Ketamine is a drug used in human and veterinary medicine. Ketamine is primarily used for the induction and maintenance of general anesthesia, usually in combination with a sedative. Other uses include sedation in intensive care, analgesia (particularly in emergency medicine), and treatment of bronchospasm. Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation.
It has been shown to be effective in treating depression in patients with bipolar disorderwho have not responded to anti-depressants. In persons with major depressive disorder, it produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work. It is also a popular anesthetic inveterinary medicine.
Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist. At high, fully anesthetic level doses, ketamine has also been found to bind to opioid μ receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity – and to sigma receptorsin rats. Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels. Like other drugs of this class such as tiletamine and phencyclidine (PCP), it induces a state referred to as “dissociative anesthesia” and is used as a recreational drug.
Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine areracemic; however, some brands reportedly have (mostly undocumented) differences inenantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S. Ketamine is a core medicine in theWorld Health Organization’s “Essential Drugs List”, a list of minimum medical needs for a basic healthcare system.
Medicinal Use
One 10ml vial of 1000mg Ketamine
Indications for use as an anaesthetic:
Pediatric anesthesia (as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and endotracheal intubation)
Asthmatics or patients with chronic obstructive airway disease
As part of a cream, gel, or liquid for topical application for nerve pain — the most common mixture is 10% ketoprofen, 5% Lidocaine, and 10% ketamine. Other ingredients found useful by pain specialists and their patients as well as the compounding pharmacists who make the topical mixtures include amitriptyline,cyclobenzaprine, clonidine, tramadol, and mepivicaine and other longer-acting local anaesthetics.
In emergency medicine if entrapped patient is suffering severe trauma
Emergency surgery in field conditions in war zones
To supplement spinal / epidural anesthesia / analgesia utilizing low doses
In medical settings, ketamine is usually injected intravenously or intramuscularly. Since it suppresses breathing much less than most other available anaesthetics, ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations which may be caused by ketamine, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available. Ketamine tends to increase heart rate and blood pressure. Because ketamine tends to increase or maintain cardiac output, it is sometimes used in anesthesia for emergency surgery when the patient’s fluid volume status is unknown (e.g., from traffic accidents). Ketamine can be used in podiatry and other minor surgery, and occasionally for the treatment of migraine. There is ongoing research in France, the Netherlands, Russia, Australia and the US into the drug’s usefulness in pain therapy, depression, and for the treatment ofalcoholism and heroin addiction.
In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. 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 sometimesguaifenesin.
Ketamine may be used in small doses (0.1–0.5 mg/kg·h) as a local anesthetic, particularly for the treatment of pain associated with movement and neuropathic pain. It may also be used as an intravenous co-analgesic together with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic (pain due to vascular insufficiency or shingles are good examples). It has the added benefit of counter-acting 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 a co-analgesic, and so is most effective when used alongside a low-dose opioid; while it does have analgesic effects by itself, the higher doses required can cause disorienting side effects. The combination of ketamine with an opioid is, however, particularly useful for pain caused by cancer.
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 also a potent analgesic and can be used in sub-anesthetic doses to relieve acute pain; however, its psychotropic properties must be taken into account. Patients have reported vivid hallucinations, “going into other worlds” or “seeing God” while anesthetized, and these unwanted psychological side-effects have reduced the use of ketamine in human medicine. They can, however, usually be avoided by concomitant application of a sedative such as a benzodiazepine.
Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS), according to a retrospective review published in the October 2004 issue of Pain Medicine.Although low-dose ketamine therapy is established as a generally safe procedure, reported side effects in some patients have included hallucinations, dizziness, lightheadedness and nausea. Therefore nurses administering ketamine to patients with CRPS should do so only in a setting where a trained physician is available if needed to assess potential adverse effects on patients.
In some neurological ICUs, ketamine has been used in cases of prolonged seizures. There has been some evidence that the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.
