Ep.33 – Prilocaine For The FRCA Primary

Introduction and Series Overview

00:00 – 01:57

Hello everyone, welcome to Gas Gas Gas, the podcast designed specifically for anaesthetists in training – that’s you hopefully. I’m your host today, James aka Dr Gas, and today we are hopping off that 10-metre board, diving into a big swimming pool that’s sufficiently deep and full of prilocaine.

This is a local anaesthetic that we probably don’t think about very much because it’s overshadowed by lidocaine, but it certainly has use in your anaesthetic toolkit. Whether you’re preparing for your primary FRCA exams or just starting off in anaesthesia, understanding prilocaine means you can have some interesting conversations with your trainers about timing, dose, and the logistics of running a day surgery list using spinals.

We’re naturally going to talk pharmacodynamics and pharmacokinetics and explore the dosing strategies for these day case short-acting spinals. Openly for me, when I was first starting out, the thought of using a drug that doesn’t last as long seemed quite unsettling because naturally, what if something goes wrong? What if the surgeon takes ages? What if there are delays in getting started because they can’t find the appropriate kit? So we’re going to talk about dosing strategies for prilocaine and also patient selection.

I wanted to take this quick opportunity to thank those folk who have actually donated to the show – really appreciate it. It does make a valuable contribution both to general costs but also it is super validating, so thank you. I’m trying my best here and it clearly has value to you too. There is a link in the show notes if anyone else has cash burning a hole in their pocket. But if they’ve got loads of cash burning a hole in their pocket, I would suggest donating to the BMA Strike Fund. Dr Gas is pro-strike, but this is an apolitical podcast, at least we try to be.

Why Prilocaine Over Lidocaine?

01:57 – 04:25

So let’s get on with some prilocaine. I’m sure the first question that jumps to your mind – and it certainly jumped to my mind – is why are we messing around with this other drug called prilocaine? Why don’t we just use lidocaine? That’s because actually, unfortunately, lidocaine is a massive offender for TNS, or transient neurological symptoms.

TNS occurs after spinal anaesthesia (intrathecal local anaesthetics). It can occur after the administration of any of the common intrathecal local anaesthetic agents – bupivacaine, levobupivacaine, prilocaine, 2-chloroprocaine, and lidocaine. But what’s the dealio?

There’s a big Cochrane review that looked at oodles of patients. The line from that review that summarises it very well is: specifically, when alternative local anaesthetics were compared directly to lidocaine, the risk of developing TNS was reduced by between 82% and 90% when bupivacaine, levobupivacaine, prilocaine, procaine or ropivacaine were used rather than lidocaine.

So you can understand that means no one’s going to bother sticking lidocaine into someone’s back when there are other choices.

What is TNS, you ask? Right, TNS is something that tends to present 24 hours after doing a spinal on someone. They get buttock pain and pain down their legs and dysaesthesia – altered unpleasant sensations lasting for up to seven days. It’s naturally transient, it’s not lasting, but lidocaine is a big old offender for that. Another study before this Cochrane review found that up to 40% of intrathecal lidocaine administrations led to some degree of TNS problems.

So there we go, folks. Don’t use lidocaine. Instead, use prilocaine, which is what we’re going to talk about now.

Basic Properties and Presentation

04:25 – 05:10

Prilocaine is another one of our friendly amide local anaesthetic drugs. Its full chemical name is prilocaine hydrochloride – amide local anaesthetic – and it’s an amide derivative of toluidine. It is presented as a clear and colourless solution, and it’s a racemic mixture of R and S prilocaine. Classically comes as either a neat mix, or for us when administering spinals, you get it as heavy prilocaine – aka Prilocal seems to be the one that is in most drawers. It comes as 1%, 2% and 3% solutions. If I’m remembering correctly, our Prilocal is 2%. It’s got a molecular weight of 220 grams per mole, if that floats your boat.

Pharmacodynamics and Mechanism of Action

05:10 – 06:11

Pharmacodynamics of prilocaine. Well, you can tell me. Actually, you could probably take 30 seconds if you were to pause to tell me exactly how local anaesthetics work. You could pause it now. Pause. You paused. You’ve unpaused. So you must have thought about it.

Local anaesthetics work by sodium channel blockade, but they’re mischievous and they only work on the inside bit of that sodium channel. When I say inside, the bit that’s inside the cell – therefore that local anaesthetic agent has to cross the neuronal membrane. To do that, it has to be unionised. But further mischief befalls us because only the ionised fraction, or the cationic variant, once it’s inside the cell, acts to block that internal aspect of the sodium channel.

So there’s a few steps that have to occur. It’s not just magical jumps onto those sodium channels sort of drug. These events are governed by how lipophilic the agent is – how fat-soluble it is – and the pKa of the agent (the amount available unionised that can jump across that gap).

Clinical Uses and Dosing

06:11 – 08:14

Clinical uses: well, spinal anaesthesia, but you could also infiltrate it as a local anaesthetic if you so chose. Why would you choose to do that? Well, it lasts a bit longer than lidocaine – perhaps up to 1.5 times longer – and it is 33% unionised, and you can guess that means its onset time might be faster than lidocaine. So maybe we should be using it to do all our arterial lines and central lines. Faster onset, no dilly-dallying being like “can you feel it?” Perhaps that’s a conversation for another day.

