It is a medication used primarily to start and maintain anesthesia.
It induces a trance-like state while providing pain relief, sedation, and memory loss.
Other uses include chronic pain and intensive care sedation. Cardiac function, breathing, and reflexes of the airways usually remain functional during their effects.
The effects usually begin within five minutes when given by injection, and the main effects last up to 25 minutes.
Common side effects include psychological reactions as the medication disappears. These reactions may include agitation, confusion, or hallucinations.
High blood pressure and muscle tremors are relatively frequent, while low blood pressure and decreased breathing are less frequent.
The spasms of the larynx may occur rarely. Ketamine has been classified as an antagonist of the N-methyl-D-aspartate receptor, but its mechanisms are not well understood as of 2017.
Ketamine was discovered in 1962, first tested in humans in 1964, and approved for use in the United States in 1970. Shortly after its approval in the United States. UU was widely used for surgical anesthesia in the Vietnam War due to its safety.
It is on the list of essential medicines of the World Health Organization, the most effective and safe medicines needed in a health system. It is available as a generic medicine.
It is used as an anesthetic:
- Children’s anesthesia is the only anesthetic for minor procedures or an induction agent followed by muscle relaxant and tracheal intubation.
- Asthmatics or people with chronic obstructive airways 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 with low doses.
As it suppresses breathing much less than most other anesthetics available, Ketamine is used in medicine as an anesthetic; however, due to the hallucinations it can cause, it is usually not used as a primary anesthetic, although it is the anesthetic of choice when reliable ventilation equipment is not available.
Ketamine is often used in severely injured people and seems safe in this group. A clinical practice guide of 2011 supports the use of Ketamine as a dissociative sedative in emergency medicine.
It is the drug of choice for people with traumatic shock who are at risk of hypotension. Low blood pressure is harmful in people with severe head injuries, and Ketamine is less likely to cause low blood pressure and often can even prevent it.
The effect of Ketamine on the respiratory and circulatory systems is different from the effect of other anesthetics. When used in anesthetic doses, it will generally stimulate rather than depress the circulatory system.
It is sometimes possible to perform anesthesia with Ketamine without protective measures in the respiratory tract. Ketamine is considered relatively safe because protective reflexes of the respiratory tract are preserved.
Ketamine is used as a bronchodilator in the treatment of severe asthma. However, the evidence of clinical benefit is limited.
Ketamine can be used for the management of postoperative pain. Low doses of Ketamine can reduce morphine consumption, nausea, and vomiting after surgery.
It can also be used as an intravenous analgesic with opioids to treat otherwise intractable pain, especially if this pain is neuropathic. It also benefits from counteracting spinal sensitization or the liquidation phenomena experienced with chronic pain.
Psychotropic side effects are less evident in these doses and are well managed with benzodiazepines.
Ketamine is an analgesic that is most effective when used with a low-dose opiate; However, it has analgesic effects by itself; the doses required for adequate pain relief when used as the sole analgesic agent are considerably higher and are much more likely to produce disorienting side effects.
A review article in 2013 concluded, “Despite the limitations in the breadth and depth of the available data, there is evidence that Ketamine may be a viable option for cancer pain refractory to treatment.”
Low-dose Ketamine is sometimes used in the treatment of complex regional pain syndrome. A 2013 systematic review found only low-quality evidence to support the use of Ketamine for complex regional pain syndrome.
Ketamine has been tested as a fast-acting antidepressant for treatment-resistant depression in bipolar disorder and major depressive disorder. The antidepressant effect of Ketamine has a short duration action.
Meta-analyses have shown overwhelming clinical evidence to support the acute efficacy of Ketamine in severely ill populations, but the lack of data on optimal dosing and the effect of long-term treatment.
Currently, Ketamine is not approved for the treatment of depression, so this is an unapproved use. As of June 2017, Esketamine, the S (+) enantiomer of Ketamine, is in Phase III clinical trials for the intranasal treatment of depression.
