Ketamine

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of ketamine
Structural formula without stereochemistry
General
Non-proprietary name
other names
  • 2- (2-chlorophenyl) -2- (methylamino) cyclohexan-1-one
  • CI-581
Molecular formula C 13 H 16 ClNO
Brief description

white, crystalline solid (ketamine hydrochloride)

External identifiers / databases
CAS number 6740-88-1 (racemate, free base)
EC number 229-804-1
ECHA InfoCard 100,027,095
PubChem 3821
DrugBank DB01221
Wikidata Q243547
Drug information
ATC code
Drug class
properties
Molar mass 237,74 g · mol -1
Melting point
  • 92–93 ° C (racemate, free base)
  • 262–263 ° C (racemate hydrochloride)
pK s value

7.5

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 302-315-319-335
P: 261-305 + 351 + 338
Toxicological data

77 mg kg −1 ( LD 50 ,  mouse ,  iv )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ketamine is a chiral arylcyclohexylamine and a medicinal substance used in human and veterinary medicine . It is mainly used in anesthesia and pain treatment. Among other things, by triggering dissociative anesthesia, ketamine occupies an exceptional position compared to other analgesics and narcotics , which means the generation of sleep and freedom from pain while largely preserving the protective reflexes . For use in anesthesia, ketamine is included on the World Health Organization's list of Essential Medicines . In March 2019, the US and in December 2019 the European Union approved the enantiomer ( S ) -ketamine ( esketamine ) with strict requirements for the treatment of treatment-resistant depression. As a dissociative psychotropic substance , ketamine is also used as an illegal intoxicating drug .

history

Calvin L. Stevens , chemist at Wayne State University (Detroit, Michigan, USA) synthesized as part of a research contract with the Parke-Davis company in search of a replacement for the anesthetic phencyclidine (PCP, "Angel Dust"), which has severe side effects. , in April 1962 the substance ketamine (CI-581) for the first time.

In 1966, Parke-Davis was granted a patent for the manufacture of ketamine as a drug for both human and veterinary medicine. Edward Felix Domino, professor of clinical pharmacology at the University of Michigan (USA), carried out his first (non-medical) self-experiment with ketamine on August 3, 1964 and recognized the substance's psychedelic potential. The term dissociative anesthetic for ketamine was introduced by him in the following year 1965.

During the Vietnam War , ketamine was tested on American soldiers and was soon used routinely as an anesthetic in the treatment of combat injuries. In 1970 it was approved as a medicinal product by the Food and Drug Administration . As a street drug, ketamine spread from around the mid-1970s.

chemistry

Structure and stereochemistry

Ketamine is a chiral cyclohexanone derivative and arylcyclohexylamine with a stereocenter . It is structurally related to the arylcyclohexylamines methoxetamine (MXE), phencyclidine (PCP) and 3-methoxyphencyclidine (3-MeO-PCP). Both the racemate , d. H. the 1-to-1 isomer mixture of ( S ) -ketamine and ( R ) -ketamine, as well as the enantiomerically pure eutomer ( S ) -ketamine ( INN : esketamine) are used. ( S ) -ketamine is about twice as effective as racemic ketamine.

Isomers of ketamine
Surname ( R ) -ketamine ( S ) -ketamine
other names Arketamine Esketamine
Structural formula (RS) -Ketamine-Structural Formulas V2.svg
CAS number 33643-49-1 33643-46-8
6740-88-1 (racemate)
EC number - 811-504-2
229-804-1 (racemate)
ECHA info card - 100.242.065
100.027.095 (racemate)
PubChem - 182137
3821 (racemate)
Wikidata Q20707684 Q2365493
Q243547 (racemate)

The hydrochlorides , ketamine hydrochloride and esketamine hydrochloride , are used pharmaceutically.

Manufacturing

Ketamine can be produced in a three-step synthesis from 2-chlorobenzonitrile and cyclopentyl magnesium bromide using the Grignard reaction , then reaction with bromine and then with methylamine . Heating in decalin leads to ring expansion to the racemic ketamine.

Ketamine synthesis

Pharmacological properties

Mechanism of action

The main effect of ketamine is to block the pores of the ionotropic NMDA receptor . The enantiomer esketamine is more effective in this regard because of its higher affinity. In addition, ketamine allosterically inhibits this receptor. It modulates and activates GABA A receptors of the types α 6 β 2 δ and α 6 β 3 δ and differs in this from the NMDAR antagonists phencyclidine and dizocilpine. Ketamine has a weak agonistic effect on opioid receptors .

