Ep.31 – Bupivacaine for the FRCA Primary Exam

GasGasGas – The FRCA Primary Anaesthetics Exam Podcast

The Local Anaesthetics Chapter:

Bupivacaine Classification

• Name: Bupivacaine
• Class: Amide Local Anaesthetic
• Molecular Weight: 288.43 g/mol

Appearance & Preparations

• Clear, colourless solution containing racemic mixture of R and S enantiomers
• Standard concentrations: 0.25%, 0.5%, sometimes 0.75%
• With adrenaline: 1 in 200,000 solution (improves surgical field, not block duration)
• Hyperbaric (Heavy): Mixed with 80mg/ml glucose for intrathecal use

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Pharmacodynamics of Bupivacaine

Mechanism of Action of Bupivacaine

Sodium Channel Blockade

Key Factors Affecting Action of Bupivacaine

• pKa influences onset: Lower pKa = more unionised fraction = faster onset
• Lipid solubility: Affects tissue penetration
• Protein binding: Higher binding = longer duration

Bupivacaine Specifics

• pKa: 8.1 (15% unionised at physiological pH)
• Protein binding: 95% (mainly to alpha-1 acid glycoprotein) but also albumin binding
• Highly lipophilic

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Action Potentials Compared

Neuronal Action Potential (4 Phases

• Phase 1: Initial sodium channel opening
• Phase 2: Depolarisation - widespread Na+ channel opening at -55mV threshold
• Phase 3: Repolarisation - Na+ channels close, K+ channels open
• Phase 4: Hyperpolarisation - overshoot before returning to resting potential

Key Difference: No plateau phase, rapid up-and-down pattern

Cardiac Action Potential (5 Phases)

• Phase 0: Initial depolarisation (Na+ in, K+ out). (WHERE BUPIVACAINE CAUSES SLOWER UP SLOPE)
• Phase 1: Brief rebound repolarisation (+52mV)
• Phase 2: Plateau phase - L-type Ca2+ channels open (unique to cardiac muscle)
• Phase 3: Repolarisation - Ca2+ channels close, K+ channels open
• Phase 4: Resting state (-96mV)

Key Difference: Plateau phase due to calcium influx - critical for sustained cardiac contraction

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Clinical Uses of Bupivacaine

• Post-operative pain control (TAP blocks, wound infiltration and all the regional varieties that you may do pre as well as post op)
• Intra-operative anaesthesia (spinal, epidural)
• Regional blockade (limb blocks, trauma pain relief)
• Neuraxial anaesthesia (labour epidurals, caesarean sections)

Dosing Guidelines

Route	Maximum Dose	Notes
Intrathecal	Up to 15mg (3ml of 0.5%)	Higher doses used for bilateral surgery in US
Epidural	2mg/kg	Dilute infusions (0.1%) for motor-sparing blocks, especially levobupivacaine
Infiltration	2mg/kg	Wound infiltration, rectus sheath blocks
Regional	2mg/kg	Brachial plexus, peripheral nerve blocks

Onset time: 10-20 minutes (warn patients!) Duration: 5-16 hours

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The Mixing Dilemma

Why Lidocaine + Bupivacaine Doesn't Work

Many attempt to mix fast-acting lidocaine with long-acting bupivacaine, but this fails on two counts:

1. Dilution effect: 1ml 2% lidocaine + 1ml 0.5% bupivacaine = 2ml of 1% lidocaine + 0.25% bupivacaine
2. pH incompatibility: Lidocaine's acidic pH shifts environment away from bupivacaine's preferred alkaline conditions

Bottom line: Don't mix them!

