Ep 16 – Suxamethonium for the FRCA Primary Exam

What is Suxamethonium?

Suxamethonium is a depolarizing neuromuscular blocker used for rapid muscle relaxation. It mimics acetylcholine at the neuromuscular junction, leading to sustained depolarization and paralysis.

This will not help you if your patient is half awake (or half asleep) and excitable and obstructing their airway….. but that whole situation is far from ideal. 

Paralysing agents are also an airway disaster rescue drug– check the DAS guidelines. (paralysed people are easier to hand ventilate and cam't fight you trying to ventilate them)

Mechanism by which Suxamethonium functions

• Agonistic action at the nicotinic acetylcholine receptor located in and around the neuromuscular junction
• Binds to, triggers it into an open state, and stays open  
• 2 ACh molecules ‘stuck together’ with a succinic acid in the middle
• It causes a disordered contraction of all skeletal muscle as it subverts the normal motor unit mediated muscle contraction. (hence the fasciculation)
• Binds to Alpha subunit (once it runs the gauntlet to get there)
  • Plasma cholinesterase isn’t in the NMJ so once its there it hangs on until it diffuses back out from its concentration gradient.

Chemical structure 2 ester bonds and 2 quaternary nitrogens on the end of each arm 

            Looks like two ach molecules attached back to back.

Suxamethonium Data

Name	Suxamethonium
Class	Depolarising Muscle Relaxant
Chemical/Other name	SuccinylCholine
Colour / appearance	Clear – Colourless liquid
Additive / Storage	Store at 4deg c to preserve effect, but will last at least a week out of the fridge….
Preparation	IV liquid in ampoules
Concentration	50mg/ml with 100mg Ampoule
Dose Route	IV / IM / Intra-Lingual
Dose Range	1-2mg/kg IV 4mg/kg IMLaryngospastic emergencies 0.1-0.5mg /kg IV

Pharmacodynamics of Suxamethonium

Mechanism	Nicotinic Receptor on the end plate of the neuromuscular junction, agonised, triggers an action potential, gets stuck depolarised until wears off.
Actions	Blockade of neurone > muscle transmission
Onset	IV – 30s onset ‘ clinical end point = cessation of fasciculations if seen)IM – 2-3 minutes, sub optimal
Offset times	3-5 minute duration

Side effects of Suxamethonium

CVS	Repeated doses = Bradycardia
Resp	Apnoea…. Bronchospasm (that might make you think you’re in the oesophagus or your vent circuit is blocked.
GI	Raises intra-gastric pressure , salivation,
Neuro	IOP and ICP rise
MSK	Arthralgia – Sux Apnoea Masseter spasm (like a mini MH) making intubation very awkward
Eyes	Miosis
Metabolic	Serum K transient increase due to mass depolarisation. Serum K lethal rise in those with poorly innervated skeletal muscle / Post BurnsMalignant HyperthermiaAnaphylactogenic

Pharmacokinetics of Suxamethonium

Absorption – Rapid intra-plasma metabolism on its way to the effect site courtesy of plasma pseudocholinesterase.

Distribution

pKa	Not very known.
VOD	Not very known.
Protein binding	Not very known.

Metabolism of Suxamethonium

Plasma	Plasma cholinesterase Hydrolyses - SUX > Succinyl monocholine + Choline Plasma cholinesterase Hydrolyses - Succinylmonocholine > Succinic acid and choline Succinylmonocholine (weak activity and floats around acting on mAchR’s (muscarinic) causing bradycardia. 80% of sux fails to make it to the NMJ Plasma cholinesterase is synthesized by the liver.
Phase I	N/a
Phase II	N/a
Elimination	2 – 10% gets excreted unchanged
Active Metabolites	Succinyl-Monocholine weak NMJ activity and vagal effects

Elimination

Clearance ml/kg/min
Half-life	2.7 – 4.6 mins

Other Notes

Another drug which fails to mix with thiopentone

Some patient groups have less plasma cholinesterase (a protein….)

            Pregnancy, Liver disease, Renal failure, Thyrotoxicosis, Cancer

Some drugs potentiate sux

            Lidocaine, Lithium, Magnesium, Ketamine, COCP + ? pancuronium? 

