This review focuses on the unique clinical and molecular pharmacologic features of etomidate. Among general anesthesia induction drugs, etomidate is the only imidazole, and it has the most favorable therapeutic index for single-bolus administration. It also produces a unique toxicity among anesthetic drugs: inhibition of adrenal steroid synthesis that far outlasts its hypnotic action and that may reduce survival of critically ill patients. The major molecular targets mediating anesthetic effects of etomidate in the central nervous system are specific γ-aminobutyric acid type A receptor subtypes. Amino acids forming etomidate binding sites have been identified in transmembrane domains of these proteins. Etomidate binding site structure models for the main enzyme mediating etomidate adrenotoxicity have also been developed. Based on this deepening understanding of molecular targets and actions, new etomidate derivatives are being investigated as potentially improved sedative-hypnotics or for use as highly selective inhibitors of adrenal steroid synthesis.

ETOMIDATE [R -1-(1-ethylphenyl)imidazole-5-ethyl ester] (fig. 1) is a unique drug used for induction of general anesthesia and sedation. The first report on etomidate was published in 1965 as one of several dozen aryl alkyl imidazole-5-carboxylate esters1synthesized by Janssen Pharmaceuticals (a division of Ortho-McNeil-Jannsen Pharmaceuticals, Titusville, NJ). Initially developed as antifungal agents, the potent hypnotic activity of several compounds was observed during animal testing; and several compounds, including etomidate, appeared significantly safer than barbiturates.

Fig. 1.  Chemical structure of etomidate. Critical structural features for anesthetic activity include a single methylene group between the imidazole and phenyl group and the R  (+) configuration at the chiral center (labeled with an asterisk ).

Fig. 1.  Chemical structure of etomidate. Critical structural features for anesthetic activity include a single methylene group between the imidazole and phenyl group and the R  (+) configuration at the chiral center (labeled with an asterisk ).

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Etomidate contains a chiral carbon (fig. 1). Initial studies of racemic etomidate in rats demonstrated lethality at approximately 12 times its effective hypnotic dose (median lethal dose/ED50, approximately 12) compared with barbiturates with median lethal dose/ED50ratios (therapeutic indexes) of 3–5.1Subsequent studies2,3found that the isolated R  (+)-enantiomer of etomidate has 10- to 20-fold greater hypnotic potency than S  (−)-etomidate. The median lethal dose/ED50ratio for R  (+)-etomidate is 26 in rats,4significantly higher than therapeutic indexes for other general anesthetics (table 1). Preclinical experiments in mammals also demonstrated that etomidate injection was associated with minimal hemodynamic changes or respiratory depression, features that were presumed to result in its unusually favorable safety profile.5 

Table 1.  Acute Toxicity Ratios of Intravenous Anesthetic Induction Drugs

Table 1.  Acute Toxicity Ratios of Intravenous Anesthetic Induction Drugs
Table 1.  Acute Toxicity Ratios of Intravenous Anesthetic Induction Drugs

Etomidate was introduced into clinical practice in 1972, and initial reports of its use in humans emerged in the clinical literature soon afterward.6,7Academic publications focusing on etomidate increased steadily until 1983, when the number of reports rapidly doubled after discovery of its adrenal toxicity (fig. 2). Subsequently, the number of yearly published articles focusing on etomidate diminished (apparently in parallel with its use in operating rooms), but this rate has resurged in the past decade. Renewed interest in etomidate parallels its widening use during intubations in emergency departments and intensive care units, and new concerns exist about the impact of etomidate-induced adrenal toxicity in critically ill patients. The recent increase in publications on etomidate also reflects scientific progress in understanding this drug's molecular pharmacologic features.

Fig. 2.  Etomidate publications in PubMed. The graph displays numbers of publications within a calendar year, based on PubMed searches with etomidate  as a Medical Subject Headings term (sum of red  plus blue bars ) or the subset of these publications with humans as the subjects (blue bars  only). Data are inclusive through December 2009.

Fig. 2.  Etomidate publications in PubMed. The graph displays numbers of publications within a calendar year, based on PubMed searches with etomidate  as a Medical Subject Headings term (sum of red  plus blue bars ) or the subset of these publications with humans as the subjects (blue bars  only). Data are inclusive through December 2009.

