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The Journal of Pharmacology and... Dec 2022Although propofol is among the most commonly administered general anesthetics, its mechanism of action is not fully understood. It has been hypothesized that propofol...
Although propofol is among the most commonly administered general anesthetics, its mechanism of action is not fully understood. It has been hypothesized that propofol acts via a similar mechanism as (R)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (etomidate) by binding within the GABA receptor transmembrane receptor domain at the two / subunit interfaces with resultant positive allosteric modulation. To test this hypothesis, we leveraged the ability of diazepam to bind to those sites and act as a competitive antagonist. We used oocyte-expressed GABA receptors to define the actions of diazepam (± flumazenil) on currents activated or potentiated by propofol and a zebrafish activity assay to define the impact of diazepam and flumazenil on propofol-induced anesthesia. We found that diazepam increased the amplitudes of GABA receptor-mediated currents at nanomolar concentrations but reduced them at micromolar concentrations. The current amplitude changes produced by nanomolar diazepam concentrations were inhibited by flumazenil whereas those produced by micromolar diazepam concentrations were not. Studies of agonist potentiation showed that the micromolar inhibitory action of diazepam was surmountable by high concentrations of propofol and produced a rightward shift in the propofol concentration-response curve characterized by a Schild slope not statistically significantly different from 1, consistent with competition between diazepam and propofol. Although micromolar concentrations of diazepam (plus flumazenil) similarly reduced GABA receptor currents modulated by propofol and etomidate, it only reduced the anesthetic actions of etomidate. We conclude that while both propofol and etomidate can modulate GABA receptors by binding to the / subunit interfacial sites, propofol-induced anesthesia likely involves additional target sites. SIGNIFICANCE STATEMENT: Although the drug combination of diazepam and flumazenil reverses the GABA receptor positive modulatory actions of both propofol and ()-ethyl 1-(1-phenylethyl)-1-imidazole-5-carboxylate (etomidate), it only reverses the in vivo anesthetic actions of etomidate. These results strongly suggest that distinct mechanisms of action account for the anesthetic actions of these two commonly administered anesthetic agents.
Topics: Animals; Receptors, GABA-A; Propofol; Diazepam; Zebrafish; Etomidate; gamma-Aminobutyric Acid
PubMed: 36167415
DOI: 10.1124/jpet.122.001337 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jan 2021To explore the effect of etomidate on the neuronal activity of ventral thalamic reuniens nucleus and the underlying mechanisms.
OBJECTIVES
To explore the effect of etomidate on the neuronal activity of ventral thalamic reuniens nucleus and the underlying mechanisms.
METHODS
Whole-cell patch clamp method was used to explore the effect of etomidate on the activity of ventral thalamic reuniens neurons in the acute brain slices obtained from 4-5 weeks old C57BL/6J mice. The electrophysiological characteristics of ventral thalamic reuniens neurons were recorded in the current clamp mode, and then the effects of etomidate (0.5, 2.0, 8.0 μmol/L etomidate groups) and intralipid (intralipid group) on the discharge frequency and membrane potential of ventral thalamic reuniens neurons were recorded. During the experiment, the ventral thalamic reuniens neuron firing rates (RNFRs) were recorded as F, F and F before, after administration, and after elution; and the membrane potential was recorded as MP and MP before, after administration. The chlorine channel of gamma-amino butyric acid Type A (GABAA) receptor was blocked with 100 μmol/L picrotoxin (PTX). The RNFRs were recorded as F, F and F before, after perfusing etomidate with sub-anesthesia concentration (0.5 μmol/L) and after perfusing both PTX and etomidate.
RESULTS
In the intralipid group, there was no significant difference among the F, F and F (>0.05). But in the etomidate groups (0.5, 2.0, 8.0 μmol/L), the F was less than the F, there was significant difference (all <0.01); the F was higher than the F, there was significant difference (all <0.05). Moreover, there was significant difference in the inhibitory degree of the RNFRs between the 0.5 μmol/L etomidate group and the 8.0 μmol/L etomidate group (<0.05). In the experiment to explore the mechanism of etomidate (0.5 μmol/L), the F was compared with the F, there was significant difference (<0.01); but when the F was compared with the F, there was no significant difference (>0.05).
