Ketamine - Ketamine Drug

Ketamine, sold under the brand name Ketalar among others, is a medication mainly used for starting and maintaining anesthesia. It induces a trance-like state while providing pain relief, sedation, and memory loss. Other uses include for chronic pain and for sedation in intensive care. Heart function, breathing, and airway reflexes generally remain functional. Effects typically begin within five minutes when given by injection with the main effects lasting up to 25 minutes.

Common side effects include psychological reactions as the medication wears off. These reactions may include agitation, confusion, or hallucinations. Elevated blood pressure and muscle tremors are relatively common, while low blood pressure and a decrease in breathing are less so. Spasms of the larynx may rarely occur. Ketamine has been classified as an NMDA receptor antagonist; it also acts on opioid receptors and monoamine transporters among others.

Ketamine was discovered in 1962. It is on the World Health Organization's List of Essential Medicines, of the most important medications needed in a basic health system. It is available as a generic medication. The wholesale cost in the developing world is between 0.08 and 0.32 USD per dose. Ketamine is also used as a recreational drug.

Uses

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
• Emergency surgery in field conditions in war zones
• To supplement spinal or epidural anesthesia/analgesia using low doses

Since it suppresses breathing much less than most other available anaesthetics, ketamine is used in medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available.

Ketamine is frequently used in severely injured people and appears to be safe in this group. A 2011 clinical practice guideline supports the use of ketamine as a dissociative sedative in emergency medicine. It is the drug of choice for people in traumatic shock who are at risk of hypotension. Low blood pressure is harmful in people with severe head injury and ketamine is least likely to cause low blood pressure, often even able to prevent it.

The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. When used at anesthetic doses, it will usually stimulate rather than depress the circulatory system. It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is considered relatively safe because protective airway reflexes are preserved.

Ketamine is used as a bronchodilator in the treatment of severe asthma. However, evidence of clinical benefit is limited.

Pain management

Ketamine may be used for postoperative pain management. Low doses of ketamine reduce morphine use and nausea and vomiting after surgery. High quality evidence in acute pain is insufficient to determine if ketamine is useful in this situation.

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. 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. 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".

Low-dose ketamine is sometimes used in the treatment of complex regional pain syndrome (CRPS). A 2013 systematic review found only low-quality evidence to support the use of ketamine for CRPS.

Depression

Ketamine has been tested in treatment-resistant bipolar disorder, major depressive disorder, and people in a suicidal crisis in emergency rooms. Benefit is often of a short duration. The quality of the evidence supporting benefit is generally low.

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 1â€"2 weeks long) reduction in symptoms in some people. Initial studies have resulted in interest due to its rapid onset, and because it appears to work by blocking NMDA receptors for glutamate, a different mechanism from most modern antidepressants that operate on other targets.

Recreational

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. They include accidental poisonings, drownings, traffic accidents, and suicides. The majority of deaths were among young people. This has led to increased regulation (e.g., upgrading ketamine from a Class C to a Class B banned substance in the U.K.).

Unlike the other well-known dissociatives phencyclidine (PCP) and dextromethorphan (DXM), ketamine is very short-acting. It takes effect within about 10 minutes, while its hallucinogenic effects last 60 minutes when insufflated or injected and up to two hours when ingested orally.

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. At sufficiently high doses, users may experience what is called the "K-hole", a state of extreme dissociation with visual and auditory hallucinations. John C. Lilly, Marcia Moore and D. M. Turner (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with ketamine. Both Moore and Turner died prematurely (due to hypothermia and drowning respectively) during presumed unsupervised ketamine use.

Side effects

Ketamine is generally safe for those critically ill, when administered by trained medical professionals. Even in these cases, there are known side effects that include one or more of the following:

• 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.
• 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. 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. Patients who experience severe reactions may require treatment with a small dose of a short- or ultrashort-acting barbiturate.

Tonic-clonic movements are reported at higher anesthetic doses in greater than 10% of patients.