Pain Management
The dissociative anesthetic effects of ketamine have also been applied within the realm of postoperative pain management. Low doses of ketamine have been found to significantly reduce morphine consumption as well as reports of nausea following abdominal surgery.
Oral Ketamine
Ketamine can be started using the oral route or patients may be changed from a subcutaneous infusion when pain is controlled.
Starting dose: 5-10mg four times daily.
Increase dose in 5-10mg increments.
Usual dose range: 10mg-60mg four times daily.
Subcutaneous ketamine infusion
Starting dose: 50-150mg/24 hours.
Review daily; increase dose in 50-100mg increments.
Usual dose range: 50mg- 600mg/24 hours
Converting from a 24 hour SC ketamine infusion to oral ketamine
Oral ketamine is more potent than SC ketamine (due to liver metabolism). Many patients require a dose reduction of 25-50% when changing to oral ketamine.
Titrate dose in 5-10mg increments.
Some specialists stop the SC infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.
Side Effects
Short Term
Up to 40% of patients may experience side effects with continuous subcutaneous infusion (side effects are less common upon oral administration). These include:
Delirium
Dizziness
Diplopia
Blurred Vision
Nystagmus
Altered Hearing
Hypertension
Tachycardia
Hypersalivation
Nausea and Vomiting
Erythema
Pain at Injection Site
Psychomimetic Phenomenon
Euphoria
Aphasia
Blunted Affect
Psychomotor Retardation
Vivid Dreams
Nightmares
Impaired Attention, Memory and Judgement
Illusions
Hallucinations
Altered Body Image
Tonic-clonic movements are also reported at higher anesthetic doses in greater than 10% of patients.
Long Term
Because ketamine is typically administered as a few repeated doses in a clinical setting, long-term effects are primarily reported and investigated in recreational ketamine users.
Neurological Effects
Main article:
Olney’s lesions
Chronic use of ketamine may lead to cognitive impairments including memory problems. In 1989, psychiatry professor John Olneyreported that ketamine caused irreversible changes in two small areas of the rat brain, which however has significant differences in metabolism from the human brain and therefore may not occur in humans.
The first large-scale, longitudinal study of ketamine users found that heavy ketamine users had impaired memory by several measures, including verbal, short-term memory and visual memory. However, occasional (1-2 times per month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests that occasional use of ketamine does not lead to prolonged harm and that any damage that might occur may be reversible when ketamine use is stopped; however, depression worsened even in the abstinent user group over the period of the study (one year), along with dissociative symptoms still existing among infrequent users.
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 non-cell-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 that 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 morphology and thus might lead to dysfunctions of neural networks.
There is a long list of medicines that could counteract these potential toxic effects, including clonidine,anticholinergics, benzodiazepines, barbiturates and risperidone.
Urinary Tract Effects
According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist. 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 it has been suggested that mononuclear inflammatoryinfiltration in the renal papilla resulting from ketamine dependence is 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 grams per day reported symptoms of the lower urinary tract. Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug 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 combinedpentosan polysulphate 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 polysulphate, or both. Further follow-up is required to fully assess the efficacy of these treatments.
Case reports of Hepato-Toxicity in Chronic Pain Management
In case reports of three patients treated with S(+)ketamine 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 that liver enzymes have to be monitored during such treatment.
Drug Interactions
Ketamine may increase the effects of other sedatives, including but not limited to: benzodiazepines, barbiturates, opiates/opioids,anesthetics, and alcoholic beverages.
Mechanism of Action
Central nervous system:
Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. More specifically, ketamine binds to the allosteric site of the NMDA receptor, effectively inhibiting its channel. The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively. NMDAR antagonism effects analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine’s actions interfere with pain transmission in the spinal cord. Ketamine also inhibits nitric oxide synthase, inhibiting production of nitric oxide, a neurotransmitter involved in pain perception, and hence further contributing to analgesia. Ketamine also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.