If you look at the show notes, I’m going to break down dosing in all the various areas. The important things to note: a toxic dose is considered 6 milligrams per kilogram and a maximum dose might be 400 milligrams. You could choose to use it for peripheral nerve blocks, infiltration at sites, caudal anaesthesia, as well as epidural top-ups, although I think most UK practice is limited to spinal anaesthesia and topicalising kiddies, because EMLA is made up of prilocaine and lidocaine, 2.5% each. EMLA stands for eutectic mixture of local anaesthetic – eutectic because it wouldn’t be a gel if it was just one or the other, but mixed together it seems to behave quite happily.

Prilocaine is also used for intravenous regional anaesthesia. You probably just fell off your chair, crashed your car, or you’ve been slung off the back of a treadmill. Intravenous regional anaesthesia? Yeah, Bier’s blocks. This is where you stick a tourniquet on someone’s arm that’s sufficiently tight and then inject local anaesthetic in sufficient quantity into the veins of that arm to numb it so that you can adjust a fracture. I’m going to put a link to the Royal College Emergency Medicine leaflet in the show notes for further reading. Not something that’s done terribly often these days. I’ve seen it once when I was a medical student, and that was a while ago now, but it’s kind of cool.

Side Effects and Toxicity

08:14 – 12:19

Continuing with our conversation about pharmacodynamics of prilocaine, we need to talk about the side effect profile. Side effects, as we know, are dictated chiefly by systemic absorption of that agent into plasma and then it tottering off to other sodium channels elsewhere in your human patient.

In low concentrations, prilocaine can push up your systemic vascular resistance – cause a little bit of vasoconstriction. However, as with most other local anaesthetic agents, toxicity leads to cardiovascular collapse – hypotension, dysrhythmias, etc. In low concentrations, from a respiratory perspective, it can cause a bit of bronchodilation. But again, from a toxicity perspective, apnoea and insufficient breathing become a problem.

CNS-wise, we’re going down that same route of CNS toxicity that we described for our bupivacaine episodes. What comes about in the CNS if you put local anaesthetic in someone’s vein and it totters up to their brain? Well, it’s biphasic, and that’s because initial inhibition occurs to inhibitory interneurons. These are little neurons that are like the conductors in your brain – they put the brakes on everyone else and only let them communicate just the right amount. When you inhibit those inhibitory interneurons, the brakes are off and your brain gets a bit more lively.

This leads to light-headedness, dizziness and those sensory disturbances like visual changes, auditory changes, circumoral tingling, tinnitus, etc. However, as the situation progresses and the local anaesthetic soaks in further to the brain, you then end up in the state of sedation, coma, etc. This is why you might see a bit of seizure activity between these two phases. These inhibitory interneurons are also implicated in that seizure-like weirdness that sometimes happens with propofol.

Methemoglobinemia: Prilocaine is less toxic than some other drugs, but it also has another complicating effect – in large doses, you can cause methemoglobinemia. That’s because a metabolite of prilocaine has a proclivity for haemoglobin and it likes to oxidise it. That metabolite, which might come up in an exam, is O-toluidine or ortho-toluidine.

The treatment for methemoglobinemia is to give people methylene blue, 1 to 2 milligrams per kilogram. That tends to shift the haemoglobin back to an unoxidised state, but it also causes havoc with your SATS probe and sometimes patients are allergic to it and then you get a really weird urticarial blue blotchy patient and you have no idea if they’re hypoxic or not. That’s always fun.

Now 600 milligrams is quite a big dose – that’s 10 times the max dose recommended for spinals. So it’s only really going to be happening if you’re doing infiltration of prilocaine in massive doses. You might be more likely to have that problem if the patient is also on other drugs that tend to oxidise haemoglobin or predispose haemoglobin to oxidation – sulfonamides and all those fun drugs. When we’re talking sulfonamides, we mean things like sulfasalazine (used in IBD) and sulfamethoxazole (one component of Septrin, used for PCP and generally very poorly patients on ITU who seem to be getting to the end of the antibiotic road).

Pharmacokinetics

12:19 – 14:07

Pharmacokinetics of prilocaine. Absorption – well, it depends where you inject it. If you inject it somewhere where there are loads of blood vessels, you’re going to have more absorption. If you inject it into somewhere that’s relatively avascular, less absorption. So it follows that same structured absorption ladder that is described – in order of highest plasma concentration evident to lowest: if you stick it in someone’s vein, it’s going to be high, then tracheal, intercostal, caudal, epidural, brachial plexus, subcutaneous. It’s important to remember that because it might come up as an SBA – which is associated with the most or the least absorption, blah blah blah.

Prilocaine has a pKa of either 7.7 or 7.9, depending on what you read, and it is approximately a third unionised at physiological pH. So there’s quite a lot free to get jiggy with those sodium channels eventually. It is 55% protein-bound – again, there’s a higher fraction – and it has a tendency to bind to alpha-1 acid glycoprotein, which is not dissimilar to bupivacaine, which also has a preference for that. It has a volume of distribution of 190 to 260 litres, but we’re not really interested in sticking it in someone’s vein and then measuring a concentration later because that’s madness.

Metabolism of prilocaine? It’s an amide. Amides are metabolised in the liver. That’s why they theoretically last longer. It is metabolised via hydrolysis to that O-toluidine or ortho-toluidine as it’s otherwise known, and then that is hydroxylated to variants of hydroxy-toluidine. It’s got an elimination half-life in the plasma of 1.6 hours and you pee those metabolites out via kidneys.

