rashes at the injection site
Neuromuscular and skeletal: Increased skeletal muscle tone (tonic-clonic movements)
Ocular: Double vision, increased intraocular pressure, involuntary eye movements, tunnel vision
Respiratory: Airway obstruction,cessation of breathing, increased bronchial secretions, reduced effort to breathe,
spasm of the vocal cords (larynx)
Other: Anaphylaxis, dependence, emergence reaction
At anesthetic doses, 10–20% of people experience adverse reactions that occur during emergence from anesthesia, reactions that can
manifest as seriously as hallucinations and delirium.[21] These reactions may be less common in some people 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 person during recovery and pretreating with a benzodiazepine, alongside a lower dose of ketamine.[21]
barbiturate.[56]
People who experience severe reactions may require treatment with a small dose of a short- or ultrashort-acting
[15]
Tonic-clonic movements are reported at higher anesthetic doses in greater than 10% of people.
Neurological
In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes, known as Olney's lesions, 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.[58]
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
[59]
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 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.[60][61]
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.[62] 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.[62] 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.[63]
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
[64]
other drugs that share the same mechanism of action of NMDA receptor antagonism as ketamine.
The acute effects of ketamine cause cognitive impairment, including reductions in vigilance, verbal fluency, short-term memory, and
[65]
executive function, as well as schizophrenia-like perceptual changes.
Urinary tract
A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from ketamine recreational use.[66] 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 blood in
urine. Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases.[66][67] The pathogenesis of
papillary necrosis has been investigated in mice, and mononuclear inflammatory infiltration in the renal papilla resulting from
[68]
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 g/day reported symptoms of the lower urinary tract.[66] Urinary tract
symptoms appear to be most common in daily ketamine users who have used the drug recreationally for an extended period of
time.[67] These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the
symptoms remitted.[67]
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.[66] Both hyaluronic acid instillation and
combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some people, 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.[66]
Liver
In case reports of three people 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
[69]
cessation of the drug. The result suggests liver enzymes must be monitored during such treatment.
Interactions
Plasma concentrations of ketamine are increased by CYP3A4 inhibitors (e.g., diazepam) and CYP2B6 inhibitors (e.g., orphenadrine)
due to inhibition of its metabolism.[15][70] CYP2B6 and CYP3A4 inducers like carbamazepine, phenobarbital, phenytoin, and
rifampicin may reduce plasma levels of ketamine.[70]
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: alcohol,[71]
benzodiazepines,[72] opioids,[73] quinazolinones, phenothiazines, anticholinergics, and barbiturates.[74]
Benzodiazepines may diminish the antidepressant effects of ketamine.[70] Most conventional antidepressants can likely be combined
fectiveness or increased side effects.[70]
with ketamine without diminished antidepressant ef
Pharmacology
Pharmacodynamics
Ketamine acts as a selective antagonist of the NMDA receptor, an ionotropic glutamate receptor.[23] It binds specifically to the
dizocilpine (MK-801) site of the NMDA receptor, near the channel pore, and is an uncompetitive antagonist.[78] Ketamine may also
interact with and inhibit the NMDAR via another allosteric site on the receptor.[94] Its full mechanism of action is not well-
understood as of 2017.[23]
A study conducted in mice found that ketamine's antidepressant activity is not caused by ketamine inhibiting the NMDA receptor, but
rather by sustained indirect/downstream activation of another type of ionotropic glutamate receptor, the AMPA receptor, by a
metabolite, (2R,6R)-hydroxynorketamine; as of 2017 it is unknown if this is the case in humans.[23][95] Arketamine is also an
indirect/downstream AMPA receptor activator.[96]
Activity profile
Known actions of ketamine include:
Uncompetitive antagonist(channel pore blocker) of theNMDA receptor[97][98]