A single intravenous infusion administers Ketamine at doses lower than those used in anesthesia. Preliminary data indicate that it produces a rapid (in 2 hours) and relatively sustained (around 1 to 2 weeks duration) reduction of symptoms in some people.
Initial studies have aroused interest because of its rapid onset. It works by blocking the N-methyl-D-aspartate receptors for glutamate, a mechanism different from most modern antidepressants that operate on other targets.
It warns against the use of Ketamine in cases of:
- The conditions are worsened by increased blood pressure or heart rates, such as angina, stroke, poorly controlled high blood pressure, etc., since Cetamine increases both heart rate and blood pressure.
- In psychiatric disorders, Ketamine can cause hallucinations that can exacerbate the symptoms of specific psychiatric disorders.
- High intracranial pressure, Ketamine can further increase intracranial pressure.
- Elevated intraocular pressure, Ketamine can also increase intraocular pressure.
- Penetrating eye injury may increase the risk of loss of eye contents due to increased intraocular pressure.
- Acute porphyria, Ketamine is considered porphyrinogenic; that is, it can cause an attack of acute porphyria in susceptible people.
Ketamine is generally safe for those who are in critical condition when it is administered by trained medical professionals. Even in these cases, side effects are known 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 due to concerns about Cetamine that causes increased intracranial pressure. Intracranial hypertension does not increase more than opioids.
Dermatological: transient reddening of the skin, transient rash similar to measles.
Gastrointestinal: decreased appetite, nausea, increased salivation, vomiting.
Local area: pain, general eruptions, or eruptions 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: obstruction of the respiratory tract, interruption of breathing, increased bronchial secretions, reduced effort to breathe, spasm of the vocal cords (larynx).
Other: Anaphylaxis, dependence, emergency reaction.
In anesthetic doses, 10-20% of people experience adverse reactions during the emergence of anesthesia, reactions that can manifest as seriously as hallucinations and delirium.
These reactions may be less common in some people’s subpopulations and, when administered intramuscularly, may occur up to 24 hours after the operation.
The possibility of this happening can be reduced by minimizing stimulation to the person during recovery and pretreating with a benzodiazepine, along with a lower dose of Ketamine.
People who experience severe reactions may require treatment with a small dose of a short-acting or ultra-low-acting barbiturate.
Tonic-clonic movements are reported at higher anesthetic doses in more than 10% of people.
In 1989, professor of psychiatry John Olney reported that Cetamine caused irreversible changes, known as Olney’s injuries, in two small areas of the rat’s brain.
However, the rat’s brain has significant differences in the metabolism of the human brain; therefore, such changes may not occur in humans.
The first large-scale longitudinal study of Ketamine users found that frequent users of Ketamine (averaging 20 days/month) had increased depression and memory impairment by several measures, including verbal, short-term memory, and visual.
It was not found that the current frequent users of Ketamine (average of 3.25 days/month) and former users of Ketamine differed from the controls in memory tests, attention, and psychological well-being.
This suggests that the infrequent use of Ketamine does not cause cognitive deficits and that any deficiencies that may occur can be reversible when the use of Ketamine is discontinued. However, abstinent, frequent, and infrequent users scored higher than controls in a test of delusional symptoms.
Short-term exposure of cultures of GABAergic neurons to Cetamine at high concentrations led to a significant loss of differentiated cells in one study, and Ketamine concentrations (10 μg / ml) that do not induce death can still initiate long-term alterations of arbor dendritic neurons in differentiated.
The same study also demonstrated the chronic (> 24h) administration of Ketamine at concentrations as low as 0.01 μg / ml could interfere with maintaining the dendritic tree architecture.
These results increase the possibility that chronic exposure to low and subanesthetic Cetamine concentrations, while not affecting cell survival, may still affect maintenance and neuronal development.
The most recent studies of Ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents.
One of these studies administered daily doses of Ketamine consistent with typical recreational doses (1 mg/kg IV) to adolescent cynomolgus monkeys for varying periods.
The decrease in locomotor activity and the indicators of increased cell death in the prefrontal cortex were detected in monkeys who received daily injections for six months but not in those who received daily injections for one month.