Dosing Strategies and Patient Selection

14:07 – 19:17

So that’s all well and good. We now know enough about prilocaine to think about it in a safe and sensible manner. But how are we going to use it?

I’d hope on the wall of your anaesthetic rooms, there is Dr R. Erskine’s excellent flowchart that basically tells you exactly what to do. There’s going to be a link to that seminal paper in the BJA from Erskine et al. There’s also an excellent Block It Like It’s Hot podcast episode where they interviewed Dr Erskine and they had a lovely long chat. He works at the Royal Derby Hospital and he sounds like a pretty top bloke. So anyone who’s working there, you’re a lucky sausage.

Anyway, it’ll be on your anaesthetic room wall, but we’re just going to go through it to try and make sense of it. If you just look at it and try and understand it, I actually found myself a bit bamboozled because it sort of works a bit back to front. It makes sense once you understand it.

The Decision Tree:

First question: Are you just trying to get a saddle block? A saddle block is where you’re really just catching those sacral nerves – patient’s quite numb around the area where they would be wearing some boxer shorts or underwear and it doesn’t catch much else. If you’re aiming for that, you only need a smidge of heavy prilocaine (Prilocal). Half a mil to one mil, 10 to 20 milligrams. So not very much at all. You inject it, you let it sink down and soak in and let it fix. The important thing with prilocaine is it does fix quite quickly. So if you’re doing an injection and you don’t want a saddle block, don’t dilly-dally – lie the patient down. Even if they start trying to tell you about their cat, just grab their legs and swing them around whilst learning about their cat.

If you don’t require just a saddle block: How high does your block need to go? If you’re aiming for above T10 (above the umbilicus), then you need to give 3 mils of Prilocal, heavy prilocaine, and that’s about 60 milligrams. That will cover you for things like umbilical hernia, diagnostic gynaecological laparoscopy (looking for endometriosis), and ureteroscopy plus/minus stents and lasers, depending on how high up they’re going with those stents.

If it’s not above T10: Does it need to last longer than an hour? If the answer is yes – it’s knee surgery, but they’re going to take a while because they’ve got to drape and clean and scrub and re-drape and then change their gloves and then have a shower and then put more gloves on and then start – then it recommends 2 to 3 mils of heavy prilocaine. That’ll cover things like inguinal hernias, ACL repairs and TURPs (transurethral resections of prostates).

Final option: We don’t need a block above T10, it doesn’t need to last longer than an hour. Therefore, we come to the final option, which is actually using Ampres. Ampres is 2-chloroprocaine, and this is for really short interventions, like stripping some varicose veins, having just a look inside someone’s knee without any surgical interventions, check cystoscopies, and then like a whiff of diathermy for those people with bladder cancers.

2-Chloroprocaine (Ampres)

17:17 – 18:12

2-chloroprocaine – probably there isn’t enough clinical use to justify a whole extra episode, but this is a very interesting drug because it’s the only one that you’re going to put in someone’s intrathecal space that’s an ester as opposed to an amide. This in part is why it doesn’t last as long. The advantages of an ester is there’s no pseudocholinesterase – or at least very little pseudocholinesterase – in your CSF space, so it’s not broken down blisteringly fast. If you were to just inject it in the skin or put it in someone’s vein, it actually will get chomped down pretty hard by pseudocholinesterases.

That means that with Ampres, you’d have to undergo a Herculean effort to achieve toxicity with Ampres in the doses we’re using. There’s some interesting bits and pieces on the internet about using it for epidural top-ups because of its blistering onset time. There’s a few links in the show notes, and I’ll put the data for chloroprocaine in the show notes for this episode – that would be your really short-acting spinal anaesthetic.

Patient Selection Criteria

18:12 – 19:17

When do we pick a patient to do a short-acting spinal anaesthetic on? Because you shouldn’t just do it willy-nilly because you might end up feeling daft with a patient who needs a general anaesthetic halfway through an operation because you didn’t think ahead.

The things that really jump out to my mind:

• You should make sure that you have a surgeon who gets on with it and doesn’t get trapped in indecision
• You need to make sure that the patient is relatively calm and easygoing, and if you were to need to convert to a general anaesthetic, you could manage them without lots of panic and stress
• You should make sure that the surgical procedure itself is a simple one – not a tricky hernia, not a hernia that was incarcerated and now is incarcerated, because you don’t want the surgeon to find it more challenging. So it needs to be like a routine simple operation
• You also need to be assured that the theatre team is slick and that everyone’s aware that you’re using a shorter-acting spinal agent, because bupivacaine lasts quite a hecking while, which means there’s a lot of room and margin for error

Advantages in Day Surgery

19:17 – 20:52

Why are we thinking about using prilocaine? Because in day surgery, you can turn patients over faster. They get a return of motor function faster and they can be discharged sooner.

Just to give you a bit of a gist about the differences between prilocaine and bupivacaine, there’s a cohort study looking at 60 milligrams (3 mls of prilocaine) versus 12.5 milligrams (2.5 ml dose of bupivacaine). Both had additional sufentanil and morphine because these were for elective caesarean sections.

When looking at time to return of motor block in prilocaine versus bupivacaine: prilocaine was 158 minutes, whereas bupivacaine was 220 minutes. So that’s 40 minutes less before they can move their legs again. This was in France, so I don’t quite know what their recovery discharge criteria are, but it was 135 minutes versus 180 minutes of PACU/recovery time – but three hours in recovery seems excessive.