Pre-Curarisation was a thing, give a sub paralysing dose of roc/trac, fasiculations not so bad, less myalgia.

Define or Die

Hyper Serum K issues 

This is due to the untoward proliferation of fetal gamma subunit nicotinic receptors that spread over the whole muscle, many, many more receptors able to cause K efflux from myocyte (most K+ is intracellular after all). 

Patients also at risk:

• Neuromuscular disease) gets proportionally worse as disease progresses)
• Paraplegia (worst in their first 6m), 
• Trauma induced immobility are at risk too.
• Burns at risk from >24hrs to 18months.

When sux binds to these and opens them = bad

Malignant Hyperthermia (1:200k Autosomal dominant)

Runaway muscle metabolism secondary to contractile activity within the myocyte. 

Ryanodine receptor implicated – causing calcium release from muscle sarcoplasmic reticulum causing the contractility. Leading to CO2 production, heat generation, myoglobinaemia and hyperkalaemia. Generally bad but survivable with prompt removal of cause, dantrolene, active cooling, hyperventilation, monitoring for renal failure, hydration. See the QRH for exact care, and don’t forget to..

Send them for testing / refer them to clinical genetics!

Sux Apnoea - AKA Pseudo-choline-esterase deficiency 

Plasma Cholinesterase activity is influenced by genetics and / or acquired factors.

Chromosome 3

Allele / Name of Enzyme	Incidence	Offset
Normal / Normal (Eu)	96% of population normal.	Normal
Normal / Abnormal	Almost 4% of the population	10 mins
Atypical (dibucaine resistant)	0.03% (3:10000)	Hours
Silent	0.001%  (1:100 k)	Hours
Fluoride Resistant	0.0003% (3:1 mil)	Hours

Identification: if you TOF everyone post sux then you might find a few atypicals…

Don’t get caught out, mivacurium is also broken down by pseudocholinesterase Miv Apnoea would catch you out!

Treatment = Keep the patient sedated instead of wheeling them around the hospital for a CT scan thinking something intra-cranial happened….. with no sedation aboard whilst also forgetting to check the TOF. Trifecta of badness.

You could transfuse FFP, providing pseudocholinesterase and making it all better, but most of the time a wait occurs – I don’t know what the plasma HL of pseudocholinesterase is, but seeing as once its gone its gone, the sux probably couldn’t re-paralyse the patient….. bold to send them home. 

They will eventually pee it out….

Send them for testing / refer them to clinical genetics

Take Away Points

1. Suxamethonium is still considered an emergency drug and knowing the doses you would reach for in disasters is reasonable knowledge.
2. Unable to manage airway in gas induction with no IV access you could reach for Sux....
3. Laryngospasm peri-extubation
4. For interventions that are brief but require a tube (patient or surgical factors) it’s a good choice
5. It still seems to be drug of choice in emergency obstetric intubations at least where I have trained.
6. The side effect profile is a great topic to discuss in a viva – with multiple interesting pharmacologic and physiologic avenues.

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Transcript

Suxamethonium - Gas Gas Gas Podcast for FRCA Primary

Introduction and Podcast Overview

00:00-00:37

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.

Topic Introduction: Suxamethonium Overview

00:37-02:11

Hello everyone, this is James at Gas Gas Gas. Today we are covering suxamethonium. AKA sucks. A speedy onset depolarising muscle relaxant, and the only depolarising one really. It seems to have a bad reputation. Some people call it a mean and awful terrible drug. I'm quite sure that every time it is used a panda spontaneously expires somewhere in the world.

Generally speaking, it is used less and less as the familiarity of rocuronium continues to climb, and probably further enabled by the presence and existence of sugammadex, enabling that rapid reversal of an RSI dose that probably means rocuronium has the edge.

Now I've never ended up giving the sixteen milligram per kilo emergency sugammadex dose, but if it works anything like as quickly as when you're reversing someone with one or two twitches only, then you're probably going to have a quicker return of muscle power compared to waiting for the suxamethonium to wear off.

Side note, if you think you're in a situation where you're going to be giving that reversal, just count how many ampoules you think you're going to need to give, because then someone could just draw up and give, draw up and give, draw up and give. Or you pre-draw it up if it looks like it's an absolute disaster.