Ketamine also interacts with a host of other receptors to effect analgesia. It blocks voltage-sensitive calcium channels and depressessodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it acts as a noradrenergic and serotonergic uptake inhibitor, which are involved in descending antinociceptive pathways.
It has been shown to be effective in treating depression in patients with bipolar disorderwho have not responded to anti-depressants. In persons with major depressive disorder, it produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work. It is also a popular anesthetic inveterinary medicine.
Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist. At high, fully anesthetic level doses, ketamine has also been found to bind to opioid μ receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity – and to sigma receptorsin rats. Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels. Like other drugs of this class such as tiletamine and phencyclidine (PCP), it induces a state referred to as “dissociative anesthesia” and is used as a recreational drug.
Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine areracemic; however, some brands reportedly have (mostly undocumented) differences inenantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S. Ketamine is a core medicine in theWorld Health Organization’s “Essential Drugs List”, a list of minimum medical needs for a basic healthcare system.
Medicinal Use
One 10ml vial of 1000mg Ketamine
Indications for use as an anaesthetic:
Pediatric anesthesia (as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and endotracheal intubation)
Asthmatics or patients with chronic obstructive airway disease
As part of a cream, gel, or liquid for topical application for nerve pain — the most common mixture is 10% ketoprofen, 5% Lidocaine, and 10% ketamine. Other ingredients found useful by pain specialists and their patients as well as the compounding pharmacists who make the topical mixtures include amitriptyline,cyclobenzaprine, clonidine, tramadol, and mepivicaine and other longer-acting local anaesthetics.
In emergency medicine if entrapped patient is suffering severe trauma
Emergency surgery in field conditions in war zones
To supplement spinal / epidural anesthesia / analgesia utilizing low doses
In medical settings, ketamine is usually injected intravenously or intramuscularly. Since it suppresses breathing much less than most other available anaesthetics, ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations which may be caused by ketamine, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available. Ketamine tends to increase heart rate and blood pressure. Because ketamine tends to increase or maintain cardiac output, it is sometimes used in anesthesia for emergency surgery when the patient’s fluid volume status is unknown (e.g., from traffic accidents). Ketamine can be used in podiatry and other minor surgery, and occasionally for the treatment of migraine. There is ongoing research in France, the Netherlands, Russia, Australia and the US into the drug’s usefulness in pain therapy, depression, and for the treatment ofalcoholism and heroin addiction.
In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. 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 sometimesguaifenesin.
Ketamine may be used in small doses (0.1–0.5 mg/kg·h) as a local anesthetic, particularly for the treatment of pain associated with movement and neuropathic pain. It may also be used as an intravenous co-analgesic together with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic (pain due to vascular insufficiency or shingles are good examples). It has the added benefit of counter-acting 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 a co-analgesic, and so is most effective when used alongside a low-dose opioid; while it does have analgesic effects by itself, the higher doses required can cause disorienting side effects. The combination of ketamine with an opioid is, however, particularly useful for pain caused by cancer.
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 also a potent analgesic and can be used in sub-anesthetic doses to relieve acute pain; however, its psychotropic properties must be taken into account. Patients have reported vivid hallucinations, “going into other worlds” or “seeing God” while anesthetized, and these unwanted psychological side-effects have reduced the use of ketamine in human medicine. They can, however, usually be avoided by concomitant application of a sedative such as a benzodiazepine.
Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS), according to a retrospective review published in the October 2004 issue of Pain Medicine.Although low-dose ketamine therapy is established as a generally safe procedure, reported side effects in some patients have included hallucinations, dizziness, lightheadedness and nausea. Therefore nurses administering ketamine to patients with CRPS should do so only in a setting where a trained physician is available if needed to assess potential adverse effects on patients.
In some neurological ICUs, ketamine has been used in cases of prolonged seizures. There has been some evidence that the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.
Pain Management
The dissociative anesthetic effects of ketamine have also been applied within the realm of postoperative pain management. Low doses of ketamine have been found to significantly reduce morphine consumption as well as reports of nausea following abdominal surgery.