The real information that we’re actually curious about is the time to urination when we’re thinking about day surgery, because most day surgery units use patient being able to urinate as a discharge criteria, and this seems to be the last to return. Although a few places discharge patients even if they haven’t peed, but they have quite robust return to hospital criteria and they safety net quite heavily. I couldn’t find any robust evidence to really make a decent comparison between prilocaine and bupivacaine for time to urination, although I’m sure it may exist. If anyone can find that or knows anything about that, please drop me a message or an email and maybe we can add something on.

Summary and Conclusion

20:52 – 22:13

So we’ve covered quite a lot there. We’ve explored prilocaine and touched on 2-chloroprocaine (Ampres), remembering that prilocaine is an amide, whereas Ampres is an ester. We’ve touched on TNS – transient neurological symptoms – something that can happen after spinal anaesthetics and is starkly more common with lidocaine, particularly hyperbaric lidocaine, which is what they were using. We’ve started to consider approaches to patient selection for spinal anaesthesia in order to not end up in a pickle feeling very daft and having to do a general anaesthetic halfway through a procedure, which is far harder than doing it at the start.

Anyway, folks, thank you very much for listening. I hope you have a lovely week, and I’ll see you next week for… oh, would you look at that – lidocaine! How organised of me.

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’s like drinking from a fire hose. Take it day by day, don’t overcook yourself, don’t freak out, and keep studying.

This is the full Show Transcript – Courtesy of Whisper LLM

Hello everyone, welcome to Gas Gas Gas, the podcast

00:40-00:45
designed specifically for anaesthetists in training, that’s you hopefully. I’m your host today, James aka

00:46-00:52
Dr Gas and today we are hopping off of that 10 meter board, diving into a big swimming pool that’s

00:53-00:57
sufficiently deep enough and full of prilocaine. So this is a local anaesthetic that we probably

00:57-01:04
don’t think about very much because it’s overshadowed by lidocaine, but it certainly carries use in your

01:04-01:09
anaesthetic toolkit. So whether or not you’re preparing for your primary FRCA exams or just

01:09-01:12
starting off in anaesthesia, understanding prilocaine means that you can have some interesting

01:13-01:19
conversations with your trainers about timing, dose, etc. and the logistics of running a day

01:19-01:25
surgery list using spinals. We’re naturally going to talk pharmacodynamics and pharmacokinetics

01:25-01:31
and explore the dosing strategies for these day case short-acting spinals.

01:32-01:34
Openly for me, when I was first starting out,

01:34-01:39
the thought of using a drug that doesn’t last as long seemed quite unsettling

01:40-01:42
because naturally, what if something goes wrong?

01:42-01:43
What if the surgeon takes ages?

01:43-01:48
What if there’s delays in getting started because they can’t find the appropriate kit?

01:48-01:51
So we’re going to talk a little bit about the dosing strategies for prilocaine

01:51-01:53
and also patient selection.

01:57-02:01
I just wanted to take the quick opportunity guys to thank those folk who have actually

02:01-02:07
donated to the show really appreciate it it does make a valuable contribution both to general costs

02:07-02:13
but also it is super validating guys so thank you I’m trying my best here and it clearly has value

02:13-02:21
to you too so thank you very much for those donations so far folks there is a link in the

02:21-02:27
show notes if anyone else has cash burning a hole in their pocket. But if they’ve got loads of cash

02:27-02:32
burning a hole in their pocket, then I would suggest donating to the BMA Strike Fund. And Dr.

02:32-02:38
Gas is pro-strike, but this is an apolitical podcast, at least we try to be. So let’s get on

02:38-02:42
with some prilocaine. I’m sure the first question that jumps to your mind, and it certainly jumped

02:42-02:46
to my mind, is why are we messing around with this other drug called prilocaine? Why don’t we

02:46-02:52
just use lidocaine. That’s because actually, unfortunately, lidocaine is a massive offender

02:52-03:00
for TNS, or transient neurological symptoms. TNS occurs after spinal anaesthesia, i.e. intrathecal

03:00-03:06
local anaesthetics. It can occur after the administration of any of the common intrathecal

03:06-03:13
local anaesthetic agents, i.e. bupivacaine, levobupivacaine, prilocaine, 2-chloroprocaine,

03:14-03:21
and lidocaine. But what’s the dealio? So there’s a big Cochrane review that looked at oodles of

03:21-03:26
patients. And the line from that patient that summarises it very well is, specifically,

03:26-03:32
when alternative local anaesthetics were compared directly to lidocaine, the risk of developing TNS

03:32-03:39
was reduced by between 82% and 90% when bupivacaine, levobupivacaine, prilocaine,

03:39-03:42
Procane or repivacane were used rather than lidocaine.

03:42-03:46
So you can understand that that means no one’s going to bother sticking lidocaine

03:46-03:47
into someone’s back when there are other choices.

03:48-03:49
What is TNS, you ask?

03:49-03:54
Right, TNS is something that tends to present 24 hours after doing a spinal on someone.

03:55-03:59
They get buttock pain and they get pain down their legs and dysesthesia,

03:59-04:04
so altered unpleasant sensations lasting for up to seven days.

04:04-04:05
It’s naturally transient.

