Ep 9 – Atracurium For The FRCA Primary

Introduction and Podcast Overview

00:00-00:33

Please listen carefully. Hello, and welcome to Gas, Gas, Gas, your one-stop podcast for the FRCA primary exam. This podcast will fill your brain with information. Listen to it, think about it, and check out the show notes on the website. There you will find the core diagrams you need to be able to draw and describe for the exam.

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Host Introduction and Episode Preview

00:34-01:18

Hi everyone, this is James at Gas Gas Gas. Today we’re going to talk about atracurium. But before we get into that, I just want to say to everyone who’s been listening, thanks very much. I’m glad people are hopefully finding it useful. Feel free to either like, subscribe, or maybe rate the podcast. If you rate the individual episodes, I’ll know what you like.

I don’t know if people want more compartmentalised volatiles - I know that was a pretty hefty podcast, but it’s an interesting concept - or if they want more of a focus on straight up pharmacology to start with.

Anyway, atracurium, brand name Tracrium, some people call it trach, is a non-depolarising competitive neuromuscular blocking agent, and it’s of the mouthful benzylisoquinolinium class. Interestingly, it was discovered at Strathclyde University in Scotland. Chemists were trying to create a neuromuscular blocking drug which intrinsically degraded in vivo, because that’s quite a handy thing, isn’t it? If you have a predictable offset.

Historical Context and Clinical Use

01:18-02:22

This was perhaps in the times when pancuronium, vecuronium, and some of the other once-upon-a-time paralysing drugs were more commonly used - tubocurarine and gallamine and all that sort of stuff. Perhaps they were thinking, “Oh well, let’s try and invent a better drug.” And they did.

Another side note is that it doesn’t seem to be used in rapid sequence induction. You could use it at about one milligram per kilo for RSI, but the research suggests that it’s still pretty pants for an intubating condition perspective, so just use the rock.

Right, model answer wise, I don’t need to pinch my nose today because I’ve got a cold. But Doctor, what is atracurium?

Pharmacological Properties and Presentation

02:22-03:26

Atracurium is a non-depolarising neuromuscular blocking agent, and the class is benzylisoquinolinium. It is a mix of ten stereoisomers with four chiral centres, and is presented as a clear colourless liquid that comes in a ten milligram per mil concentration in twenty-five milligram and fifty milligram ampoules generally.

It needs to be refrigerated at 4 degrees Celsius and it has a pH of 3.25. Its mechanism is competitively binding to the nicotinic acetylcholine receptor within the neuromuscular junction, antagonising the action of acetylcholine at that point and leading to flaccid paralysis.

It has an onset time of ninety seconds to two minutes, and its offset is fifteen to thirty-five minutes. Its volume of distribution is small, much like the other muscle relaxants, at 0.16 litres per kilo, and it’s fifteen percent protein bound. Of note, it scantly crosses the placenta.

Metabolism and Hoffmann Elimination

03:26-04:39

Atracurium is quite interesting from a metabolism breakdown perspective, as it spontaneously breaks down in the temperature and pH environment of the human. This is called Hoffmann elimination, whereby the molecule spontaneously degrades when at physiological pH and temperature, which is much different to its stored pH and temperature of 3.25 and four degrees, respectively.

You can therefore make the conclusion that in an acidotic hypothermic patient, atracurium takes longer to wear off. There is also an element of metabolism by ester hydrolysis. There are contentious points as to whether or not this plays a key role or a minimal role in atracurium breakdown.

The argument is confused here because some of the breakdown products of Hoffmann elimination undergo ester hydrolysis. What I’m interested in is the metabolism of a molecule that has a clinical effect to a molecule that does not have a clinical effect. My understanding of this pathway is that Hoffmann elimination is the chief route of clearance from a drug to something that just floats around as a metabolic byproduct.

Metabolic Products and Clearance

04:39-05:30

Of note, from a metabolic byproduct perspective, laudanosine is a product of the breakdown of atracurium. Eventually this is cleared by the liver. However, in high concentrations laudanosine has been noted to cause seizures in animal models. To achieve such a concentration in a human would be rather challenging, even with prolonged atracurium infusions on intensive care.

As a side note there, laudanosine antagonises glycine. From an elimination perspective going forward, the clearance of atracurium is five to six mils per kilo per minute. Its half-life is seventeen to twenty-one minutes. And it’s unaffected by renal or liver function because of Hoffmann elimination. So it’s a great choice for your renal failure or liver failure patients or those with impaired function.