Furthermore, ketamine has an inhibitory effect on the peripheral re- uptake of catecholamines such as norepinephrine and dopamine at the synaptic endplate with intensification of endogenous and exogenous catecholamine effects. These mechanisms lead to pronounced stimulation of the cardiovascular system , for example increased heart rate, increased blood pressure and (briefly) increased heart rate. Overstimulation of the central nervous system or induction of a cataleptic stage causes amnesia . The thalamoneocortical system is dampened and the limbic system is activated. Ketamine acts on the peripheral nervous system both depressively (by blocking the membrane flow) and excitatory (by modifying the sodium channel fraction). It has only minor visceral analgesic effects, but pronounced somatic ones .

The cause of the rapid onset of antidepressant effects of ketamine is still unclear. There are many attempts at explanation. One of the more recent approaches explains this special effect with the inhibition of NMDA receptors in the lateral habenula and the disinhibition of downstream monoamine reward centers. In addition, microRNAs came into focus. The expression of miR-29b-3p in the prefrontal cortex is increased by ketamine, which has a favorable effect on the regulation of the metabotropic glutamate receptor type 4 . In addition, the extent to which the metabolite (2 R , 6 R ) - hydroxynorketamine has its own antidepressant effect is investigated .

The general pharmacological profile of ( S ) -ketamine largely corresponds to that of the racemate . The analgesic and anesthetic potency of ( S ) -ketamine is about three times higher than that of the ( R ) -form and twice as high as that of the racemate; To achieve similar effects, a dose reduction by half is possible with ( S ) -ketamine compared to the racemate. In addition, ( S ) -ketamine is eliminated more quickly and is therefore easier to control overall. In addition to the reduced substance exposure, this leads to clearly reduced wake-up times. The different effects of ( R ) - and ( S ) -ketamine have been proven by clinical studies.

Pharmacokinetic data

  • Plasma half-life : with clinical administration, the terminal elimination half-life for ( S ) -ketamine hydrochloride is between 79 minutes (after continuous infusion) and 186 minutes (after low-dose intravenous administration), with other administration forms two to three and a half hours.
  • Therapeutic dose : Depending on the objective (analgesia, anesthesia), co-medication and circulatory situation, as well as to be adjusted on a case-by-case basis.
  • Bioavailability : oral 17%, sublingual 33%, intranasal 25 to 50%, intramuscular 93%.

Clinical application

Anesthesia and analgesia

Ketamine is approved as a general anesthetic for the induction and implementation of general anesthesia, as a supplement to regional anesthesia and as an anesthetic and analgesic in emergency medicine. In general anesthesia in adults, it is often used in combination with a sleeping pill (hypnotic), for example from the benzodiazepine group, while in pediatric surgery and emergency medicine it is used without hypnotics.

Due to its bronchodilator properties, ketamine is also approved for intubation in combination with a muscle relaxant in the case of a therapy-resistant asthmatic status . Comparably higher doses of ketamine are used with 1 to 2 and if necessary up to five milligrams per kilogram of body weight. There is insufficient evidence for low-dose use outside the approval ( off-label use ) in adults with an acute asthma attack. Aside from individual case reports, there is also no evidence that ketamine is effective for use in an acute asthma attack in children.

Another approved field of application of ketamine is the treatment of pain (analgesia) in intubated intensive care patients.

Ketamine is also used in veterinary medicine (for example in combination with xylazine in the Hellabrunn mixture ) and in pediatrics . Ketamine can be administered nasally, orally, intravenously, and intramuscularly.

Ketamine is both a sleep-inducing agent ( hypnotic ) and a potent analgesic. The generation of dissociative anesthesia is characteristic of its effect . H. the generation of sleep and freedom from pain while largely maintaining the reflex activity, including the protective reflexes . This in particular eliminates the risk of life-threatening respiratory arrest associated with other anesthetics , and the associated need for breathing and circulatory monitoring with the corresponding expenditure on equipment and personnel.

Therapy for depression

A 2010 study with 18 participants investigated the intravenous administration of ketamine, which ended the depressive episodes in patients with bipolar disorder within 40 minutes. However, the effect was not permanent.

A study conducted in 2013 with 26 participants described the ongoing anti-depressive effects of low sublingual Ketamindosen with stubborn depression and depression in bipolar disorder. In 20 participants (77%) there was a constant improvement in mood and improved sleep. Ten milligrams ( RS ) - (±) -ketamine were taken sublingually every two to three days or weekly , with a slight drowsiness - but no euphoria or dissociation - becoming noticeable as a side effect .