Successful Additives for Bupivacaine

Additive	Compatibility	Effect	Evidence
Bicarbonate	❌ Precipitates with bupivacaine	'would' cause Faster onset	Use with lidocaine only
Clonidine	✅ Compatible	May prolong block	Mixed evidence
Dexmedetomidine	⚠️ Technically incompatible	Extends duration	Some positive studies
Steroids	✅ Good evidence	Prolongs effect	IV route may be equally effective
Ketamine	⚠️ Potential neurotoxicity	Some analgesia benefit	Concerns about nerve damage

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Side Effects & Toxicity of Bupivacaine

Cardiovascular Toxicity - Bupivacaine has particular affinity for cardiac tissues:

• Blocks cardiac sodium channels (impairs phase 0)
• Reduces peripheral vascular resistance
• Decreases myocardial contractility
• Highly arrhythmogenic
• Prolongs PR, QRS intervals and QT

CNS Toxicity of Bupivacaine

Progressive symptoms based on plasma concentration:

• Early: Tinnitus, metallic taste, circumoral tingling
• Moderate: Sensory disturbances, excitation/agitation
• Severe: Seizures, coma, respiratory depression

Toxic Dose of Bupivacaine

>2mg/kg Ideal Body Weight - but this is infiltrative safe dose, NOT intravenous safe dose!

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Pharmacokinetics of Bupivacaine

Absorption

Varies dramatically by injection site - in most to least absorbed: Intercostal > Caudal >Epidural > Brachial plexus > Subcutaneous

Note: Vasoconstrictors don't significantly help with bupivacaine due to its inherent vasodilatory effect.

Distribution & Elimination

• Volume of distribution: 21-103 litres
• Clearance: 0.47 L/min
• Elimination half-life: 20-40 minutes (IV)
• Metabolism: Hepatic N-dealkylation to inactive pipecoloxylide

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Levobupivacaine (Chirocaine)

Why the S-Enantiomer?

Levobupivacaine is the S-enantiomer of the racemic bupivacaine mixture, offering several advantages:

Key Differences

• Reduced cardiotoxicity - the major selling point
• Less motor block at low concentrations
• Preferential sensory blockade
• Slightly less potent than racemic mixture

Dosing

• Maximum single dose: 150mg
• 24-hour maximum: 400mg
• Weight-based: Some Folk go to 2.5mg/kg (vs 2mg/kg for standard bupivacaine)
  • in the exam, stick with 2mg/kg as it is safe to say so.

Clinical Preference

The reduced cardiotoxicity makes levobupivacaine the preferred choice - CNS toxicity (generally temporary) is more manageable than cardiac toxicity (potentially fatal).

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Key Takeaways for Bupivacaine Know how

1. Bupivacaine is highly cardiotoxic - respect the dosing limits
2. Don't mix with lidocaine - it doesn't work as intended
3. Warn patients about onset time - 10-20 minutes to avoid looking "daft"
4. Levobupivacaine is safer - less cardiotoxic, preferred choice
5. Understand action potentials - cardiac has plateau phase, neuronal doesn't
6. Additives have mixed evidence - steroids show most promise

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Cross-References to Other Gas, Gas, Gas Episodes

• Local Anaesthetics Introduction- An excellent primer!
• Episode 2 - Propofol - Understanding pKa and pharmacokinetic principles
• TIVA Models for Propofol - Polycompartmental models referenced in this episode
• Episode 7 - Compartmentalised Volatiles - Compartmental thinking for drug kinetics
• Rocuronium Episode - First episode covering drug classification approach

Essential References

Primary Literature

• Nestor et al. "Pharmacological and clinical implications of local anaesthetic mixtures: a narrative review." Anaesthesia 2022. DOI: 10.1111/anae.15641 - The definitive review on why mixing local anaesthetics doesn't work
• Christie et al. "Local anaesthetic systemic toxicity." BJA Education 2015. DOI: 10.1093/bjaceaccp/mku027 - Comprehensive LAST review

Cardiotoxicity & Levobupivacaine

• Bardsley et al. "A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine." British Journal of Anaesthesia 2001. PMC1873676 - Human volunteer study showing reduced cardiotoxicity
• Morrison et al. "Electrocardiographic cardiotoxic effects of racemic bupivacaine, levobupivacaine, and ropivacaine." Anesthesia & Analgesia 2000. PMID: 10825312 - Animal model comparing cardiotoxicity
• Whiteside & Wildsmith. "Developments in local anaesthetic drugs." BJA 2001. DOI: 10.1093/bja/87.1.27 - Historical development of safer local anaesthetics