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.

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.

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.

More recent studies of ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents. One such study administered daily ketamine doses consistent with typical recreational doses (1 mg/kg IV) to adolescent cynomolgus monkeys for varying periods of time. Decreased locomotor activity and indicators of increased cell death in the prefrontal cortex were detected in monkeys given daily injections for six months, but not those given daily injections for one month. A study conducted on rhesus monkeys found a 24-hour intravenous infusion of ketamine caused signs of brain damage in five-day-old but not 35-day-old animals. Some neonatal experts do not recommend the use of ketamine as an anesthetic agent in human neonates because of the potential adverse effects 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 anta gonism as ketamine.

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.

Urinary tract effects

A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from ketamine recreational use. Urinary tract symptoms have been collectively referred as "ketamine-induced ulcerative cystitis" or "ketamine-induced vesicopathy", and they include urge incontinence, decreased bladder compliance, decreased bladder volume, detrusor overactivity, and painful haematuria (blood in urine). Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases. The pathogenesis of papillary necrosis has been investigated in mice, and mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence has been suggested as a possible mechanism.

The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use corresponds linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 g/day reported symptoms of the lower urinary tract. Urinary tract symptoms appear to be most common in daily ketamine users who have used the drug recreationally for an extended period of time. These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.

Management of these symptoms primarily involves ketamine cessation, for which compliance is low. Other treatments have been used, including antibiotics, NSAIDs, steroids, anticholinergics, and cystodistension. Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some patients, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulfate, or both. Further follow-up is required to fully assess the efficacy of these treatments.

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.

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, benzodiazepines, opioids, quinazolinones, phenothiazines, anticholinergics and barbiturates.

Pharmacology

Pharmacodynamics

Ketamine acts primarily as an antagonist of the NMDA receptor, and this action accounts for most of its effects. However, the complete pharmacology of ketamine is more complex, and it is known to directly interact with a variety of other sites to varying degrees.

A study conducted in mice found that ketamine's antidepressant activity 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.

Known actions of ketamine include:

• Non-competitive antagonist of the NMDA receptor (NMDAR)
• Negative allosteric modulator of the nACh receptor
• Weak agonist of the μ-opioid and κ-opioid receptors (10- and 20-fold less affinity relative to NMDAR, respectively), and very weak agonist of the δ-opioid receptor
• Agonist of the D₂ receptor
• Weak mACh receptor antagonist (10- to 20-fold less affinity relative to NMDAR)
• Inhibitor of the reuptake of serotonin, dopamine, and norepinephrine
• Voltage-gated sodium channel and L-type calcium channel blocker, and HCN1 cation channel blocker
• Inhibitor of nitric oxide synthase
• σ receptor 1 and 2 agonist (μM affinities).
• Activation of AMPA receptors

Ketamine appears to inhibit the NMDAR by binding both in the open channel and at an allosteric site. The S(+) and R(-) stereoisomers bind with different affinities: K_i = 3200 and 1100 nM, respectively.

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. Dopamine reuptake inhibition is likely to underlie the euphoria the drug produces, although an additional involvement of μ-opioid receptor activation cannot be excluded. The mechanisms of action for the possible antidepressant effects of ketamine at lower doses have yet to be elucidated.

NMDAR antagonism results in analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine's actions interfere with pain transmission in the spinal cord. Inhibition of nitric oxide synthase lowers the production of nitric oxide â€" a neurotransmitter involved in pain perception, hence further contributing to analgesia. The action of ketamine at sigma and μ-opioid receptors is relatively weak, and evidence is mixed as to whether the latter is of significance to its analgesic effects.

Ketamine also interacts with a host of other targets to cause analgesia. In particular, it blocks voltage-dependent calcium channels and sodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it inhibits the reuptake of serotonin and norepinephrine, which are involved in descending antinociceptive pathways.

