Etomidate

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Etomidate
Etomidate.svg
(R)-etomidate
Clinical data
Trade names Amidate, Hypnomidate, Tomvi
AHFS/Drugs.com Monograph
License data
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 76%
Metabolism Ester hydrolysis in plasma and liver
Elimination half-life 75 minutes
Excretion Urine (85%) and Bile duct (15%)
Identifiers
  • Ethyl 3-[(1R)-1-phenylethyl]imidazole-5-carboxylate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.046.700 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H16N2O2
Molar mass 244.294 g·mol−1
3D model (JSmol)
Melting point 67 °C (153 °F)
Boiling point 392 °C (738 °F)
  • O=C(OCC)c1cncn1C(c2ccccc2)C
  • InChI=1S/C14H16N2O2/c1-3-18-14(17)13-9-15-10-16(13)11(2)12-7-5-4-6-8-12/h4-11H,3H2,1-2H3 Yes check.svgY
  • Key:NPUKDXXFDDZOKR-UHFFFAOYSA-N Yes check.svgY
   (verify)

Etomidate [3] (USAN, INN, BAN; marketed as Amidate) is a short-acting intravenous anaesthetic agent used for the induction of general anaesthesia and sedation [4] for short procedures such as reduction of dislocated joints, tracheal intubation, cardioversion and electroconvulsive therapy. It was developed at Janssen Pharmaceutica in 1964 and was introduced as an intravenous agent in 1972 in Europe and in 1983 in the United States. [5]

Contents

The most common side effects include venous pain on injection and skeletal muscle movements. [6]

Medical uses

Sedation and anesthesia

In emergency settings, etomidate can be used as a sedative hypnotic agent. It is used for conscious sedation [7] [8] and as a part of a rapid sequence induction to induce anaesthesia. [9] [10] It is used as an anaesthetic agent since it has a rapid onset of action and a safe cardiovascular risk profile, and therefore is less likely to cause a significant drop in blood pressure than other induction agents. [11] [12] In addition, etomidate is often used because of its easy dosing profile, limited suppression of ventilation, lack of histamine liberation and protection from myocardial and cerebral ischemia. [10] Thus, etomidate is a good induction agent for people who are hemodynamically unstable. [9] Etomidate also has interesting characteristics for people with traumatic brain injury because it is one of the only anesthetic agents able to decrease intracranial pressure and maintain a normal arterial pressure. [5] [13] [14] [15] [16]

In those with sepsis, one dose of the medication does not appear to affect the risk of death. [17]

Speech and memory test

Another use for etomidate is to determine speech lateralization in people prior to performing lobectomies to remove epileptogenic centres in the brain. This is called the etomidate speech and memory test, or eSAM, and is used at the Montreal Neurological Institute. [18] [19] However, only retrospective cohort studies support the use and safety of etomidate for this test. [20]

Steroidogenesis inhibitor

In addition to its action and use as an anesthetic, etomidate has also been found to directly inhibit the enzymatic biosynthesis of steroid hormones, including corticosteroids in the adrenal gland. [21] [22] As the only adrenal steroidogenesis inhibitor available for intravenous or parenteral administration, it is useful in situations in which rapid control of hypercortisolism is necessary or in which oral administration is unfeasible. [21] [22] [23]

Use in executions

The U.S. state of Florida used the drug in a death penalty procedure when Mark James Asay, 53, was executed on August 24, 2017. He became the first person in the U.S. to be executed with etomidate as one of the drugs. Etomidate replaces midazolam as the sedative. Drug companies have made it harder to buy midazolam for executions. The etomidate was followed by rocuronium bromide, a paralytic, and finally, potassium acetate in place of the commonly used potassium chloride injection to stop the heart. Potassium acetate was first used for this purpose inadvertently in a 2015 execution in Oklahoma. [24]