Guidelines & Safety

• AAGBI Safety Guideline: "Management of Severe Local Anaesthetic Toxicity" 2010. Available online - Essential emergency management
• Local anaesthetic systemic toxicity: Current perspectives. PMC 2018. PMC6087022 - Modern understanding of LAST mechanisms

Pediatric Considerations

• Chalkiadis et al. "Pharmacokinetics of levobupivacaine 0.25% following caudal administration in children." BJA2004. DOI: 10.1093/bja/aeh017 - Important pediatric dosing considerations

Pivotal Mallard Duck Paper

• Brenner DJ, Larsen RS, Dickinson PJ, Wack RF, Williams DC, Pascoe PJ. Development of an avian brachial plexus nerve block technique for perioperative analgesia in mallard ducks (Anas platyrhynchos). J Avian Med Surg. 2010 Mar;24(1):24-34. doi: 10.1647/1082-6742-24.1.24. PMID: 20496603.

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Episode length: ~24 minutes Release: Gas, Gas, Gas Podcast Host: James

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Transcript

Episode 31: Bupivacaine and Friends - Consolidated Transcript

Introduction and Welcome

00:00-01:25

Please listen carefully and let's get on with the show. Hi everyone, this is James at Gas, Gas, Gas. Today we are getting stuck into bupivacaine, thinking about friends that you might mix with bupivacaine, going to touch on action potentials in cardiac and neuronal tissues, break down all the additives that you might want to introduce alongside your local anaesthetic agent, and then touch on levobupivacaine, why it's different, why we seem to like it.

Since the last episode, I have managed to set up a donation system that's using PayPal. If you think you want to support the show, there's a link in the show notes for it. Any sort of donation is appreciated. Or if you don't fancy that, just leave me a review. Tell me if you like it or not, because that'll keep me going. Because sometimes it does sound and feel like you're sort of shouting into the ether. Although I know the stats for the podcast are always on the upward trend, it always helps to know if I can do anything better. Anyway, on to bupivacaine.

Bupivacaine Overview and Preparations

01:26-02:26

This is a local anaesthetic agent, but it's an amide local anaesthetic agent. We touched on it in the introduction episode. Remember, the other local anaesthetic agent is esters. It's a clear colourless solution, and it contains a racemic mixture of R and S enantiomers of bupivacaine.

Classically, it is provided in concentrations of 0.25% and 0.5% solution, although there are 0.75% preparations as well. There are a number of preparations also combined with adrenaline in a 1 in 200,000 solution, noting that this doesn't improve the length of block, but improves the surgical field for the surgeons, so there's less blood sloshing around. Bupivacaine is also supplied as a hyperbaric mixture, aka heavy bupivacaine, and this is mixed with 80 milligrams per ml of glucose, creating that higher specific gravity that means that we can manipulate how local anaesthetic works in people's CSF spaces. Its molecular weight for those who are deeply excited by such a thing is 288 grams per mole.

Pharmacodynamics and Mechanism of Action

02:38-04:00

Pharmacodynamics of bupivacaine. It works by sodium channel blockade. Let's remember that there are sodium channels in a number of places in the human. We're interested in the sodium channels you will find on neuronal membranes, at least initially. But first, let's think about the details of this mechanism.

We know that the pKa influences onset time because the unionised fraction is the one we're interested in when it comes to drug getting in the right place to work. We also know that its lipid solubility plays a role in this and let's recall that protein binding plays a role in how prolonged the action of the local anaesthetic is. The more protein bound generally the longer it lasts. We need to bear in mind that this unionised fraction gets into the nerve but then it's going to re-dissociate because everything is in a dynamic equilibrium. It's the ionised fraction of the re-dissociated molecule that's got into the nerve that is the one that actually does the sodium channel blockade.

