Ep.40 –Etomidate For The FRCA Primary

Introduction and Show Updates

00:00-00:30

I do hope that anyone who’s been out there sitting CRQs and SBAs for the final FRCA this week are having a tolerable time. It is almost over, folks.

I want to just quickly say that this show is going from strength to strength. And that is in part because you guys are listening, giving me feedback, sending me emails and helping me understand things that maybe come across a bit weird or could do with sharpening up. I really appreciate you taking the time to do that. Feel free to fire off questions, emails, etc.

Anyway, getting on with it.

What is Etomidate?

00:30-01:29

It’s etomidate. I’m sure we’ve all used it. I can say that I’ve seen it used once. My only thought was this seems to take a long time. However, it has useful properties and a number of downfalls.

So, what is it? It is a carboxylated imidazole derivative and it is an ester. When was it synthesised? In 1964, and it saw use clinically from 1972.

How does it look? The vintage option is a clear, colourless, aqueous solution with thirty-five percent propylene glycol. Its pH is five point one. The modern millennial vibe is a milky lipid emulsion with a pH of seven point six, so it can look a lot like propofol, although it comes in a different concentration in a different size ampoule. So you shouldn’t make too much of a mistake there.

It is clinically used in its enantiopure form – it’s R enantiomer. And it is, for those who are superbly riveted to know, molecular weight is two hundred and forty-four point two nine grams per mole.

Mechanism of Action and Pharmacology

01:29-02:45

As you might guess, it messes around with GABA-A receptors. For those needing a quick refresher: GABA-A receptors are ligand-gated chloride channels. When GABA binds, chloride flows into the neuron, making it more negative (hyperpolarised) and less likely to fire. Etomidate enhances this effect by increasing the affinity of GABA for its receptor and prolonging the opening time of the chloride channel – essentially making the brain’s main “off switch” work more effectively.

Noting that etomidate obviously has a chiral centre, that’s why you’ve got an R and an S enantiomer. The R enantiomer is ten times as potent as the S enantiomer.

pKa: This pKa is four point two, and in some texts it simply describes it as very hydrophobic at physiological pH, which you could sort of presume because we’ve had to make an acidic preparation with propylene glycol to make it soluble in water. And it stings when you use that, versus our novel millennial lipid emulsion, pH of seven point six, doesn’t sting because A, not acidic, B, nice gentle lipid emulsion without the propylene glycol. That will be important later.

If you look on the Internet for pKa and unionised fraction for etomidate, not really much there. But our Handbook of Experimental Pharmacology, which is biblically interesting but perhaps not completely useful for the FRCA primary exam, does have its moment. So I can tell you that etomidate is 99% unionised at physiological pH, and this also fits when you try and stick it in a Henderson-Hasselbalch pKa calculator.

Dosing and Administration

02:45-03:21

Generally speaking, intravenous is the route here, although there is some information that it’s been used rectally and transmucosally to achieve sedation, much like thiopentone has been used rectally. Not first line, folks.

The IV dose of etomidate is zero point three milligrams per kilogram, ranging from ten to sixty-five to one hundred and fifty seconds to reach effect, depending on what you read, lasting for 6 to 10 minutes. So in our 75 kilogram average adult, you’d give them 22.5 milligrams. In old folk, you might be inclined to use a lower dose, but we’ll get into pharmacokinetics more later.

Pharmacodynamics – Effects by System

03:21-07:08

It’s always important to divide questions on drugs into pharmacodynamics and pharmacokinetics. Dynamics, as we know, is the effect the drug has on the person. When you’re thinking about effects, you could simply break it down into organ system, but it might be worth pointing out that the chief effect of etomidate is inducing hypnosis and general anaesthesia.

Cardiovascular Effects

It is incredibly stable cardiovascularly. It will cause a very slight drop in systemic vascular resistance and cardiac output, but it doesn’t alter your cardiac oxygen consumption or supply very much at all. In unstable coronary artery disease type patients, it’s a great choice.

One paper did note that patients with valvular disease, like mitral valve regurgitation, seemed to see a slightly worse drop in blood pressure. But you’re going to expect that across any drug, and etomidate, I think, still causes less of a drop. Of note, then, it has no role in obtunding any sort of response to laryngoscopy because it’s not dropping blood pressure.

