Ep37.1 –Comparing Local Anaesthetics For The FRCA Primary

GasGasGas – The FRCA Primary Anaesthetics Exam Podcast

Drug Classification Overview

All local anaesthetic agents have some similarities and some differences. The similarities, they all have a lipophilic aromatic ring aka a benzene ring. This offers up reasonably good lipid solubility for local anaesthetic agents and you’ll find that on one side of the local anaesthetic molecule. On the other side of the local anaesthetic molecule you will find an amine group and this is the bit that does more of the local anaesthetic side of things

Memory Aid for Classification

A cheeky trick, if you’re not sure, in an exam which is which, is that cocaine, tetracaine, and procaine all have one I, one letter I in them, whereas bupivacaine, levobupivacaine, lidocaine, ropivacaine, prilocaine, two i’s therefore must be an amide

Amide Local Anaesthetics (2 i’s):

• Bupivacaine
• Levobupivacaine
• Lidocaine
• Ropivacaine
• Prilocaine

⠀Ester Local Anaesthetics (1 i):

• Cocaine
• Amethocaine (Tetracaine)
• Procaine

Comprehensive Pharmacological Comparison

Basic Properties Table

Drug	Class	pKa	% Unionised at pH 7.4	Protein Binding	Molecular Weight
Bupivacaine	Amide	8.1	15%	95%	288 g/mol
Levobupiv..	Amide	8.1	15%	95%	Same as bupivacaine
Lidocaine	Amide	7.7	25%	64-70%	234 g/mol
Ropivacaine	Amide	8.1	15%	94%	274 g/mol
Prilocaine	Amide	7.7-7.9	33%	55%	220 g/mol
Cocaine	Ester	8.6	6%	95%	311 g/mol
Ampres	Ester	8.7		‘lowest’ fractions	270g/mol

Clinical Characteristics Table

Drug	Onset Time	Duration	Maximum Dose	Special Features
Bupivacaine	10-20 min	5-16 hours	2 mg/kg	Highly cardiotoxic – respect the dosing limits
Levobupivacaine	Similar to bupivacaine	Similar to bupivacaine	2 mg/kg (some say 2.5 mg/kg)	Less cardiotoxic – safer choice
Lidocaine	20-30 seconds (skin), 3-5 min (nerve)	90min-3hrs (plain), 4-5hrs (with adrenaline)	3 mg/kg (7 mg/kg with adrenaline)	Avoid for spinal anaesthesia – TNS risk up to 33%
Ropivacaine	Sensory: similar to bupivacaine, Motor: slower	Sensory: similar to bupivacaine, Motor: faster recovery	3 mg/kg	Differential blockade – less motor block relative to sensory block
Prilocaine	Fast (33% unionised)	1.5x lidocaine duration	6 mg/kg	Risk of methaemoglobinaemia at >600mg
Cocaine	Intranasal: 5 min	Intranasal: 60-90 min	1.5 mg/kg topically	Dual mechanism: local anaesthetic AND sympathomimetic

Mechanism of Action Comparison

All local anaesthetics share the same basic mechanism: Unionised fraction crosses nerve membrane → Re-equilibration occurs inside the nerve → Ionised fraction blocks sodium channels → Use-dependent block – higher affinity for open channels

Key Differences:

• Cocaine: Central monoamine reuptake inhibition by blocking post synaptic reuptake protein transporters causing increased concentrations of monamines – Dopamine/noradrenaline/adrenaline/serotonin concentrations in synaptic clefts
• Ropivacaine: Preferential sensory blockade
• Lidocaine: Also acts as Class 1b antiarrhythmic

Side Effects & Toxicity Comparison 

Cardiovascular Toxicity (Most to Least Cardiotoxic)

1. Bupivacaine – Highly arrhythmogenic, prolongs PR, QRS intervals and QT
2. Lidocaine – Moderate cardiotoxicity
3. Ropivacaine – Less cardiotoxic than bupivacaine
4. Levobupivacaine – Reduced cardiotoxicity – the major selling point
5. Prilocaine – Least cardiotoxic

Dont forget that Cocaine is bad for your health- Tachycardia, Hypertension, Myocardial ischaemia secondary to coronary vasospasm. can have a rip roaring MI due to it.

