Etomidate and its Analogs: A Review of Pharmacokinetics and Pharmacodynamics

Abstract

Etomidate is a hypnotic agent that is used for the induction of anesthesia. It produces its effect by acting as a positive allosteric modulator on the γ-aminobutyric acid type A receptor and thus enhancing the effect of the inhibitory neurotransmitter γ-aminobutyric acid. Etomidate stands out among other anesthetic agents by having a remarkably stable cardiorespiratory profile, producing no cardiovascular or respiratory depression. However, etomidate suppresses the adrenocortical axis by the inhibition of the enzyme 11β-hydroxylase. This makes the drug unsuitable for administration by a prolonged infusion. It also makes the drug unsuitable for administration to critically ill patients. Etomidate has relatively large volumes of distributions and is rapidly metabolized by hepatic esterases into an inactive carboxylic acid through hydrolyzation. Because of the decrease in popularity of etomidate, few modern extensive pharmacokinetic or pharmacodynamic studies exist. Over the last decade, several analogs of etomidate have been developed, with the aim of retaining its stable cardiorespiratory profile, whilst eliminating its suppressive effect on the adrenocortical axis. One of these molecules, ABP-700, was studied in extensive phase I clinical trials. These found that ABP-700 is characterized by small volumes of distribution and rapid clearance. ABP-700 is metabolized similarly to etomidate, by hydrolyzation into an inactive carboxylic acid. Furthermore, ABP-700 showed a rapid onset and offset of clinical effect. One side effect observed with both etomidate and ABP-700 is the occurrence of involuntary muscle movements. The origin of these movements is unclear and warrants further research.

Structural Modification in Anesthetic Drug Development for Prodrugs and Soft Drugs

“…Recent studies have shown no correlation between involuntary muscle movement and epilepsy (Valk et al, 2019), although, disinhibitory effects of the Bispectral Index (BIS) are associated with involuntary muscle movements . The mechanisms underlying clinical excitation are still unclear, and ABP-700 was restarted in 2020 with funding by Mass General Brigham (Boston, MA, United States), which still needs further investigation (Valk and Struys, 2021).…”

What’s New in Intravenous Anaesthesia? New Hypnotics, New Models and New Applications

“…This was shown to be caused by etomidate-induced inhibition of the 11β-hydroxylase enzyme causing adrenocortical suppression [ 48 ]. Since then, the use of etomidate has been limited to the induction of general anaesthesia in select patient groups, in whom the proposed haemodynamic stability after etomidate induction outweighs the risk of adrenal suppression [ 3 ]. Since the late 2000s, analogues of etomidate have been in development with the aim to eliminate the adrenocortical suppressive action while retaining its haemodynamically stable profile.…”

Polymorphisms of pharmacogenetic candidate genes affect etomidate anesthesia susceptibility

“…Etomidate mainly acts on the α and β subunits of GABAA ( Forman, 2011 ). Besides, Etomidate inhibits the adrenal cortical axis by inhibiting the enzyme 11β-hydroxylase and mainly is metabolized by hepatic esterase ( Valk and Struys, 2021 ). Etomidate metabolism in animals and humans depends on hepatic esterase activity, which hydrolyzes it to a carboxylic acid and an ethanol leaving group ( Forman, 2011 ).…”