Respiratory Effects

You get a dose-related drop in respiratory rate and tidal volumes. Sometimes you can get a transient apnoea and you may see coughing and hiccupping, and that’s part of this spectrum of involuntary movements that we’re going to talk about in a jiffy.

GI Effects

If you’re using the propylene glycol vintage preparation, then 2 to 15% of patients were getting post-operative nausea and vomiting. And if you were also using opiates, that went up to 40%. Although the opiates when this study was done might have been morphine or pethidine, whereas the lipid emulsion version, the Millennial Delight, has a similar incidence of post-operative nausea and vomiting to propofol. Great.

CNS Effects

We know it causes hypnosis, general anaesthesia, but also patients can end up in a bit of a weird situation, and this is a spectrum of having involuntary muscle movements.

We see this with a lot of general anaesthetic agents, you know, the twitchy epileptiform movements of propofol, etc., the increased laryngospasm risk with thiopentone. We end up in a situation where we might be modulating different parts of the brain at different times and ending up with inhibited circuits and disinhibited circuits depending on where you’re putting the brakes on.

Patients can end up with tremors, myoclonus, and again I mentioned coughing and hiccupping, so they can be a bit jerky. Naturally, this would be fixed by paralysing the patient.

Etomidate also drops intracranial pressure, drops intraocular pressure, and decreases cerebral blood flow by twenty to thirty percent. Twenty percent of patients would have epileptiform changes on their EEG. But we know this doesn’t quite really mean epilepsy.

The Critical Issue: Metabolic Effects and Steroidogenesis

07:08-08:59

But what about the metabolic consequences of etomidate? Because that’s really where the money is, isn’t it?

Once upon a time, they did not know that etomidate impairs steroid synthesis. Patients were dying because of this. We’re going to talk about the history in a moment.

Etomidate is an inhibitor of adrenal eleven-beta-hydroxylase and seventeen-alpha-hydroxylase. These are two of the most critical enzymes used in your steroidogenesis pathway. But what does it cause? It causes depressed levels of cortisol and aldosterone for twenty-four to forty-eight hours post-dose. A single dose has an effect, an infusion has a bigger effect.

You could say, and there are a few suggestions that, well, this probably isn’t an issue in a healthy person, but then a healthy person would tolerate another anaesthetic agent. So why would you pick one that bonks their cortisol on the head?

If you have low cortisol levels, you feel like arse. You know, when you’re doing your night shift and the sun comes up and you look outside and you’re like, oh wow, I feel just I feel a bit better actually. That’s because you’ve seen blue light in your eyeballs and it’s stimulated your body to produce cortisol and you feel better for it. Imagine taking that away. It’d be like making the patient do a night shift the day after their operation. Poor buggers.

Toxic Effects and Safety Profile

07:08-09:12

With our vintage preparation, twenty-five to thirty percent of patients got pain on injection. And this is probably in part because of the pH and the propylene glycol is actually a big offender here. Don’t give someone with porphyria etomidate – not compatible. So Archie Cochrane of Cochrane Library Research Meta-Analysis fame, he wouldn’t have done well with etomidate. He had porphyria.

Now, an interesting segue in toxicity. One of the papers I read before producing this show pointed out diligently in comparative manner the LD50 of etomidate versus other anaesthetic agents, saying, “Gosh, if only we could use it, it is so incredibly safe.” The LD50 of etomidate is twenty-six times the ED50 dose. That’s cracking. That means that you could really draw up like twenty-six times the dose you needed to give before you’d actually kill a patient with etomidate. So there’s a huge margin for error.

But folks, we actually use drugs at their LD50 dose daily. Can anyone guess what the LD50 for rocuronium is? And we’re going to think about this in milligrams per kilogram because it’s easier than fractions. The LD50 to kill a rat with rocuronium is 0.3 milligrams per kilogram. Now what might you imagine is the therapeutic dose to achieve paralysis to ventilate a rat? Well, 0.3 milligrams per kilogram.

So using the argument, well etomidate has got an excellent therapeutic index of treatment dose versus lethal dose kind of doesn’t really work when you’re an anaesthetist and you’re actually using poisons for your nefarious anaesthetic intentions.

ED50 and LD50 Definition Review

09:15-10:06

Let’s just remind ourselves in a define-or-die moment, because we’re bringing it back, what ED50 and LD50 is, just in case it comes up in your exam.

