VivaCast 03 – NMJ inhibiting agents – Suxamethonium vs Rocuronium – Reversal

What are the differences between Rocuronium and Suxamethonium?

Rocuronium is a non-depolarizing neuromuscular blocker with slightly slower onset but longer duration, reversible with agents like Sugammadex. Suxamethonium is a depolarizing agent with rapid onset and short duration, but associated with more side effects.

Agents that Influence the Neuromuscular Junction

Structure

• Impairing ACh Synthesis
  • Hemicholiniums
• Impairing ACh Vesicles releasing into cleft
  • Gentamicin
  • Magnesium
  • Lidocaine
• Depletion of ACh Stores
  • Tetanus toxins local effect (also has main central tetanic effect)
• Impairing ACh Binding to Nicotinic Receptors
  • Aminosteroids
  • Benzylisoquinoliniums
  • Suxamethonium

Instead of piling in and answering the question based on common base knowledge and your comfort zone- look for the slightly broader undertone, the give away in this question is ‘AGENTS’ not drugs, not paralysing drugs.

A quick Categorise or Cry moment will help you structure your answer.

Comparing and Contrasting Rocuronium and Suxamethonium –

In addition we explore the suxamethonium side effect profile and the definition, immediate treatment and physiology of Malignant hyperthermia.

A hard question to answer without meandering across two drugs in a hap-hazard way.

It is probably worth outlining each drug – and their particular class and mechanism before going onto directly comparing onset times, offset times, metabolism and side effect profile.

The Side Effect Profile of Suxamethonium Includes

• Severe
  • Malignant Hyperthermia
  • Suxamethonium Apnoea (Particularly if no one notices)
  • Anaphylaxis
  • Bronchospasm
• Less Severe
  • Myalgia
  • Transient Bradycardia (more so in kiddies)
  • Hyperkalaemia (Severe if administered to a burnt or paralyse patient)
  • Raised IOP
  • Raised ICP

Finishing with approaching reversal

The Goal of reversal is to return full neuromuscular function to the patient in order to avoid post operative pulmonary complications / patient distress if partially reversed and aware.
Depth of motor blockade is subjectively or objectively measured using a train of four nerve stimulator test, assessing for presence of muscle twitch as well as fade across these 4 twitches.

Define or die

Reversal can be achieved with

• Time – these drugs will eventually clear through metabolism
• Neostigmine, opposing the effects of the competitive NMBs
  • (no direct effect on sux, but increasing the ACH content in the NMJ will alter the characteristics of NMJ transmission
• Suggamadex – Only effective with Rocuronium and to a degree Vecuronium.
  • Can’t use suggammadex for a while after – need to advise pt re COCP.
• In sux apnoea – FFP can be used to introduce psuedo-cholinesterase to the patient

The FRCA physiology viva can range far and wide in its content – we are going to cover the slightly more unexpected stations so you are maximally prepared.

In a nutshell the primary FRCA viva consists of 4×15 minute stations, comprising of generally 3×5 min sub sections each.

The stations are

• Physiology
• Pharmacology
• Physics and Clinical Measurement
• Clinical station

GasGasGas will endeavour to produce plenty of example stations and question sets to help with your revision and preparation!

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Transcript

Gas, Gas, Gas Pharmacology Viva: Neuromuscular Junction and Paralysis

Introduction and Episode Overview

00:00-01:30

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. This podcast can squeeze into your day. Listen while you’re driving to work, cooking dinner, maybe when you’re on call, or in the gym. Eventually the revision is going to end, but for now, expect facts, concepts, model answers, and the odd tangent. Remember to rate and follow the show to hear much, much, much more.

So, Tom, welcome to your Pharmacology Viva. It’s going to be three topics, five minutes each, total of fifteen minutes. I’ll stop you when we hit five minutes, and I will move you on as able. Are you ready? As ready as I’ll ever be. Right.

Agents Affecting the Neuromuscular Junction

01:30-05:00

Summary: Tom discusses various agents that influence neuromuscular junction function, including blockers, reversal agents, and adjuncts.

So, Tom, what agents are you aware of that influence the function of the neuromuscular junction?

Broadly speaking, there are neuromuscular blocking agents or paralytic agents, which are commonly used in anaesthesia, that influence the neuromuscular junction. There are reversal agents which also have an effect at the neuromuscular junction, either directly or indirectly. And then there are adjunct medications which can modulate the effects of the neuromuscular junction, such as magnesium and calcium.