Indirect/downstream activation of AMPA receptors[99]
Ligand of the μ-, κ-, and δ-opioid receptors[97]
Sigma σ1 and σ2 receptor agonist[97][100][101]
Partial agonist of the high-affinity state of the dopamine D2 receptor[83][85]
Ligand of the serotonin 5-HT2A receptor[83]
Potentiator of the serotonin 5-HT3 receptor[87][88]
Muscarinic acetylcholine receptorantagonist[4][97]
Negative allosteric modulatorof nicotinic acetylcholine receptors(e.g., α7, α4β2)[4][97]
Inhibitor of cholinesterase[4]
Inhibitor of the reuptake of serotonin, norepinephrine, and dopamine[97]
Ligand of the PCP site 2[92]
Blocker of voltage-gated/dependent sodiumand calcium channels[97][102]
Blocker of HCN1 cation channels[93][103]
Inhibitor of nitric oxide synthase[97][100]
With the exception of partial agonism of the high-affinity state of the D2 receptor (and indirect/downstream activation of AMPA
receptors), all of these actions are far weaker than ketamine's antagonism of the NMDA receptor (see table to the right; minimum of
more than 10-fold selectivity for the NMDA receptor relative to the site with the next highest affinity).[4][104] A binding study
assessed ketamine at 56 sites including neurotransmitter receptors and transporters and found that ketamine had Ki values of
>10,000 nM at all sites except the dizocilpine site of the NMDA receptor (Ki = 659 nM), indicating a minimum of 15-fold selectivity
for the NMDA receptor over any other site.[78]
The S(+) and R(–) stereoisomers of ketamine bind to
the dizocilpine site of the NMDA receptor with Ketamine[75][4][76]
different affinities, the former showing approximately Site Value (μM) Type Action Species Ref
2- to 3-fold greater affinity for the receptor than the Ki [77][78]
NMDA 0.25–0.66
latter.[89] Antagonist Human [77]
(PCP) 0.35 IC50
[76]
Although ketamine is a very weak ligand of the GABAA IA ND ND ND
monoamine transporters (Ki > 60,000 nM), it has MOR 26–42.1 Ki Antagonist? Various [4][79]
been suggested that it may interact with allosteric [80]

MOR2 12.1 Ki Antagonist Human
sites on the monoamine transporters to produce
Ki [4][79]
monoamine reuptake inhibition.[78] However, no DOR 66.0–272 ND Various
functional inhibition (IC50) of the human monoamine KOR 28.1–85.2 Ki ND Various [4][79]
transporters has been observed with ketamine or its [79]

NOP IA ND ND Human
metabolites at concentrations of up to
[81][76][78]
10,000 nM.[82][105] Moreover, animal studies and at σ1 66.0–140 Ki Agonist Rat
least three human case reports have found no σ2 26.3 Ki Agonist? Rat [81][78]
interaction between ketamine and the monoamine [78][82]

D2 >10 Ki ND Human
oxidase inhibitor (MAOI) tranylcypromine.[106][107]
0.5 Ki Human [83][84]
Collectively, these findings shed doubt on the D High Agonist
2 1.03 EC50 Rat [85]
involvement of monoamine reuptake inhibition in the
[78]
effects of ketamine in humans.[106][105][82][107] 5-HT2A >10 Ki ND Human
Ketamine has been found to increase dopaminergic 5-HT Hi ≥15 Ki Agonist? Rat [83][86]
2A
neurotransmission in the brain, but instead of due to
5-HT3 96.9 Ki Potentiator Mouse [87][88]
dopamine reuptake inhibition, this may be via
indirect/downstream mechanisms, namely through M1 45 Ki Antagonist Human [4][89]
antagonism of the NMDA receptor.[105][82] M2 Ki [4][89]

294 Antagonist Human
Metabolites of ketamine including M3 246 Ki Antagonist Human [4][89]
dehydronorketamine, hydroxynorketamine, and IC50 [4]

α7 20 Antagonist Human
norketamine have been found to act as negative
α4β2 50 IC50 Antagonist Human [4]
allosteric modulators of the α7 nicotinic acetylcholine
receptor in the KXa7R1 cell line (HEK293 cells ChE 494 Ki Inhibitor Human [4]
transfected with rat nicotinic acetylcholine receptor Ki [78]

>10 Human
genes) with subanesthetic and nanomolar potencies SERT 162 Ki Inhibitor Rat [90][91]
>10 IC50 Human [82]
(e.g., IC50 = 55 nM for dehydronorketamine),
whereas ketamine itself was inactive at the same Ki [90][91][78]
66.8 Human
NET Inhibitor
concentrations (< 1 µM).[108] These findings suggest >10 IC50 Human [82]
that metabolites may contribute importantly to the [78]