04:05-04:09
It’s not lasting, but lidocaine is a big old offender for that.

04:10-04:19
Another study before this Cochrane review found that up to 40% of intrathecal lidocaine administrations led to some degree of TNS problems.

04:19-04:25
So there we go, folks. Don’t use lidocaine. Instead, use prilocaine, which is what we’re going to talk about now. Great!

04:25-04:30
So prilocaine is another one of our friendly amide local anaesthetic drugs.

04:30-04:36
Its full chemical name is prilocaine hydrochloride, amide local anaesthetic,

04:36-04:39
and it’s an amide derivative of toluidine.

04:39-04:42
It is presented as a clear and colourless solution,

04:42-04:46
and it’s a racemic mixture of R and S prilocaine,

04:46-04:48
and classically comes as either a neat mix,

04:48-04:51
or for us when administering spinals,

04:51-04:53
you get it as heavy prilocaine,

04:53-04:57
aka prilotical seems to be the one that is in most drawers,

04:57-05:01
And it comes as 1%, 2% and 3% solutions.

05:02-05:05
If I’m remembering correctly, our Prilatecal is 2%.

05:05-05:08
It’s got a molecular weight of 220 grams per mole.

05:08-05:09
If that floats your boat.

05:09-05:10
Pharmacodynamics of Prilacane.

05:11-05:12
Well, you can tell me.

05:12-05:15
And actually, you could probably take 30 seconds if you were to pause it

05:15-05:17
to tell me exactly how local anaesthetics work.

05:17-05:18
You could pause it now.

05:18-05:19
Pause.

05:19-05:20
You paused.

05:20-05:20
You’ve unpaused.

05:20-05:22
So you must have thought about it.

05:22-05:24
Local anaesthetics work by sodium channel blockade.

05:25-05:28
but they’re mischievous and they only work on the inside bit of that sodium channel.

05:28-05:31
And when I say inside, the bit that’s inside the cell,

05:31-05:35
therefore that local anaesthetic agent has to cross the neuronal membrane.

05:35-05:37
To do that, it has to be unionised.

05:37-05:40
But further mischief befalls us because only the ionised fraction,

05:41-05:44
or the cationic variant, once it’s inside the cell,

05:45-05:48
acts to block that internal aspect of the sodium channel.

05:49-05:50
So there’s a few steps that have to occur.

05:50-05:55
It’s not just a magical jumps onto those sodium channels sort of drug.

05:55-06:01
these events are governed by how lipophilic the agent is how fat soluble it is and the pk of the

06:01-06:06
agent i.e the amount available unionized that can jump across that gap but we’re going to cover that

06:06-06:11
in a moment clinical uses well spinal anesthesia but you could also infiltrate it as a local

06:11-06:16
anesthetic if you so chose why would you choose to do that well it lasts a bit longer than lidocaine

06:16-06:24
perhaps up to 1.5 times longer and it is 33 percent unionized and you can guess that that means that

06:24-06:29
its onset time might be faster than lidocaine. So maybe we should be using it to do all our art

06:29-06:34
lines and our central lines. Faster onset, no dilly-dallying being like, can you feel it?

06:34-06:37
Perhaps that’s a conversation for another day. So if you look at the show notes, I’m going to break

06:37-06:44
down dosing in all the various areas. The important things to note is a toxic dose is considered six

06:44-06:49
milligrams per kilo and a maximum dose might be 400 milligrams. Well, I say might, it is 400

06:49-06:54
milligrams quoted. You could choose to use it for peripheral nerve blocks, infiltration at sites,

06:55-07:01
cordial anaesthesia, as well as epidural top-ups, although I think most UK practice is limited to

07:01-07:08
spinal anaesthesia, and topicalising kiddies, because EMLA is made up of prilocaine and lidocaine,

07:09-07:16
2.5% each, and EMLA stands for eutetic mixture of local anaesthetic. Eutetic because it wouldn’t

07:16-07:20
be a gel if it was just one or the other, but mixed together it seems to behave quite happily.

07:21-07:24
Go and have a read up about that if you want to know more about Emla. Not really the focus of

07:24-07:30
today’s episode. Prilocaine is also used for intravenous regional anaesthesia. You probably

07:30-07:34
just fell off your chair, crashed your car, or you’ve been slung off the back of a treadmill.

07:35-07:40
Intravenous regional anaesthesia? Yeah, beers, blocks. This is where you stick a tourniquet on

07:40-07:46
someone’s arm that it’s sufficiently tight and then inject local anesthetic to a sufficient

07:46-07:52
quantity into the veins of that arm to numb it so that you can adjust a fracture. I’m going to put

07:52-07:58
a link to the Royal College Emergency Medicine leaflet guidebook information contraption in the

07:58-08:03
show notes for a bit of a further read. Not something that’s done terribly often these days.