So in terms of the neuromuscular blocking agents, these can be divided broadly into two classes: depolarising and non-depolarising neuromuscular blockers. The non-depolarising class is significantly larger, and that can be divided into benzylisoquinoliniums and aminosteroid compounds. In the depolarising neuromuscular blockers we only have suxamethonium. So suxamethonium is presented as a clear, colourless solution.

Okay, just holding you there a second. Can you think of any other ways the neuromuscular junction can be affected by agents and any pathological…?

Yeah, so we do have drugs similar to neuromuscular reversing agents that act at the neuromuscular junction and can be used in conditions such as myasthenia gravis, such as pyridostigmine and neostigmine. So these act as competitive agonists at the neuromuscular junction to inhibit the effect of competitive antagonists, which we use for neuromuscular block.

Rocuronium vs Suxamethonium Comparison

05:00-10:00

Summary: Detailed comparison of these two neuromuscular blocking agents, including onset, offset, and side effect profiles.

And could you please compare and contrast rocuronium versus suxamethonium for me, please?

For an ideal neuromuscular blocking agent, we’d want something that is stable at room temperature, has rapid onset, has reliable neuromuscular blocking effect and has predictable and preferably fairly quick offset. Alongside that as well, we want it to have minimal effects outside the neuromuscular junction metabolically and physiologically.

So, suxamethonium certainly has rapid onset. It also wears off rapidly within five minutes or so. It can cause surges in serum potassium, which can be an unwanted effect. And because it depolarises, it can have significant side effects. It can cause muscle aches, particularly in younger women, after its use, because of the depolarisation of the neuromuscular junction and contraction of the muscles.

Comparing to rocuronium, it has a slightly slower and slightly less reliable onset, but still can be rapid if given at high enough doses. It has a fairly low potency, so it can be given at high doses to produce a good concentration gradient to increase the speed of onset. It doesn’t depolarise the neuromuscular junction, so it doesn’t lead to muscle aches. And because it doesn’t depolarise the muscle cells, it also doesn’t lead to a spike in potassium as you have with suxamethonium.

Suxamethonium itself is broken down by plasma cholinesterases, which leads to its rapid degradation and fairly reliable offset. Rocuronium doesn’t have such a reliable offset. It is metabolised in the liver and excreted via the kidneys. There seems to be quite a lot of variability in how this affects different patients. So some people – a standard induction dose may have been completely reversed by about forty minutes or so, but some people can still be significantly paralysed well beyond an hour, even with appropriate dosing.

So you mentioned the spike in potassium with suxamethonium and myalgia with suxamethonium. Tell me more about the side effect profile of suxamethonium, please.

So as well as spikes in potassium and possible muscle aches following its administration, it is specifically contraindicated in patients with significant myopathies and people who are forty-eight hours or greater post having significant burns. This is because of the production of extrajunctional nicotinic receptors created in these conditions, which cause greater, potentially dangerous spikes in serum potassium concentration if given to patients forty-eight hours following burns or significant neuromuscular problems or paralysis.

Suxamethonium itself can cause effects on the cardiovascular system, including tachycardia and bradycardia, particularly in children. It has very little effect on the respiratory system beyond paralysing the respiratory muscles, and it has a minimal effect on the CNS, although it can cause a transient increase in intracranial pressure.

In terms of adverse effects rather than just side effects, there is a significant rate of anaphylaxis with suxamethonium. But the same is true of rocuronium as well. And rocuronium itself can also cause histamine release, which could be of concern in patients with asthma.

Importantly, when giving anyone suxamethonium, we need to be certain that they don’t have a history of malignant hyperthermia, because along with volatile agents, it is a known trigger for malignant hyperthermia and, as such, can be life-threatening.

Any other side effects at all there, Tom?

All neuromuscular blocking agents, given a sufficient dose, will cause apnoea, and that indeed is part of their desired effect. But I mentioned before there’s reliable quick offset of suxamethonium, but in some patients they do not have reliable breakdown of the suxamethonium by plasma cholinesterases due to mutations in the gene that transcribes those plasma cholinesterases. These patients can get suxamethonium apnoea. There are different levels of severity of this, but it can leave people unable to breathe for hours after administration of suxamethonium, and it’s obviously very important to recognise so as to avoid awareness.