>10 Ki Human
pharmacodynamics of ketamine by means other than DAT 62.9 Ki Inhibitor Rat [90][91]
NMDA receptor antagonism.[108] >10 IC50 Human [82]
[92]
Ketamine has been found to act as a potent partial PCP2 59.4 Ki ND Human
agonist of the high-affinity state of the human and rat VGSC mM IC50 Inhibitor Human [89]
dopamine D2 receptors in multiple studies.[83][84][85] [89]

VDCC 209 IC50 Inhibitor Human
Its apparent potency for this action is similar to that of
EC50 [93]
its NMDA receptor antagonism.[83][84][85] However, HCN1 8–16 Inhibitor Mouse
there are also contradictory data, with studies finding The smaller the value, the stronger the interaction with the site.
an affinity of ketamine of >10,000 nM for the regular
human and rat D2 receptors,[78][82][109] and direct interactions with the D2 receptor are controversial.[110] Moreover, whereas D2
receptor agonists like bromocriptine are able to rapidly and powerfully suppress prolactin secretion,[111] subanesthetic doses of
ketamine have not been found to do this in humans and in fact have been found to significantly and dose-dependently increase
prolactin levels.[112][113] Imaging studies have shown mixed results on inhibition of striatal [11C] raclopride binding by ketamine in
humans, with some studies finding a significant decrease and others finding no such effect.[114] However, changes in [11C]raclopride
binding may be due to changes in dopamine concentrations induced by ketamine rather than binding of ketamine to the D2
receptor.[114]
Effects in the brain and the body

Antagonism of the NMDA receptor is thought to be responsible for the anesthetic, amnesic, dissociative, and hallucinogenic effects
of ketamine.[97] The mechanism(s) of action for the antidepressant effects of ketamine at lower doses have yet to be fully
elucidated.[115] NMDA receptor 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.[15] Inhibition of nitric oxide synthase lowers the
[116]
production of nitric oxide – a gasotransmitter involved in pain perception, hence further contributing to analgesia.
Ketamine produces measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory
systems:[116]
Cardiovascular: Ketamine stimulates thesympathetic nervous system, resulting in cardiovascular changes.

[97][84]
Gastrointestinal: Ketamine produces nausea and vomiting in 15 to 25% of individuals at anesthetic doses.
Respiratory: Ketamine causesbronchodilation.[117] Several mechanisms have been hypothesized to explain this
effect.[117]
The exact mechanisms of these effects are not fully understood.
Relationship between concentrations and effects

Drowsiness, dissociation, and psychosis-like effects (e.g., hallucinations, delirium) are reported in patients treated with ketamine
starting at circulating concentrations of around 50 to 200 ng/mL (210–841 nM), while analgesia begins at levels of approximately
100 to 200 ng/mL (421–841 nM).[118][10] The typical intravenous antidepressant dosage of ketamine used to treat depression is low
and results in maximal plasma concentrations of 70 to 200 ng/mL (294–841 nM).[119] Circulating concentrations of around 2,000 to
3,000 ng/mL (8,413–12,620 nM) are employed during anesthesia, and patients may start to awaken once levels of ketamine have
decreased to about 500 to 1,000 ng/mL (2,103–4,207 nM).[118][10] There is wide variation in the peak concentrations of ketamine
that have been reported in association with anesthesia in the literature, with values ranging from 2,211–3,447 ng/mL (9,300–
14,500 nM) to as high as 22,370 ng/mL (94,100 nM).[79][83] Bioactive concentrations of ketamine are lower than total plasma levels
due to plasma protein binding,[79] although plasma protein binding is relatively low with ketamine (approximately 12 to 47% protein-
bound).[13] Concentrations of ketamine in thebrain have been reported to be several-fold higher than in plasma.
[83]
Pharmacokinetics
In medical settings, ketamine is usually injected intravenously or intramuscularly.[120] Ketamine can be started using the oral route,
or people may be changed from a subcutaneous infusion once pain is controlled. Oral ketamine is easily broken down by bile acids,
thus has a low bioavailability. 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
[121]
given. Others gradually reduce the infusion dose as the oral dose is increased.
Ketamine is absorbable by intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities.[116] 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.[10] 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.[122] As
the major metabolite of ketamine, norketamine is one-third to one-fifth as potent as an anesthetic, and plasma levels of this metabolite
are three times higher than ketamine following oral administration.[116][123] Bioavailability through the oral route reaches 17–20%;
bioavailability through other routes are: 93% intramuscularly, 25–50% intranasally, 30% sublingually, and 30% rectally.[15][10] Peak
plasma concentrations are reached within a minute intravenously, 5–15 min intramuscularly, and 30 min orally.[123] Ketamine's
.[15]
duration of action in a clinical setting is 30 min to 2 h intramuscularly and 4–6 h orally
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,[124] while the less active enantiomer, arketamine (R-ketamine), has never been marketed as an enantiopure drug for
clinical use.
Skeletal formula of (R)- Ball-and-stick model of Skeletal formula of (S)- Ball-and-stick model of
ketamine (R)-ketamine ketamine (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.[125] In the hydrochloride salt, the positions are reversed, with the o-chlorophenyl group axial and the methylamino group
equatorial.[126] Not all salts of ketamine show different optical rotation to the free base: (S)-ketamine (R,R)-tartrate is levorotatory,
like (S)‑ketamine.[127]
(S)-(−)-ketamine (S)-(+)-ketamine (S)-(−)-ketamine in the (S)-(+)-ketamine in the