Some neonatal experts do not recommend using Ketamine as an anesthetic agent in human newborns due to the possible adverse effects it can have on the developing brain.
These neurodegenerative changes in early development have been seen with other drugs that share the exact mechanism of action of the antagonism of N-methyl-D-aspartate receptors, such 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 perceptual changes similar to schizophrenia.
Aspects in the urinary tract
A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from the recreational use of Ketamine.
Urinary tract symptoms have been collectively termed “Ketamine-induced ulcerative cystitis” or “Ketamine-induced retinopathy” and include urge incontinence, decreased compliance of the bladder, decreased bladder volume, detrusor overactivity, and painful blood in the 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 has been suggested due to the dependence of Ketamine as a possible mechanism.
The timing of the onset of lower urinary tract symptoms varies, in part, depending on the severity and chronicity of the use of Ketamine; however, it is not clear if the severity and chronicity of the use of Ketamine correspond linearly with the presentation of these symptoms.
All reported cases in which the user consumed more than 5 g / day reported lower urinary tract symptoms. Urinary tract symptoms seem to be more common in daily users of Ketamine who have used the drug recreationally for a prolonged period.
These symptoms have been presented in only one case of the medical use of Ketamine. However, after reducing the dose, the symptoms subsided.
The management of these symptoms mainly involves the cessation of Ketamine, whose compliance is low. Other treatments have been used, including antibiotics, non-steroidal anti-inflammatory drugs, steroids, anticholinergics, and cystodistension.
It has been shown that both the installation of hyaluronic acid and the combined pentosan cytosulfate and Cetamine cessation provide relief in some people. Still, in the latter case, it is unclear whether the reserve was a consequence of ketamine cessation, the administration of polysulfate of pentosan, or both.
Additional follow-up is required to evaluate the effectiveness of these treatments fully.
Aspects in the liver
In the case reports of three people treated with Esketamine to relieve chronic pain, abnormalities in liver enzymes occurred after repeated treatment with Ketamine infusions, and liver enzyme values returned below the upper reference limit of the range regular when the drug stops.
The result suggests that liver enzymes should be monitored during said treatment.
The potential for Ketamine dependence has been established in several operant conditioning paradigms, including conditioned place preferences and self-management. The rats demonstrate locomotor sensitization after repeated exposure to Ketamine.
Increased subjective ” high ” sensations have been observed in healthy human volunteers exposed to Ketamine. In addition, it is believed that the rapid onset of effects after smoking, insufflation, or intramuscular injection increases the recreational use potential of the drug.
The short duration of the effects promotes binge eating, tolerance can develop, and withdrawal symptoms, such as anxiety, tremors, and palpitations, may be present in some daily users after cessation of use.
Ketamine can cause a variety of urinary tract problems that are more likely to occur with more intense use and higher doses, especially in those who do not seek a healthy lifestyle, according to a study from the United Kingdom.
Interactions with other medications
Plasma concentrations of Ketamine have increased by inhibitors of the cytochrome P450 3A4 isoenzyme (CYP3A4) (e.g., diazepam) and CYP2B6 inhibitors (e.g., orphenadrine) due to inhibition of their metabolism.
Other medications that increase blood pressure may interact with Cetamine by having an additive effect on blood pressure, including stimulants, serotonin-norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors.
Increased blood pressure and heart rate, palpitations, and arrhythmias can be potential effects.
Ketamine can increase the effects of other sedatives in a dose-dependent manner, which includes, among others: alcohol, benzodiazepines, opioids, quinazolinones, phenothiazines, anticholinergics, and barbiturates.
Benzodiazepines may decrease the antidepressant effects of Ketamine. Most conventional antidepressants can be combined with Ketamine without reducing antidepressant efficacy or increasing side effects.
Ketamine acts as a selective antagonist of the N-methyl-D-aspartate receptor, an ionotropic glutamate receptor.
It binds specifically to the site of dizocilpine (MK-801) of the N-methyl-D-aspartate receptor near the channel pore and is a non-competitive antagonist.
