Etomidate

Etomidate
(R)-etomidate
Names
Trade namesAmidate, Hypnomidate, others
IUPAC name
  • Ethyl 3-[(1R)-1-phenylethyl]imidazole-5-carboxylate
Clinical data
Drug classNonbarbiturate hypnotic[1]
Main usesGeneral anaesthesia, procedural sedation, tracheal intubation[2]
Side effectsPain at injection site, skeletal muscle movement[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: C (Risk not ruled out)
    BreastfeedingSafe[3]
    Routes of
    use    		Intravenous[2]
    Onset of actionWithin 1 min[2]
    Duration of actionUp to 10 min[2]
    Typical dose0.15–0.3 mg/kg[4]
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only
    Pharmacokinetics
    Protein binding76%
    MetabolismEster hydrolysis in plasma and liver
    Elimination half-life75 minutes
    ExcretionUrine (85%) and Bile duct (15%)
    Chemical and physical data
    FormulaC14H16N2O2
    Molar mass244.294 g·mol−1
    3D model (JSmol)
    Melting point67 °C (153 °F)
    Boiling point392 °C (738 °F)
    SMILES
    • O=C(OCC)c1cncn1C(c2ccccc2)C
    InChI
    • 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 checkY
    • Key:NPUKDXXFDDZOKR-UHFFFAOYSA-N checkY

    Etomidate, sold as Amidate among others, is a medication used to start general anaesthesia and for sedation for procedures such as joint reduction, cardioversion, or tracheal intubation.[2] Onset of effects is within a minute and last up to 10 minutes.[2] It is given by slow injection into a vein.[2][4]

    Common side effects include pain at the site of injection and skeletal muscle movement.[2] Other side effects may include apnea, low blood pressure, vomiting, adrenal insufficiency, and increased salivation.[4] Thought, it is generally stable from a blood pressure point of view.[5] Muscle movements may be decreased with the use of fentanyl.[2] Breastfeeding after use is safe.[3] People are advised not to drive for at least 24 hours after use.[4] It works by binding to GABA receptors.[5]

    Etomidate was developed in 1964 and was approved for medical use in 1972 in Europe and in 1982 in the United States.[6][7][2] It is avaliable as a generic medication.[8] In the United Kingdom, it costs the NHS about 1.4 pound per 2 mg dose as of 2020.[4]

    Medical uses

    Sedation and anesthesia

    In emergency settings, etomidate was one of the most frequently used sedative hypnotic agents, however propofol is now usually the drug of choice due to its significantly better properties. It is used for conscious sedation[9][10] and as a part of a rapid sequence induction to induce anaesthesia.[11][12] 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.[13][14] 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.[12] Thus, etomidate is a good induction agent for people who are hemodynamically unstable.[11] 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.[7][15][16][17][18]

    In those with sepsis, one dose of the medication does not appear to affect the risk of death.[19]

    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.[20][21] However, only retrospective cohort studies support the use and safety of etomidate for this test.[22]

    Steroid 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.[23][24] As the only adrenal steroidogenesis inhibitor available for intravenous administration, it is useful in situations in which rapid control of hypercortisolism is necessary or in which by mouth administration is not feasible.[23][24][25]

    Dosage

    The typical dose is 0.15 to 0.3 mg per kg.[4]

    Side 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.[26][27] 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.[28] 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.[28]

    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.[12] For this reason, many authors have suggested that etomidate should never be used for critically ill patients with septic shock[29][30][31] because it could increase mortality.[31][32] 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.[15][33] 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.[34] In addition, a recent meta-analysis done by Hohl could not conclude that etomidate increased mortality.[12] 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.[12] Other authors[35][36][37] advise giving a prophylactic dose of steroids (e.g. hydrocortisone) if etomidate is used, but only one small prospective controlled study[37] 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 2.5-fold increase in the risk of dying compared with those given propofol.[38] People given etomidate also had significantly greater odds of having cardiovascular morbidity and significantly longer hospital stay.[38] These results, especially given the large size of study, strongly suggest that, at the very least, clinicians should use etomidate judiciously.[38] However, given this is a retrospective study, it is clearly misinterpreting how etomidate is typically used: etomidate is a drug that is reserved for sicker patients whom may not tolerate the more severe hemodynamic liability (towards lower mean pressures) and, thus the bias of this retrospective study is inconclusive, at best.

