Clinical and molecular pharmacology of etomidate

Abstract

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.

Figure 1. Chemical Structure of Etomidate

Critical structural features for anesthetic activity include a single methylene group between the imidazole and the phenyl group and the R(+) configuration at the chiral center (labeled with an asterix).

Figure 2. Etomidate Publications in PubMed

The graph displays numbers of publications within a calendar year, based on PubMed searches with “etomidate” as a MESH term (gray + white bars), or the subset of these publications with humans as the subjects (white bars). Data are inclusive through December, 2009.

Figure 3. Single Intravenous Bolus Pharmacokinetics of Etomidate

The etomidate plasma concentration following a single intravenous bolus (3 mg/kg) is depicted on a semi-logarithmic plot with the early decline period expanded. This concentration versus time profile is based on pharmacokinetic parameters determined by Van Hamme et al, showing three distinct decline phases with half-times of 2 minutes, 21 minutes, and 3.9 hours. Graded colored areas indicate etomidate plasma concentration ranges associated with hypnosis (blue) and adrenocortical suppression (red). Together, these data illustrate why the duration of hypnosis (~ 8 minutes) is much shorter than the duration of adrenocortical suppression (~ 8 hours) following a single etomidate dose.

Figure 4. Molecular Structure of GABA_A Receptors

A GABA_A receptor 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, Harvard Medical School, Boston, MA).

Figure 5. A Monod-Wyman-Changeux Two-State Equilibrium Model for Etomidate and GABA Activation of GABA_A Receptors

The scheme depicts allosteric co-agonism for GABA_A receptors with two equivalent GABA (G; orthosteric agonist) sites and two equivalent etomidate (E; allosteric agonist) sites. The L₀ parameter describes the basal equilibrium between the two canonical states: inactive (R) and active (O). K_G is the dissociation constant for GABA interactions with R-state receptors and K_G* is the dissociation constant for GABA interactions with O-state receptors. The GABA efficacy factor, c, is defined as K_G*/K_G. K_E is 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 K_E*/K_E. The different size arrows illustrate how equilibria shift as ligands bind and functional state changes.

Figure 6. Homology model for etomidate binding to CYP11B1

The binding pocket of CYP11B1 is depicted, based on high resolution crystal structures of related cytochromes. Etomidate is shown 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 Miller and Shunmugasundararaj Sivananthaperumal, Massachusetts General Hospital, Boston, MA).

Figure 7. Structures of MOC-etomidate and Carboetomidate

Panel A shows the structure of methoxycarbonyl etomidate (MOC-etomidate), a rapidly metabolized “soft analog” of etomidate. The dashed box outlines the parent molecule, which is depicted in Figure 1. Panel B shows the 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, Massachusetts General Hospital, Boston, MA).