Adverse effects

Etomidate suppresses corticosteroid synthesis in the adrenal cortex by reversibly inhibiting 11β-hydroxylase, an enzyme important in adrenal steroid production; it leads to primary adrenal suppression. [25] [26] Using a continuous etomidate infusion for sedation of critically ill trauma patients in intensive care units has been associated with increased mortality due to adrenal suppression. [27] Continuous intravenous administration of etomidate leads to adrenocortical dysfunction. The mortality of patients exposed to a continuous infusion of etomidate for more than 5 days increased from 25% to 44%, mainly due to infectious causes such as pneumonia. [27]

Because of etomidate-induced adrenal suppression, its use for patients with sepsis is controversial. Cortisol levels have been reported to be suppressed up to 72 hours after a single bolus of etomidate in this population at risk for adrenal insufficiency. [10] For this reason, many authors have suggested that etomidate should never be used for critically ill patients with septic shock [28] [29] [30] because it could increase mortality. [30] [31] However, other authors continue to defend etomidate's use for septic patients because of etomidate's safe hemodynamic profile and lack of clear evidence of harm. [13] [32] A study by Jabre et al. showed that a single dose of etomidate used for Rapid Sequence Induction prior to endrotracheal intubation has no effect on mortality compared to ketamine even though etomidate did cause transient adrenal suppression. [33] In addition, a recent meta-analysis done by Hohl could not conclude that etomidate increased mortality. [10] The authors of this meta-analysis concluded more studies were needed because of lack of statistical power to conclude definitively about the effect of etomidate on mortality. Thus, Hohl suggests a burden to prove etomidate is safe for use in septic patients, and more research is needed before it is used. [10] Other authors [34] [35] [36] advise giving a prophylactic dose of steroids (e.g. hydrocortisone) if etomidate is used, but only one small prospective controlled study [36] in patients undergoing colorectal surgery has verified the safety of giving stress dose corticosteroids to all patients receiving etomidate.

In a retrospective review of almost 32,000 people, etomidate, when used for the induction of anaesthesia, was associated with a 2.5-fold increase in the risk of dying compared with those given propofol. [37] People given etomidate also had significantly greater odds of having cardiovascular morbidity and significantly longer hospital stay. [37] Given the retrospective design of this study, it is difficult to draw any firm conclusions from the data.

In people with traumatic brain injury, etomidate use is associated with a blunting of an ACTH stimulation test. [26] The clinical impact of this effect has yet to be determined.

In addition, concurrent use of etomidate with opioids and/or benzodiazepines, is hypothesized to exacerbate etomidate-related adrenal insufficiency. [38] [39] However, only retrospective evidence of this effect exists and prospective studies are needed to measure the clinical impact of this interaction.

Etomidate is associated with a high incidence of burning on injection, postoperative nausea and vomiting, and superficial thrombophlebitis (with rates higher than propofol). [40]

Pharmacology

Side view of the EM structure of the a1b3g2 GABAA receptor. GABA and etomidate are coloured magenta. Subunits in different colours. One alpha and one beta subunit is hidden. Green chloride ions illustrated in the channel pore. 6x3v GABAA-Rezeptorstruktur.png
Side view of the EM structure of the α1β3γ2 GABAA receptor. GABA and etomidate are coloured magenta. Subunits in different colours. One alpha and one beta subunit is hidden. Green chloride ions illustrated in the channel pore.

Pharmacodynamics

(R)-Etomidate is tenfold more potent than its (S)-enantiomer. At low concentrations (R)-etomidate is a modulator at GABAA receptors [42] containing β2 and β3 [43] subunits. At higher concentrations, it can elicit currents in the absence of GABA and behaves as an allosteric agonist. Its binding site is located in the transmembrane section of this receptor between the beta and alpha subunits (β+α−). β3-containing GABAA receptors are involved in the anesthetic actions of etomidate, while the β2-containing receptors are involved in some of the sedation and other actions that can be elicited by this drug. [44]

Pharmacokinetics

At the typical dose, anesthesia is induced for the duration of about 5–10 minutes, though the half-life of drug metabolism is about 75 minutes, because etomidate is redistributed from the plasma to other tissues.