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Formulation and Dosing

Etomidate formulations for clinical use contain the purified R  (+)-enantiomer. Etomidate has a pK  aof 4.2 and is hydrophobic at physiologic pH. To increase solubility, it is formulated as a 0.2% solution either in 35% propylene glycol (Amidate; Hospira, Inc, Lake Forest, IL) or lipid emulsion (Etomidate-Lipuro; B. Braun, Melsungen, Germany).8Formulations in cyclodextrins have also been developed.9,10 

Early clinical studies determined that intravenous bolus doses of 0.2–0.4 mg/kg provided hypnosis for 5–10 min. After a bolus, maintenance of general anesthesia can be achieved by continuous infusion of etomidate at 30–100 μg · kg−1· min−1.11–13Oral transmucosal etomidate has been used to induce sedation,14and rectal administration has been used to induce general anesthesia in pediatric patients.15 

Systemic Effects

Etomidate does not inhibit sympathetic tone or myocardial function,16,17and typical anesthetic induction doses produce minimal blood pressure and heart rate changes in patients, including those with valvular or ischemic heart disease.12,18–20For the same reason, etomidate does not block sympathetic responses to laryngoscopy and intubation; these responses are often blunted by premedication with opioids.21,22Etomidate produces less apnea than barbiturates or propofol, no histamine release, and rare allergic reactions. Because of its remarkably benign hemodynamic effects, etomidate has proved useful for general anesthetic induction in patients undergoing cardiac surgery and in those with poor cardiac function.23 

Etomidate also provides advantages for induction of anesthesia in the setting of hemorrhagic shock. In a pig model of hemorrhagic shock, the pharmacodynamics and pharmacokinetics of etomidate are minimally altered,24in contrast to other anesthetic drugs.25,26As a result of its favorable profile for anesthetic induction in a variety of critically ill patients, etomidate has been adopted by many emergency medicine physicians as the hypnotic drug of choice for rapid-sequence induction and intubation.27–29 

Hepatic blood flow is modestly reduced after induction of general anesthesia with etomidate, but this has minimal impact on pharmacokinetics and metabolism of anesthetic agents.30,31Cerebral blood flow is reduced, along with cerebral metabolic rate and intracranial pressure, whereas cerebral perfusion pressure is maintained or increased during etomidate-induced anesthesia.32–34Electroencephalographic changes during hypnosis with etomidate are similar to those seen with barbiturates.35Bispectral index monitor values decrease after etomidate bolus administration and return to baseline during recovery of consciousness.36During brief etomidate infusions, bispectral index values correlate well with sedation scores.37Etomidate increases latency and decreases amplitude of auditory evoked potentials.38The duration of epileptiform activity after electroconvulsive therapy is longer after anesthetic induction with etomidate versus  methohexital or propofol.39Somatosensory evoked potential amplitudes are enhanced by etomidate,40and motor evoked potential amplitudes are suppressed less by etomidate than propofol, thiopental, or methohexital.41 

Pharmacokinetics and Metabolism

In healthy patients, etomidate is approximately 75% protein bound.42Etomidate is characterized by a large central volume of distribution, 4.5 l/kg, and a large peripheral volume of distribution, 74.9 l/kg, because of its high solubility in fat.30,37,43The single-bolus pharmacokinetic profile of plasma etomidate concentration is described by a three-compartment model (fig. 3).30The fast, intermediate, and slow declines in plasma etomidate are thought to correspond to distribution into highly perfused tissues, redistribution into peripheral tissues (mostly muscle), and terminal metabolism, respectively. The hypnotic effect of an intravenous bolus of 3 mg/kg etomidate terminates as redistribution into the peripheral compartment starts to dominate the plasma concentration profile. Etomidate metabolism in laboratory animals and humans depends on hepatic esterase activity, which hydrolyzes the drug to a carboxylic acid and an ethanol-leaving group.44The carboxylate metabolite is excreted mostly in urine and to a lesser degree in bile. Total plasma clearance is 15–20 ml · kg−1· min−1, and the terminal metabolic half-life of etomidate in humans ranges from 2 to 5 h. Elderly or ill patients often require decreased etomidate doses because of reduced protein binding and reduced clearance.42,45,46The pharmacokinetic parameters for etomidate indicate its suitability for use as a continuous infusion, with a context-sensitive half-time shorter than that of propofol.47Prolonged etomidate infusion for anesthesia and sedation was practiced during the first decade of clinical availability.32,48–52Other considerations (adrenal toxicity) preclude this application. (The Adrenal Toxicity, Sepsis, and Exogenous Steroids section provides further details.)

Fig. 3.  Single intravenous bolus pharmacokinetics of etomidate. The etomidate plasma concentration after a single intravenous bolus (3 mg/kg) is depicted on a semilogarithmic plot with the early decline period expanded. This concentration versus  time profile is based on pharmacokinetic parameters determined by Van Hamme et al. ,30showing three distinct decline phases with half-times of 2 min, 21 min, and 3.9 h. Colored dashed lines  indicate approximate threshold etomidate plasma concentrations associated with hypnosis (blue line  at 200 ng/ml) and adrenocortical suppression (green line  at 8 ng/ml). Together, these data illustrate why the duration of hypnosis (approximately 8 min) is much shorter than the duration of adrenocortical suppression (approximately 8 h) after a single etomidate dose.