ED50 is the dose that achieves your desired therapeutic response in fifty percent of the population you administered it to. So if you had 10 people and you all gave them a milligram per kilogram and then half of them were nicely asleep and you could prod them and they wouldn’t be bothered and that was your therapeutic target, then that’s your ED50.

LD50 is the dose that kills half your tested population. So here we go, we’ve got 10 people, and we give them all a milligram of propofol per kilogram, and half of that cohort die, then a milligram per kilogram is your LD50.

Now we find ourselves in a situation where we now know what an LD50 is and an ED50 is, and we’ve realised that actually we’re knocking about administering lethal doses of drugs on paper, but our patients aren’t dying because we are intervening.

Clinical Applications and Limitations

10:06-10:53

Would etomidate be an optimal sedation agent for endoscopy if it didn’t cause impaired steroidogenesis? We know that its blood pressure stability is excellent. We know that we get a dose-dependent response to reduction in breathing and tidal volume, but it doesn’t completely impair this. So you’d have a breathing unconscious patient.

What’s the stickler? Well, you could do this. It’s a pity it messes up your cortisol. But as long as your surgeon or endoscopist doesn’t mind twenty percent of their patients jerking, hiccupping, having a spot of myoclonus now and again, then it would be a great agent for that, wouldn’t it? But I can imagine the look on their face as they’re trying to stick an endoscope down someone and they’re jerking around in a myoclonic manner. Very pesky.

Pharmacokinetics

10:53-12:27

Kinetics, because we don’t want to get in the long grass here.

Absorption: Well, it’s IV dosing, folks. I could not tell you the rectal bioavailability of etomidate, so let’s not go there.

Distribution: It’s 76.5% protein bound almost entirely to albumin. It crosses the placenta. Its volume of distribution is 4.5 litres per kilogram. So reasonable. It spreads out quite a lot. I’ve mentioned it’s pKa 4.2 and then at physiological pH it’s 99% unionised, so there’s a massive fraction that can pile across those lipid membranes and get where it needs to go.

Metabolism: I mentioned earlier it’s an ester. It is chiefly broken down by hepatic esterases into an inactive carboxylic metabolite. A teensy bit of plasma esterase activity seems to get involved, but it’s almost chiefly the liver folks.

Excretion: Seventy-five to eighty-seven percent excreted via the urine as its metabolite. 2-3% unchanged in the urine.

If you are clever and you’re thinking about three compartmental models and plasma half-lives – I know this kind of crosses into metabolism here, guys – plasma half-life is 2.7 minutes, but its V2 and V3 compartment half-times, you know, the things that influence that decay curve, twenty-seven and two hundred and seventy-five minutes respectively.

Excretion is prolonged in cirrhotic patients and of interest it has been withdrawn from use in the United States, the Republic of Ireland, Canada, and Australia. But the Brits, we like to be different.

Historical Context and Withdrawal

12:27-14:21

Why was it withdrawn? Well, I hope you already know that it’s because we’ve stumbled across the unfortunate reality that it knackers steroid synthesis and folks in ITU were faring very poorly for that knackering steroid synthesis effect.

The first time this was reported was by Ledingham and Watt in 1983, and they had observed in their ITU trauma patients, that those who were mechanically ventilated and sedated with etomidate – 69% of those were dying versus the 25% who were sedated with benzos on their unit. That’s bad news, isn’t it?

I think there were one or two other studies, and then it was rapidly withdrawn as an agent of choice in intensive cares and ended up being withdrawn from use when it came to induction of anaesthesia.

One of these studies found that if you actually gave a patient steroid repletion alongside their etomidate infusion for sedation, their incidence of death diminished and returned back to at least somewhat back to their baseline odds of death.

What about a single dose of etomidate? Is a single dose of etomidate okay? Well, one dose led to six to eight hours of adrenal suppression. They found that the dose to achieve sedation, i.e., the ED50 patient snoozing dose, is quite high, but the ED50 to trigger adrenal suppression is quite low. I think the plasma concentrations were 400 nanograms per millilitre or 10 nanograms per millilitre, respectively.

And actually, some folk have reached for etomidate to treat severe Cushing’s when you need to stop their steroid synthesis, ’cause you only need to give them a tiddly tiny bit.