Unique Side Effects

Drug	Specific Toxicity	Treatment
Prilocaine	Methaemoglobinaemia (O-toluidine metabolite)	Methylene blue 1-2mg/kg IV
Cocaine	Serotonin Syndrome, Euphoria, Psychosis	Benzodiazepines first line for everything except cardiac arrest (then add bicarbonate)

Clinical Applications Table

Application	First Choice	Alternative	Avoid
Spinal Anaesthesia	Bupivacaine/Levobupivacaine	Prilocaine (day surgery), Ropivacaine if your in Europe!	Lidocaine (TNS risk 82-90% higher than alternatives) (cocaine…)
Epidural Anaesthesia	Levobupivacaine	Bupivacaine, Lidocaine (top-ups) (some places use ampres for uber fast onset obstetric epidurals
Infiltration	Lidocaine	Prilocaine
Topical (Airway)	Lidocaine	Cocaine (ENT mostly)
Regional Blocks	Levobupivacaine	Bupivacaine, Ropivacaine	Lidocaine if youre sewing someone up in ED quickly

Special Clinical Scenarios

Day Surgery Spinals

Prilocaine offers significant advantages over bupivacaine in terms of recovery profile. Using data from studies comparing 60mg prilocaine versus 12.5mg bupivacaine for day surgery: prilocaine showed faster recovery with motor block

Prilocaine Dosing for Day Surgery:

• Saddle block: 10-20mg (0.5-1ml)
• Above T10: 60mg (3ml)
• Below T10, >1 hour: 40-60mg (2-3ml)
• Below T10, <1 hour: Consider 2-chloroprocaine

ENT Surgery

Cocaine is still used a lot in ENT surgery because of its potent vasoconstricting effects that really do open up the nasal cavity and allow the surgeon to get in there without scraping along too much mucosa

Motor-Sparing Blocks

Ropivacaine demonstrates differential blockade – sensory block onset similar to bupivacaine, whereas motor blockade takes longer to develop and recovers more quickly

Absorption Hierarchy (All Drugs)

Remember: “ICEBS” – Intercostal (highest absorption) > Caudal > Epidural > Brachial plexus > Subcutaneous (lowest absorption)

Emergency Management

Local Anaesthetic Systemic Toxicity (LAST) Recognition: Early: Tinnitus, metallic taste, circumoral tingling → Moderate: Sensory disturbances, excitation/agitation → Severe: Seizures, coma, respiratory depression

Treatment:

• ABC approach + ALS protocols
• Intralipid 20%: 1.5ml/kg bolus, then 15ml/kg/hr infusion + 2 further bolues at 5 and 10 mins

Mechanism:

• If you’ve a revolver to your head blurt out sodium channel blockade at secondary sites CNS/Myocardium.
• I would be surprised if they want more after that – but then feel free to wax lyrical on K channels, and oxidative phosphorylation impairment.
• Rember Intralipid works by speeding up re-distribution via a shuttling effect courtesy of the lipid molecules

Drug-Specific Emergencies

• Cocaine toxicity: Benzodiazepines are first-line for most complications
• Prilocaine methaemoglobinaemia: Methylene blue 1-2mg/kg over 5 minutes (makes their urine green for days)

Key Clinical Pearls

Onset Speed: Lower pKa = more unionized molecules = faster onset

Duration: High protein binding = longer duration

Safety: Levobupivacaine is safer – less cardiotoxic, preferred choice

TNS Avoidance: 82-90% reduction in TNS when any other LA used instead of lidocaine

Mixing Drugs: Don’t mix lidocaine with bupivacaine – it doesn’t work as intended

Contraindications Summary

Drug	Specific Contraindications
All LAs	Known allergy, infection at injection site – esters more likely to irritate
Cocaine	IHD/Vascular disease, Uncontrolled Hypertension, Porphyria
Prilocaine	G6PD deficiency, Neonates (reduced methaemoglobin reductase), Concurrent oxidising drugs
Lidocaine	Spinal anaesthesia (TNS risk)

Future Considerations

IV Lidocaine Infusions: Current status: Controversial – evidence shows heterogeneity with unclear distinct benefit, check out the lidocaine episode

Supply Chain: Ropivacaine gained prominence during levobupivacaine shortages, highlighting the importance of understanding alternative agents

Conclusion

Understanding the pharmacological differences between local anaesthetic agents is crucial for safe clinical practice. While all share the basic mechanism of sodium channel blockade, their unique properties – from onset times and duration to specific toxicities – make each suited to particular clinical scenarios. The key is matching the right drug to the right patient and procedure while always respecting maximum doses and understanding emergency management protocols.

