Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate

Ge, Rile; Pejo, Ervin; Cotten, Joseph F.; Raines, Douglas E.

doi:10.1186/cc12494

Cited by 34 publications

(31 citation statements)

References 32 publications

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“…25 As in rats, adrenocortical responsiveness to ACTH 1-24 stimulation in dogs is suppressed during CPMM infusion. However after infusion, ACTH 1-24 -stimulated plasma cortisol concentrations recover much more quickly after CPMM than after etomidate.…”

Section: Discussionmentioning

confidence: 90%

Advancing Novel Anesthetics

et al. 2014

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Background Cyclopropyl-methoxycarbonyl metomidate (CPMM, also known as ABP-700) is a second-generation “soft” (i.e., metabolically-labile) etomidate analogue. The purpose of these studies was to characterize CPMM's pharmacology in beagle dogs in preparation for potential first in human phase 1 clinical trials. Methods CPMM's and etomidate's hypnotic activity and duration of action were assessed using loss of righting reflex and anesthesia score assays in three or four dogs. Their pharmacokinetics were defined after single bolus administration and single bolus followed by 2-h infusion. Adrenocortical recovery times after single bolus followed by 2-h infusion of CPMM, propofol, etomidate, and vehicle were measured using an adrenocorticotropic hormone stimulation test. Results Compared to etomidate, CPMM was half as potent as a hypnotic (ED50 ~ 0.8 mg/kg), more rapidly metabolized, and had a shorter duration of sedative-hypnotic action. Recovery times after CPMM administration were also independent of infusion duration. After hypnotic infusion, adrenocorticotropic hormone-stimulated plasma cortisol concentrations were 4- to 27-fold higher in dogs that received CPMM versus etomidate. Adrenocortical recovery was faster in dogs after CPMM infusion versus etomidate infusion (half-time: 215 min vs. 1623 min, respectively). Adrenocortical responsiveness assessed 90 min after CPMM infusion was not significantly different from that after propofol infusion. Conclusion Our studies in dogs confirm that CPMM has hypnotic and adrenocortical recovery profiles that are superior than those of etomidate, supporting the continued development of CPMM as a clinical sedative-hypnotic to be used as a single bolus and by continuous infusion to induce and maintain general anesthesia or procedural sedation.

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Section: Discussionmentioning

confidence: 90%

Advancing Novel Anesthetics

et al. 2014

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“…During continuous infusion, CPMM reduced plasma corticosterone concentrations in adrenocorticotropin hormone-stimulated and endotoxin-treated rats; however, this reduction was less than that produced by etomidate and corticosterone levels returned to control values faster with CPMM than with etomidate once the infusion was terminated. 21,24 Dexmedetomidine inhibited in vitro corticosterone production by rat adrenocortical cells and suppressed in vivo cortisol production in dogs. 26 However at equi-hypnotic doses, the magnitude of this suppression was less than that produced by etomidate.…”

Section: Discussionmentioning

confidence: 96%

“…This “soft analog” approach is exemplified by cyclopropyl methoxycarbonyl metomidate (CPMM), which is rapidly hydrolyzed to form CPMM-CA. 20,21 CPMM is currently undergoing clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Sedative-hypnotic Binding to 11β-hydroxylase

et al. 2016

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Background Etomidate potently suppresses adrenocortical steroid synthesis with potentially deleterious consequences by binding to 11β-hydroxylase and inhibiting its function. The authors hypothesized that other sedative-hypnotics currently in clinical use or under development (or their metabolites) might bind to the same site at clinically relevant concentrations. The authors tested this hypothesis by defining etomidate’s affinity for this site and the potencies with which other sedative-hypnotics (and their metabolites) inhibit etomidate binding. Methods 3H-etomidate’s binding to adrenal membranes from Sprague-Dawley rats was characterized with a filtration assay, and its dissociation constant was defined using saturation and homologous ligand competition approaches. Half-inhibitory concentrations of sedative-hypnotics and metabolites were determined from the reduction in specific 3H-etomidate binding measured in the presence of ranging sedative-hypnotic and metabolite concentrations. Results Saturation and homologous competition studies yielded 3H-etomidate dissociation constants of 40 and 21 nM, respectively. Half-inhibitory concentrations of etomidate and cyclopropyl methoxycarbonyl metomidate (CPMM) differed significantly (26 vs. 143 nM, respectively; P < 0.001), and those of the carboxylic acid (CA) metabolites etomidate-CA and CPMM-CA were greater than or equal to 1,000× higher than their respective parent hypnotics. The half-inhibitory concentration of dexmedetomidine was 2.2 µM, whereas those of carboetomidate, ketamine, and propofol were greater than or equal to 50 µM. Conclusion Etomidate’s in vitro dissociation constant for 11β-hydroxylase closely approximates its in vivo adrenocortical half-inhibitory concentration. CPMM produces less adrenocortical suppression than etomidate not only because it is metabolized faster but also because it binds to 11β-hydroxylase with lower affinity. Other sedative-hypnotics and metabolites bind to 11β-hydroxylase and inhibit etomidate binding only at suprahypnotic concentrations.

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“…DMM-metomidate shows some modest context-sensitive accumulation after a 2-hour infusion, which may be in part because of its longer blood half-life (Table 1). 16,17 The Pharmacodynamic Approach As discussed, etomidate is an exceptionally potent inhibitor of CYPB1 enzyme function, and CYPB1 is critical for cortisol, corticosterone, and aldosterone synthesis. CYPB1 is a heme-containing cytochrome P450 enzyme, which coordinates iron in its active site.…”

Section: The Soft Drug Pharmacokinetic Approachmentioning

confidence: 99%

Toward a Better Etomidate

Cotten

Raines

2013

ICU Director

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More than 45 years after its development, etomidate still sees widespread use as a hypnotic agent for singledose sedation of critically ill and hemodynamically unstable patients. Potent and prolonged inhibition of cortisol synthesis by etomidate, even following single-dose administration, is controversial and a legitimate concern for clinicians. This article will briefl y review etomidate pharmacology. It will also discuss some recent basic science and translational studies that have yielded several novel and clinically promising etomidate analogues designed to circumvent etomidate adrenal suppression.

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Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate

Cited by 34 publications

References 32 publications

Advancing Novel Anesthetics

Advancing Novel Anesthetics

Sedative-hypnotic Binding to 11β-hydroxylase

Toward a Better Etomidate

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