REVIEW ARTICLE David S. Warner, M.D., Editor Clinical and Molecular Pharmacology of Etomidate Stuart A. Forman, M.D., Ph.D.* ABSTRACT TOMIDATE [R-1-(1-ethylphenyl)imidazole-5-ethyl E ester] (fig. 1) is a unique drug used for induction of general anesthesia and sedation. The first report on etomi- This review focuses on the unique clinical and molecular date was published in 1965 as one of several dozen aryl alkyl pharmacologic features of etomidate. Among general anes- imidazole-5-carboxylate esters1 synthesized by Janssen Phar- thesia induction drugs, etomidate is the only imidazole, and maceuticals (a division of Ortho-McNeil-Jannsen Pharma- it has the most favorable therapeutic index for single-bolus ceuticals, Titusville, NJ). Initially developed as antifungal administration. It also produces a unique toxicity among agents, the potent hypnotic activity of several compounds anesthetic drugs: inhibition of adrenal steroid synthesis that was observed during animal testing; and several com- far outlasts its hypnotic action and that may reduce survival pounds, including etomidate, appeared significantly safer of critically ill patients. The major molecular targets mediat- than barbiturates. ing anesthetic effects of etomidate in the central nervous Etomidate contains a chiral carbon (fig. 1). Initial studies ␥ system are specific -aminobutyric acid type A receptor sub- of racemic etomidate in rats demonstrated lethality at ap- types. Amino acids forming etomidate binding sites have proximately 12 times its effective hypnotic dose (median been identified in transmembrane domains of these proteins. lethal dose/ED50, approximately 12) compared with barbi- Etomidate binding site structure models for the main en- turates with median lethal dose/ED50 ratios (therapeutic in- zyme mediating etomidate adrenotoxicity have also been de- dexes) of 3–5.1 Subsequent studies2,3 found that the isolated veloped. Based on this deepening understanding of molecu- R(ϩ)-enantiomer of etomidate has 10- to 20-fold greater lar targets and actions, new etomidate derivatives are being hypnotic potency than S(Ϫ)-etomidate. The median lethal investigated as potentially improved sedative–hypnotics ϩ 4 dose/ED50 ratio for R( )-etomidate is 26 in rats, signifi- or for use as highly selective inhibitors of adrenal steroid cantly higher than therapeutic indexes for other general an- synthesis. esthetics (table 1). Preclinical experiments in mammals also demonstrated that etomidate injection was associated with minimal hemodynamic changes or respiratory depression, * Associate Professor of Anaesthesia, Harvard Medical School, Boston, Massachusetts, and Associate Anesthetist, Department of features that were presumed to result in its unusually favor- Anesthesia, Critical Care, and Pain Medicine, Massachusetts General able safety profile.5 Hospital, Boston, Massachusetts. Etomidate was introduced into clinical practice in 1972, Received from Massachusetts General Hospital, Boston, Massa- chusetts. Submitted for publication July 6, 2010. Accepted for pub- and initial reports of its use in humans emerged in the clinical 6,7 lication September 17, 2010. Supported by grant P01GM58448 from literature soon afterward. Academic publications focusing the National Institutes of Health (Bethesda, Maryland); and the on etomidate increased steadily until 1983, when the num- Department of Anesthesia, Critical Care, and Pain Medicine, Massa- chusetts General Hospital, Boston, Massachusetts. Massachusetts ber of reports rapidly doubled after discovery of its adrenal General Hospital has submitted patent applications for MOC etomi- toxicity (fig. 2). Subsequently, the number of yearly pub- date, carboetomidate, and related analogs. The author and his lished articles focusing on etomidate diminished (apparently laboratory, department, and institution could receive royalties relat- ing to the development or sale of these drugs. in parallel with its use in operating rooms), but this rate Address correspondence to Dr. Forman: Department of Anes- has resurged in the past decade. Renewed interest in eto- thesia, Critical Care, and Pain Medicine, Jackson 444, Massachusetts midate parallels its widening use during intubations in General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. [email protected]. Information on purchasing reprints may be emergency departments and intensive care units, and new found at www.anesthesiology.org or on the masthead page at the concerns exist about the impact of etomidate-induced ad- beginning of this issue. ANESTHESIOLOGY’s articles are made freely renal toxicity in critically ill patients. The recent increase accessible to all readers, for personal use only, 6 months from the cover date of the issue. in