Fig. 3.  Single intravenous bolus pharmacokinetics of etomidate. The etomidate plasma concentration after a single intravenous bolus (3 mg/kg) is depicted on a semilogarithmic plot with the early decline period expanded. This concentration versus  time profile is based on pharmacokinetic parameters determined by Van Hamme et al. ,30showing three distinct decline phases with half-times of 2 min, 21 min, and 3.9 h. Colored dashed lines  indicate approximate threshold etomidate plasma concentrations associated with hypnosis (blue line  at 200 ng/ml) and adrenocortical suppression (green line  at 8 ng/ml). Together, these data illustrate why the duration of hypnosis (approximately 8 min) is much shorter than the duration of adrenocortical suppression (approximately 8 h) after a single etomidate dose.

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Adverse Effects

Several unfavorable effects associated with etomidate were noted in early studies, including pain on injection and myoclonic movements during induction of general anesthesia.53–55Pain on injection was worse with etomidate in aqueous solutions compared with the formulation in 35% propylene glycol.56Formulation into medium chain-length lipids or cyclodextrins appears to decrease the incidence of injection pain and hemolysis further.9,57The incidence of myoclonus increases with etomidate dose and can be attenuated by split-dose induction58or premedication with benzodiazepines,59thiopental, dexmedetomidine,60and/or opioids.22,61,62 

Postoperative nausea and vomiting are cited as frequent adverse effects of etomidate, but few studies have formally compared postoperative nausea and vomiting after etomidate versus  other agents used for induction of general anesthesia. Early investigators reported that the incidence of postoperative nausea and vomiting after induction with etomidate is approximately 40%,50,55comparable with that after barbiturates,43,56and higher than that after propofol.63More recently, the reported incidence of nausea after induction with etomidate in lipid emulsion was similar to that associated with propofol,64,65whereas the incidence of vomiting was higher with etomidate.65 

Adrenal Toxicity, Sepsis, and Exogenous Steroids

Adrenal cortical inhibition by etomidate has received much attention and significantly limits its use as both an anesthetic and a sedative. Nevertheless, the effect of etomidate on clinical outcomes has never been carefully studied in a large population of surgical or intensive care patients.

1n 1983, a decade after its introduction into clinical use, Ledingham and Watt66reported retrospective data showing increased mortality among intensive care patients receiving prolonged etomidate infusions for sedation compared with patients receiving benzodiazepines (69% vs.  25%).67Soon afterward, McKee and Finlay68reported that cortisol replacement therapy could reduce the mortality in a similar group of critically ill patients receiving etomidate infusions. At that time, there was emerging preclinical evidence that etomidate suppressed adrenocortical function in rats,69and clinical investigators70,71rapidly confirmed this toxicity in patients. Etomidate suppressed normal cortisol and aldosterone increases after surgery and adrenal responses to corticotrophin. Adrenal suppression lasted 6–8 h in patients after a single-induction dose of etomidate72,73and more than 24 h after etomidate infusion.74 

The clinical community reacted to revelations about adrenal toxicity by ceasing the use of etomidate for long-term infusions. Some editorials75,76recommended halting its use altogether, whereas others suggested that etomidate had value as a single-dose induction drug for selected patients.77The drug package insert was amended to state that etomidate use is approved for induction of general anesthesia and anesthetic maintenance for short operative procedures. It specifically warns against administration by prolonged infusion.

Subsequent research78showed that etomidate is far more potent as an inhibitor of steroid synthesis than as a sedative–hypnotic agent. Etomidate plasma concentrations associated with hypnosis in patients are higher than 200 ng/ml (1 μm), whereas concentrations less than 10 ng/ml are associated with adrenal cortical suppression.72The in vitro  IC50for etomidate inhibition of cortisol synthesis in cultured adrenal cells is 1 nm, which closely matches the apparent dissociation constant for etomidate binding to membranes of these cells.79Together, the disparate etomidate concentration dependence values for hypnosis versus  adrenotoxicity and multiphase pharmacokinetics account for the dramatic difference in the durations of these two actions after a single intravenous bolus (fig. 3).72 

Recently, concern about etomidate-induced adrenal toxicity in critically ill patients and the use of corticosteroids to treat this effect has reemerged. Exposure to single-dose etomidate was a confounding variable in a large multicenter trial evaluating the use of supplemental corticosteroids in septic patients with and without adrenal insufficiency.80Enrollment in this study was from September 1995 to March 1999; in July 1996, inclusion criteria were altered to exclude patients who had received etomidate within 6 h. At that point, 72 enrollees had received etomidate, and 68 of these individuals were nonresponders to corticotrophin.81Thus, at least 30% of the nonresponders in this study (229 in total) had received etomidate; it is likely that additional patients received etomidate between 6 and 24 h before enrollment. In a 500-patient follow-up study of low-dose corticosteroid therapy of septic shock (CORTICUS),82etomidate was administered to 20% of patients before enrollment and 8% of patients after enrollment. Although etomidate was given on average 14 h before testing for adrenal insufficiency, it was associated with a 60% nonresponse rate to corticotrophin, significantly higher than that of enrollees who did not receive etomidate. Similar results have been reported by others.83The CORTICUS study82concluded that supplemental steroids did not improve the long-term outcome of septic shock patients with adrenal insufficiency. Retrospective analyses of the CORTICUS cohort suggest that patients receiving etomidate before enrollment had a 28-day mortality significantly higher than other patients in the trial and that steroids provided no benefit to those who received etomidate.82,84,85 