hydrochloride crystal structure of the crystal structure of the
free base hydrochloride
Analogues
Other arylcyclohexylamines and analogues of ketamine include eticyclidine (PCE), 3-MeO-PCE, methoxetamine (MXE), tiletamine,
phencyclidine (PCP), tenocyclidine (TCP), and many others.[128]
History
Medical use
Ketamine was first synthesized in 1962 by Calvin L. Stevens, a
professor of Chemistry at Wayne State University and a Parke
Davis consultant conducting research on alpha-hydroxyimine
rearrangements.[129] After promising preclinical research in
animals, ketamine was introduced to testing in human prisoners
in 1964.[24][130] 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.[131] Following FDA approval in 1970, ketamine
anesthesia was first given to American soldiers during the
Vietnam War.[132] Ketamine and other arylcyclohexylamines.
Nonmedical use
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.[132] Early use was documented in underground literature such as The
Fabulous Furry Freak Brothers. It was used in psychiatric and other academic
Ketamine vials.
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.[134] The incidence of nonmedical ketamine use increased through the
end of the century, especially in the context ofraves and other parties.[135] 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;[136] in
addition, there are reports of ketamine being sold as "ecstasy".[137] The use of
ketamine as part of a "postclubbing experience" has also been documented.[138]
Ketamine's rise in the dance culture was rapid in Hong Kong by the end of the
1990s.[136] 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.[130]
Much of the current ketamine diverted for nonmedical use originates in China and
India.[130]
Society and culture

"Just Say Neigh" T-shirts making
Generic names reference to ketamine became
popular in the late 2000s, parodying
Ketamine is the English generic name of the drug and its INN and BAN, while the Just Say No campaign and
ketamine hydrochloride is its USAN, USP, BANM, and JAN.[139][140][6] Its generic ketamine's reputation as a drug for
name in Spanish and Italian and its DCIT are ketamina, in French and its DCF are horses.[133]
kétamine, in German is ketamin, and in Latin is ketaminum.[140]
The S(+) stereoisomer of ketamine is known asesketamine, and this is its BAN while esketamine hydrochloride is its BANM.[141]
Brand names
Ketamine is primarily sold throughout the world under the brand name Ketalar.[140][6] It is also marketed under a variety of other
brand names, including Calypsol, Ketamin, Ketamina, Ketamine, Ketaminol, Ketanest, Ketaset, Tekam, and Vetalar among
others.[140][6]
[141]
Esketamine is sold mainly under the brand names Ketanest and Ketanest-S.
Legal status
[140] it is also a controlled substance in many countries.[4]
While ketamine is legally marketed in many countries worldwide,
Australia
In Australia Ketamine is listed as a schedule 8 controlled drug under the Poisons Standard (October 2015).[142] 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,
[143]
distribution, possession and use to reduce abuse, misuse and physical or psychological dependence."
Canada
[144]
In Canada, ketamine is classified as a Schedule I narcotic, since 2005.
Hong Kong
In Hong Kong, as of 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can
[145][146]
only be used legally by health professionals, for university research purposes, or with a physician's prescription.
Taiwan
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.[122][147]
India
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.[148][149]
United Kingdom
In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[122][150] 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,[151] and
on 12 February 2014 the Home Office announced they would follow this advice "in light of the evidence of chronic harms associated
[152][153]
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 the issue of its recheduling
[152]
for medical and veterinary use would be addressed "separately to allow for a period of consultation."
United States
The increase in recreational use prompted ketamine's placement in Schedule III of the United States Controlled Substance Act in
August 1999.[154]
Recreational use
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.[155] They
include accidental poisonings, drownings, traffic accidents, and suicides.[155] The
majority of deaths were among young people.[156] This has led to increased
regulation (e.g., upgrading ketamine from a Class C to a Class B banned substance
in the U.K.).[157]
Unlike the other well-known dissociatives phencyclidine (PCP) and

