The NMDA receptor is anchored in the membrane (sky blue) by the PSD‐95 protein, linked to the Src tyrosine kinase. The four sub‐units (2 NR1 and 2 NR2) form an NMDA receptor channel selective for the cathions, which is shown open in (A). (A) The binding site of glutamate (red polyhedron), selectively activated by NMDA, is in ABD clam shaped NR2 subunit. The site for glycine (dark blue polyhedron), which acts as a co‐agonist of glutamate, is located in the ABD area of the NR1 subunit.
For example, some experts have attributed the higher incidence of ulcerative cystitis in recreational users to the adulterants with which the drug is mixed. Emergency medicine providers should be aware of the various mechanisms to treat ketamine toxicity and to prevent acute complications such as rhabdomyolysis, seizures, and chronic complications such as psychiatric disturbances and ulcerative cystitis. The 12 included studies comprised 1 controlled trial, 2 retrospective case series, and 9 case reports.
Clinical trials confirm ketamine’s effectiveness in reducing depressive symptoms, though its impact is often transient, lasting one to two weeks after infusion, with limited long-term effects reported8,9. Nurses and pharmacists can play a crucial role during ordering and administration, guarding against improper dosing and checking for adverse events and drug interactions. Important discharge education includes informing patients not to drive, use heavy machinery, or perform potentially hazardous activities for 24 hours after the administration of ketamine. An interprofessional team approach is necessary to improve patient outcomes related to ketamine and minimize adverse drug reactions.
Given the safety concerns and risks, including its potential for abuse, healthcare providers must follow strict guidelines to ensure ketamine’s safe use in clinical settings13. Healthcare providers need to apply these guidelines to ensure the safe and effective use of ketamine in clinical practice12. This review will cover safety considerations and risk mitigation strategies to minimize adverse effects and promote recovery.
- The onset of action occurs within approximately 10 to 30 seconds, while the duration of action lasts about 5 to 15 minutes.
- Program evaluation questionnaires classify participants into five groups by asking questions about age, gender, education level, what they know about ketamine, and how to detect the stage of ketamine cessation.
- Ketamine is highly effective for brief medical procedures that do not necessitate skeletal muscle relaxation and can be utilized as a pre-anesthetic for the induction of general anesthesia when combined with other general anesthetic agents.
- Receptor activation requires the simultaneous binding of one glycine molecule at a separate site in the ABD area on NR1 unit.
- Despite its rapid antidepressant effects, more rigorous empirical research is needed to refine administration protocols and evaluate long-term safety and efficacy across diverse populations.
- Low intravenous doses of ketamine have shown comparable analgesic efficacy to IV morphine for acute pain but are typically combined with other pain medications.
Consequences of the Opening of the NMDA Channel
Salicylate toxicity is another entity that can be a diagnostic challenge, and serum concentrations can help guide management. In conclusion, ketamine toxicity and addiction pose significant risks to a small segment of the population, and given increasing utilization, the prevalence of these phenomena is expected to increase. Having been in use for more than 50 years, ketamine has proven to be a safe anesthetic drug with potent analgesic properties.
Ketamine could allow the identification of a biophysical or biochemical process implicated in psychosis or the evaluation of the antipsychotic efficiency of a molecule susceptible to inhibit ketamine effects in healthy volunteers 57. On a neurophysiological basis, prefrontal cortex 58 and locus ceruleus 59 activation has been demonstrated. From a pharmacological point of view, there is an alteration 60, also a possible hypofunction 61 of NMDA receptors, with a hyperglutamatergic state 62. Positive drug screens in patients without clinical symptoms may reflect the detection of metabolites and previous use, and not lead to any changes in management.
Adverse effects of ketamine use
While consent is recommended before such testing, some patients may not be able to provide consent for whatever reason. In such scenarios, as long as the clinician is acting in good faith for the benefit of the patient or a legal warrant, then testing can be done without consent. Both before and after ketamine administration, monitoring CV, neuropsychiatric, and GI markers is critical for managing treatment-emergent adverse events (TEAEs). Adverse event monitoring strategies include pre-treatment physical and mental examinations, continuous CV monitoring, and patient supervision for neuropsychiatric symptoms such as dissociation and psychotomimetic effects45. Furthermore, GI problems can be addressed by fasting before administration, using antiemetics, and educating patients about typical side effects, with emergency measures in place for extreme responses46,47.
Provenance and peer review
- Independently of its action on NMDA receptors, ketamine might directly inhibit NO‐synthase, which could act in its analgesic and anesthetic effects 114.
- All clinicians who administer ketamine should understand the indications and contraindications.
- Baseline psychiatric status should guide dosing, with lower doses for episodic depression and higher doses for chronic pain.