    In people with traumatic brain injury, etomidate use is associated with a blunting of an ACTH stimulation test.[27] 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.[39][40] 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).[41]

    Pharmacology

    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 alpha and beta subunits (α−β+). 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.

    • Onset of action: 30–60 seconds
    • Peak effect: 1 minute
    • Duration: 3–5 minutes; terminated by redistribution
    • Distribution: Vd: 2–4.5 L/kg
    • Protein binding: 76%
    • Metabolism: Hepatic and plasma esterases
    • Half-life distribution: 2.7 minutes
    • Half-life redistribution: 29 minutes
    • Half-life elimination: 2.9 to 5.3 hours[7]

    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.

    Society and culture

    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]

    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.[48]

    References

    1. ↑ "Drugs to Aid Intubation - Critical Care Medicine". Merck Manuals Professional Edition. Archived from the original on 26 February 2021. Retrieved 14 April 2021.
    2. 1 2 3 4 5 6 7 8 9 10 11 "Etomidate Monograph for Professionals". Drugs.com. Archived from the original on 13 April 2021. Retrieved 14 April 2021.
    3. 1 2 "Etomidate (Amidate) use while Breastfeeding". Drugs.com. Archived from the original on 26 October 2020. Retrieved 14 April 2021.
    4. 1 2 3 4 5 6 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1400. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    5. 1 2 Williams, LM; Boyd, KL; Fitzgerald, BM (January 2021). "Etomidate". PMID 30570985. {{cite journal}}: Cite journal requires |journal= (help)
    6. ↑ Alston, R. Peter; Myles, Paul S.; Ranucci, Marco. Oxford Textbook of Cardiothoracic Anaesthesia. Oxford University Press. p. 5. ISBN 978-0-19-965347-8. Archived from the original on 2021-08-29. Retrieved 2021-04-14.
    7. 1 2 3 Bergen, JM; Smith, DC (1998). "A review of etomidate for rapid sequence intubation in the emergency department". J Emerg Med. 15 (2): 221–230. doi:10.1016/S0736-4679(96)00350-2. PMID 9144065.
    8. ↑ "FDA Approves Mylan's Generic Anesthesia Drug Etomidate". www.beckershospitalreview.com. Archived from the original on 22 January 2021. Retrieved 14 April 2021.
    9. ↑ Di Liddo, L; D'Angelo, A; Nguyen, B; Bailey, B; Amre, D; Stanciu, C (2006). "Etomidate versus midazolam for procedural sedation in pediatric outpatients: a randomized controlled trial". Ann Emerg Med. 48 (4): 433–440. doi:10.1016/j.annemergmed.2006.03.004. PMID 16997680.
    10. ↑ Miner, JR; Danahy, M; Moch, A; Biros, M (2007). "Randomized clinical trial of etomidate versus propofol for procedural sedation in the emergency department". Ann Emerg Med. 49 (1): 15–22. doi:10.1016/j.annemergmed.2006.06.042. PMID 16997421.
    11. 1 2 Sivilotti, ML; Filbin, MF; Murray, HE; Slasor, P; Walls, RM; Near, Investigators (2003). "Does the sedative agent facilitate emergency rapid sequence intubation?". Acad Emerg Med. 10 (6): 612–620. doi:10.1197/aemj.10.6.612. PMID 12782521.
    12. 1 2 3 4 5 Hohl, CM; Kelly-Smith, CH; Yeug, TC; Sweet, DD; Doyle-Waters, MM; Schulzer, M (2010). "The effect of a bolus dose of etomidate on cortisol levels, mortality, and health services utilization: a systematic review". Ann Emerg Med. 56 (2): 105–113. doi:10.1016/j.annemergmed.2010.01.030. PMID 20346542.
    13. ↑ Zed, PJ; Abu-Laban, RB; Harrison, DW. (2006). "Intubating conditions and hemodynamic effects of etomidate for rapid sequence intubation in the emergency department: an observational cohort study". Acad Emerg Med. 13 (4): 378–83. doi:10.1111/j.1553-2712.2006.tb00313.x. PMID 16531603.