Other studies of patients with sepsis and trauma have examined the duration of adrenal insufficiency after single-dose etomidate and its effect on outcomes. In this population, the duration of adrenal suppression after a single dose of etomidate is longer than 24 h87,88and may last up to 72 h.86However, the impact of single-dose etomidate on outcomes in critically ill patients remains unclear. Hildreth et al.  89reported that trauma patients randomized to intubation using etomidate had longer hospital and intensive care unit lengths of stay than a group intubated using fentanyl and midazolam. In contrast to these and the CORTICUS study results, a nonrandomized study by Tekwani et al.  90found no difference in mortality among septic patients who received etomidate for intubation in the emergency department versus  those who received other agents. Ray and McKeown91also found no evidence of excess mortality associated with etomidate in a retrospective study. A recent randomized controlled trial92comparing etomidate with ketamine for intubation of critically ill, mostly nonseptic, patients also found no difference in mortality. Clearly, large well-designed trials are needed to define the clinical impact of single-dose etomidate in critically ill patients. Meanwhile, a vigorous debate about the use of etomidate for intubation of these patients continues.93,94 

There are fewer clinical studies focusing on etomidate than on either propofol or isoflurane†, yet the molecular pharmacologic features of etomidate are understood far better than other intravenous or inhaled general anesthetics. Etomidate appears to produce hypnosis, amnesia, and inhibition of nociceptive responses, almost exclusively via  actions at one class of neuronal ion channels (i.e ., γ-aminobutyric acid type A receptors [GABAAreceptors]).95,96Molecular targets mediating adrenal steroid inhibition and pain on injection have also been identified.

GABAAReceptors: Mediators of Etomidate Anesthesia

Soon after etomidate became available for clinical use, it was noted to produce effects similar to the endogenous neurotransmitter GABA in the nervous system.97Indeed, it is firmly established that the molecular targets underlying the anesthetic actions of etomidate are GABAAreceptors, which are the major inhibitory neurotransmitter receptors in mammalian brains.98GABAAreceptors are neurotransmitter-activated ion channels that selectively conduct chloride ions. Under normal conditions, their activation stabilizes neuronal membrane voltage near the chloride Nernst potential of −70 mV. GABAAreceptors are members of the superfamily of Cys loop ligand-gated ion channels that includes nicotinic acetylcholine receptors from muscle and nerve, glycine receptors, and serotonin type 3A receptors. All of these receptors are structurally similar and are formed from five polypeptide subunits surrounding an ion-conductive transmembrane channel. All Cys loop receptor subunits consist of a large amino-terminal extracellular domain, four hydrophobic transmembrane domains (M1 through M4), and a large intracellular domain between M3 and M4. Structural models of GABAAreceptors (fig. 4A–C) are based on high-resolution studies of crystallized acetylcholine-binding protein from snail synapses, homologous to extracellular domains,99,Torpedo  nicotinic acetylcholine receptors,100and crystallized pentameric prokaryotic channels.101–103 

Fig. 4.  Molecular structure of GABAAreceptors. A GABAAreceptor homology model, based on the structure of Torpedo  nicotinic acetylcholine receptors, is shown in two views. The subunits are color coded: α, yellow ; β, blue ; γ, green . (A ) The receptor is depicted in a membrane cross-sectional view, showing the extracellular domains containing GABA binding sites (purple ) and the transmembrane domains forming the etomidate sites (red ) between α and β subunits. Two amino acid residues, αM236 (blue ) and βM286 (yellow ), are shown adjacent to the etomidate binding site. The intracellular domains between M3 and M4 are not shown; their structures remain undefined. (B ) The pentameric model is depicted as viewed from the extracellular space with subunits labeled. The ion channel is formed by the M2 domains at the center of the subunits. (C ) The transmembrane domains are depicted with the extracellular domains removed. Transmembrane domains of one α subunit are labeled. (This figure was kindly provided by David Chiara, M.D., Ph.D., Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.)

Fig. 4.  Molecular structure of GABAAreceptors. A GABAAreceptor homology model, based on the structure of Torpedo  nicotinic acetylcholine receptors, is shown in two views. The subunits are color coded: α, yellow ; β, blue ; γ, green . (A ) The receptor is depicted in a membrane cross-sectional view, showing the extracellular domains containing GABA binding sites (purple ) and the transmembrane domains forming the etomidate sites (red ) between α and β subunits. Two amino acid residues, αM236 (blue ) and βM286 (yellow ), are shown adjacent to the etomidate binding site. The intracellular domains between M3 and M4 are not shown; their structures remain undefined. (B ) The pentameric model is depicted as viewed from the extracellular space with subunits labeled. The ion channel is formed by the M2 domains at the center of the subunits. (C ) The transmembrane domains are depicted with the extracellular domains removed. Transmembrane domains of one α subunit are labeled. (This figure was kindly provided by David Chiara, M.D., Ph.D., Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.)