You can imagine that the amount of agent you give, the amount that actually makes it to the effect site is quite a small fraction and we know that this plays out in most drugs we administer to humans. Go back and listen to any of those other episodes if you don't have a clue what I'm on about, maybe start with the polycompartmental model episodes or the TCI propofol episode.

Sodium Channels and States

04:00-05:06

Let's focus back in on local anaesthetics and this sodium channel they act on. This sodium channel, you'll find it in your neuron, generally speaking in those nodes of Ranvier, and it has three states, two natural human-y type states, i.e. open, it's letting sodium in, or closed, it's not letting sodium in, but then also a local anaesthetic bound state, because we know that if you have a protein and then you stick something to that protein, it causes a conformational change to that thing. That's why all these drugs have influences on all these proteins, protein coupled receptors, channels, tyrosine kinase receptors, etc. Something binds to something changing the shape of the thing and altering its activity.

Now interestingly local anaesthetic agents prefer the open state i.e. that open state enables a higher affinity of local anaesthetic to sodium channel. This is called use dependent or phasic block if you want to apply a buzzword to it.

Neuronal Action Potentials (Four Phases)

05:06-06:58

Before I get back into the depths of bupivacaine let's just quickly touch on these neuronal action potential phases because we're going to do it properly in perhaps three and a half decades when we finally get onto physiology. The curriculum is massive, but remember this is something you might be asked to draw in the exam.

For a neuron, i.e. a nerve that is conducting something in your peripheral nervous system, there are four phases and the graph is a graph of a line running at a sort of basal electronegative state with then a rapid upshoot and then a rapid down shoot. There's no middle ground, there's no plateau phase in a nerve action potential.

When your action potential comes along, some voltage-gated sodium channels open, because naturally there has to be a degree of conduction at this point in time. However, once a sufficient number of voltage-gated sodium channels open, you hit a shift in your neuronal electronegativity, deflecting back towards positive, i.e. when you hit about minus 55 millivolts, you trigger widespread voltage-gated channel opening. Loads of sodium pours into the cell. Remember that there's lots of sodium outside of a cell, not much in. There's loads of potassium inside a cell and there's not much out. All that sodium piles in and the neuronal membrane becomes positive.

These sodium channels don't stay open forever. However, once you hit that positive state, voltage-gated potassium channels trigger open, allowing efflux of potassium, triggering a repolarisation of that nerve into the world of electronegativity. Interestingly nerves of the peripheral nervous system overshoot their electronegativity as they repolarise. They dip down a little bit more negative than they otherwise would rest at before returning to that resting negative neuronal potential waiting for a new action potential to flow along. Four phases one two three and four, no plateau.

Clinical Uses of Bupivacaine

07:04-08:03

Back to bupivacaine what do we use bupivacaine for? I'm sure you're all thinking this is daft, but you might get asked it in the exam. It is used for post-operative pain control when you've administered a block at the end of surgery, i.e. you've done a TAP block, or the surgeons have done an iliohypogastric block for an inguinal hernia. You could utilise it for intra-operative pain control. This is the realms of your spinal anaesthetic, or you're thinking you want to actually cover the operative intervention with some form of local anaesthesia, a spinal and GA for example.

And then regional blockade either to facilitate surgery upper limb blocks lower limb blocks or regional blockade following traumatic injury. I think we're ending up using erector spinae plane blocks and serratus anterior blocks and paravertebral blocks much more frequently to provide pain control. You could break this down further into anaesthesia that achieves sensory blockade or sensory and motor blockade because we like to differentiate some limb blocks as motor sparing, which the orthopaedic surgeons love for their knee replacements. But that's more detail than we're going into today.