08:03-08:08
I’ve seen it once when I was a medical student and that was a while ago now but anyway it’s kind of

08:08-08:14
Cool. So continuing on with our conversation about pharmacodynamics of prilocaine, we need to talk

08:14-08:19
about the side effect profile of prilocaine. So side effects, as we know, are dictated chiefly by

08:19-08:26
systemic absorption of that agent into plasma and then it tottering off to other sodium channels

08:26-08:32
elsewhere in your human patient. In low concentrations, prilocaine can push up your

08:32-08:37
systemic vascular resistance, i.e. cause a little bit of vasoconstriction. However, as with most

08:37-08:42
other local anesthetic agents, toxicity leads to cardiovascular collapse, you know, hypotension,

08:43-08:47
dysrhythmias, etc, etc. In low concentrations, from a respiratory perspective, it can cause a bit

08:47-08:53
of bronchodilation. But again, from a toxicity perspective, apneas and insufficient breathing

08:53-09:00
become a problem. CNS-wise, we’re going down that same route of CNS toxicity that we described for

09:00-09:04
our bupivacaine episodes, and we’re going to go into a deep dive when we do our local anesthetic

09:04-09:11
toxicity episode, but we’re all about the primers in gas, gas, gas. And I’d like to dribble bread

09:11-09:15
crumbs throughout the whole thing so that you’re getting more than just a bland conversation about

09:15-09:20
the molecular weight of prilocaine, which would make me just throw myself off the back of that

09:20-09:25
treadmill. So what comes about in the CNS if you put local anaesthetic in someone’s vein and it

09:25-09:30
totters up to their brain? Well, it’s biphasic. We mentioned that earlier. And that’s because

09:30-09:37
initial inhibition occurs to inhibitory interneurons. These are little neurons that

09:37-09:42
are like the conductors in your brain and they put the brakes on everyone else and only let them

09:43-09:48
communicate just the right amount. When you inhibit those inhibitory interneurons, the brakes are off

09:48-09:54
and your brain gets a bit more lively. This leads to lightheadedness, dizziness and those sensory

09:54-10:01
disturbances like visual changes, auditory changes, circumoral tingling, tinnitus, etc. However,

10:01-10:06
as the situation progresses and the local anaesthetic soaks in further to the brain,

10:06-10:12
you then end up in the state of sedation, coma, etc. This is why you might see a bit of seizure

10:12-10:18
activity between these two phases. These inhibitory interneurons are also implicated in that

10:19-10:24
seizure-like weirdness that sometimes happens with propofol, either because you’ve given a little bit

10:24-10:28
than you might normally and they get a bit lively and do something that looks like a seizure and

10:28-10:33
then they’re off to sleep or if they’re seemingly young kiddies seem to do it a bit more they do a

10:33-10:38
bit of a weird dance and then they’re out it’s because those inhibitory interneurons appear to

10:38-10:43
be more susceptible to inhibition than the rest of your brain and there’s a chapter on it in

10:43-10:48
miller’s anesthesia for anyone who’s excited about interneurons like me so what about toxicity so

10:48-10:54
prilocaine is less toxic than some other drugs but it also has another complicating effect which is

10:54-11:00
large doses, you can cause methemoglobinemia. And that’s because a metabolite of prilocaine

11:00-11:06
has a proclivity for hemoglobin and it likes to oxidise it. And that metabolite, which might come

11:06-11:13
up in an exam, is O-toluidine or orthotolidine. The treatment for methemoglobinemia is to give

11:13-11:19
people methylene blue, one to two milligrams per kilo. And that tends to shift the hemoglobin back

11:19-11:25
to an unoxidised state, but it also causes havoc with your SATs probe and sometimes patients are

11:25-11:30
allergic to it and then you get a really weird urticarial blue blotchy patient and you have no

11:30-11:35
idea if they’re hypoxic or not. That’s always fun. Now 600 milligrams is quite a big dose. That’s 10

11:35-11:40
times the max dose recommended for spinals. So it’s only really going to be happening if you’re

11:40-11:45
doing infiltration of prilocaine in massive doses. You might be a bit more likely to have that problem

11:45-11:52
if the patient is also on other drugs that tend to oxidise haemoglobin or predispose haemoglobin

11:52-11:57
to oxidation, i.e. sulfonamides and all those fun drugs. And when we’re talking sulfonamides,

11:58-12:05
we mean things like sulfazalazine, that’s used in IBD, and sulfamethoxazole, which is one component

12:05-12:11
of septrin, which is used for PCP and generally very poorly patients on ITU who seem to be getting

12:11-12:15
to the end of the antibiotic road. Hopefully you got the gist of that, folks. And if you’re excited

12:15-12:19
inhibitory into neurons, drop me a message. We can be excited about that together.

12:19-12:24
Pharmacokinetics of prilocaine. So absorption, well, it depends where you inject it. If you

12:24-12:27
inject it somewhere where there’s loads of blood vessels, you’re going to have more absorption.

12:27-12:32
If you inject it into somewhere that’s relatively avascular, less absorption. So it follows that

12:32-12:39
same structured absorption ladder that is described, which in order of highest plasma

12:39-12:43
concentration evident to lowest, if you stick it in someone’s vein, it’s going to be high.

12:43-12:45
then tracheal, intercostal,

12:45-12:46
cordal, epidural,

12:46-12:48
brachial plexus, subcutaneous.

12:49-12:50
It’s important to remember that

12:50-12:52
because it might come up as an SBA,

12:53-12:55
which is associated with the most

12:55-12:57
or the least absorption, blah, blah, blah.

12:57-13:01
Prilocaine has a PKA of either 7.7 or 7.9,

13:01-13:02
depending on what you read.

13:03-13:05
And it is approximately a third unionized

13:05-13:07
at physiological pH.

13:07-13:09
So there’s quite a lot free to get jiggy

13:10-13:11
with those sodium channels eventually.

13:11-13:13
It is 55% protein bound.