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Eighteen distinct GABAAreceptor subunits are encoded in the human genome,104but only approximately a dozen subunit combinations form neuronal channels. Most of these consist of two α subunits, two β subunits, and one γ subunit arranged γ-β-α-β-α counterclockwise when viewed from the extracellular space.105Heterologously expressed receptors containing α1, β2, and γ2 subunits display GABA sensitivity, drug sensitivity, and open-closed transition rates similar to synaptic GABAAreceptors in the brain.106Synaptic GABA concentrations are thought to briefly reach several millimolar and to decay within milliseconds because of uptake via  GABA transporters. Postsynaptic GABAAreceptor channels open within a millisecond, generating an inhibitory postsynaptic current, which deactivates over tens of milliseconds, far longer than GABA remains in the synapse.107During an inhibitory postsynaptic current, action potential generation is impaired in the postsynaptic neuron; therefore, current deactivation is thought to be a factor in regulating the frequency response of neuronal circuits.108,109Some GABAAreceptors, formed from α and β subunits in combination with δ or ϵ subunits, are expressed on neuronal cell bodies and axons.110These extrasynaptic receptors produce small tonic chloride “leak” currents in response to low micromolar concentrations of GABA in the extrasynaptic space.111,112 

Etomidate Actions at GABAAReceptors

Two effects on GABAAreceptors, produced by different concentrations of etomidate, have been described. At concentrations associated with clinical doses, etomidate positively modulates GABAAreceptor activation by agonists.98In other words, when etomidate is present, GABAAreceptors are activated by concentrations of GABA lower than required under normal conditions.2,113,114Clinical concentrations of etomidate also slow the inhibitory postsynaptic current decay mediated by synaptic GABAAreceptors,115,116prolonging postsynaptic inhibition and reducing the frequency response of neuronal circuits. Enhanced activation of extrasynaptic receptors is also observed at clinical etomidate concentrations, increasing the tonic inhibitory “leak” current and reducing neuronal excitability. Yang and Uchida115noted that etomidate effects on tonic currents mediated by extrasynaptic GABAAreceptors may be more important than effects on synaptic currents. Etomidate at supraclinical concentrations also directly activates synaptic GABAAreceptor channels in the absence of GABA, an action variously termed direct activation, GABA-mimetic activity, or allosteric agonism.2,114,115,117 

Both positive modulation of GABA-mediated activity and direct activation of GABAAreceptors display parallel dependences on drug and receptor structures. For both etomidate actions, stereoselectivity for the R  (+)-enantiomer is of the same magnitude (10- to 20-fold) seen in animal studies of hypnotic and antinociceptive activity.2,114,118,119Both etomidate actions also show similar dependence on GABAAreceptor subunit makeup. Receptors containing β2 and/or β3 subunits are modulated and activated by etomidate, whereas those containing β1 are much less sensitive to both etomidate actions.113,117,120Etomidate sensitivity is also affected by the presence of a γ subunit113and weakly by the α subtype.117 

These parallels suggest that a single class of etomidate sites on GABAAreceptors mediates both modulation of GABA activation and direct activation. Indeed, both of these effects in α1β2γ2L receptors can be quantitatively modeled with an equilibrium Monod–Wyman–Changeux allosteric coagonist mechanism, by which etomidate binding to its sites is determined by whether the receptor is in one of two canonical states: open versus  closed (fig. 5).114In essence, etomidate binds weakly (KE, approximately 35 μm) to closed receptors but tightly (KE*, approximately 0.27 μM) to open receptors; therefore, the drug stabilizes open states whether GABA is bound or not bound. This class of model was optimal with two equivalent etomidate sites.

Fig. 5.  Monod–Wyman–Changeux two-state equilibrium model for etomidate and GABA activation of GABAAreceptors. The scheme depicts allosteric coagonism for GABAAreceptors with two equivalent GABA (G ; orthosteric agonist) sites and two equivalent etomidate (E ; allosteric agonist) sites. The L0parameter describes the basal equilibrium between the two canonical states: inactive (R ) and active (O ). KGis the dissociation constant for GABA interactions with R -state receptors; and KG* is the dissociation constant for GABA interactions with O -state receptors. The GABA efficacy factor, c , is defined as KG*/KG. KEis the dissociation constant for etomidate interactions with R -state receptors; and K  E* is the dissociation constant for etomidate interactions with O -state receptors. The etomidate efficacy factor, d , is defined as KE*/KE. The differently sized arrows  illustrate how equilibria shift as ligands bind and functional state changes.