Investigations from 2014 at the Charité indicate, due to the rapid therapeutic effect, a suitable application option for the acute treatment of therapy-resistant and above all suicidal depressed patients.

In a study from 2014 with 21 patients (bipolar disorder), effects of ketamine in brain regions that are of particular importance in depression were registered by means of imaging procedures . Among other things, the improvement in symptoms with ketamine was significantly correlated with changes in the right ventral striatum .

A 2015 meta-analysis of eight randomized controlled trials confirmed the effect of ketamine after a single dose for the immediate treatment of unipolar and bipolar depression. According to another meta-analysis from 2015, a single dose resulted in a significant improvement over a period of at least seven days. A 2015 overview of nine individual studies on the treatment of a total of 137 patients at risk of suicide ( suicidality ) reported a rapid improvement (from 40 minutes) in each of the nine individual studies.

Various studies in the USA investigate the potential of ketamine in severe depression , treatment-resistant depression, and anxiety and depression in cancer patients (as of 2015).

On 12 February 2019, a independent committee of experts recommended that the US Food and Drug Administration approval of the enantiomeric pure eutomer ( S ) -ketamine ( generic name : Esketamin) as a nasal spray for the treatment of treatment-resistant depression, in March 2019 was followed by the approval under strict conditions as Spravato . Spravato has been approved for the treatment of treatment-resistant depression in the European Union since December 2019 .

Side effects and interactions

Very common side effects can be psychotropic effects ( pseudohallucinations , unpleasant dreams), nausea and vomiting, increased salivation ( hypersalivation ), visual disturbances, dizziness and motor restlessness. In addition, ketamine is the only narcotic that increases blood pressure and heart rate; this is desirable for specific indications. In the context of emergency medicine, it is the only drug that can be used to combine circulatory stabilizing and narcotic effects. However, its use in patients with severe coronary heart disease (e.g. heart attack ) is to be rejected because the drug increases the work of the heart by increasing the heart rate and blood pressure and thus increases the oxygen consumption of the heart muscle.

Ketamine increases eye and intracranial pressure , which is why it should not be used as the only anesthetic in injuries there. The muscle tone of the larynx muscles is maintained under ketamine. However, there is no reliable aspiration protection. In higher doses, ketamine also has a bronchospasmolytic effect. Rescue medication ketamine can increase the risk of post-traumatic stress disorder . In routine anesthesia, ketamine is largely rejected due to its psychotropic side effects. The combination with a benzodiazepine can partially prevent the occurrence of nightmares and hallucinations. A stimulus shield is also useful.

Experimental treatment of rabies

Like midazolam, ketamine is part of the so-called Milwaukee Protocol , an experimental treatment regimen for a rabies disease. The patient is placed in an artificial coma. Experiments with cell cultures as well as with rats had shown that ketamine slows down the viral gene transcription in the nerve cells. As with other substances, ketamine has not yet been shown to be clinically effective against rabies in humans. Nevertheless, there are indications of possible target molecules for pharmacological research .

Use as an intoxicant

Acute psychological effects

Because of its dissociative effects, ketamine is also used worldwide as a narcotic drug .

In low doses, ketamine induces a distortion of the perception of space and time, pseudo-hallucinations and mild dissociative effects. Ketamine users indicated that the most desirable effects were 'melting into the surroundings', visual hallucinations, out-of-body experiences, and silliness. The psychoactive effects associated with the intoxicating effect of ketamine ( derealization , depersonalization , auditory and visual hallucinations, unusual thoughts , euphoria , increased color perception, loss of sense of time and novel body sensations) were generally rated as positive. However, 20% of all ketamine users stated that such effects were undesirable and psychologically stressful. In addition, 38% said they knew someone who had already had bad experiences with ketamine.

The symptoms of waking up after anesthesia that occur with ketamine can include delusions , hallucinations, delirium , confusion , and occasionally out-of-body experiences and near-death experiences . The clinical use of ketamine has therefore always been restricted by such symptoms, but this also aroused interest in its use as an intoxicant from the 1960s. One of the partly desired, partly unpleasant and frightening effects is the K-Hole (ketamine hole), a 30-minute complete dissociation from reality. Here can ataxia , dysarthria , muscular hypertension and myoclonus occur. Outwardly, the condition often resembles unconsciousness. The risk of a K-hole has been linked to increased ketamine use, especially in users who had consumed ketamine more than 20 times. The presence of other people (such as friends, staff in clubs or at festivals) can help deal with the experience.

Risks

There is a risk of psychological dependence if ketamine is not used medicinally for long periods of time. Sporadic ketamine use is not associated with cognitive impairment, but chronic use causes considerable impairment of short and long-term memory; Whether these are reversible is still open (as of 2013).