Ketamine can also interact and inhibit the N-methyl-D-aspartate receptor through another allosteric site in the receptor. Its complete mechanism of action is not well understood as of 2017.
A study in mice found that the antidepressant activity of Ketamine is not caused by Cetamine that inhibits the N-methyl-D-aspartate receptor, but rather by the indirect/downward sustained activation of another type of ionotropic glutamate receptor.
The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, also known as AMPA receptor or quisqualate receptor, by a metabolite, (2R, 6R) -hydroxinnorpetamine; As of 2017, it is unknown if this is the case in humans.
The Aquitaine is also an indirect/downstream AMPA receptor activator.
Effects on the brain and the body
It is believed that the antagonism of the N-methyl-D-aspartate receptor is responsible for the anesthetic, amnestic, dissociative, and hallucinogenic effects of Ketamine.
The mechanisms of action for the antidepressant effects of Ketamine at lower doses have not yet been fully elucidated.
Antagonism of the N-methyl-D-aspartate receptor results in analgesia by avoiding central sensitization in the dorsal horn neurons; In other words, the actions of Ketamine interfere with the transmission of pain in the spinal cord.
The inhibition of nitric oxide synthase reduces nitric oxide production, a gasotransmitter involved in the perception of pain, which contributes to analgesia.
Ketamine produces measurable changes in the peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:
Cardiovascular: Ketamine stimulates the sympathetic nervous system, resulting in cardiovascular changes.
Gastrointestinal: Ketamine produces nausea and vomiting in 15 to 25% of people with anesthetic doses.
Respiratory: Ketamine causes bronchodilation. Several mechanisms have been hypothesized to explain this effect.
The exact mechanisms of these effects are not fully understood.
Relationship between concentrations
In patients treated with Ketamine somnolence, dissociation and psychosis-like effects are reported, such as hallucinations and delirium, at circulating concentrations of around 50 to 200 ng/ml (210-841 nM), while analgesia begins at levels from about 100 to 200 ng/ml (421-841 nM).
The typical intravenous antidepressant dose of Ketamine used to treat depression is low and results in peak plasma concentrations of 70 to 200 ng/ml (294-841 nM).
Circulating concentrations of around 2,000 to 3,000 ng/ml (8,413-12,620 nM) are used during anesthesia, and patients may begin to awaken once Cetamine levels have dropped to approximately 500 to 1,000 ng/ml (2,103 a). 4.207 nM).
There is a wide variation in the maximum concentrations of Ketamine reported in association with anesthesia in the literature, with values ranging from 2,211 to 3,447 ng/ml (9,300-14,500 nM) up to a maximum of 22,370 ng/ml (94,100 nM).
The bioactive concentrations of Ketamine are lower than the total plasma levels due to the binding to plasma proteins, although the binding to plasma proteins is relatively low with Ketamine (approximately 12 to 47% bound to proteins).
It has been reported that Ketamine concentrations in the brain are several times higher than in plasma.
In medical settings, Ketamine is usually injected intravenously or intramuscularly. Ketamine can be started using the oral route, or people can switch from a subcutaneous infusion once the pain is controlled.
Oral Ketamine is easily broken down by bile acids, which have low bioavailability. Often, sublingual or buccal absorption pills prepared by a specialized pharmacy are used to combat this problem.
Some specialists suspend the subcutaneous infusion when the first dose of oral Ketamine is administered. Others gradually reduce the infusion dose as the oral dose increases.
Ketamine is absorbable intravenously, intramuscularly, orally, and topically due to its solubility in water and lipids.
When administered orally, it undergoes first-pass metabolism, where it is biotransformed in the liver by isozymes CYP3A4 (central), CYP2B6 (minor), and CYP2C9 (minor) in norcetamine (through N-demethylation) and finally dehydronorquemine.
As the primary metabolite of Ketamine, nor examine is one third to one fifth as potent as an anesthetic, and the plasma levels of this metabolite are three times higher than Cetamine after oral administration.
