Etomidate

Summary

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]

Etomidate
(R)-etomidate ethyl ester
Clinical data
Trade namesAmidate, Hypnomidate, Tomvi
AHFS/Drugs.comMonograph
License data
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding76%
MetabolismEster hydrolysis in plasma and liver
Elimination half-life75 minutes
ExcretionUrine (85%) and Bile duct (15%)
Identifiers
  • Ethyl 3-[(1R)-1-phenylethyl]imidazole-5-carboxylate
CAS Number
  • 33125-97-2 checkY
PubChem CID
  • 36339
DrugBank
  • DB00292 checkY
ChemSpider
  • 33418 checkY
UNII
  • Z22628B598
KEGG
  • D00548 checkY
ChEMBL
  • ChEMBL23731 checkY
CompTox Dashboard (EPA)
  • DTXSID5023033 Edit this at Wikidata
ECHA InfoCard100.046.700 Edit this at Wikidata
Chemical and physical data
FormulaC14H16N2O2
Molar mass244.294 g·mol−1
3D model (JSmol)
  • Interactive image
Melting point67 °C (153 °F)
Boiling point392 °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 checkY
  • Key:NPUKDXXFDDZOKR-UHFFFAOYSA-N checkY
  (verify)

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

Medical uses edit

Sedation and anesthesia edit

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 edit

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 edit

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 edit

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 edit

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 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 edit

 
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.[41]

Pharmacodynamics edit

(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+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 edit

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[5]

Metabolism edit

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 edit

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]

References edit

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Further reading edit

  • Cotton BA, Guillamondegui OD, Fleming SB, Carpenter RO, Patel SH, Morris JA, Arbogast PG (January 2008). "Increased risk of adrenal insufficiency following etomidate exposure in critically injured patients". Archives of Surgery. 143 (1): 62–7, discussion 67. doi:10.1001/archsurg.143.1.62. PMID 18209154.; discussion 67.
  • den Brinker M, Hokken-Koelega AC, Hazelzet JA, de Jong FH, Hop WC, Joosten KF (January 2008). "One single dose of etomidate negatively influences adrenocortical performance for at least 24h in children with meningococcal sepsis". Intensive Care Medicine. 34 (1): 163–168. doi:10.1007/s00134-007-0836-3. PMC 2668631. PMID 17710382.
  • Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, et al. (American College of Critical Care Medicine) (June 2008). "Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine". Critical Care Medicine. 36 (6): 1937–1949. doi:10.1097/CCM.0b013e31817603ba. PMID 18496365. S2CID 7861625.
  • Mullins ME, Theodoro DL (August 2008). "Lack of evidence for adrenal insufficiency after single-dose etomidate". Archives of Surgery. 143 (8): 808–9, author reply 809. doi:10.1001/archsurg.143.8.808-c. PMID 18711047.; author reply 809.
  • Sacchetti A (July 2008). "Etomidate: not worth the risk in septic patients". Annals of Emergency Medicine. 52 (1): 14–16. doi:10.1016/j.annemergmed.2008.01.001. PMID 18565379.
  • Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. (January 2008). "Hydrocortisone therapy for patients with septic shock". The New England Journal of Medicine. 358 (2): 111–124. doi:10.1056/NEJMoa071366. PMID 18184957.
  • Tekwani KL, Watts HF, Chan CW, Nanini S, Rzechula KH, Kulstad EB (November 2008). "The effect of single-bolus etomidate on septic patient mortality: a retrospective review". The Western Journal of Emergency Medicine. 9 (4): 195–200. PMC 2672284. PMID 19561744.
  • Tekwani KL, Watts HF, Rzechula KH, Sweis RT, Kulstad EB (January 2009). "A prospective observational study of the effect of etomidate on septic patient mortality and length of stay". Academic Emergency Medicine. 16 (1): 11–14. doi:10.1111/j.1553-2712.2008.00299.x. PMID 19055676.
  • Vinclair M, Broux C, Faure P, Brun J, Genty C, Jacquot C, et al. (April 2008). "Duration of adrenal inhibition following a single dose of etomidate in critically ill patients". Intensive Care Medicine. 34 (4): 714–719. doi:10.1007/s00134-007-0970-y. PMID 18092151. S2CID 23538535.

External links edit

  • "Etomidate". Drug Information Portal. U.S. National Library of Medicine.