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Pharmacology Not Taught in Medic School: Etomidate Edition

Let’s talk all things Etomidate. Then again, when we decide to use this drug, typically we are dealing with a rather low frequency/high-risk clinical procedure, right? In this short (but in-depth!) blog we will cover its mechanism, why it causes adrenal suppression, and some interesting things to note about the drug to supplement this RSI Blog.

Welcome back to “Pharmacology not taught in medic school – Etomidate Edition”.

I. Mechanism of Action

a. GABA Receptors

Every medic class that comes through I hear the same thing, “it acts on the GABA receptor”. And then I ask, “well, how does the GABA receptor work to cause the effects we see with Etomidate?”. And unfortunately, most of our paramedic pharmacology educations stops right about there.

Before we get into how Etomidate works, let's understand how the GABA receptor is structured as well as how it functions. The GABA receptor is the Gamma Amino-Butyric Acid receptor, so named because it responds to the GABA neurotransmitter. GABA receptors are the primary inhibitory receptor of the central nervous system. Our CNS has a red light (the GABA receptor) as well as a green light (NMDA receptors). Both are functionally active at the same time and a balance is established much like our sympathetic and parasympathetic nervous system is balanced.

GABA receptors come in two forms: GABA-A receptors and GABA-B Receptors. GABA-A is the primary one we will touch on with Etomidate. The receptor is structurally similar to the following diagram:

It is composed of 5 surrounding protein subunits (alpha 1 & 2, beta 1 & 2, & gamma subunits). These subunits surround a central chloride pore (Richter et al., 2012). When the GABA receptor is activated, the subunits change shape (known as a conformational change) and open the chloride pore allowing extracellular chloride to enter the cell down its concentration gradient.

Chloride influx into CNS cells is what causes the inhibitory effect of these receptors. Remember, depolarization of neuronal cells is caused by a rapid influx of cations (namely sodium) into the cells. Sodium is a positively charged ion and increases the membrane potential of the cell past the threshold to elicit depolarization (aka an action potential). So, when a highly negative anion, like Chloride, enters the cell, it keeps that membrane potential very low and therefore doesn’t allow the cell to depolarize – rather, it maintains a very low resting membrane potential.

In fact, when Chloride enters the cell, it drives the membrane potential to roughly -65 mV inside the cell – this is known as its “Nernst Potential”(Delpire & Staley, 2014). Sodium also carries a Nernst Potential of +55 mV, hence when sodium enters a cell it drives the potential up to +55 mV to cause depolarization (the green dotted line in the image above). What is important to take away is that when GABA receptors activate, they open the Chloride pore in the center of the receptor and Chloride floods the inside of the cell. And due to its very negative Nernst potential, it keeps the membrane potential very low and does not allow CNS cells to depolarize.

b. Etomidate and its GABA lover…

The GABA receptor is structured with alternating alpha, beta, and gamma subunits. GABA receptor sites sit between the alpha and beta subunits as shown below:

The literature is quite sparse regarding receptor structure but what is best understood is that Etomidate binds to the GABA receptor site between the alpha and beta subunits thereby creating a conformational change that increases the GABA receptor’s affinity for its own GABA neurotransmitter or by opening the Chloride membrane pore on its own. Either mechanism results in the same effect – Chloride pore opening and Chloride influx resulting in hyperpolarization of the cell (Pejo et al., 2016).

Once the cell is flooded with Chloride and not able to depolarize, we then see the clinical effects of Etomidate (i.e. Unconsciousness, anesthetic effect). Interestingly enough, about 0.1 mg/kg is good for about 100 seconds of unconsciousness. So, at 0.3 mg/kg, this gives us roughly 300 seconds (or 5 minutes) of unconsciousness. Anecdotally, Etomidate is great for combative head patients as you can give the etomidate, pre-oxygenate without the issue of them fighting you, and then proceed to paralysis.

II. Adverse Effects/Contraindications

The biggest adverse effect/contraindication we see with Etomidate is adrenal suppression. But why is that exactly?

Etomidate blocks the formation of cortisol. Cortisol is derived from cholesterol through a series of several intermediate steps as illustrated below:

Where Etomidate acts on this pathway specifically is in the second to last step where the enzyme 11-betahydroxylase converts 11-deoxycortisol to cortisol. Etomidate inhibits the production of the 11-betahydroxylase enzyme to convert the last intermediate to cortisol (Ginnard DO & Nella MD, 2019).

Remember, cortisol is our primary “stress” hormone and if we remove the ability of our body to secrete cortisol during high-stress states, we would not be able to mount an effective sympathetic response to shock. Hence, in septic patients who require a lot of sympathetic outflow to combat their distributive shock, Etomidate would take away some of this ability via inhibiting cortisol.

III. Is Etomidate a hemodynamically unstable drug??

With the way many of our protocols are written, it gives the sense that Etomidate is a hemodynamically unstable drug that will drop your blood pressure no matter what. Therefore, its avoided in peri-hypotensive patients, to begin with. However, beyond our EMS protocols and into the anesthesia world, Etomidate is categorized as a hemodynamically neutral drug! In one critical care article, the authors stated that “etomidate is used for its hemodynamic stability after anesthesia induction and also allows good intubation conditions, especially in more severely ill patients”.

In a study recently published in the Air Medical Journal, clinicians looked at the prevalence of hypotension after Etomidate or Ketamine administration during RSI. 113 patients were sampled and there was no difference in episodes of hypotension between Etomidate and Ketamine (16% vs 18%, respectively). Moreover, 80 patients received Etomidate while 33 received Ketamine (Stanke et al., 2021). One would suspect that a higher sample of those receiving Etomidate may indicate a higher prevalence of hypotension but that was not the case in this study.

For the majority of patients requiring RSI, Etomidate is a very safe and hemodynamically stable drug. With the exception of adrenal suppression and shock/sepsis, Etomidate does not behave in a hemodynamically unstable fashion, as eluded to in many of our pre-hospital education programs.


Delpire, E., & Staley, K. J. (2014). Novel determinants of the neuronal Cl− concentration. The Journal of Physiology, 592(Pt 19), 4099–4114. Ginnard DO, O., & Nella MD, K. (2019, February 14). Adrenal disorders (cortex and medulla). Pejo, E., Santer, P., Wang, L., Dershwitz, P., Husain, S. S., & Raines, D. E. (2016). γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs. Anesthesiology, 124(3), 651–663. Richter, L., de Graaf, C., Sieghart, W., Varagic, Z., Mörzinger, M., de Esch, I. J. P., Ecker, G. F., & Ernst, M. (2012). Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands. Nature Chemical Biology, 8(5), 455–464. Stanke, L., Nakajima, S., Zimmerman, L. H., Collopy, K., Fales, C., & Powers, W. (2021). Hemodynamic Effects of Ketamine Versus Etomidate for Prehospital Rapid Sequence Intubation. Air Medical Journal. Williams, L. M., Boyd, K. L., & Fitzgerald, B. M. (2020). Etomidate. PubMed; StatPearls Publishing.


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