In the U.S. alone, nearly 30 million general anesthetics are administered each year. At the doses required to produce anesthesia, all general anesthetics produce serious side effects. Depression of cardiovascular and respiratory function is of greatest concern, particularly in the critically ill. Such depression explains why anesthetics have among the lowest therapeutic indices of any class of drugs. This proposal focuses on etomidate, which is distinguished from other general anesthetics by its favorable hemodynamic and respiratory effects and its unusually high therapeutic index. However because etomidate potently inhibits 112- hydroxylase, leading to prolonged suppression of adrenocortical steroid synthesis with potentially fatal consequences, its clinical use is effectively limited in the critically ill to single bolus administration for the induction of anesthesia. The broad, long-term goal of this work is to provide the groundwork for the development of novel anesthetics that retain etomidate's beneficial properties, but whose impact on steroid synthesis is greatly reduced. This would extend clinical utility beyond bolus administration to include continuous infusion for anesthetic maintenance and possibly long-term sedation. The proposed studies will define structure-activity relationships for novel etomidate analogues and test new two strategies for developing analogues of etomidate that can be continuously infused because their abilities to inhibit adrenocortical function are significantly reduced in duration or magnitude. The first strategy is to design etomidate analogues that are so rapidly metabolized that suppression of adrenocortical function terminates when their infusion is stopped at the end of surgery rather than persisting for days afterward. Such agents are also expected to produce more rapid and predictable emergence from anesthesia. The second strategy is to design anesthetic etomidate analogues that do not bind to 112-hydroxylase with high affinity and, therefore, do not inhibit steroid synthesis at clinically relevant doses.
Specific Aim 1 is to define in vitro structure-activity relationships for novel metabolically-labile etomidate analogues (etomidate esters) and their carboxylic acid metabolites.
Specific Aim 2 is to determine in a rat model whether continuous infusions of etomidate esters depress adrenocortical, cardiovascular, or respiratory function and if so, to compare such depression to that produced by continuous infusions of etomidate.
Specific Aim 3 is to locate and characterize the etomidate binding site(s) on human 112-hydroxylase and to define structure-activity relationships for novel etomidate analogues whose abilities to coordinate with 112-hydroxylase's heme iron vary.

Public Health Relevance

There is a great need for safer general anesthetics, particularly for use in critically ill patients. Etomidate possesses many properties that make it an ideal anesthetic agent, but because it produces prolonged and potentially deadly suppression of adrenocortical function, its clinical utility is limited in the critically ill to single bolus administration for the induction of anesthesia. The proposed studies will define structure-activity relationships and test two novel strategies (one pharmacokinetic and the other pharmacodynamic) for developing analogues of etomidate that retain etomidate's beneficial properties, but may be safely administered by continuous infusion to maintain anesthesia because their abilities to suppress adrenocortical function are reduced in duration or magnitude. The successful application of one or both of these strategies to develop novel etomidate analogues will improve human health by permitting anesthesia to be administered more safely to patients who are at greatest risk: the critically ill.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087316-04
Application #
8401548
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2010-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$505,714
Indirect Cost
$220,000
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Pejo, Ervin; Santer, Peter; Wang, Lei et al. (2016) γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs. Anesthesiology 124:651-63
Pejo, Ervin; Zhou, Xiaojuan; Husain, S Shaukat et al. (2016) Sedative-hypnotic Binding to 11β-hydroxylase. Anesthesiology 125:943-951
Pejo, Ervin; Liu, Jifeng; Lin, Xiangjie et al. (2016) Distinct Hypnotic Recoveries After Infusions of Methoxycarbonyl Etomidate and Cyclopropyl Methoxycarbonyl Metomidate: The Role of the Metabolite. Anesth Analg 122:1008-14
Raines, Douglas E (2015) The pharmacology of etomidate and etomidate derivatives. Int Anesthesiol Clin 53:63-75
Santer, Peter; Pejo, Ervin; Feng, Yan et al. (2015) Cyclopropyl-methoxycarbonyl Metomidate: Studies in a Lipopolysaccharide Inflammatory Model of Sepsis. Anesthesiology 123:368-76
Ge, Rile; Pejo, Ervin; Gallin, Hilary et al. (2014) The pharmacology of cyclopropyl-methoxycarbonyl metomidate: a comparison with propofol. Anesth Analg 118:563-7
Pejo, Ervin; Santer, Peter; Jeffrey, Spencer et al. (2014) Analogues of etomidate: modifications around etomidate's chiral carbon and the impact on in vitro and in vivo pharmacology. Anesthesiology 121:290-301
Campagna, Jason A; Pojasek, Kevin; Grayzel, David et al. (2014) Advancing novel anesthetics: pharmacodynamic and pharmacokinetic studies of cyclopropyl-methoxycarbonyl metomidate in dogs. Anesthesiology 121:1203-16
Shanmugasundararaj, Sivananthaperumal; Zhou, Xiaojuan; Neunzig, Jens et al. (2013) Carboetomidate: an analog of etomidate that interacts weakly with 11β-hydroxylase. Anesth Analg 116:1249-56
Desai, Rooma; Miller, Keith W; Raines, Douglas E (2013) The pyrrole etomidate analog carboetomidate potently inhibits human 5-HT3A receptor function: comparisons with etomidate and potential implications for emetogenesis. Anesth Analg 116:573-9

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