Metabolism

Etomidate is highly protein-bound in blood plasma and is metabolised by hepatic and plasma esterases to inactive products. It exhibits a biexponential decline.[ citation needed ]

Formulation

Etomidate is usually presented as a clear colourless solution for injection containing 2 mg/mL of etomidate in an aqueous solution of 35% propylene glycol, although a lipid emulsion preparation (of equivalent strength) has also been introduced. Etomidate was originally formulated as a racemic mixture, [45] but the R form is substantially more active than its enantiomer. [46] It was later reformulated as a single-enantiomer drug, becoming the first general anesthetic in that class to be used clinically. [47]

Society and culture

Etomidate has been made into an e-cigarette liquid known as space oil (Chinese :太空油) in Hong Kong since 2023, and may be mixed with other drugs, including cannabis and ketamine. [48] [49]

Hong Kong

Etomidate is regulated as Part 1 poison under the Pharmacy and Poisons Regulations (Cap. 138A), which states that possessing etomidate without provisions is punishable by a fine of up to HK$100,000 and imprisonment for two years. [50] Due to the increasing imports of space oil, the 2024 Policy Address has stated that the control of etomidate will be tightened. Etomidate will be classed as a controlled drug on 14 February 2025 by the Dangerous Drugs Ordinance (Cap. 134), which states that illegal possession or smoking, inhaling, ingesting and injecting space oil is liable to a maximum penalty of imprisonment of seven years and a fine of HK$1,000,000, while trafficking or illegal importing etomidate is liable to a maximum penalty of life imprisonment and a fine of HK$5,000,000. [48] [51]