CONCLUSIONS
Etomidate can inhibit the activity of ventral thalamic reuniens neurons in concentration-dependent manner, and which is reversible. Etomidate with sub-anesthetic concentration inhibits the activity of ventral thalamic reuniens neurons via targeting the GABA receptor.
Topics: Animals; Etomidate; Mice; Mice, Inbred C57BL; Neurons; Patch-Clamp Techniques; Receptors, GABA-A
PubMed: 33678635
DOI: 10.11817/j.issn.1672-7347.2021.190576 -
Emergency Medicine Journal : EMJ Nov 2004The ideal induction agent for emergency airway management should be rapidly acting, permit optimum intubating conditions, and be devoid of significant side effects. This... (Review)
Review
The ideal induction agent for emergency airway management should be rapidly acting, permit optimum intubating conditions, and be devoid of significant side effects. This review was performed to ascertain whether etomidate should be the induction agent of choice for rapid sequence intubation (RSI) in the emergency department, specifically examining its pharmacology, haemodynamic profile, and adrenocortical effects. A search of Medline (1966-2002), Embase (1980-2002), the Cochrane controlled trials register, and CINAHL was performed. In addition, the major emergency medicine and anaesthesia journals were hand searched for relevant material. Altogether 144 papers were identified of which 16 were relevant. Most studies were observational studies or retrospective reviews with only one double blind randomised controlled trial and one un-blinded randomised controlled trial. Appraisal of the available evidence suggests that etomidate is an effective induction agent for emergency department RSI; it has a rapid onset of anaesthesia and results in haemodynamic stability, even in hypovolaemic patients or those with limited cardiac reserve. Important questions regarding the medium to long term effects on adrenocortical function (even after a single dose) remain unanswered.
Topics: Adrenal Cortex Hormones; Anesthetics, Intravenous; Cerebrovascular Circulation; Emergencies; Emergency Treatment; Etomidate; Hemodynamics; Humans; Intubation, Intratracheal
PubMed: 15496686
DOI: 10.1136/emj.2003.009043 -
Critical Care (London, England) Jul 2012Etomidate is an induction agent known for its smooth intubating conditions and cardiovascular stability. Studies, however, have shown that a single dose of etomidate can... (Review)
Review
Etomidate is an induction agent known for its smooth intubating conditions and cardiovascular stability. Studies, however, have shown that a single dose of etomidate can result in a prolonged adrenal insufficiency. The impact of this in patients with sepsis has been a matter for debate. This review presents a pro/con case for using etomidate in hemodynamically unstable critically ill patients and provides guidance for alternative induction techniques and when the use of etomidate might be justified despite these concerns.
Topics: Adrenal Insufficiency; Critical Care; Critical Illness; Etomidate; Hemodynamics; Humans; Hypnotics and Sedatives; Intubation, Intratracheal; Patient Safety
PubMed: 22809235
DOI: 10.1186/cc11242 -
Hormones (Athens, Greece) Dec 2022Endogenous Cushing's syndrome (CS) is associated with increased morbidity and mortality. Early diagnosis and initiation of therapy are essential, but effective treatment... (Review)
Review
Endogenous Cushing's syndrome (CS) is associated with increased morbidity and mortality. Early diagnosis and initiation of therapy are essential, but effective treatment remains a challenge. In a long-term follow-up, biochemical control of hypercortisolemia, especially when severe, is difficult to achieve. Life-threatening hypercortisolemia is difficult to control due to the limitations of pharmacotherapy, including its side effects, and may require etomidate infusion in the intensive care unit (ICU) to rapidly lower cortisol levels. The effectiveness of hypercortisolemia management can be increased by a dual blockade of cortisol production. We report the efficacy, safety, and tolerability of combined therapy with two steroidogenesis inhibitors, etomidate, and osilodrostat, in a 32-year-old woman diagnosed with severe ACTH-dependent hypercortisolemia, subsequently maintaining a stable level of cortisol with osilodrostat monotherapy. This approach enabled achievement of relatively rapid control of the hypercortisolemia while using an etomidate infusion and concomitant increasing doses of oral osilodrostat applying a "titrations strategy." Our experience shows that it is worth taking advantage of the synergistic anticortisolic action of etomidate with osilodrostat.