LA infusions in those with knackered livers should be thought about extra hard. 

Always double check your drug concentrations!

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Transcript

Gas Gas Gas – Local Anaesthetics Compare and Contrast Part 1

Episode Introduction

00:35-01:50

Hello, everyone. This is James at Gas Gas Gas, welcome to episode 37. Today we are summarising all our local anaesthetic studying that we’ve thus done and then exploring some questions that might come up in the exam.

I’ve got to stress that local anaesthetics are ubiquitous – ubiquitous in our practice from simple cannulation and sticking arterial lines in to spinal anaesthesia and emergency epidural top-ups on Labour Ward for Category One sections. Now, is it a Category One section if it can wait for an epidural to top up? That’s a question for another time.

Anyway, today, this episode, episode 37, is going to explore and summarise everything we’ve done thus far on local anaesthetics and then smash through some questions. Now, questions, I’m going to actually try and get you to think of some answers instead of just telling you everything. So, I’m going to pose a question, gonna give you 15 seconds or so, and then give you the bullet pointy topics that should be covered. Hopefully, those things match up, and then you’ll gain a bit more from it than just hearing the sound of my delightful voice.

So I’ve got a new catchphrase today, which is if you think the podcast is great, then please donate. Very much appreciate you helping keeping the lights on. I really do hope you’ve enjoyed these local anaesthetic episodes. It’s certainly been great revision for me as well. Anyhow, let’s get on with it.

Fundamental Classification

01:50-03:03

So, when approaching any sort of question, the phrase “classify or die” will get your mouth producing some sounds that hopefully make a modicum of sense to an examiner whilst you think about the topic to address.

For local anaesthetic agents, the classification is ester or amide, and that is specific to the linkage between the two ends of the molecule. There is a lipophilic end, which is a benzene ring, and then a hydrophilic end, which is an amine group. These are either bound by an ester linkage or an amide linkage. This linkage also dictates how that molecule is metabolised.

We know that esters typically get smashed to bits by plasma and tissue esterases. So, their clearance is quite rapid, whereas the amide agents have to be tidied up by the liver. So, that means they’ve got to be lifted from where they are, transferred in the plasma, and then metabolised by the liver.

On earth, can you remember the differences in terms of names, like is cocaine an amide, etc.? So, very scientifically, if it has two i’s in the name, then it’s an amide, so lidocaine, two i’s, whereas cocaine has one i, so it’s an ester local anaesthetic. It makes sense even if it has no scientific basis in reality. Utilise it.

Pharmacokinetic Comparison

03:04-04:21

So we then probably need to be thinking about how do we compare these agents. And there’s a number of different criteria that you could hold local anaesthetics against. So there’s onset times, their offset times, their pharmacokinetic data like pKa’s and protein bindings of these different agents or if they have any unusual side effects.

It’s probably absolutely worth having a table of pKa’s of all the main sort of drugs, like the hypnotic agents, the opiates, the local anaesthetics, etc. The main ones, so that you can weigh up which has a higher or lower pKa than the other, which certainly could come up in exams.

I’m going to run through that very briefly here for local anaesthetic agents. So you can lump bupivacaine, levobupivacaine, and ropivacaine together – pKa 8.1, 15% unionised at physiological pH. Everything else, there’s a greater available fraction. So lidocaine has a pKa 7.7, 25% unionised. Prilocaine, pKa 7.7-ish, apparently 33% unionised, whereas cocaine, pKa 8.6, so high, 6% unionised.

You either need to put these into Anki to study from a flashcard perspective, have it written on the wall in the bathroom, or just do something to memorise these. Come across someone who rote dogged it and recorded themselves in the car stating these out loud and they would just repeat the pKa’s as they drove to work. Desperate times, folks.

Protein Binding Data

04:21-05:02

So, protein binding, somewhat forgiving again in that bupivacaine, levobupivacaine, ropivacaine, and also cocaine can be lumped together at 95%. So, you could almost choose to learn that everything else is something, and then if you’re not sure what it is, it’s just probably 95%.

So, lidocaine, 64 to 70% protein bound. Prilocaine, 55% protein-bound. And if someone asks you about Amprez, the data is really thin on the internet about Amprez. It has been described as having the lowest fraction of protein-bound molecule, but don’t quote me on that.