Malignant Hyperthermia Management

10:00-12:00

Summary: Tom discusses the treatment and underlying mechanism of malignant hyperthermia.

Now you mentioned malignant hyperthermia there. Could you just very quickly talk me through the treatment and management of that?

Once malignant hyperthermia has been recognised, it’s important to give dantrolene as early as possible. It’s important to remove the triggering agents. So if you’re using volatiles, they need to be replaced with another hypnotic or the patient awoken if suitable, and the employment of carbon filters – charcoal filters – to remove any remnants of volatile agents from the circle system is also essential so as to prevent continual triggering of the malignant hyperthermia.

And what is the underlying mechanism?

So the underlying mechanism for malignant hyperthermia is mutation and dysfunction of the ryanodine receptor in muscle cells that leads to uncontrolled calcium release and then uncontrolled increased metabolism within muscle cells, which is what produces downstream carbon dioxide, which is one of the things that we can notice clinically when someone is in malignant hyperthermia – a high end-tidal CO₂.

Rocuronium Reversal Strategies

12:00-15:00

Summary: Discussion of reversal agents and their mechanisms, including sugammadex and neostigmine.

So moving on, going back towards rocuronium here, could you describe how you would approach reversing someone who has been paralysed with rocuronium?

So when rocuronium has been used as a paralysing agent, we have a couple of different reversal options. We have sugammadex and we have neostigmine.

Now sugammadex is a drug that completely encapsulates rocuronium when it’s administered, therefore prevents it having any interaction with the neuromuscular junction and provides complete reversal. You need careful consideration of whether you might want to be using rocuronium again when you give sugammadex, because it will be rendered ineffective if you need to give subsequent doses. Sugammadex can be given at any depth of paralysis with rocuronium.

On the other hand, when giving neostigmine, we need to be aware of the depth of neuromuscular blockade before attempting to reverse. This is traditionally done with muscle twitches and a train-of-four assessment. More up-to-date guidelines recommend the use of quantitative measuring of neuromuscular blockade using train-of-four. And based on the depth of blockade, this can tell us whether or not it’s safe to reverse using neostigmine, what dose might be appropriate of sugammadx as well if people are too deeply paralysed to be reversed with neostigmine.

Usually glycopyrrolate is co-administered because the neostigmine itself is a non-selective muscarinic agonist and can cause bradycardia.

And what would happen if you were to administer unopposed neostigmine?

So, administering unopposed neostigmine would cause, first of all, the competitive agonism of nicotinic acetylcholine receptors at the neuromuscular junction, which is the desired effect, leading to increased action at the postjunctional membrane and allowing normalised muscle contraction.

In addition to this, there can be activation of muscarinic receptors in the parasympathetic nervous system causing increased parasympathetic tone, bradycardia, vasodilatation, and this can have obvious cardiovascular effects such as hypotension and in extreme cases asystole.

We’ll call it there, I think, on that. I think that’s our fifteen minutes, Tom.

Post-Viva Discussion and Feedback

15:00-25:00

Summary: Tom and James discuss the viva performance and provide detailed feedback on structuring pharmacology answers.

How do you feel that went?

Not that well. So that one felt a bit less structured than previously and found myself in the similar situation of scrabbling round in my head for what I thought the examiner was after, because obviously it’s a big topic. You moved me on quite quickly at the point where I was considering going down the structured approach to each individual drug, but that would have taken too long for what this station was after. So I luckily didn’t waste too much time doing that, but also figuring out what depth to go to kind of wrong-footed me a bit and it felt not particularly fluid and a bit lacking on detail.

Comprehensive Answer Structure for Neuromuscular Junction

The first question was “what agents are you aware of that influence the neuromuscular junction?” It’s a good idea to try and subcategorise this because there are agents which:

• Block the synthesis of acetylcholine
• Deplete your stores of acetylcholine
• Block release
• Block action of acetylcholine on your neuromuscular junction

So in the exam they have a tendency to want more than just the straight up answer of, well, that would be aminosteroids, benzylisoquinoliniums and depolarising relaxants like suxamethonium. They want you to demonstrate that you know the physiological basis of transmission of an action potential from brain to muscle.