Topics: Female; Humans; Adult; Cushing Syndrome; Etomidate; Hydrocortisone; Imidazoles
PubMed: 36129663
DOI: 10.1007/s42000-022-00397-4 -
Molecular Pharmacology Jun 2021The anesthetic etomidate modulates synaptic 12/32 GABA receptors via binding sites located in transmembrane +/- interfaces. Various approaches indicate that etomidate...
Substituted Cysteine Modification and Protection with -Alkyl- Methanethiosulfonate Reagents Yields a Precise Estimate of the Distance between Etomidate and a Residue in Activated GABA Type A Receptors.
The anesthetic etomidate modulates synaptic 12/32 GABA receptors via binding sites located in transmembrane +/- interfaces. Various approaches indicate that etomidate binds near 2/3M286 side chains, including recent cryogenic electron microscopy images in 122L receptors under nonphysiologic conditions with ∼3.5-Å resolution. We hypothesized that substituted cysteine modification and protection experiments using variably sized -alkyl-methanethiosulfonate (MTS) reagents could precisely estimate the distance between bound etomidate and 3M286 side chains in activated functional receptors. Using voltage-clamp electrophysiology in oocytes expressing 13M286C2L GABA receptors, we measured functional changes after exposing GABA-activated receptors to -alkyl-MTS reagents, from methyl-MTS to -decyl-MTS. Based on previous studies using a large sulfhydryl reagent, we anticipated that cysteine modifications large enough to overlap etomidate sites would cause persistently increased GABA sensitivity and decreased etomidate modulation and that etomidate would hinder these modifications, reducing effects. Based on altered GABA or etomidate sensitivity, ethyl-MTS and larger -alkyl-MTS reagents modified GABA-activated 13M286C2L GABA receptors. Receptor modification by -propyl-MTS or larger reagents caused persistently increased GABA sensitivity and decreased etomidate modulation. Receptor-bound etomidate blocked 3M286C modification by -propyl-MTS, -butyl-MTS, and -hexyl-MTS. In contrast, GABA sensitivity was unaltered by receptor exposure to methyl-MTS or ethyl-MTS, and ethyl-MTS modification uniquely increased etomidate modulation. These results reveal a "cut-on" between ethyl-MTS and -propyl-MTS, from which we infer that --(-propyl) is the smallest 3M286C appendage that overlaps with etomidate sites. Molecular models of the native methionine and --ethyl and --(-propyl) modified cysteines suggest that etomidate is located between 1.7 and 3.0 Å from the 3M286 side chain. SIGNIFICANCE STATEMENT: Precise spatial relationships between drugs and their receptor sites are essential for mechanistic understanding and drug development. This study combined electrophysiology, a cysteine substitution, and -alkyl-methanethiosulfonate modifiers, creating a precise molecular ruler to estimate the distance between a α1β3γ2L GABA type A receptor residue and etomidate bound in the transmembrane +/- interface.