13:14-13:15
Again, there’s a higher fraction

13:15-13:20
and it has a tendency to bind to alpha-1 acid glycoprotein,

13:20-13:22
which is not dissimilar to bupivacaine,

13:22-13:24
which also has a preference for that.

13:24-13:28
It has a volume of distribution of 190 to 260 litres,

13:28-13:31
but we’re not really interested in sticking it in someone’s vein

13:32-13:33
and then measuring a concentration later

13:33-13:34
because that’s madness.

13:35-13:36
Metabolism of prilocaine?

13:37-13:38
It’s an amide.

13:38-13:40
Amides are metabolised in the liver.

13:40-13:42
That’s why they theoretically last longer.

13:42-13:49
And it is metabolised via hydrolysis to that otoluidine or orthotolidine as it’s otherwise

13:49-13:49
known.

13:50-13:54
And then that is hydroxylated to variants of hydroxytolidine.

13:54-14:00
It’s got an elimination half-life in the plasma of 1.6 hours and you pee those metabolites

14:01-14:01
out via kidneys.

14:02-14:03
So that’s all well and good.

14:03-14:07
We now know enough about prilocaine to think about it in a safe and sensible manner.

14:07-14:08
But how are we going to use it?

14:08-14:16
Now, I’d hope on the wall of your anaesthetic rooms, there is Dr. R. Erskine’s excellent flowchart that basically tells you exactly what to do.

14:17-14:25
There’s going to be a link to that seminal paper in the BJA from Erskine et al., although it’s not Erskine, it’s someone else who got the first author.

14:25-14:33
But there’s also an excellent Block It Like It’s Hot podcast episode where they interviewed Dr. Erskine and they had a lovely long chat.

14:33-14:36
He works at the Royal Derby Hospital and he sounds like a pretty top bloke.

14:37-14:39
So anyone who’s working there, you’re a lucky sausage.

14:39-14:41
Anyway, it’ll be on your anaesthetic room wall,

14:42-14:44
but we’re just going to go through it to try and make sense of it.

14:44-14:46
Because if you just look at it and try and understand it,

14:46-14:50
I actually found myself a bit bamboozled because it sort of works a bit back to front.

14:51-14:52
It makes sense once you understand it.

14:52-14:55
So the first question that comes up is, are you just trying to get a saddle block?

14:56-14:59
Now, a saddle block is where you’re really just catching those sacral nerves.

14:59-15:04
patient’s quite numb around the area where they would be wearing, you know, some boxer shorts or

15:04-15:09
some underwear and it doesn’t catch much else. So if you’re aiming for that, you only need a tadge

15:09-15:15
of heavy prilocaine, i.e. prilotecal. Half a mil to one mil, 10 to 20 milligrams. So not very much

15:15-15:21
at all. You inject it, you let it sink down and soak in and let it fix. The important thing with

15:21-15:25
prilocaine is it does fix quite quickly. So if you’re doing an injection and you don’t want a

15:25-15:30
saddle block, don’t dilly-dally lie the patient down. And even if they start trying to tell you

15:30-15:35
about their cat, just grab their legs and swing them around whilst learning about their cat.

15:35-15:40
So if you don’t require just a saddle block, the next question to think about is how high does your

15:40-15:46
block need to go? Now, if you’re aiming for above T10, that is above the umbilicus, then you need to

15:46-15:52
give three mils of prilotecal, heavy prilocaine, and that’s about 60 milligrams. And that will cover

15:52-15:59
you for things like umbilical hernia, diagnostic gynealaparoscopy, i.e. looking for endometriosis,

15:59-16:05
and then ureteroscopy plus minus stents and lasers, depending on how high up they’re going with those

16:06-16:11
stents, if they’re fiddling around in the kidneys, might not quite cover it. So then you’re thinking,

16:11-16:16
well, no, I don’t need a block above T10. It’s actually a bit lower than that. The next question

16:16-16:21
you ask yourself is, does it need to last longer than an hour? And if the answer is, yeah, even

16:21-16:22
no, it’s not above T10.

16:22-16:23
Yeah, it’s knee surgery,

16:23-16:24
but they’re going to take a while

16:24-16:25
because they’ve got to drape

16:25-16:26
and they’ve got to, you know,

16:27-16:28
clean and scrub and re-drape

16:28-16:29
and then change their gloves

16:29-16:30
and then have a shower

16:30-16:31
and then put more gloves on

16:32-16:32
and then start.

16:32-16:34
Then it recommends two to three mils

16:34-16:35
of heavy prilocaine.

16:36-16:36
And that’ll cover things like

16:37-16:39
inguinal hernias, ACL repairs

16:40-16:42
and TIRPS, transurethral resections

16:43-16:43
of prostates.

16:44-16:45
But then we come to our final decision

16:46-16:48
where we don’t need a block above T10.

16:48-16:49
It doesn’t need to last longer than an hour.

16:50-16:54
And therefore, we come to the final option, which is actually using Ampres.

16:54-16:57
And Ampres is 2-chloroprocaine.

16:57-17:01
And this is for really short interventions, like stripping some varicose veins,

17:02-17:06
having just a look inside someone’s knee without any surgical interventions,

17:07-17:11
check cystoscopies, and then it’ll be like a WAF of diathermy for those people with

17:11-17:12
bladder cancers and stuff like that.