Fig. 5.  Monod–Wyman–Changeux two-state equilibrium model for etomidate and GABA activation of GABAAreceptors. The scheme depicts allosteric coagonism for GABAAreceptors with two equivalent GABA (G ; orthosteric agonist) sites and two equivalent etomidate (E ; allosteric agonist) sites. The L0parameter describes the basal equilibrium between the two canonical states: inactive (R ) and active (O ). KGis the dissociation constant for GABA interactions with R -state receptors; and KG* is the dissociation constant for GABA interactions with O -state receptors. The GABA efficacy factor, c , is defined as KG*/KG. KEis the dissociation constant for etomidate interactions with R -state receptors; and K  E* is the dissociation constant for etomidate interactions with O -state receptors. The etomidate efficacy factor, d , is defined as KE*/KE. The differently sized arrows  illustrate how equilibria shift as ligands bind and functional state changes.

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Mutations That Alter Etomidate Sensitivity of GABAAReceptors

A β subunit region containing the M2 domain influences the differential etomidate sensitivity of GABAAreceptors containing β1 versus β2 subunits.121The only amino acid in M2 that differs between β1 and β2 is at position 265 of the mature protein. β265 is a serine (S) in β1 and an asparagine (N) in β2 and β3. A point mutation replacing β1S265 with N (β1S265N) increases etomidate sensitivity, whereas replacing β2 or β3N265 with S (β2/3N265S) dramatically reduces etomidate sensitivity.121Similarly, an anesthetic-insensitive mutant Drosophila melangaster  (fruit fly) line contains a methionine (M) at the homologous amino acid in M2, instead of the N found in the wild type. A mutation from N265 to M in the β2 or β3 subunit of mammalian GABAAreceptors also confers insensitivity to etomidate.122–124Mutations at βN265 produce parallel changes in etomidate modulation of GABA-activated receptor-mediated currents and direct activation of channels. Quantitative electrophysiologic analysis of GABAAreceptors containing both β2N265S and β2N265M mutations show little impact on basal or GABA-mediated activation and different degrees of reduced etomidate sensitivity.125The β2N265M mutation totally eliminates etomidate sensitivity, whereas the β2N265S mutation reduces etomidate-induced shifts in GABA EC50(EC50ratio) more than 8-fold relative to the wild type (table 2).

Table 2.  GABAAReceptor Mutant Effects on GABA and Etomidate Sensitivity

Table 2.  GABAAReceptor Mutant Effects on GABA and Etomidate Sensitivity
Table 2.  GABAAReceptor Mutant Effects on GABA and Etomidate Sensitivity

All GABAAreceptor β subunits contain a methionine at position 286 in their M3 domains, and βM286 mutations also influence etomidate sensitivity. The βM286W mutation eliminates etomidate modulation of receptors, whereas the homologous αA291W mutation has no effect on etomidate actions.123,124,126Quantitative electrophysiologic analysis demonstrates that GABAAreceptors containing the β2M286W mutation display both enhanced sensitivity to GABA and spontaneous activity, effects that mimic the actions of etomidate on wild-type channels (table 2).127 

Etomidate Anesthesia in Transgenic Animals

Mutations at β2N265 and β3N265 have been incorporated into transgenic “knock-in” mice to test the role of these subunits in anesthetic actions. Jurd et al.  128reported that β3N265M knock-in animals have grossly normal morphological and behavioral phenotypes but are resistant to both loss of righting reflexes and antinociceptive (immobilizing) actions of etomidate and propofol at doses higher than those affecting 100% of wild-type animals. Reynolds et al.  129developed β2N265S knock-in mice and reported that they also have normal morphological features and behavior, including sleep and electroencephalographic activity. The β2N265S knock-in mice show normal sensitivity to etomidate for loss of righting reflexes and antinociceptive actions, but these mice are resistant to sedative and hypothermic actions of etomidate.129,130Etomidate enhancement of tonic currents associated with extrasynaptic receptors is lost in neurons from β2N265S transgenic mice.131Further evidence implicating extrasynaptic receptors derives from knock-out mice lacking GABAAreceptor α5 subunits, which are insensitive to the amnestic effects of etomidate.132However, sedative–hypnotic actions in α5−/−animals are similar to those in wild-type littermates. Similarly, δ−/−knock-out animals show normal sensitivity to etomidate hypnosis.133Transgenic animal studies, such as these, confirm that etomidate acts via  GABAAreceptors and that different clinical actions of etomidate are mediated by specific receptor subtypes containing different subunits. Hypnotic and immobilizing actions are mediated by receptors containing β3 subunits, whereas sedation is linked to receptors containing β2. Extrasynaptic receptors, which often contain α5 and δ subunits, appear to be linked to etomidate-induced amnesia but not to hypnosis and immobility.