Topics: Anesthetics, Intravenous; Animals; Cysteine; Etomidate; Female; Humans; Indicators and Reagents; Mesylates; Receptors, GABA-A; Xenopus laevis; gamma-Aminobutyric Acid
PubMed: 33766924
DOI: 10.1124/molpharm.120.000224 -
Anesthesiology Aug 2009
Topics: Anesthesiology; Anesthetics; Anesthetics, Intravenous; Etomidate; Humans
PubMed: 19625797
DOI: 10.1097/ALN.0b013e3181ae8460 -
Anesthesiology Nov 2012Methoxycarbonyl etomidate is the prototypical soft etomidate analog. Because it has relatively low potency and is extremely rapidly metabolized, large quantities must be...
BACKGROUND
Methoxycarbonyl etomidate is the prototypical soft etomidate analog. Because it has relatively low potency and is extremely rapidly metabolized, large quantities must be infused to maintain hypnosis. Consequently with prolonged infusion, metabolite reaches sufficient concentrations to delay recovery. Dimethyl-methoxycarbonyl metomidate (DMMM) and cyclopropyl-methoxycarbonyl metomidate (CPMM) are methoxycarbonyl etomidate analogs with higher potencies and slower clearance. Because of these properties, we hypothesized that dosing would be lower and electroencephalographic and hypnotic recoveries would be faster - and less context-sensitive - with DMMM or CPMM versus methoxycarbonyl etomidate or etomidate.
METHODS
Etomidate, DMMM, and CPMM where infused into rats (n = 6 per group) for either 5 min or 120 min. After infusion termination, electroencephalographic and hypnotic recovery times were measured. The immobilizing ED50 infusion rates were determined using a tail clamp assay.
RESULTS
Upon terminating 5-min infusions, electroencephalographic and hypnotic recovery times were not different among hypnotics. However, upon terminating 120-min infusions, recovery times varied significantly with respective values (mean ± SD) 48 ± 13 min and 31 ± 6.5 min (etomidate), 17 ± 7.0 min and 14 ± 3.4 min (DMMM), and 4.5 ± 1.1 min and 4.2 ± 1.6 min (CPMM). The immobilizing ED50 infusion rates were (mean ± SD) 0.19 ± 0.03 mg · kg · min (etomidate), 0.60 ± 0.12 mg · kg · min (DMMM), and 0.89 ± 0.18 mg · kg · min (CPMM).
CONCLUSIONS
Electroencephalographic and hypnotic recoveries following prolonged infusions of DMMM and CPMM are faster than those following methoxycarbonyl etomidate or etomidate. In the case of CPMM infusion, recovery times are 4 min and context-insensitive.
Topics: Animals; Electroencephalography; Etomidate; Hypnotics and Sedatives; Infusions, Intravenous; Male; Rats; Rats, Sprague-Dawley; Reflex, Righting; Time Factors
PubMed: 22929726
DOI: 10.1097/ALN.0b013e31826d3de2 -
Drug Design, Development and Therapy 2013The aim of this study was to investigate and evaluate the safety, recovery time, and side effects of general anesthesia with different doses of etomidate emulsion... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The aim of this study was to investigate and evaluate the safety, recovery time, and side effects of general anesthesia with different doses of etomidate emulsion combined with remifentanil.
METHODS
One hundred ten patients of American Society of Anesthesiologists class 1 or 2 who underwent gynecological general anesthesia with a 1-3-hour operation time were randomly divided into the following groups: etomidate emulsion group 1 ([E1] n = 30); etomidate emulsion group 2 ([E2] n = 30); etomidate emulsion group 3 ([E3] n = 20); and propofol group ([P group] n = 30). For induction of anesthesia, 0.3 mg/kg etomidate emulsion, and the continuous remifentanil infusion also to induce anesthesia (0.1~0.3 μg · kg(-1) · min(-1)), was applied in all cases. Afterwards, continuous infusion of etomidate emulsion and remifentanil, respectively (E1: 10 μg · kg(-1) · min(-1) and 0.1 μg · kg(-1) · min(-1); E2: 15 μg · kg(-1) · min(-1) and 0.2 μg · kg(-1) · min(-1); E3: 20 μg · kg(-1) · min(-1) and 0.2 μg · kg(-1) · min(-1)), and propofol (P group: 6~10 mg · kg(-1) · h(-1)) were administered. Changes in blood flow kinetics and adverse reactions were noted and compared between the four groups.