17:13-17:17
Now, 2-chloroprocaine, probably there isn’t enough clinical use to justify a whole extra

17:18-17:19
episode, but this is a very interesting drug.

17:20-17:24
because it’s the only one that you’re going to put in someone’s intrathecal space that isn’t ester

17:24-17:29
as opposed to an amide. This in part is why it doesn’t last as long. The advantages of an ester

17:29-17:35
is there’s no pseudocholinesterase or at least very little pseudocholinesterase in your CSF space

17:35-17:40
so it’s not broken down blisteringly fast. If you were to just inject it in the skin or put it in

17:40-17:46
someone’s vein it actually will get chomped down pretty hard by pseudocholinesterases so that means

17:46-17:52
that Amperez, you’d have to undergo a Herculean effort to achieve toxicity with Amperez in the

17:53-17:57
doses we’re using. There’s some interesting bits and pieces on the internet about using it for

17:57-18:01
epidural top-ups because of its blistering onset time. There’s a few links in the show notes and

18:01-18:07
I’ll put the data for chloroprocaine in the show notes for this episode but that would be your

18:07-18:12
really short-acting spinal anaesthetic. But when do we pick a patient to do a short-acting spinal

18:12-18:16
anesthetic on because you shouldn’t just do it willy-nilly because you might end up feeling daft

18:17-18:21
with a patient who needs a general anesthetic halfway through an operation because you didn’t

18:21-18:27
think ahead. So the things that really jump out to my mind is that you should make sure that you have

18:27-18:33
a surgeon who gets on with it and doesn’t get trapped within decision. You need to make sure

18:33-18:40
that the patient is relatively calm and easygoing and if you were to need to convert to a general

18:40-18:44
anaesthetic, you could manage them without lots of panic and stress. You should make sure that the

18:44-18:50
surgical procedure itself is a simple one, i.e. not a tricky hernia, not a hernia that was incarcerated

18:50-18:56
now is incarcerated, etc etc, because you don’t want the surgeon to find it more challenging. So it

18:56-19:01
needs to be like a routine simple operation. And then you also need to be assured that the theatre

19:01-19:06
team is slick and that everyone’s aware that you’re using a shorter acting spinal agent because

19:06-19:11
bupivacaine lasts quite a hecking while, which means that there’s a lot of room and margin for

19:11-19:17
error. So why are we thinking about using prilocaine? Because in day surgery, you can turn patients over

19:17-19:24
faster. They get a return of motor function faster and they can be discharged sooner. Just to give you

19:24-19:30
a bit of a gist about the differences between prilocaine and bupivacaine, there’s a cohort study

19:30-19:38
looking at 60 milligrams, i.e. 3 mls of prilocaine versus 12.5 milligrams, i.e. a 2.5 ml dose of

19:38-19:44
bupivacaine. Both had additional sufentanyl and morphine in because these were for elective

19:44-19:50
cesarean sections. When we’re looking at time to return of motor block in prilocaine versus

19:50-19:58
bupivacaine, prilocaine was 158 minutes, whereas bupivacaine was 220 minutes. So that’s 40 minutes

19:58-20:03
less before they can move their legs again. Now this was in France so I don’t quite know what

20:03-20:11
their recovery discharge criteria are but it was 135 minutes versus 180 minutes of PACU slash

20:11-20:16
recovery time but three hours in recovery seems excessive. Now the real information that we’re

20:16-20:20
actually curious in is the time to urination when we’re thinking about day surgery and that’s because

20:21-20:27
most day surgery units use patient being able to urinate as a discharge criteria and this is the

20:27-20:32
that seems to be the last to return. Although a few places discharge patients even if they haven’t

20:32-20:38
peed but they have quite robust return to hospital criteria and they safety net quite heavily. Now I

20:38-20:42
couldn’t find any robust evidence to really make a decent comparison between prilocaine and

20:42-20:47
bupivacaine for time to urination although I’m sure it may exist. If anyone can find that or

20:47-20:52
knows anything about that please drop me a message or an email and maybe we can add something on.

20:52-20:56
So we’ve covered quite a lot there. We’ve explored prilocaine and touched on

20:57-21:04
2-chloroprocaine, i.e. Ampres, remembering that prilocaine is an amide, whereas Ampres is an

21:05-21:11
ester. We’ve touched on TNS, transient neurological symptoms, something that can happen after spinal

21:11-21:17
anaesthetics and is starkly more common with lidocaine, particularly hyperbaric lidocaine,

21:17-21:25
which is what they were using, and started to consider approaches to patient selection for

21:25-21:32
spinal anaesthesia in order to not end up in a pickle feeling very daft and having to do a

21:32-21:36
general anaesthetic halfway through a procedure, which is far harder than doing it at the start.

21:38-21:41
Anyway, folks, thank you very much for listening. I hope you have a lovely week,

21:41-21:47
and I’ll see you next week for… Oh, would you look at that lidocaine, how organised of me.

21:49-21:52
Thanks for listening, guys. I hope you found it useful, but if you found it awful,

21:52-21:57
do let me know. Please like and subscribe, register with whichever podcast platform you find yourself

21:58-22:02
using, and leave a comment if you think I need to square something away. I just want to make sure

22:02-22:06
that you guys know that every day you are getting better at this. There is a bucket of content to

22:06-22:11
try and consume, and it is like drinking from a fire hose. Take it day by day, don’t overcook

22:11-22:13
yourself, don’t freak out, and keep studying.