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ "Summary Basis of Decision (SBD) for Tomvi". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  3. ↑ US Patent 3354173 'Imidazole carboxylates'
  4. ↑ Vinson DR, Bradbury DR (June 2002). "Etomidate for procedural sedation in emergency medicine". Annals of Emergency Medicine. 39 (6): 592–598. doi:10.1067/mem.2002.123695. PMID   12023700.
  5. 1 2 3 Bergen JM, Smith DC (1998). "A review of etomidate for rapid sequence intubation in the emergency department". The Journal of Emergency Medicine. 15 (2): 221–230. doi:10.1016/S0736-4679(96)00350-2. PMID   9144065.
  6. ↑ "Coronavirus (COVID-19) Update: December 22, 2020". U.S. Food and Drug Administration. 22 December 2020. Retrieved 23 December 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. ↑ Di Liddo L, D'Angelo A, Nguyen B, Bailey B, Amre D, Stanciu C (October 2006). "Etomidate versus midazolam for procedural sedation in pediatric outpatients: a randomized controlled trial". Annals of Emergency Medicine. 48 (4): 433–40, 440.e1. doi:10.1016/j.annemergmed.2006.03.004. PMID   16997680.
  8. ↑ Miner JR, Danahy M, Moch A, Biros M (January 2007). "Randomized clinical trial of etomidate versus propofol for procedural sedation in the emergency department". Annals of Emergency Medicine. 49 (1): 15–22. doi:10.1016/j.annemergmed.2006.06.042. PMID   16997421.
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  10. 1 2 3 4 5 Hohl CM, Kelly-Smith CH, Yeung TC, Sweet DD, Doyle-Waters MM, Schulzer M (August 2010). "The effect of a bolus dose of etomidate on cortisol levels, mortality, and health services utilization: a systematic review". Annals of Emergency Medicine. 56 (2): 105–13.e5. doi:10.1016/j.annemergmed.2010.01.030. PMID   20346542.
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  21. 1 2 Davies TF (2015). A Case-Based Guide to Clinical Endocrinology. Springer. pp. 11–. ISBN   978-1-4939-2059-4.
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  27. 1 2 Ledingham IM, Watt I (June 1983). "Influence of sedation on mortality in critically ill multiple trauma patients". Lancet. 1 (8336): 1270. doi:10.1016/S0140-6736(83)92712-5. PMID   6134053. S2CID   305277.
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  36. 1 2 Stuttmann R, Allolio B, Becker A, Doehn M, Winkelmann W (September 1988). "[Etomidate versus etomidate and hydrocortisone for anesthesia induction in abdominal surgical interventions]". Der Anaesthesist. 37 (9): 576–582. PMID   3056084.
  37. 1 2 Komatsu R, You J, Mascha EJ, Sessler DI, Kasuya Y, Turan A (December 2013). "Anesthetic induction with etomidate, rather than propofol, is associated with increased 30-day mortality and cardiovascular morbidity after noncardiac surgery". Anesthesia and Analgesia. 117 (6): 1329–1337. doi: 10.1213/ANE.0b013e318299a516 . PMID   24257383. S2CID   23165849.
  38. ↑ Daniell H (November 2008). "Opioid and benzodiazepine contributions to etomidate-associated adrenal insufficiency". Intensive Care Medicine. 34 (11): 2117–8. doi: 10.1007/s00134-008-1264-8 . PMID   18795258. S2CID   36288054.
  39. ↑ Daniell HW (December 2008). "Opioid contribution to decreased cortisol levels in critical care patients". Archives of Surgery. 143 (12): 1147–1148. doi:10.1001/archsurg.143.12.1147. PMID   19075164.
  40. ↑ Kosarek L, et al. Increase in Venous Complications Associated With Etomidate Use During a Propofol Shortage: An Example of Clinically Important Adverse Effects Related to Drug Substitution. The Ochsner Journal. 2011;11:143-146.
  41. ↑ Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, et al. (September 2020). "Shared structural mechanisms of general anaesthetics and benzodiazepines". Nature. 585 (7824): 303–308. doi:10.1038/s41586-020-2654-5. PMC   7486282 . PMID   32879488.{{cite journal}}: CS1 maint: overridden setting (link)
  42. ↑ Vanlersberghe C, Camu F (2008). "Etomidate and other non-barbiturates". Modern Anesthetics. Handbook of Experimental Pharmacology. Vol. 182. Springer. pp. 267–282. doi:10.1007/978-3-540-74806-9_13. ISBN   978-3-540-72813-9. PMID   18175096.
  43. ↑ Drexler B, Jurd R, Rudolph U, Antkowiak B (September 2009). "Distinct actions of etomidate and propofol at beta3-containing gamma-aminobutyric acid type A receptors". Neuropharmacology. 57 (4): 446–455. doi:10.1016/j.neuropharm.2009.06.014. PMID   19555700. S2CID   26796180.
  44. ↑ Chiara DC, Dostalova Z, Jayakar SS, Zhou X, Miller KW, Cohen JB (January 2012). "Mapping general anesthetic binding site(s) in human α1β3 γ-aminobutyric acid type A receptors with [³H]TDBzl-etomidate, a photoreactive etomidate analogue". Biochemistry. 51 (4): 836–847. doi:10.1021/bi201772m. PMC   3274767 . PMID   22243422.
  45. ↑ International Non-Proprietary Names for Pharmaceutical Preparations – Rec. I.N.N. List 6
  46. ↑ Servin FS, Sear JW (2011). "Chapter 27. Pharmacokinetics of intravenous anesthetics". In Evers AS, Maze M, Kharasch ED (eds.). Anesthetic Pharmacology: Basic Principles and Clinical Practice (2nd ed.). Cambridge University Press.
  47. ↑ Tomlin SL, Jenkins A, Lieb WR, Franks NP (March 1998). "Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals". Anesthesiology. 88 (3): 708–717. doi: 10.1097/00000542-199803000-00022 . PMID   9523815. S2CID   11665790.
  48. 1 2 "LCQ7: Combating vaping of "space oil"" (Press release). Government of Hong Kong Special Administrative Region. 2024-10-23. Retrieved 2025-01-15.
  49. ↑ "Narcotics Division, Security Bureau - Space Oil Drug". Narcotics Division of the Security Bureau . Retrieved 2025-01-15.
  50. ↑ "Customs seizes suspected space oil, and illicit cigarettes at West Kowloon Station". The Standard . 2025-01-06. Retrieved 2025-01-15.
  51. ↑ Wang W, Lam E (2025-01-14). "'Space oil' to be classed as a controlled drug from February 14". The Standard.

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