Onset and Offset Comparisons

05:02-06:27

They then say, “oh, well, you know, compare and contrast the onset times of these local anaesthetic agents you’ve just mentioned, Doctor,” when you’ve gone and listed out bupivacaine and lidocaine, etc., as some drugs with names to the examiner. And that’s because some lumping in action can again occur.

So, bupivacaine, which is a racemic mixture, remember, levobupivacaine, which is the enantiomerically pure levo fraction of bupivacaine and ropivacaine will have a similar onset time, but note that ropivacaine seems to prefer causing a sensory blockade, and the motor onset takes quite a bit longer, whereas lidocaine and prilocaine are faster in onset.

Offset times, again, lumping in action. You can probably describe those first three offset at a similar time. You will regain motor function more quickly relative to bupivacaine-like molecules, but prilocaine and lidocaine will be faster.

If given the opportunity, it might make your life easier to describe the onset and offsets of these agents in the intrathecal space, as opposed to trying to weigh everything, because then you can say, well, lidocaine isn’t classically used for intrathecal anaesthesia given its transient neurological symptoms problems, but we do know that it has a relatively fast offset of 90 minutes to three hours in peripheral tissues.

And then you can go on to say: prilocaine works quite quickly and wears off quite quickly. 2-chloroprocaine Amprez, even faster in onset and offset, and then ropivacaine, levobupivacaine, bupivacaine, all about the same-ish.

Mechanism of Action

06:27-07:11

How do local anaesthetic agents work? Now, I’ve described this in a multitude of ways, but I’m gonna just keep it simple again here, guys, because this is a summary.

They work by getting into the axoplasm, which is another word for the cytoplasm inside a neuron, and blocking sodium channels from the inside. To get there, the molecule has to be unionised. That’s why we’re so interested in the pKa’s. But for it to work, once it’s in that axoplasm, it has to be ionised again. It tends to bind with a positive molecule becoming a cation again and then blocking its way into that sodium channel.

But don’t worry, because I do have an excellent analogy for local anaesthetic systemic toxicity when you’ve just about lost your mind on this episode. It’ll be there, and it’s a strange one.

Additional Mechanisms and Uses

07:11-07:57

Now, you could also be asked about additional mechanisms of action or additional uses or sequelae of these local anaesthetic agents. Now the two real ones to talk about would be cocaine being a central monoamine reuptake inhibitor, so you’re going to end up with increased concentrations of monoamines in your synaptic cleft. Monoamines, folks: dopamine, noradrenaline, adrenaline, serotonin. That’s why people end up with those sympathetic symptoms and those euphoric “I’m king of the world!” sort of vibes, which really probably isn’t that useful in a patient in recovery. They think they’re king of the world, they might start being really rowdy.

Anyway, and then lidocaine, because remember, lidocaine can also be used as a class Ib anti-arrhythmic. Although obviously you have the CNS toxicity implications, which could come about. That’s why amiodarone is better.

Side Effect Profiles

07:57-08:38

If you were to be asked a bit more broadly, “would you compare and contrast the side effect profiles of these local anaesthetic agents?” you could consider mentioning a comparison of cardiotoxicity, so bupivacaine being perhaps the most cardiotoxic, levobupivacaine being the enantiomerically pure, safer agent of those two, ropivacaine being safer again, they might say.

“Oh which drugs cause methaemoglobinaemia doctor?” and you could say well prilocaine classically is described as causing methaemoglobinaemia noting that it’s found in EMLA cream and if too much is administered to a child they might experience it but also lidocaine has been implicated.

And then, naturally, you could talk about the side effect profile of cocaine again there.

Systemic Absorption Factors

08:38-09:18

Someone might ask you: “what influences the systemic absorption of these local anaesthetic agents?” And you could say, well, where you stick that local anaesthetic agent is probably the biggest influence. If it is an inadvertent IV injection, then your plasma concentration of anaesthetic agent is going to be very high.

The next highest place of absorption would be the intercostal space, followed by caudal injections of local anaesthesia, epidural injections, brachial plexus injections, and subcutaneous injections. The acronym here, ICEBS or intercostal caudal epidural brachial plexus subcutaneous, but it’s a crap acronym. So maybe think of something else. If you do have a good one, please email me. I’ll stick it on the show notes.