Location of Etomidate Sites on GABAAReceptors

Etomidate, with its high potency and stereoselectivity, proved an excellent candidate for creating photoreactive derivatives that covalently modify target channels. Husain et al.  3synthesized a diaziryl derivative, azietomidate; and Bright et al.  134produced an azide. These photolabels display stereoselectivity and pharmacologic activity almost identical to that of etomidate in both animals and GABAAreceptors.3,134,135In the presence of ultraviolet light, azietomidate effects on GABAAreceptors become irreversible.116Radiolabeled azietomidate was used to photolabel affinity-purified bovine GABAAreceptor protein, leading to the identification of two photomodified amino acids: M236 in M1 on α subunits and M286 in M3 on β subunits.136The addition of etomidate blocked photoincorporation at both positions in parallel, suggesting that they contribute to the same binding pockets formed where α subunits abut β subunits (fig. 4A). Two such interfacial sites are predicted to be formed by most GABAAreceptors, consistent with the predictions from functional analysis.114 

More evidence that αM236 and βM286 are involved in etomidate binding comes from recent molecular studies of mutations at these residues. GABAAreceptors with tryptophan mutations at either α1M236 or β2M286 display functional characteristics that mimic the reversible effects of etomidate on wild-type receptors.127Both α1M236W and β2M286W also reduce receptor sensitivity to etomidate, perhaps because the large tryptophan side chains occupy the space where etomidate binds. Cysteine mutations have been used to introduce free sulfhydryls at α1M236 and β2M286, which are accessible to modification by selective reagents.137Sulfhydryl modification of α1M236C or β2M286C is blocked by etomidate (Deirdre Stewart, Ph.D., Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston; unpublished research findings; April 1, 2010), confirming that the drug binds close to both residues. The hypothesis that etomidate binds between transmembrane helices on two adjacent GABAAreceptor subunits differs from previous proposals that anesthetics bind within a single subunit.138Recently, Bali et al.  137provided further evidence that αM236 and βM286 residues of GABAAreceptors are on nearby helical domains and oriented toward interfacial clefts between subunits. Their experiments showed that β2M286C forms intersubunit cross-linking disulfide bonds with cysteines substituted at two α subunit M1 domain loci on the same helical face as α1M236.

Etomidate Interactions With Adrenal Steroidogenesis Enzymes

During etomidate infusion, plasma concentrations of cortisol, cortisone, and aldosterone decrease, whereas those of 11-deoxycorticosterone, 11-deoxycortisol, progesterone, and 17-hydroxyprogesterone increase.139These clinical results, and related in vitro  studies,140indicate that etomidate inhibits adrenal steroid synthesis primarily by blocking the activity of CYP11B1, also known as 11β-hydroxylase or P450c11. This mitochondrial cytochrome enzyme converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone and is 95% homologous to the CYP11B2 (aldolase) enzyme in the pathway leading to aldosterone.141 

The imidazole ring of etomidate is likely to be a major determinant of its binding to adrenal cytochrome enzymes. Many other imidazole compounds inhibit CYP11B enzymes,142and a variety of crystal structure studies confirm that imidazole nitrogens coordinate (form dipolar bonds with) heme irons located at the active sites of prokaryotic and eukaryotic cytochromes.143–145High-efficiency in vitro  production of purified human CYP11B1 has recently been reported,146and high-resolution structural data for the molecule may be available in the near future. Homology models based on crystal structures of related enzymes have been developed and used for in silico ligand etomidate docking studies (fig. 6).147 

Fig. 6.  Homology model for etomidate binding to CYP11B1. The binding pocket of CYP11B1 is depicted based on high-resolution crystal structures of related cytochromes.147Etomidate is bound within the binding pocket, oriented to form a strong coordinate bond between its free imidazole nitrogen and the heme iron of the enzyme. (This figure was kindly provided by Keith W. Miller, D. Phil., and Shunmugasundararaj Sivananthaperumal, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.)

Fig. 6.  Homology model for etomidate binding to CYP11B1. The binding pocket of CYP11B1 is depicted based on high-resolution crystal structures of related cytochromes.147Etomidate is bound within the binding pocket, oriented to form a strong coordinate bond between its free imidazole nitrogen and the heme iron of the enzyme. (This figure was kindly provided by Keith W. Miller, D. Phil., and Shunmugasundararaj Sivananthaperumal, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.)

Close modal

Adrenergic Receptors and Cardiovascular Stability With Etomidate

α-2 Adrenergic receptors are activated by etomidate, but this action is unrelated to its hypnotic effects in mice.148However, the transient hypertension produced by etomidate in wild-type mice is absent in knockout mice lacking either α2B or α2A adrenergic receptor subtypes. This result indicates that α2 adrenergic receptors may contribute to the hemodynamic effects of etomidate.