RESULTS
Both arterial blood pressure (BP) and heart rate (HR) decreased after induction of anesthesia (P < 0.05). Systolic (SBP) and diastolic (DBP) BP changed only slightly, and HRs were slightly infected in E1, E2, and E3. SBP, DBP, and HR during the operation all decreased significantly in P group (P < 0.05). Muscle tremor at the time of induction occurred in 13 cases (11.8%). Following etomidate emulsion anesthesia maintenance, postoperative agitation occurred in seven cases (8.75%), lethargy in 20 cases (25%), and vomiting in 19 cases (23.75%). No adverse reactions were found in P group.
CONCLUSION
Continuous infusion of etomidate emulsion at 10 μg · kg(-1) · minute(-1) combined with remifentanil during anesthesia has the advantages of hemodynamic stability, quick wake-up, and few adverse reactions. Increasing the dose of etomidate emulsion increases the incidence of adverse reactions.
Topics: Adult; Anesthesia Recovery Period; Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Dose-Response Relationship, Drug; Emulsions; Etomidate; Female; Gynecologic Surgical Procedures; Heart Rate; Humans; Middle Aged; Piperidines; Propofol; Remifentanil
PubMed: 23990706
DOI: 10.2147/DDDT.S45979 -
Anesthesiology Apr 2024Severe traumatic brain injury is a leading cause of morbidity and mortality among young people around the world. Prehospital care focuses on the prevention and treatment...
BACKGROUND
Severe traumatic brain injury is a leading cause of morbidity and mortality among young people around the world. Prehospital care focuses on the prevention and treatment of secondary brain injury and commonly includes tracheal intubation after induction of general anesthesia. The choice of induction agent in this setting is controversial. This study therefore investigated the association between the chosen induction medication etomidate versus S(+)-ketamine and the 30-day mortality in patients with severe traumatic brain injury who received prehospital airway management in the Netherlands.
METHODS
This study is a retrospective analysis of the prospectively collected observational data of the Brain Injury: Prehospital Registry of Outcomes, Treatments and Epidemiology of Cerebral Trauma (BRAIN-PROTECT) cohort study. Patients with suspected severe traumatic brain injury who were transported to a participating trauma center and who received etomidate or S(+)-ketamine for prehospital induction of anesthesia for advanced airway management were included. Statistical analyses were performed with multivariable logistic regression and inverse probability of treatment weighting analysis.
RESULTS
In total, 1,457 patients were eligible for analysis. No significant association between the administered induction medication and 30-day mortality was observed in unadjusted analyses (32.9% mortality for etomidate versus 33.8% mortality for S(+)-ketamine; P = 0.716; odds ratio, 1.04; 95% CI, 0.83 to 1.32; P = 0.711), as well as after adjustment for potential confounders (odds ratio, 1.08; 95% CI, 0.67 to 1.73; P = 0.765; and risk difference 0.017; 95% CI, -0.051 to 0.084; P = 0.686). Likewise, in planned subgroup analyses for patients with confirmed traumatic brain injury and patients with isolated traumatic brain injury, no significant differences were found. Consistent results were found after multiple imputations of missing data.
CONCLUSIONS
The analysis found no evidence for an association between the use of etomidate or S(+)-ketamine as an anesthetic agent for intubation in patients with traumatic brain injury and mortality after 30 days in the prehospital setting, suggesting that the choice of induction agent may not influence the patient mortality rate in this population.
Topics: Adolescent; Humans; Brain Injuries; Brain Injuries, Traumatic; Cohort Studies; Emergency Medical Services; Etomidate; Intubation, Intratracheal; Ketamine; Retrospective Studies; Observational Studies as Topic
PubMed: 38190220
DOI: 10.1097/ALN.0000000000004894