    14. ↑ Sokolove, PE; Price, DD; Okada, P. (2000). "The safety of etomidate for emergency rapid sequence intubation of pediatric patients". Pediatr Emerg Care. 16 (1): 18–21. doi:10.1097/00006565-200002000-00005. PMID 10698137. S2CID 24913220.
    15. 1 2 Walls, RM; Murphy, MF; Schneider, RE (2000). "Manual of emergency airway management". {{cite journal}}: Cite journal requires |journal= (help)
    16. ↑ Marx, J (2002). "Rosen's emergency medicine: concepts and clinical practice". {{cite journal}}: Cite journal requires |journal= (help)
    17. ↑ Wadbrook, PS (2000). "Advances in airway pharmacology. Emerging trends and evolving controversy". Emerg Med Clin North Am. 18 (4): 767–788. doi:10.1016/S0733-8627(05)70158-9. PMID 11130938.
    18. ↑ Yeung, JK; Zed, PJ (2002). "A review of etomidate for rapid sequence intubation in the emergency department". CJEM. 4 (3): 194–198. doi:10.1017/S1481803500006370. PMID 17609005.
    19. ↑ Gu, WJ; Wang, F; Tang, L; Liu, JC (Sep 25, 2014). "Single-Dose Etomidate Does Not Increase Mortality in Patients with Sepsis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Studies". Chest. 147 (2): 335–346. doi:10.1378/chest.14-1012. PMID 25255427.
    20. ↑ Jones-Gotman, M; Sziklas, V; Djordjevic, J (2009). "Intracarotid amobarbital procedure and etomidate speech and memory test". Can J Neurol Sci. 36 Suppl 2: S51–4. PMID 19760903.
    21. ↑ Jones-Gotman, M; Sziklas, V; Djordjevic, J; Dubeau, F; Gotman, J; Angle, M; Tampieri, D; Olivier, A; Andermann, F (2005). "Etomidate speech and memory test (eSAM): a new drug and improved intracarotid procedure". Neurology. 65 (11): 1723–1729. doi:10.1212/01.wnl.0000187975.78433.cb. PMID 16344513. S2CID 1835535.
    22. ↑ Patel, Akta; Wordell, Cindy; Szarlej, Dorota (2011). "Alternatives to sodium amobarbital in the Wada test". Ann Pharmacother. 45 (3): 395–401. doi:10.1345/aph.1P476. PMID 21325100. S2CID 207264114.
    23. 1 2 Terry F. Davies (2015). A Case-Based Guide to Clinical Endocrinology. Springer. pp. 11–. ISBN 978-1-4939-2059-4. Archived from the original on 2021-04-13. Retrieved 2017-06-09.
    24. 1 2 J. Larry Jameson; Leslie J. De Groot (2015). Endocrinology: Adult and Pediatric E-Book. Elsevier Health Sciences. pp. 250–. ISBN 978-0-323-32195-2. Archived from the original on 2021-04-13. Retrieved 2017-06-09.
    25. ↑ McGrath M, Ma C, Raines D (2017). "Dimethoxy-etomidate: A Non-hypnotic Etomidate Analog that Potently Inhibits Steroidogenesis". J. Pharmacol. Exp. Ther. 364 (2): 229–237. doi:10.1124/jpet.117.245332. PMC 5783534. PMID 29203576.
    26. ↑ Wagner, RL; White, PF; Kan, PB; Rosenthal, MH; Feldman, D. (1984). "Inhibition of adrenal steroidogenesis by the anesthetic etomidate". N Engl J Med. 310 (22): 1415–21. doi:10.1056/NEJM198405313102202. PMID 6325910.
    27. 1 2 Archambault, P; Dionne, CE; Lortie, G; LeBlanc, F; Rioux, A; Larouche, G (September 2012). "Adrenal inhibition following a single dose of etomidate in intubated traumatic brain injury victims". CJEM. 14 (5): 270–82. doi:10.2310/8000.2012.110560. PMID 22967694.
    28. 1 2 Ledingham, IM; Watt, I (1983). "Influence of sedation in critically ill multiple trauma patients". Lancet. 1 (8336): 1270. doi:10.1016/S0140-6736(83)92712-5. PMID 6134053. S2CID 305277.
    29. ↑ Morris, C; McAllister, C (2005). "Etomidate for emergency anaesthesia; mad, bad and dangerous to know?". Anaesthesia. 60 (8): 737–740. doi:10.1111/j.1365-2044.2005.04325.x. PMID 16029220. S2CID 27825801.