Anyway, reversing their paralysis won't help if they're halfway between anaesthetised and awake, and therefore apnoeic or refusing to breathe or clenching. So, anyway, now that we've waffled about that, we're going to focus on sucks.

Model Answer: Mechanism of Action

02:11-03:13

So, Doctor, what depolarising muscle relaxant are you aware of? And how does it work?

The chief drug that comes to mind here is suxamethonium. Suxamethonium has an agonistic action at the nicotinic acetylcholine receptor that is located in and around the neuromuscular junction. It binds to this receptor, triggers it into an open state, and then holds it in the open state until the drug wears off.

You could describe this drug as two acetylcholine molecules bound together with a succinic acid. Of note, it causes a disordered contraction of all skeletal muscle at its onset, as it subverts the normal motor unit mediated muscle contraction, hence why you get the fasciculations. Suxamethonium itself binds to the alpha subunits of the nicotinic acetylcholine receptor proteins.

"Excellent. And how is suxamethonium metabolised?"

Suxamethonium is broken down by plasma or pseudocholinesterases. These are not present in the neuromuscular junction, unlike acetylcholinesterase. This means that once given IV, suxamethonium begins to be broken down, about 20% of the dose of suxamethonium will make it to the neuromuscular junction, and it diffuses into this space and has its action. It will not be further broken down until it diffuses out of this space back down its concentration gradient as the plasma is cleared of any existing suxamethonium from that bolus dose.

Suxamethonium is initially broken down into succinylmonocholine and a choline molecule, and then the plasma cholinesterase again breaks that down from succinylmonocholine to succinic acid and a choline molecule. Of note, the succinylmonocholine has weak activity from a paralysis perspective, but also acts on muscarinic cholinergic receptors, causing the bradycardia that's sometimes noted with suxamethonium use. A second dose of sucks would much more significantly cause the bradycardia.

Complete Drug Profile: Suxamethonium

05:10-09:00

So suxamethonium is a depolarising muscle relaxant. Its chemical name, succinylcholine, reflects the fact that it's two choline molecules bound together with a succinic acid. It is a clear, colourless liquid that is stored at four degrees Celsius to preserve its effect, but of note it can stay out of cold storage for a period of time and remain functional for at least a week.

It is an IV preparation in fifty milligrams per mil, classically with one hundred milligrams in an ampoule. Its routes include intravenous, intramuscular or intralingual, the latter two being for emergent use.

Dosing:

Its dose range is one to two milligrams per kilo IV in RSI, two to four milligrams per kilo IM, and in laryngospastic emergencies zero point one to zero point five milligrams per kilo IV is sufficient to break the laryngospasm.

Pharmacodynamics:

From a pharmacodynamics perspective, it binds to the nicotinic receptor which is found on the end plate of the neuromuscular junction on the muscle side. This triggers an action potential on that muscle, causing depolarisation. The IV onset time is thirty seconds or so, and its clinical end point would be cessation of fasciculations, if you've seen them. It lasts three to five minutes.

Side Effects:

Its side effect profile, from a cardiovascular perspective, is quite stable. It may cause bradycardia with one dose, and it certainly has a chance of causing bradycardia with two doses. The odds of bradycardia are higher when given to children.

From a respiratory perspective, well, it's naturally going to cause apnoea once the patient is paralysed, but it has been known to trigger bronchospasm also. GI wise, it increases intragastric pressure and can cause some salivation.

Thinking about your brain or your eyes, it raises intraocular pressure and raises intracranial pressure. Its MSK effects include myalgia afterwards, borne out by the fasciculations generally, more common in women. It can cause a prolonged paralysis situation. This is called sux apnoea. And sometimes you can note masseter spasm with administration of suxamethonium.

It also has a number of metabolic side effects. It can cause a transient increase in serum potassium levels, and a lethal serum potassium level increase in those with poorly innervated skeletal muscle and those who are post burns. It can also trigger malignant hyperthermia and is prone to triggering anaphylaxis also.