Oral bioavailability reaches 17-20%; Bioavailability through other routes is 93% intramuscularly, 25-50% intranasally, 30% sublingually, and 30% rectally.
The maximum plasma concentrations are reached in one minute intravenously, 5 to 15 minutes intramuscularly, and 30 minutes orally. The duration of action of Ketamine in a clinical setting is 30 minutes to 2 hours intramuscularly and 4 to 6 hours orally.
History of its medical use
Ketamine was first synthesized in 1962 by Calvin L. Stevens, professor of chemistry at Wayne State University and a Parke-Davis consultant who researched rearrangements of alpha-hydroxylamine.
After the promising preclinical research in animals, Ketamine was introduced to human prisoners in 1964. These investigations showed that the short-lived action of Ketamine and reduced behavioral toxicity made it a good choice over phencyclidine (PCP) as an anesthetic dissociative.
After the approval of the food and medicine administration in 1970, anesthesia with Ketamine was administered for the first time to the American soldiers during the war in Vietnam.
In veterinary anesthesia, Ketamine is often used for its anesthetic and analgesic effects in cats, dogs, rabbits, rats, and other small animals. It is widely used in induction and anesthetic maintenance in horses.
It is an integral part of the “rodent cocktail,” a mixture of drugs used to anesthetize rodents. Veterinarians often use Ketamine with sedative medications to produce balanced anesthesia and analgesia and as a constant-frequency infusion to help prevent the end of pain.
Ketamine is used to control pain in large animals, although it has a more negligible effect on cattle. It is the primary intravenous anesthetic agent used in equine surgery, often combined with detomidine and thiopental or occasionally with guaifenesin.
The recreational use of Ketamine was documented in the early 1970s in underground literature (for example, in The Fabulous Furry Freak Brothers ).
It was used in psychiatric and academic research during the 1970s, culminating in 1978 with the publication of The Scientist by psychiatrist John Lilly and Journeys into the Bright World by Marla Moore and Howard Alltounian, which documented the unusual phenomenology of Ketamine poisoning.
The incidence of non-medical use of Ketamine increased until the end of the century, especially in raves and other parts.
Its appearance as a club drug differs from other club drugs (e.g., MDMA); however, due to its anesthetic properties (eg, difficulty speaking, immobilization) at higher doses; In addition, reports that Ketamine is sold as “ecstasy” are common.
In the book E for Ecstasy of 1993 (on ecstasy street drug uses in the United Kingdom), ecstasy writer, activist, and advocate Nicholas Saunders highlighted the results of tests showing that specific medicines shipments contain Ketamine.
The ecstasy shipments known as ” Strawberry ” contained what Saunders described as a “potentially dangerous combination of Ketamine, ephedrine, and selegiline,” as well as a consignment of ” Sitting Duck ” ecstasy tablets.
The use of Ketamine as part of a “post-party experience” has also been documented. Ketamine’s rise in dance culture was faster in Hong Kong in the late 1990s.
Ketamine as a recreational drug has been implicated in deaths worldwide, with more than 90 deaths in England and Wales in the years 2005-to and 2013. They include accidental poisonings, drownings, traffic accidents, and suicides.
The majority of deaths occurred among young people. This has led to increased regulation (for example, the improvement of Ketamine from a banned substance from Class C to Class B in the United Kingdom).
Unlike other well-known dissociative phencyclidine (PCP) and dextromethorphan (DXM), Ketamine has a concise action. 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.
In anesthetic doses, in low doses from a medical point of view, Ketamine produces a dissociative state, characterized by a sense of detachment from the physical body and the external world, known as depersonalization and derealization.
At sufficiently high doses, users may experience the “K-hole,” a state of extreme dissociation with visual and auditory hallucinations. John C. Lilly, Marcia Moore, and DM Turner (among others) have written extensively about their entheogenic use and their psychometrical experiences with Ketamine.
Both Moore and Turner died prematurely (due to hypothermia and drowning, respectively) during the alleged unsupervised use of Ketamine.