    30. ↑ Jackson, WL (2005). "Should we use etomidate as an induction agent for endotracheal intubation in patients with septic shock? A critical appraisal". Chest. 127 (3): 1031–1038. doi:10.1378/chest.127.3.1031. PMID 15764790.
    31. 1 2 Annane, D; Sebille, V; Bellissant, E (2006). "Exploring the role of etomidate in septic shock and acute respiratory distress syndrome". Crit Care Med. 34 (6): 1858–1859. doi:10.1097/01.ccm.0000220048.38438.40. PMID 16715011.
    32. ↑ Cuthbertson, BH; Sprung, CL; Annane, D; Chevret, S; Garfield, M; Goodman, S; Laterre, PF; Vincent, JL; et al. (2009). "The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock". Intensive Care Med. 35 (1): 1868–1876. doi:10.1007/s00134-009-1603-4. PMID 19652948. S2CID 24371957.
    33. ↑ Murray, H; Marik, PE (2005). "Etomidate for endotracheal intubation in sepsis: acknowledging the good while accepting the bad". Chest. 127 (3): 707–709. doi:10.1378/chest.127.3.707. PMID 15764747.
    34. ↑ Jabre, P; Combes, X; Laposttolle, F; Dhaouadi, M; Ricard-Hibon, A; Vivien, B; Bertrand, L; Beltramini, A; et al. (2009). "Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomized controlled trial". Lancet. 374 (9686): 293–300. doi:10.1016/S0140-6736(09)60949-1. PMID 19573904. S2CID 52230993.
    35. ↑ Den Brinker, M; Joosten, KF; Liem, O; de Jong, FH; Hop, WC; Hazelzet, JA; van Dijk, M; Hokken-Koelega, AC. (2005). "Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality". J Clin Endocrinol Metab. 90 (9): 5110–7. doi:10.1210/jc.2005-1107. PMID 15985474.
    36. ↑ Schulz-Stubner, S (2005). "Sedation in traumatic brain injury: Avoid etomidate". Crit Care Med. 33 (11): 2723. doi:10.1097/01.ccm.0000187093.71107.a8. PMID 16276231.
    37. 1 2 Stuttmann, R; Allolio, B; Becker, A (1988). "etomidate versus etomidate and hydrocortisone for anesthesia induction in abdominal surgical interventions". Anaesthesist. 37 (9): 576–582. PMID 3056084.
    38. 1 2 3 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): 1329–37. doi:10.1213/ANE.0b013e318299a516. PMID 24257383. S2CID 23165849.
    39. ↑ Daniell, Harry (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.
    40. ↑ Daniell, HW (2008). "Opioid contribution to decreased cortisol levels in critical care patients". Arch Surg. 143 (12): 1147–1148. doi:10.1001/archsurg.143.12.1147. PMID 19075164.
    41. ↑ 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.
    42. ↑ Vanlersberghe, C; Camu, F (2008). Etomidate and other non-barbiturates. Handbook of Experimental Pharmacology. Vol. 182. pp. 267–82. 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 (2009). "Distinct actions of etomidate and propofol at beta3-containing gamma-aminobutyric acid type A receptors". Neuropharmacology. 57 (4): 446–55. 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 (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): 836–47. doi:10.1021/bi201772m. PMC 3274767. PMID 22243422.
    45. ↑ "International Non-Proprietary Names for Pharmaceutical Preparations – Rec. I.N.N. List 6" (PDF). Archived (PDF) from the original on 2020-08-10. Retrieved 2020-10-04.
    46. ↑ Servin, Frédérique S.; Sear, John W. (2011). "Chapter 27. Pharmacokinetics of intravenous anesthetics". In Evers, Alex S.; Maze, Mervyn; Kharasch, Evan D. (eds.). Anesthetic Pharmacology: Basic Principles and Clinical Practice (2nd ed.). Cambridge University Press.
    47. ↑ Tomlin, Sarah L.; Jenkins, Andrew; Lieb, William R.; Franks, Nicholas P. (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. ↑ Jason Dearon. "Florida executes convicted killer Mark Asay using new drug". Sun Sentinel. Archived from the original on 2017-08-25. Retrieved 2017-08-24.
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