Drug Interactions and Side Effects

05:30-06:31

Incompatible with thiopentone, but then we could make that assumption with most things because thiopentones are baddies when it comes to mixing with other drugs. So just don’t. Also, it looks like cefuroxime, so be careful.

Atracurium’s side effect profile chiefly focuses around its potential to cause histamine release, and this can affect a number of systems. There’s perhaps up to a 15% chance of a transient hypotension, a 0.2% incidence of bronchospasm, again due to histamine. Two to three percent of patients might get a bit flushed, either at injection site or more systemically.

There’s a direct link between the amount of atracurium you give and the amount of histamine release. And there are long-term effects of this atracurium infusion that some patients on critical care may end up with, where its use is linked to critical illness myopathy, which makes sense.

Pharmacodynamics vs Pharmacokinetics

06:31-07:17

Right guys, so I’ve talked fairly clearly there about the introductory waffle that you go through with these questions. You can then define either the pharmacodynamics, that is, the effect that drug has on the person, or the pharmacokinetics, that is the effect that person has on the drug. First, try and stick to a structured approach.

Now we’re going to move on to a few things we’ve mentioned here to try and define. So these drugs are competitive, i.e., they float around in this receptor space, and if their concentrations are sufficient they have an effect. But they could be crowded out by something else.

Neuromuscular Junction Anatomy and Function

07:17-08:35

If we imagine this space as the gap between the nerve getting to the muscle and the muscle itself, this is a very small realm which normally is inhabited by acetylcholinesterases, a normal mix of plasma anions and cations, or in this situation, extracellular plasma anions and cations, which is about the same, and transiently large quantities of acetylcholine as that nerve terminal is triggered to dump neurotransmitter into this space for it to percolate across and bind to receptors on the muscle membrane.

Important things that I’ve mentioned here: acetylcholine and acetylcholinesterase, which tidies up after that depolarisation of the terminal nerve occurs and transmitter is dumped. How much transmitter is dumped depends on the potency of that transmission down the motor neurone, and how much muscle depolarisation occurs depends on whether or not there’s enough acetylcholine getting across that space and binding to nicotinic acetylcholine receptors on the other end.

Competitive Antagonism and Hoffmann Elimination Chemistry

08:35-09:04

The competitive nature of this situation is that depending on concentration of neuromuscular blocker atracurium versus acetylcholine, they fight it out. If there’s more atracurium, then more of that binds. If there’s more acetylcholine, more of that binds.

We’ve also mentioned Hoffmann elimination. So this is a chemical reaction that produces alkenes and tertiary amines from a quaternary ammonium compound.

Detailed Neuromuscular Junction Structure

09:04-10:40

Just to focus in a little bit further on the neuromuscular junction, you’ve got to imagine that motor neuron coming in to the muscle. It widens up at the end in something called the terminal bouton, and it interacts very closely with the surface of the motor unit, the muscle that it acts upon.

Within this there are folds within the membrane of that motor unit, and within those folds deeply are voltage-gated sodium channels, and atop them are nicotinic acetylcholine receptors. Don’t mix up nicotinic and muscarinic - they’re different things.

A nicotinic receptor is a pentameric receptor with a number of subunits. The alpha subunit is the one where you will find the receptor site for acetylcholine. There are two alpha subunits, and for the conformational change of that pentameric receptor cum pore complex - because it’s a pore across this membrane to allow cations to move from the extracellular space to the intracellular space of the muscle - it requires each alpha subunit to have one acetylcholine bound.

This is perhaps a fail-safe, whereby you need a fair quantity of acetylcholine to trigger opening of these pores.

Muscle Depolarisation and Threshold

10:40-11:18

Now these pores open and hopefully enough of them open because the resting membrane potential of this muscle is about minus eighty and the threshold is minus fifty. So a reasonable degree of depolarisation has to occur for the threshold to be met and the muscle to depolarise.

When that threshold is met, the voltage-gated sodium channels found deeper in these invaginations of muscle membrane open, sodium pours in and the muscle cell depolarises. A number of other things occur to actually trigger contraction - that’s a different podcast, I’m not going into it now.

These pores only open for like a millisecond, so it’s very brief. Of note, this system is very resilient to paralysing actions. You can imagine from an evolutionary standpoint, if you were easily paralysed, you wouldn’t survive terribly well. So quite a lot of acetylcholine needs to wing across the cleft in order to cause a muscle depolarisation. Otherwise you’d depolarise really easily, be jittering around all over the place, all discoordinated with all your motor units of your biceps contracting at the wrong time. So it’s fairly all or nothing, and that’s a good thing.