Effects in peripheral systems

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:

• Cardiovascular: Ketamine inhibits the reuptake of catecholamines, stimulating the sympathetic nervous system, resulting in cardiovascular symptoms.
• Gastrointestinal: Serotonin reuptake inhibition is thought to underlie nausea and vomiting.
• Respiratory: Catecholamine elevation and stimulation of β₂ adrenergic receptors 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. When administered orally, it undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) isoenzymes into norketamine (through N-demethylation) and finally dehydronorketamine. Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine. As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent anesthetically, and plasma levels of this metabolite are three times higher than ketamine following oral administration. Bioavailability through the oral route reaches 17â€"20%; bioavailability through other routes are: 93% intramuscularly, 25â€"50% intranasally, 30% sublingually, and 3 0% rectally. Peak plasma concentrations are reached within a minute intravenously, 5â€"15 min intramuscularly, and 30 min orally. Ketamine's duration of action in a clinical setting is 30 min to 2 h intramuscularly and 4â€"6 h orally.

Plasma concentrations of ketamine are increased by diazepam and other CYP3A4 inhibitors due to inhibition of conversion to norketamine.

Administration

In medical settings, ketamine is usually injected intravenously or intramuscularly.

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.

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, while the less active enantiomer, arketamine (R-ketamine), has never been marketed as an enantiopure drug for clinical use.

The optical rotation of a given enantiomer of ketamine can vary between its salts and free base form. The free base form of (S)â€'ketamine exhibits dextrorotation and is therefore labelled (S)â€'(+)â€'ketamine. However, its hydrochloride salt shows levorotation and is thus labelled (S)â€'(âˆ')â€'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. In the hydrochloride salt, the positions are reversed, with the o-chlorophenyl group axial and the methylamino group equatorial. Not all salts of ketamine show different optical rotation to the free base: (S)-ketamine (R,R)-tartrate is levorotatory, like (S)â€'ketam ine.

History

Medical use

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. After promising preclinical research in animals, ketamine was introduced to testing in human prisoners in 1964. 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. Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.

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. Early use was documented in underground literature such as The Fabulous Furry Freak Brothers. It was used in psychiatric and other academic research through the 1970s, culminating in 1978 with the publishing of psychonaut John Lilly's The Scientist, and Marcia Moore and Howard Alltounian's Journeys into the Bright World, which documented the unusual phenomenology of ketamine intoxication. The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties. However, its emergence as a club drug differs from other club drugs (e.g. MDMA) due to its anesthetic properties (e.g., slurred speech, immobilization) at higher doses; in addition, there are reports of ketamine being sold as "ecstasy". The use of ketamine as part of a "postclubbing experience" has also been documented. Ketamine's rise in the d ance culture was rapid in Hong Kong by the end of the 1990s. Before becoming a federally controlled substance in the United States in 1999, ketamine was available as diverted pharmaceutical preparations and as a pure powder sold in bulk quantities from domestic chemical supply companies. Much of the current ketamine diverted for nonmedical use originates in China and India.

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).

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.

The increase in illicit use prompted ketamine's placement in Schedule III of the United States Controlled Substance Act in August 1999.

In the United Kingdom, it became labeled a Class C drug on 1 January 2006. 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, and on 12 February 2014 the Home Office announced they would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage".

The UK Minister of State for Crime Prevention, Norman Baker, responding to the ACMD's advice, said the issue of its recheduling for medical and veterinary use would be addressed "separately to allow for a period of consultation."

In Australia Ketamine is listed as a schedule 8 controlled drug under the Poisons Standard (October 2015). 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."

In Canada, ketamine is classified as a Schedule I narcotic, since 2005.

In Hong Kong, as of 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals, for university research purposes, or with a physician's prescription. By 2002, ketamine was classified as class III in Taiwan; given the recent rise in prevalence in East Asia, however, rescheduling into class I or II is being considered.

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.

Ketamine is legally marketed in many countries worldwide, under many brand names.

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. Krupitsky and Kolp summarized their work to date in 2007.

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. 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.