Ketamine has a wide therapeutic range , so that an overdose is difficult or hardly possible. The median lethal dose (LD 50 ) observed in animals is approximately 100 times the average human intravenous dose and 20 times the average human intramuscular dose used for anesthesia in the clinical setting. Furthermore, ketamine can damage the urinary tract if used over a long period of time . Urological complaints ( LUTS ) and cystitis with the formation of ulcers (ulcerative cystitis) can occur. Symptoms are mostly reversible if ketamine use is stopped, but chronic use requires surgery.

The dissociative effects of ketamine can put users in a state in which they are vulnerable to accidents, robbery, assault and rape. In a study of ninety ketamine users, 13% reported that they were involved in an accident as a direct result of the ketamine intoxication, while 83% knew someone who had an accident due to ketamine use.

A magnetic resonance tomographic examination of 21 chronic ketamine users showed brain damage in all test persons, the severity of which correlated with the duration of consumption. Slight damage was already detectable after half a year of daily consumption (1 g / day). While initially only the white matter of the cerebral cortex was superficially affected, after prolonged use (from 1–3 years) the lesions spread to deeper brain areas such as the internal capsule and a little later the pons and the cerebellum . Finally, the limbic system and the brain stem were also affected in test subjects who had been using it for 4–5 years . The damage was classified as "severe" at this stage - with five or more regions affected. Mixed consumption with other drugs or higher daily doses are suspected of increasing the harmful effect.

statistics

Public data on the use of ketamine as a narcotic drug were available for France , Great Britain , Italy , the Czech Republic and Hungary until 2011 .

The European Drugs Report 2015 of the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) mentions a non-representative online survey with 25,790 participants between the ages of 15 and 34 who regularly took part in “nightlife events”, according to which the 12th Monthly prevalence of ketamine use was lower than that of cannabis , MDMA , cocaine and amphetamine . In the UK, there were 93 deaths related to the use of ketamine as an intoxicant from 1997 to April 2013 according to official statistics. Of the 93 people, 86% were male and the mean age was 30.9 years (15.8 to 60.6 years). An additional drug (such as alcohol) was involved in 70 of these cases.

Legal position

In Germany, Switzerland and Austria, ketamine requires a prescription .

In the UK, the increased use of ketamine as a drug has led the government to classify the drug as a Class C drug since January 2006. Since in the following period the damage was even higher than expected, the classification was tightened in 2014 and the substance was upgraded to class B. Since then, illegal private property has been punishable by up to five years in prison instead of up to two years (since 2006). The illegal trade can still be punished with up to 15 years in prison. In the meantime, ketamine is also placed under restriction in countries where it was previously freely available (e.g. India).

Trade names

Ketalar (CH), Ketanest S (active ingredient Esketamine, D), numerous generics

Veterinary medicine: Anesketin, Ketaset, Ketavet, Narketan, Ursotamin

literature

Web links

Commons : Ketamine  - Collection of pictures, videos, and audio files

Individual evidence

  1. ↑ a b c data sheet (±) -Ketamine hydrochloride from Sigma-Aldrich , accessed on April 7, 2011 ( PDF ).
  2. ↑ a b Entry on (RS) -ketamine in the ChemIDplus database of the United States National Library of Medicine (NLM)
  3. ^ The Merck Index. An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition, 2006, pp. 916-917, ISBN 978-0-911910-00-1 .
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  5. ^ [April 2013] WHO Model List of Essential Medicines , 18th. Edition, World Health Organization , October 2013, p. 1 [p. 5 of pdf] (accessed April 22, 2014).
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  7. ↑ patent US3254124 . ‌
  8. ↑ External identifiers or database links for ketamine hydrochloride : CAS number: 1867-66-9, EC number: 217-484-6, ECHA InfoCard: 100.015.895 , PubChem : 15851 , ChemSpider : 15065 , DrugBank : DBSALT000396 , Wikidata : Q27105184 .
  9. ↑ External identifiers or database links for esketamine hydrochloride : CAS number: 33643-47-9, EC number: 687-681-3, ECHA InfoCard: 100.213.809 , PubChem : 44632368 , ChemSpider : 26332012 , DrugBank : DBSALT002086 , Wikidata : Q27128597 .
  10. ↑ entry to Ketamine in DrugBank the University of Alberta , accessed on June 18 of 2019.
  11. ↑ entry to Esketamine in DrugBank the University of Alberta , accessed on June 18 of 2019.
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