Neuromuscular Monitoring and Residual Paralysis

11:18-12:44

However, when you start introducing paralysing agents, you can create quite a spectrum of paralysis, and this is reflected with your neuromuscular monitoring equipment, whereby you might do post-tetanic counts, train-of-fours, double bursts, etcetera. You’re doing all these things to try and identify how much residual paralysing agent lurks in your neuromuscular junction.

This spectrum is from entire paralysis to a lingering mild fatigability when there are lower concentrations of blocking agent in your neuromuscular junction. This mild fatigability, you can imagine would be quite a concern for your respiratory muscles and the muscles that defend your lungs from sputum etcetera trickling down on in.

That’s why most clinicians are inclined to reverse patients with glycopyrrolate neostigmine if they’ve been paralysed. It’s important to note that you could give reversal early, and you might see a return to strength. However, because of the nature of the reversal agents against the nature of the paralysing agent, it might be that your reversal wears off before paralysis and you just end up in the same place again.

Once upon a time they said, “Oh, reverse when you’ve got three twitches,” and now we reverse when we have four twitches and some fade. That’s the window of safety, and that’s the important thing.

Factors Prolonging Neuromuscular Blockade

12:44-14:02

Not thinking about things in terrible isolation, there are a number of ways that your neuromuscular drug blockade can be prolonged. We’ve mentioned acidosis and hypothermia - this is the case for atracurium, but for other paralysing agents as well.

Low levels of potassium or calcium - you can imagine they’re important for depolarisation - as well as high levels of magnesium, or if you’ve given the patient magnesium or a magnesium infusion. Volatile anaesthetics also prolong your neuromuscular blockade. So actually, sometimes it’s sensible to turn off your sevoflurane, having done some twitches, and then see where you are before reversing. Don’t accidentally have a paralysed aware patient at this point, though, because that’s very bad.

Interestingly, gentamicin can prolong neuromuscular blockade - we’ll talk about that in a future podcast - and calcium channel blockers, and other things that mess with electrolyte states like your diuretics.

There are a bunch of other things that can influence how your neuromuscular junction behaves or is blocked. And it’s important not to get mixed up and drawn in with things that prolong neuromuscular blocking drugs and things that block your neuromuscular junction - I’m talking botulinum, tetanus, etcetera. Nerve agents. Future podcast material.

Stereoisomerism and Cis-Atracurium

14:02-15:32

One last thing of note is we’ve mentioned that atracurium is a stereoisomer. So it’s a medley of ten stereoisomers, all of which have varying clinical effects. Some are pretty crap, some are pretty good.

Stereoisomers are molecules with the same chemical makeup and same bond structure, but a different three-dimensional configuration. There are a multitude of subtypes of this: enantiomers, diastereomers and cis-trans stereoisomerism.

One of these of particular interest for this podcast is cis-atracurium. This is one of the stereoisomers that we find within atracurium. It’s three to four times as potent as atracurium, which sounds great, and its potential for causing histamine release is super-duper low, so something you might stretch to in your very bronchospastic patient.

Because it’s more potent, its onset time is slower for the dose you would give, so you might have to bump up the dose to get a reasonable onset time. It doesn’t undergo any esterase hydrolysis - it’s Hoffmann elimination only. It’s perhaps considered pricey compared to atracurium, and it might just be that they thought, “Ooh, well, let’s see if we can isolate this and sell it. Tell everyone it doesn’t cause any histamine release - oh that’s spiffy.”

But you could just use rocuronium, which also doesn’t really cause much histamine release, unless, of course, your patient gets anaphylaxis.

Summary and Conclusion

15:32-16:38

So what have we covered? We’ve talked about atracurium, its kinetics and dynamics. We’ve mentioned that Strathclyde University - I’m not affiliated with them - discovered it. We’ve gone into further detail on the neuromuscular junction relative to the rocuronium podcast, talked about how the neuromuscular blockade of drugs can be prolonged, discussed stereoisomerism in a whiff of detail - you need to know more - and discussed competitive drug interactions. There’s more detail to be had on this, too.

Thanks for listening, everyone. Sorry if my voice is a bit hoarse - I have the disease that everyone seems to have been sharing in the last few weeks. If you found it useful or awful, please like and subscribe and rate the show. Definitely check out the show notes for those diagrams and the detail of this content. It is a bucket of content to get to grips with.

Keep working at it and you will get better, faster, and stronger. It is vital to keep your interest alive for the science that we’re covering and not overcook yourself. You will be amazed by what you know come exam day. Don’t freak out. Keep studying.