dextromethorphan (DXM), ketamine is very short-acting. It takes effect within about
Ketamine poured onto glass and left
10 minutes,[158] while its hallucinogenic effects last 60 minutes when insufflated or
to dry.
.[159]
injected and up to two hours when ingested orally
At anesthetic 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.[160] At sufficiently high doses, users may experience what is called the "K-hole", a state of
extreme dissociation with visual and auditory hallucinations.[161] 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.[162] Both Moore and
[163]
Turner died prematurely (due to hypothermia and drowning respectively) during presumed unsupervised ketamine use.
Because of its ability to cause confusion andamnesia, ketamine can leave users vulnerable todate rape.[158][132]
Clinics
After the publication of the NIH-run antidepressant clinical trial, clinics began opening in which the medication is given.[164] This
practice is an off label use of ketamine in the United States.[164] As of 2015 there were about 60 such clinics in the US, the procedure
was not covered by insurance, and people paid between $400 and $1700 out of pocket for a treatment.[165] A chain of such clinics in
Australia run by Aura Medical Corporation was closed down by regulatory authorities in 2015, because the clinics' marketing was not
supported by scientific research and because the clinic sent people home with ketamine and needles to administer infusions to
themselves.[166]
Research
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.[167][168] Krupitsky and Kolp summarized their work to date in
2007.[169]
Two studies of depressed people with suicidal thoughts found that a single dose of ketamine may cause a reduction in suicidal
thinking that is rapid and lasts up to a week.[170][171]
Veterinary medicine
In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats,[172] dogs,[173] rabbits, rats, and other
small animals.[174][175] It is highly used in induction and anesthetic maintenance in horses. It is an important part of the "rodent
cocktail", a mixture of drugs used for anesthetizing rodents.[176] 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.
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External links
Ketamine on RxList
DEA: Ketamine Fact Sheet
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Ketamine

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Ketamine

Ketamine, sold under the brand name Ketalar among others, is a

Common side effects include psychological reactions as the

Ketamine was discovered in 1962, first tested in humans in 1964,

Medical uses Addiction Low–moderate[1]

History CA: Schedule I

Medical uses Protein binding 12–47% (low)[10][13][9]

Uncompetitive antagonist(channel pore blocker) of theNMDA receptor[97][98]

been suggested that it may interact with allosteric [80]

transporters has been observed with ketamine or its [79]

interaction between ketamine and the monoamine [78][82]

antagonism of the NMDA receptor.[105][82] M2 Ki [4][89]

Metabolites of ketamine including M3 246 Ki Antagonist Human [4][89]

dehydronorketamine, hydroxynorketamine, and IC50 [4]

transfected with rat nicotinic acetylcholine receptor Ki [78]

that metabolites may contribute importantly to the [78]

NMDA receptor antagonism.[108] >10 IC50 Human [82]

dopamine D2 receptors in multiple studies.[83][84][85] [89]

Effects in the brain and the body

Cardiovascular: Ketamine stimulates thesympathetic nervous system, resulting in cardiovascular changes.

Relationship between concentrations and effects

(S)-(−)-ketamine (S)-(+)-ketamine (S)-(−)-ketamine in the (S)-(+)-ketamine in the

Society and culture

Unlike the other well-known dissociatives phencyclidine (PCP) and

At anesthetic doses, under-dosaged from a medical point of view, ketamine produces

Alltounian & Moore 1978

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