Oral Ketamine
Ketamine can be started using the oral route or patients may be changed from a subcutaneous infusion when pain is controlled.
Starting dose: 5-10mg four times daily.
Increase dose in 5-10mg increments.
Usual dose range: 10mg-60mg four times daily.
Subcutaneous ketamine infusion
Starting dose: 50-150mg/24 hours.
Review daily; increase dose in 50-100mg increments.
Usual dose range: 50mg- 600mg/24 hours
Converting from a 24 hour SC ketamine infusion to oral ketamine
Oral ketamine is more potent than SC ketamine (due to liver metabolism). Many patients require a dose reduction of 25-50% when changing to oral ketamine.
Titrate dose in 5-10mg increments.
Some specialists stop the SC infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.
Side Effects
Short Term
Up to 40% of patients may experience side effects with continuous subcutaneous infusion (side effects are less common upon oral administration). These include:
Delirium
Dizziness
Diplopia
Blurred Vision
Nystagmus
Altered Hearing
Hypertension
Tachycardia
Hypersalivation
Nausea and Vomiting
Erythema
Pain at Injection Site
Psychomimetic Phenomenon
Euphoria
Aphasia
Blunted Affect
Psychomotor Retardation
Vivid Dreams
Nightmares
Impaired Attention, Memory and Judgement
Illusions
Hallucinations
Altered Body Image
Tonic-clonic movements are also reported at higher anesthetic doses in greater than 10% of patients.
Long Term
Because ketamine is typically administered as a few repeated doses in a clinical setting, long-term effects are primarily reported and investigated in recreational ketamine users.
Neurological Effects
Main article:
Olney’s lesions
Chronic use of ketamine may lead to cognitive impairments including memory problems. In 1989, psychiatry professor John Olneyreported that ketamine caused irreversible changes in two small areas of the rat brain, which however has significant differences in metabolism from the human brain and therefore may not occur in humans.
The first large-scale, longitudinal study of ketamine users found that heavy ketamine users had impaired memory by several measures, including verbal, short-term memory and visual memory. However, occasional (1-2 times per month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests that occasional use of ketamine does not lead to prolonged harm and that any damage that might occur may be reversible when ketamine use is stopped; however, depression worsened even in the abstinent user group over the period of the study (one year), along with dissociative symptoms still existing among infrequent users.
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 non-cell-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 that 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 morphology and thus might lead to dysfunctions of neural networks.
There is a long list of medicines that could counteract these potential toxic effects, including clonidine,anticholinergics, benzodiazepines, barbiturates and risperidone.
Urinary Tract Effects
According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist. 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 it has been suggested that mononuclear inflammatoryinfiltration in the renal papilla resulting from ketamine dependence is 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 grams per day reported symptoms of the lower urinary tract. Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug 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 combinedpentosan polysulphate 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 polysulphate, or both. Further follow-up is required to fully assess the efficacy of these treatments.
Case reports of Hepato-Toxicity in Chronic Pain Management
In case reports of three patients treated with S(+)ketamine 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 that liver enzymes have to be monitored during such treatment.
Drug Interactions
Ketamine may increase the effects of other sedatives, including but not limited to: benzodiazepines, barbiturates, opiates/opioids,anesthetics, and alcoholic beverages.
Mechanism of Action
Central nervous system:
Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. More specifically, ketamine binds to the allosteric site of the NMDA receptor, effectively inhibiting its channel. The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively. NMDAR antagonism effects analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine’s actions interfere with pain transmission in the spinal cord. Ketamine also inhibits nitric oxide synthase, inhibiting production of nitric oxide, a neurotransmitter involved in pain perception, and hence further contributing to analgesia. Ketamine also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.
Ketamine also interacts with a host of other receptors to effect analgesia. It blocks voltage-sensitive calcium channels and depressessodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it acts as a noradrenergic and serotonergic uptake inhibitor, which are involved in descending antinociceptive pathways.
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