Future Developments

14:21-14:49

Fortunately for us, propofol isn’t the only option in our armamentarium. We could give thiopentone and ketamine, and there are some lab-based boffins out there trying to develop newer analogues of etomidate that eradicate the steroid synthesis issue whilst maintaining that delightful cardiovascular stability feature.

Are they going to be able to prevent that myoclonus? Who knows? It really depends on receptor selectivity, blood flow to which bit of the brain that seems to end up inhibited before other bits of the brain. It all gets very confusing.

Steroid Synthesis Pathway Overview

14:53-18:20

What is for today as a finishing off is we’re going to talk a little bit about steroid synthesis.

There are three, maybe four, steroids that we’re chiefly interested in a human: cortisol, a glucocorticoid; aldosterone, a mineralocorticoid; androstenedione, which is a sex or androgen-like hormone; and sometimes dehydroepiandrosterone, which is a precursor to the androstenedione. That’s pretty much all I’m going to talk about when it comes to sex hormones.

What is the common precursor to all these hormones? Well, it’s cholesterol. This is derived from the LDL that’s circulating around in the plasma that is provided by your liver and the fatty synthesis liver pathways that exist.

We know that there’s a number of enzymes involved in achieving cortisol, aldosterone, and androstenedione from this precursor. And then we need to also think before we go into that enzyme pathway, where do these things magically happen? Well, they occur in the adrenal cortex.

So remember, we’ve got the adrenals that are sat on top of the kidneys. There’s two chief components to it. The adrenal medulla looks a lot like a sympathetic ganglion, and it spaffs out catecholamines when stimulated, and the adrenal cortex, the outer bit of the adrenals, that is involved in steroid synthesis.

Now you can break down the cortex into three things. The acronym is GFR: Zona glomerulosa makes aldosterone; Zona fasciculata makes mostly cortisol, teensy bit of androgen; and Zona reticularis, tiny bit of cortisol, a lot of androgen.

What influences them? Well, your glomerulosa is influenced by angiotensin II and plasma potassium concentrations, because why would it not be interested when it’s the thing that modulates a lot of your plasma potassium concentration? Zona fasciculata – well, we all remember the hypothalamic-pituitary-adrenal axis. It is influenced by ACTH adrenocorticotrophin hormone from the anterior pituitary.

Cholesterol is converted to pregnenolone. That’s like the common “I’m going to be made into another steroid molecule” steroid. If in doubt in an exam, you need to choose between either seventeen-alpha-hydroxylase or twenty-one-beta-hydroxylase. I think it’s pretty criminal to ask you about any of the other enzymes involved.

If anyone asks you, how is aldosterone made? Well, it’s from corticosterone made by aldosterone synthase. So, you know, if they’re asking you that question, then it’s hopefully eminently obvious.

If you lack cortisol, you’re going to end up in an adrenal crisis. This could be due to Addison’s or iatrogenic suppression of your own body’s synthesis of cortisol because you’ve been smashing the prednisolone for months and months and months. Too much cortisol, you’re going to look Cushingoid.

Conclusion and Theoretical Considerations

18:20-19:25

Well, that was etomidate with a brief look at ED50-LD50, thinking about how as anaesthetists we are using poisons safely on a daily basis and how the LD50 is probably different for an anaesthetist than a non-anaesthetist with these drugs.

Briefly thinking about the absorption characteristics of rectal etomidate, so we’ve identified that hepatic metabolism does a great job of clearing etomidate, but we also know that the venous drainage of the rectum is two-thirds systemic and a mere one-third that ends up in the portal system. So your zero point three milligram per kilogram dose, only zero point two milligram per kilogram is actually going to end up in the systemic circulation. That third is going to end up mopped up by the liver, so you’re going to have a lower dose. So perhaps its rectal bioavailability is somewhere around 66%, if we’re presuming that it’s got a rapid first-pass metabolism for the drug that goes past the liver.

Closing Remarks

19:25-19:52

Cheers, folks. Thanks for listening. If anyone wants to drop me an email, crack on. I will see you next week when we’re doing midazolam. Enjoy your weekend.

Thanks for listening, guys. I hope you found it useful. But if you found it awful, do let me know. Please like and subscribe, register with whichever podcast platform you find yourself using, and leave a comment if you think I need to square something away. I just want to make sure that you guys know that every day you are getting better at this. There is a bucket of content to try and consume, and it is like drinking from a fire hose. Take it day by day, don’t overcook yourself, don’t freak out, and keep studying.