Etomidate's remarkably benign cardiovascular and pulmonary effects are also likely the result of its selectivity for a few molecular targets. In comparison, clinically relevant concentrations of barbiturates, propofol, and volatile anesthetics modulate a broader array of GABAAreceptor subtypes together with multiple other etomidate-insensitive ion channels found in both neurons and cardiovascular structures.149 

Channels That Mediate Etomidate Injection Pain

Transient receptor potential type A1 cation channels are involved in inflammation and pain sensation. Like propofol and other general anesthetics, etomidate at high concentrations activates transient receptor potential type A1 channels, a mechanism that may underlie pain during injection.150 

Selective Adrenal Steroid Inhibitors

Because of its unequaled potency as an inhibitor of cortisol and aldosterone synthesis, etomidate derivatives have been explored as selective biomarkers and inhibitors for diseases associated with excess adrenocortical activity. Positron-emitting derivatives of etomidate have been developed for localization of adrenal tumors,151and infusion of etomidate is gaining popularity as a short-term treatment for poorly controlled Cushing's disease.152Subhypnotic doses of etomidate effectively reduce the high systemic cortisol and aldosterone concentrations associated with this disease, with mild sedation as an adverse effect.153In addition to inhibiting steroid synthesis, etomidate inhibits proliferation of adrenal cortical cells, making it particularly useful in the treatment of metastatic adrenocortical tumors.154In a recent report79on several dozen synthetic etomidate derivatives, none demonstrated greater potency than etomidate for inhibition of cortisol synthesis by cultured adrenal cells. Several of these compounds show high potency for CYP11B binding but weak interactions with GABAAreceptors, suggesting that treatment for excess cortisol or aldosterone synthesis may be achieved without adverse sedative effects.155 

Novel Anesthetic Agents

Recent research has also aimed at modifying etomidate to improve its clinical utility as an anesthetic and sedative. Two molecular strategies have been described to maintain the favorable clinical features of etomidate while reducing the activity that most limits its clinical use: prolonged inhibition of adrenal steroidogenesis.

Methoxycarbonyl (MOC) etomidate is a “soft” analog that contains a second ester bond distal to the existing etomidate ester linkage (fig. 7A).156MOC etomidate modulates GABAAreceptors with a potency near that of etomidate but is rapidly (with a half-life of a few minutes) metabolized by nonspecific esterase enzymes in blood and tissue and converted to a carboxylic acid metabolite. The MOC etomidate metabolite is inactive as both an anesthetic and an inhibitor of adrenal steroid synthesis (Douglas Raines, M.D., Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital; oral communication; April, 2010). In rats, MOC etomidate bolus administration produced anesthesia lasting only a few minutes, whereas an equipotent bolus of etomidate produced loss of righting reflexes for nearly an hour. Thirty minutes after MOC etomidate bolus administration, no adrenal suppression is found, whereas significant adrenal suppression is associated with etomidate bolus administration. MOC etomidate is in preclinical development. Its potential use includes anesthesia induction and maintenance for up to several hours. Adrenal suppression may be present during anesthesia with MOC etomidate, but adrenal function is predicted to recover rapidly after cessation of drug infusion.

Fig. 7.  Structures of MOC etomidate and carboetomidate. (A ) Structure of MOC etomidate, a rapidly metabolized “soft analog” of etomidate. The dashed box  outlines the parent molecule, which is depicted in Fig. 1. (B ) Structure of carboetomidate, a molecule that retains the molecular shape of etomidate while replacing the imidazole ring with a pyrrole ring that is unable to form coordinate bonds with heme iron. (The structures were kindly provided by Douglas Raines, M.D., Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.)

Fig. 7.  Structures of MOC etomidate and carboetomidate. (A ) Structure of MOC etomidate, a rapidly metabolized “soft analog” of etomidate. The dashed box  outlines the parent molecule, which is depicted in Fig. 1. (B ) Structure of carboetomidate, a molecule that retains the molecular shape of etomidate while replacing the imidazole ring with a pyrrole ring that is unable to form coordinate bonds with heme iron. (The structures were kindly provided by Douglas Raines, M.D., Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.)

Close modal

Carboetomidate is an etomidate “look-alike” drug that contains a five-membered pyrrole ring instead of an imidazole (fig. 7B).157The loss of the free imidazole nitrogen eliminates coordination interactions with heme irons, reducing adrenal suppression potency by three orders of magnitude (IC50, approximately 1 μm [vs.  etomidate IC50, 1 nm]), based on adrenal cell cortisol synthesis assays. Carboetomidate retains the ability to modulate and directly activate GABAAreceptors and is a potent sedative–hypnotic with systemic effects and a duration of action similar to that of etomidate in laboratory animals.

The following individuals are thanked for contributing illustrations and valuable feedback on the manuscript: Keith W. Miller, D.Phil., Professor of Anesthesiology; Douglas Raines, M.D., Associate Professor of Anesthesiology; Joseph Cotten, M.D., Ph.D., Assistant Professor of Anesthesiology; Shunmugasundararaj Sivananthaperuma, Ph.D., Research Associate; all of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; and David Chiara, M.D., Ph.D., Senior Research Associate, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.

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