Local Anaesthetic Systemic Toxicity (LAST)

09:18-09:52

And then, you know, someone’s gonna maybe be tempted to ask you about local anaesthetic systemic toxicity. The signs of this: ringing in your ears, your mouth starts tingling, you might hear a metallic taste or you get pressure in your ears, and those are the initial sensory symptoms. You might get excited or agitated, have seizures and then coma and respiratory depression.

CVS symptoms, cardiovascular symptoms: you get brief hypertension that you’ll probably never notice. And then hypotension, contractility issues. Cardiac conduction defects, asystole, bradycardia, VF. Bad, bad, bad.

Treatment of LAST

09:52-10:02

How do you treat it? Well, you’re gonna declare the emergency, get a handbook, have an ABC approach, treat dysrhythmias in an ALS manner, and get your hands on Intralipid toot sweet.

The Boris Johnson Analogy for Intralipid

10:02-11:21

How does Intralipid work? I’ve discovered many things about Intralipid in the last episode, but now I feel like you could call a local anaesthetic agent the Boris Johnson of this situation.

So, Boris, he has two sides, he has a Jekyll and Hyde, he has the statesmanly quote Greco-Roman classical history sounding like an excellent orator, but perhaps having no substance. That’s local anaesthetic in a tissue that is ionised and not really doing very much.

And then you’ve got the unionised Boris Johnson fraction, and there’s less of this around, but when he gets carried away, he goes a bit mad and manages to get into places he shouldn’t. And this might be a nerve. But also tottering off into plasma and ionised fractions, manages are better at getting across other membranes, not just neuronal cell membranes. And piling off to cause havoc elsewhere.

So, in my mind, Rishi Sunak is Intralipid. Rishi Sunak comes along and he just gets in amongst there, kicks Boris Johnson out, takes his place, redistributes Boris Johnson out amongst the people. Boris Johnson is now on the conference circuit, but he can’t cause much mischief out there because he’s been shuttled away into talking to some rich people who are drinking port about something that doesn’t actually have any influence on the common person in this country. And Rishi Sunak has just been shuttling away, tidying up all the mess. Except for we know that actually the mess just continued and it perhaps now continues still.

Intralipid Dosing Protocol

11:21-11:45

Anyway, if you were treating Boris Johnson syndrome in your patient, Intralipid is the course of action, and you give them a 1.5mls per kilo bolus and then start a 15mls per kilo per hour infusion. At five and ten minutes of CPR, defibrillation, etc., you can give further boluses and you can double that infusion rate at any time after five minutes, I think it is. Check the handbook.

True Mechanism of LAST

11:45-12:03

The true mechanism of local anaesthetic toxicity, other than Boris Johnson causing havoc, is sodium channel blockade and probable potassium channel and calcium channel blockade in the myocardium, and then impairment of mitochondrial function and dysfunctional oxidative phosphorylation.

Key Clinical Pearls

12:03-12:40

So, key clinical pearls. Remember, guys, that pKa guides onset time of agent because the unionised fraction is the thing that dictates things getting to where they need to go to work – crossing cell membranes. Duration is chiefly influenced by the protein binding of that molecule. I try and imagine that there’s a reservoir of that molecule at the site. It doesn’t get pushed away and redistributed throughout the body quite so easily.

Transient neurological symptoms happen with lidocaine. That’s why we don’t use it intrathecally. We’ve got better drugs, and mixing drugs, i.e., lidocaine with bupivacaine, probably doesn’t make it work any better. In fact, it’s very unlikely to do so. But it sounds great if it would.

Conclusion and Clinical Applications

12:40-13:32

So in conclusion, understanding these pharmacological differences between local anaesthetic agents is A, important for clinical practice, B, allows you to tailor your drug choice to the patient and the surgical intent, and helps you just make sure you’re not missing something like accidentally giving a bulldose local anaesthetic infusion to someone with a really knackered liver, which you should think about extra hard before doing. And if you’ve got a really sick patient who’s falling in a heap and their local anaesthetic infusion from that laparotomy is still running perhaps stop it and always always always double check your drug concentrations.

Episode Transition

13:13-13:32

I’m going to split this episode into two parts published on the same day, purely because then you could think about doing these questions on the way home, having listened to the summary on the way to work, and that would be good for your learning. So, the sound engineer is going to cue the outro music, and I am going to see you in 10 to 12 hours, depending on how unfortunate you are today. See you later.