Dosing Guidelines

08:04-10:01

Dosing, how do we dose bupivacaine? It depends where you're putting it. Because you could, in theory, do two milligrams per kilo intrathecally. That isn't a toxic dose from the perspective of local anaesthetic toxicity, but you would have a total spinal and a very cardiovascularly unstable patient. Generally speaking, most people go up to 15 milligrams of intrathecal bupivacaine, i.e. 3 ml of 0.5%. You can go quite low and sometimes people go a tad higher. I do know, having had a nosy about this for bilateral hip or knee replacements, which they do in some sites in the United States, they put quite a bit more. They're going to do both hips at once. Not something that tends to happen so much in the UK.

Other routes. Remember we have intrathecal, we have epidural, and in this site you can go up to two milligrams per kilo. Infiltration, again two milligrams per kilo. That's injecting your caesarean section incision site at the end of a case or rectus sheath catheters. Topical, I don't really know how much topical bupivacaine anyone's using. If people are, let me know. And intravenous dosing. We don't tend to do that. You can use other local anaesthetics in intravenous manner, lidocaine and prilocaine in Bier's blocks, if I remember correctly. And I did because I've just checked. Can you put it intra-arterially? No, it's going to be just as toxic. It's just going to take slightly longer to work. And what I mean by work is slightly longer to cause a local anaesthetic toxicity disaster. You might get a slightly mixed picture if you were to inject that into carotid because you're going to get CNS symptoms very quickly and then cardiac symptoms a bit later because it's got to go all through the brain and back down.

Onset Time and Duration

10:01-11:03

We've mentioned toxicity quite a few times here. The toxic dose of bupivacaine is two milligrams per kilo. Now is that if you stick two milligrams per kilo into someone's vein you will get away with it? And the answer is no you won't. Two milligrams per kilo is your infiltrative safe dose. Bearing in mind we all know that local anaesthetic uptake differs depending on the site you've injected it in. Mentioned that in the previous episode, you can go back and have a listen. But now we're thinking we've chucked this dose of bupivacaine in around someone's brachial plexus. How long does it take to work? I would generally quote patients 10 to 20 minutes, but sometimes it can be even longer than that. Axillary blocks seem to take ages to work.

Now, if you've sold a regional anaesthetic to a patient with excellent skill, having balanced their risks and benefits and consented them appropriately, but then you forgot to tell them it takes a while, you've stuck that injection in, and then you've started pottering around and doing other things, and then looking at you with raised eyebrows, you've lost your patient a little bit there. Open the door with how long it takes to work, but then, you know, it does last for up to 16 hours, and sometimes a bit longer with additives.

Local Anaesthetic Mixtures and pH Issues

11:03-12:24

You might have seen some folk mixing drugs together. Wouldn't it be dandy if we could use a local anaesthetic that acts really quickly, and then mix it with one that takes longer to work, but lasts longer so that you get the best of both worlds fast acting and lasts a while unfortunately it doesn't quite 100% work like that say we take lidocaine and mix it with bupivacaine seems like a great idea we've taken one ml of two percent lidocaine and we've mixed it with one ml of 0.5 percent bupivacaine what this actually ends up giving you is a two millilitre mixture that is itself one percent lidocaine and 0.25 percent bupivacaine and you're probably thinking right now, well that's not the end of the world is it? And technically no, but there's another complicating factor here in that the pH of lidocaine in its natural form is different to that of bupivacaine. And herein lies an issue.

Now we're going to touch on bupivacaine pKa in a minute, but the pKa is 8.1 and it is 15% unionised, whereas lidocaine 7.7, 25% unionised. However, the pH of lidocaine is more acidic than the pH of the good old-fashioned ampoule of bupivacaine. Actually you create a more acidic environment for the bupivacaine to work. And as we all know, bupivacaine wants to be more alkaline. Therefore, you actually impair the function of your long acting agent. It fails on two counts of physicochemical reality. You just don't do it.

Additives and Bicarbonate

12:24-13:31

Now, there's a great paper that I'm going to link in the show notes that explores pharmacological and clinical implications of local anaesthetic mixtures. And it's a narrative review and it's really good. I would thoroughly recommend reading that. But you might have heard about mixing bicarbonate in with things. You know, you've got that bum abscess, it's grotty, it's angry, it's inflamed, the tissues are acidic around it, the local anaesthetics just barely work. Wouldn't it be dandy if we could make it more alkaline with bicarbonate? And the answer is yes you can. If you mix in bicarbonate you achieve a more alkaline environment and therefore improved onset time.