Pharmacokinetics:

From a kinetics perspective, it rapidly is metabolised by plasma cholinesterases, meaning that only twenty percent of the drug dose gets to the muscle. Its pKa is not clear, its volume of distribution is not clear, and its protein binding is not terribly clear either. So I wouldn't really talk about that in too much detail in your exam.

We've mentioned metabolism up there, however, go through it again. Suxamethonium is metabolised by plasma cholinesterase. This enzyme hydrolyses it into succinylmonocholine and a choline molecule. The succinylmonocholine has activity. It seems to like muscarinic cholinergic receptors too, and can cause some muscle depolarisation itself. The succinylmonocholine is subsequently broken down again into just a succinic acid and a choline. About two to ten percent is excreted unchanged by your kidneys. This is an important point for later. Its half life is two point seven to four point six minutes.

Now you could caveat that it's quite difficult to measure the protein binding and volume of distribution of a drug that is rapidly cleared in plasma, because as soon as you take that blood sample and trot it off to the lab, those enzymes are still quite busy in there.

Drug Interactions and Special Populations

09:17-10:23

It is another drug that doesn't mix with thiopentone, even though you have a classic thio-sux RSI. And it's important to note that some patient groups and some drugs modify the response to the sux.

So there's a group of people who have less plasma cholinesterase, and therefore the paralysis lasts longer. This is pregnant people, those with liver disease, renal failure, thyrotoxicosis and some cancers, and a number of drugs potentiate the effect of sucks, chiefly lidocaine, lithium, magnesium, apparently ketamine, and the oral contraceptive pill.

You may hear or come across people describing precurarisation. This is where you give someone who's awake and talking to you a subparalysing dose of non-depolarising muscle relaxant. Say you might give them some atracurium. Once the sux starts wearing off to keep them relatively still, you give that before in a small dose they get few to no fasciculations and their myalgia is theoretically less bad.

Deep Dive: Hyperkalaemia Mechanism

10:49-12:12

We mentioned high serum potassium issues. What's going on there? It seems to affect people with poorly innervated skeletal muscle or those with burns for some unbeknownst reason. But what's happening on a cellular level is the proliferation of the foetal subtype of the nicotinic acetylcholine receptor. These spread out across the whole muscle, as opposed to being located just in the neuromuscular junction.

And then you can imagine that if you give a dose of suxamethonium and it's now able to tickle ten times or a hundred times or a thousand times, who knows how many times, more receptors, you're going to get a significantly greater response. Now you can only depolarise muscle once, but all that muscle is a lovely home to potassium.

Remember this channel lets sodium and calcium in and potassium out of the myocyte, and this can lead to a lethally high potassium and they die on the end of your syringe. That's why people with burns from twenty-four hours onwards to eighteen months, those who are paraplegic, tetraplegic, those with neuromuscular diseases where there's poor skeletal innervation or paraplegics all have trouble with this, so you would just avoid it.

This issue is going to become less and less because rocuronium is just exceedingly prevalent. You can have a look on the show notes for that diagram that sort of elaborates on the difference between an adult and a foetal nicotinic acetylcholine receptor. Drew a lovely diagram for you, I did.

Deep Dive: Malignant Hyperthermia

12:24-14:00

So then another issue with sucks is triggering malignant hyperthermia. So this is an autosomal dominant condition with runaway muscle metabolism secondary to contractile activity within the myocyte. The ryanodine receptor on sarcoplasmic reticulum in those myocytes is the implicated offender that is altered in this autosomal dominant problem. Hence, it runs in families.

What do you get when MH is happening? You get a sudden large rise in carbon dioxide and a tachycardia. The patient then might go on to start getting very hot. Later problems include myoglobinaemia and hyperkalaemia, and subsequent renal failure if that myoglobin bungs up renal tubules.

It is generally bad, but certainly survivable with declaration of the emergency, seeking help, a hundred percent oxygen, hyperventilation, removing the cause. Sucks - it's already in. Damn. Or volatile. Turn that volatile off, start some TIVA. Dantrolene and active cooling.

So you need to not let them get hot because it's the heat that denatures the enzymes that kills the person. If you can keep them cool, then you've got time to try and achieve everything else, achieve that quiescence of muscle, and it'll all be all right. Take a look at the quick reference handbook, and don't forget to send them for testing and refer them to clinical genetics.