publications on etomidate also reflects scientific Copyright © 2011, the American Society of Anesthesiologists, Inc. Lippincott progress in understanding this drug’s molecular pharma- Williams & Wilkins. Anesthesiology 2011; 114: 695–707 cologic features. Anesthesiology, V 114 • No 3 695 March 2011 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/Journals/JASA/931111/ on 10/05/2016 Clinical and Molecular Pharmacology of Etomidate Fig. 2. Etomidate publications in PubMed. The graph dis- plays numbers of publications within a calendar year, based Fig. 1. Chemical structure of etomidate. Critical structural on PubMed searches with etomidate as a Medical Subject features for anesthetic activity include a single methylene Headings term (sum of red plus blue bars) or the subset of ϩ group between the imidazole and phenyl group and the R( ) these publications with humans as the subjects (blue bars configuration at the chiral center (labeled with an asterisk). only). Data are inclusive through December 2009. Clinical Pharmacology Systemic Effects Formulation and Dosing Etomidate does not inhibit sympathetic tone or myocardial 16,17 Etomidate formulations for clinical use contain the purified function, and typical anesthetic induction doses pro- duce minimal blood pressure and heart rate changes in pa- R(ϩ)-enantiomer. Etomidate has a pK of 4.2 and is hydro- a tients, including those with valvular or ischemic heart dis- phobic at physiologic pH. To increase solubility, it is formu- ease.12,18-20 For the same reason, etomidate does not block lated as a 0.2% solution either in 35% propylene glycol sympathetic responses to laryngoscopy and intubation; these (Amidate; Hospira, Inc, Lake Forest, IL) or lipid emulsion 8 responses are often blunted by premedication with opi- (Etomidate-Lipuro; B. Braun, Melsungen, Germany). For- 21,22 9,10 oids. Etomidate produces less apnea than barbiturates or mulations in cyclodextrins have also been developed. propofol, no histamine release, and rare allergic reactions. Early clinical studies determined that intravenous bolus Because of its remarkably benign hemodynamic effects, eto- doses of 0.2–0.4 mg/kg provided hypnosis for 5–10 min. midate has proved useful for general anesthetic induction in After a bolus, maintenance of general anesthesia can be patients undergoing cardiac surgery and in those with poor achieved by continuous infusion of etomidate at 30–100 cardiac function.23 Ϫ1 Ϫ1 11-13 ␮g ⅐ kg ⅐ min . Oral transmucosal etomidate has Etomidate also provides advantages for induction of an- been used to induce sedation,14 and rectal administration esthesia in the setting of hemorrhagic shock. In a pig model has been used to induce general anesthesia in pediatric of hemorrhagic shock, the pharmacodynamics and pharma- patients.15 cokinetics of etomidate are minimally altered,24 in contrast to other anesthetic drugs.25,26 As a result of its favorable profile for anesthetic induction in a variety of critically ill patients, etomidate has been adopted by many emergency Table 1. Acute Toxicity Ratios of Intravenous Anesthetic Induction Drugs medicine physicians as the hypnotic drug of choice for rapid- sequence induction and intubation.27-29 Acute Toxicity Ratio, Hepatic blood flow is modestly reduced after induction of Anesthetic Induction Drug LD50/ED50* general anesthesia with etomidate, but this has minimal im- ϩ 5 pact on pharmacokinetics and metabolism of anesthetic R( )-etomidate 26 30,31 Althesin (alphaxalone/alphadolone) 17.3158 agents. Cerebral blood flow is reduced, along with cere- Ketamine (racemic)† 6.3159 bral metabolic rate and intracranial pressure, whereas cere- Methohexital 4.8-9.55,158 bral perfusion pressure is maintained or increased during Thiopental 3.6-4.65,158,160 32-34 160 etomidate-induced anesthesia. Electroencephalographic Pentobarbital 3.4 changes during hypnosis with etomidate are similar to those Propofol 3.4158 seen with barbiturates.35 Bispectral index monitor values de- * Data are from therapeutic index studies in mice and rats using crease after etomidate bolus administration and return to intravenous injection. † The therapeutic index of (ϩ)-ketamine is baseline during recovery of consciousness.36 During brief 10, whereas that of the (Ϫ) enantiomer is 4.0. ϭ etomidate infusions, bispectral index values correlate well ED50 dose that is pharmacologically effective to 50% of the 37 experimental population; LD50 ϭ the dose resulting in 50% with sedation scores. Etomidate increases latency and de- mortality within 24 h. creases amplitude of auditory evoked potentials.38 The du- Anesthesiology 2011; 114:695–707 696 Stuart A. Forman Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/Journals/JASA/931111/ on 10/05/2016 EDUCATION