However, increasing cases of urological toxicity linked to ketamine misuse have led to usage restrictions in certain regions34,42. While intranasal (IN) esketamine is approved for treatment-resistant depression (TRD), regulations vary by country. Ketamine hydrochloride, commonly known as ketamine, is a medication approved by the United States Food and Drug Administration (FDA) for use as a general anesthetic either on its own or in combination with other medications. The medication is highly effective for brief medical procedures that do not necessitate skeletal muscle relaxation and can be utilized as a pre-anesthetic for the induction of general anesthesia when combined with other general anesthetic agents.
Treatment / Management
Cytochromes, belonging to the cytochromes P450 system and responsible for ketamine metabolism, are not totally identified 12, but in humans, several microsomal enzymes are responsible for norketamine demethylation. Ketamine has an inhibiting action on some cytochromes belonging to P450 complex, and this could partly explain the tachyphylaxis observed during the repeated use of the molecule 13. Ketamine is a hydrosoluble aryl‐cyclo‐alkylamine (Figure 1) with a ketamine toxicity statpearls ncbi bookshelf molecular mass of 238 g/mol and a pKa 7.5.
In addition to concurrent drugs, mental and medical comorbidities must be considered to properly manage any adverse effects. Concerning its distinct antidepressant profile, healthcare practitioners must employ monitoring techniques and protocols for ketamine-related side effects. The Ketamine Side Effect Tool (KSET) is a complete system built specifically for this purpose, with modules for screening, baseline assessment, acute therapy, and follow-up to measure both immediate and long-term adverse effects63. To address issues including momentary dissociation, hypertension, and nausea, practitioners should educate patients, maintain a calm treatment atmosphere, and be ready to change doses or deliver more drugs as needed. Specific tools such as the clinician-administered dissociative states scale (CADSS) are used to assess dissociation levels64. Ketamine toxicity can cause a variety of neurological, cardiovascular, psychiatric, urogenital, and abdominal symptoms, which are dose-dependent, and depend on whether ketamine administration was in an iatrogenic or illicit context.
Figure
Receptors composed of NR2A or NR1a subunits have an intermediate reactivity to pH with an IC50 (concentration inhibiting 50% of the receptors) of 6.9 pH units, while the NR2C units provide the receptor with virtual insensitivity. In contrast, receptors composed of NR1a/NR2B or NR1a/NR2D dimers are extremely sensitive to pH. Their IC50 close to pH 7.40 explains that, under normal conditions, half of these receptors are under the influence of a tonic inhibition of opening by protons. Thus, even moderate changes in pH can participate in the opening of these NMDA channels, which illustrates an additional pejorative aspect of alkalosis. The activation of NMDA receptors is rather complex, involving multiple agonists interacting in cooperation and regulatory mechanisms, which, on the contrary, favor the closed state of the channel. NMDA receptors have a binding site for glutamate, which is located on the ABD area of the NR2 unit (Figure 3A). Receptor activation requires the simultaneous binding of one glycine molecule at a separate site in the ABD area on NR1 unit.
EAU aims to warn about the dangerous impact of ketamine on the brain, applicable regulations and laws, and the risks and transmission methods of infectious diseases, such as HIV and hepatitis C83. According to the study, IBM is more effective at increasing awareness and knowledge about ketamine use and abuse (105). It causes muscle rigidity, spasms, or tonic-clonic movements similar to seizures, as well as increased skeletal muscle tone24. Ketamine also has a psychiatric effect such as amnesia, anxiety, sadness, disorientation, dysphoria, dissociative states, unusual thoughts, intense fear, exhilaration, illogical behavior, and sleeplessness25. Before administering ketamine, psychiatrists should assess the patient’s psychiatric history and screen for heart conditions, as ketamine can worsen issues like hypertension and arrhythmias11. Continuous monitoring of oxygen saturation and vital signs is crucial to ensure patient safety and hemodynamic stability12.
Cognitive disturbances are frequent in ketamine chronic users 143, as well as frontal white matter abnormalities 144. Ketamine and other NMDA receptor non‐competitive antagonists (PCP, MK801, dextromethorphan, and memantine 109) are fastened to an intrachannel site called phencyclidine site (Figure 3D). Ketamine decreases the amplification of the response to a repeated stimulation (stimuli summation called “wind up”, considered as an elementary form of sensitization of the CNS) 110, 111.
Especially in the presence of altered mental status, CNS infections such as meningitis and encephalitis, and CNS malignancies also merit consideration. Acute conditions affecting the central nervous system, such as head trauma and intracerebral hemorrhage, can cause mental status and vital sign changes that simulate ketamine toxicity. Acute systemic conditions such as hypoxia, hypoglycemia, sepsis, hyperthyroidism, and electrolyte abnormalities such as hyponatremia should be differentials.
Medical
The NTD domain of NR2A and NR2B subunits also plays an important role in NMDA receptor function modulation by selectively binding to non‐competitive antagonists. Allosteric sites of the NR2 subunit also allow positive or negative modulation of the activity of the NMDA receptor. Some ions play an important role in the regulation of the channel opening by altering the spatial conformation of the receptor. Ketamine interacts with many binding sites such as opioid, monoaminergic, cholinergic, nicotinic, and muscarinic receptors.