Deep Dive: Sux Apnoea (Pseudocholinesterase Deficiency)

14:01-16:31

Another of the joyous side effects of suxamethonium - great drug, really safe drug, definitely would get licensed today - is sux apnoea, AKA pseudocholinesterase deficiency. This enzyme is coded for on chromosome three, and there are four varieties that may come about. So everyone has two copies of this gene.

Most people are walking around with two normal copies of this gene. That is ninety-six percent of the population, and their offset for suxamethonium is normal. Almost the rest of the people in the population wandering around have one normal and one abnormal allele. Their offset time is only marginally prolonged because they've got quite a lot of decent plasma cholinesterase - ten minutes for it to wear off.

You've then got a group who are called the atypical group, and that is three in ten thousand people, and the wear off time is hours. You've got a silent group - one in a hundred thousand people - wear off in hours, and a fluoride resistant group - three in one million - wear off time hours.

So you can say that most people are fine. Almost four percent of people might just have a slightly prolonged response to suxamethonium, and a very tiny subgroup of about three in ten thousand, so one in three thousand, and getting rarer, might get stuck paralysed for a couple of hours.

Now you could give everyone suxamethonium, intubate them, get them maintained, and then check a train of four at five minutes and ten minutes to check for resolution of your suxamethonium. By doing this you might catch a few atypicals, but no one really tends to do this.

Treatment:

The treatment for sux apnoea can be two different things. One, a calculated dose of time whilst keeping the patient asleep and not wheeling them through the hospital without any sedation on board, wondering if they've had a stroke and putting them through a CT scanner. So keep your patients asleep, do a train of four. If they remain paralysed, you know that something's amiss.

Now you could very much go and plonk them on intensive care. Your other treatment option of choice is giving them fresh frozen plasma. You can give them someone else's plasma cholinesterase, and it'll mop up the suxamethonium and they'll stop being paralysed and you can wake them up and it's all tickety-boo.

So you can either wait or give them FFP. If you wait, they will eventually pee the suxamethonium out. Either way, you're going to send them to clinical genetics and refer them for testing afterwards.

Additional Side Effects and Clinical Pearls

16:31-17:00

Don't forget it causes anaphylaxis. It certainly causes bronchospasm, and you might think you intubated the oesophagus when you didn't. And that masseter spasm can sometimes be a precursor of the patient developing MH, and it also makes it quite hard to intubate the patient if they've got a nice tight masseter muscle.

Key Takeaway Points

17:00-18:47

Anyway, going to give you four takeaway points for suxamethonium.

1. Emergency Drug:

Suxamethonium is an emergency drug, and knowing your doses of it and where your suxamethonium is in relation to you is smart moves. It can be used when you're unable to manage an airway in a gas induction with no IV access, but the onset time of three to four minutes is going to be a very sweaty three to four minutes if you're having airway troubles in a gas induction with no IV access. And it can be used to manage laryngospasm in that periextubation period.

2. Brief Procedures:

It is useful for interventions that are brief but require a tube if there are patient or surgical factors that necessitate that. It is still used as the drug of choice in emergency obstetric intubations and general anaesthesia, at least in the places where I have trained and worked.

3. Exam Topic:

The side effect profile is a great topic to discuss in the viva, as there are multiple interesting pharmacological and physiological avenues to explore and go down several rabbit holes thereof.

4. Dosing Considerations:

The last point I'm going to say is the dose of suxamethonium is not just one hundred milligrams for everyone. 1.5 milligrams per kilo in an adult is probably where you want to be, even if that means cracking a second ampoule open. I say this having perhaps inadvertently underdosed a patient at some point in my training and finding it quite challenging. I hadn't fully appreciated at that point in time the rate of metabolism of suxamethonium before it gets to where it needs to go, i.e., muscles.

So I now give 1.5 milligrams per kilo to anyone who I am giving suxamethonium to. I can't tell you that I use it very much, but that's my two cents.

Conclusion and Call to Action

18:47-19:18

So you've been listening to Gas, Gas, Gas. My name is James. Thank you very much. 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.