You got most of them there in that we covered the blocking drugs, and you mentioned gentamicin and magnesium. But think of Botox that impairs vesicles actually fusing with and getting out of the neuromuscular junction. Tetanus depletes your stores, but also works higher up to make you spasm. And then very niche – there’s hemicholinium, it would mess up the synthesis of acetylcholine.

So if you kind of frame it like that, then they’ll just immediately be like, “okay, he’s got it.” What’s hemicholinium used for? It’s not used therapeutically – it’s like scientists fiddling around in a lab with rats.

So in terms of agents that are used, ’cause I think that was the term “agents,” I suppose you don’t automatically think of botulinum toxin, but you should ’cause it is therapeutically used. And we talked about gentamicin and magnesium. Think about tetanus toxin used therapeutically? No, but it’s a pathological cause of muscle weakness, isn’t it? Like your myasthenias and your Lambert-Eaton myasthenic syndromes and stuff. I think it’s reasonable to think about it from a pharmacological perspective.

You need to remember that you don’t need to be using them deliberately to affect the neuromuscular junction. It can be side effects, such as often with magnesium and gentamicin.

Drug Comparison Structure

And then we went on to rocuronium versus suxamethonium and you started telling me about the ideal paralysing agent. And I thought, oh, that might be quite a good structure. But then I think it actually drew you off into the long grass and it took too long.

I had my doubts before I did it, but once you commit, it’s quite hard to backtrack.

So I’d be tempted to go more like: class, mechanism of action, dose maybe, and then onset, offset, side effects. The more traditional structure for talking about any pharmacological agent. I might not go down the whole route of “they are clear colourless liquids,” but I might ask you that later if there’s some particular thing I have to find out.

Malignant Hyperthermia Response Structure

And then the other thing I noted was when I asked you about malignant hyperthermia, I think you told me all the information about malignant hyperthermia, but it seemed a bit jumpy. So if someone asks you a question, define it. So malignant hyperthermia is [definition]. It presents as [presentation]. And then I asked you how would you approach treating it, I think is what I said. So you’d say things like:

“So if I identify it, I would declare the emergency, I would stop the agent, and the treatments I would do are…”

Because they’re also just looking like, do they think you’re a good registrar, safe registrar sort of realm? And that is parroting that stuff that you’re probably more likely to parrot in the clinical question. But if you just say “the definition is this, it presents like that. I’m going to declare the emergency, get additional help, stop the offending agent and do the treatment algorithm with the quick reference handbook.” Then it’s just like “I’m done.”

When you said “how would you treat malignant hyperthermia,” there’s nothing preventing you from giving a quick definition to show that you know what it is, and there may be marks for that. If you get too hung up on the exact wording and go, “Oh, they just wanted to know about treatment, they didn’t want me to talk about what it was,” actually you can say very quickly what it is, and there may well be marks for it.

Define or Die Principle

And just to say is when you – I think it’s worth just if you’re talking about drugs, just quickly specifying what they are a bit more like “Define or Die.” So you mentioned sugammadex, but what is sugammadex? It’s a gamma-cyclodextrin or something, isn’t it?

Yeah, so that was inside my head. I was trying to remember that and I couldn’t, so I just moved on.

So that – just that casually rolling off your tongue as part of conversation just makes you come across really sharp. Just to be able to say immediately, “it’s a cyclodextrin, I think,” will probably be enough.

Clinical Safety Point

And I mean, just as an aside, I don’t know about you, but I think neostigmine is probably the most dangerous drug in the drug cupboard that isn’t a paralysing agent. It happened in a trust near me that someone accidentally gave neostigmine as opposed to glyconeostigmine and caused an asystolic arrest because they gave it so quickly. So that’s just like a learning point for all is that neostigmine is dangerous as hell if unopposed.

Especially in these days of affected supply lines, because I know that currently in our trust we do not have premixed glyconeostigmine, we just have neostigmine and glycopyrrolate separate in the cupboards, so you know, it’s a mistake that could happen.

Well, Tom, thank you very much for accepting the viva action. Are you going to come back for more?

Yes, always. I’m a masochist. But yeah, no, it’s good. It gives me some areas to think about and to sharpen up on, ’cause these are all fairly common topics, so probably should be able to give snappy answers.

Yeah, and you will. You’ll get sharper. Practice makes perfect. Thank you very much, Tom. Have a nice evening.

Closing

25:00-25:30

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.