Friday, November 22, 2013

Carboetomidate: The Answer to the Prayers of the Intubated Septic Patient?

With all the controversy surrounding the questionable association of mortality associated with the use of etomidate for the purposes of induction in the septic patient, it only seems reasonable to recommend alternative agents in this setting...or design therapeutic analogues.

Enter carboetomidate.

Carboetomidate is a derivative of etomidate that contains a pyrrole ring in its structure, as opposed to an imidazole ring that is found in etomidate.


What is the significance of this? It has been proposed that drugs that contain an imidazole ring within its chemical structure, such as etomidate, have the effect of suppressing the synthesis of adrenocortical steroids. For etomidate, this is thought to be secondary to its inhibition of the enzyme 11-β hydroyxlase. This has been shown to occur through the interaction of the nitrogen atom in the imidazole ring with the active binding site of this enzyme. With substitution of the nitrogen atom for a carbon atom, it has been hypothesized that the interaction with the enzyme will not be as strong, leading to reduced inhibition of cortisol synthesis.

A few animal studies (1, 2)  have been conducted evaluating this effect to determine the potential clinical impact. These studies have shown that even with a minimal change in the structure, hemodynamic stability and sedation was maintained with effects demonstrated to be similar to etomidate in terms of duration and potency This was demonstrated to occur due to modulation of the GABA receptor by carboetomidate. However, the onset of action of carboetomidate was shown to be a bit slower than etomidate in one animal study (4.5 ± 0.6 s with etomidate versus 33 ± 22 s with carboetomidate) (3), which may be less than desirable in the setting of rapid sequence intubation; human studies have yet to be conducted to determine if this is truly the case.

It will be interesting to see this unfold and the niche that carboetomidate will potentially have should it be approved for use as an induction agent in humans.

References:
  1. Pejo E, Feng Y, Chao W, et al. Differential effects of etomidate and its pyrrole analogue carboetomidate on the adrenocortical and cytokine responses to endotoxemia. Crit Care Med 2012; 40:187-192.
  2. Shanmugasundararaj S, Zhou X, Neunzig J, et al. Carboetomidate: an analog of etomidate that interacts weakly with 11-β hydroyxlase. Anesth Analg 2013; 116:1249-1256.
  3. Cotton JF, Forman SA, Laha JK, et al. Carboetomidate: a pyrrole analog of etomidate designed to not suppress adrenocortical function. Anesthesiology 2010; 112:637-644.