Again we hit another barrier here though in that unfortunately bupivacaine, levobupivacaine and ropivacaine have a tendency to precipitate when mixed with bicarbonate, so that's kind of in the bin. However, lidocaine behaves and therefore that is an option, mix your lidocaine with bicarbonate. It's approximately 1 ml of 8.4% sodium bicarbonate per 10 ml of local anaesthetic. Some sites use a lidocaine bicarbonate mix for rapid onset of surgical anaesthesia via the epidural route in caesarean sections. You bang it in and it works real quick.

Other Additives

13:31-14:54

There are a number of other additives that are used, were used, could be used more in the future. Noting that you could mix clonidine in, that's compatible with lidocaine and bupivacaine. The evidence is mixed, but it may improve block duration. And again, dexmedetomidine, this is technically not compatible, but seemingly folks do use it. And that appears to extend block effect in some studies far. Ketamine has been used, and it has a positive effect. Ketamine in itself has some local anaesthetic-like sodium channel blocking properties. However, there is some evidence that it is injurious to those nerves and the CNS.

There's a degree of evidence that says that magnesium prolongs regional anaesthetic blockade. You just need to make sure you don't accidentally put a humongous amount intrathecally. Apparently that's happened. Steroids. There's mounting evidence that either co-administered steroids or IV high-dose steroids prolongs the effect of your local anaesthetic on nerve, although it may actually be that intravenous steroids work just as well. With a lower risk factor, you're putting less next to very important nerve structures. Now, we know that opioids seem to improve the quality of neuraxial anaesthesia. I don't know about regional anaesthesia and if you stick some fentanyl in someone's interscalene, whether or not that has any value. Obviously, these nerves have opiate receptors, but I wonder if anyone knows that, please drop me an email.

Side Effects and Toxicity

15:01-16:32

We've dipped quite deep into pharmacodynamics there before we've even got to side effects. These drugs do have a side effect profile, chiefly ones arising from toxicity, we know they're toxic. Bupivacaine tends to favour the cardiovascular system, binding to myocardial proteins and blocking cardiac sodium channels. This impairs the phase zero of the cardiac action potential, and we're going to touch on that in a second, but also can drop your peripheral vascular resistance or your systemic vascular resistance, as well as dropping your contractility and being arrhythmogenic.

From a neuro perspective, we have sodium channels in our brains, unsurprisingly, everyone. You get a spectrum of effect here depending on how much agent has been absorbed and delivered to the brain. These could come on very quickly if you've accidentally squirted some into a vein and over a prolonged period of time if you've inadvertently overdosed someone in a highly vascular bit of tissue. Early signs, patients get some slightly excitatory effects. They get sensory disturbances like tinnitus, altered taste sensation, metallic taste in mouth, circumoral tingling. They can then progress on to seizure activity and coma. Now you could perhaps make an argument that if someone's in a coma due to local anaesthetics, then maybe they're going to not breathe very much. It's not really quite a side effect in some ways. And as I understand, there are no real quoted GI, renal, metabolic or endocrine side effects of local anaesthetics that you're going to be asked about in the exam. It's all about the toxicity.

Cardiac Action Potentials (Five Phases)

16:32-18:53

And we touched on the action potentials of nerves. I just want to quickly differentiate the action potentials you see in myocardium because this is something that interminably flummoxed me because it all sounds exactly the same and it's probably going to sound exactly the same to you but consider it cognitive priming. There are actually five phases of the cardiac action potential compared to a standard nerve with four. You have a phase zero and then a one, two, three and a four.

Now phase zero is the initial depolarisation, that uptick. You get sodium shifting in and potassium being able to shift out. There's phase one and this is a very small uptick at the top of this. If you imagine that initial depolarisation phase almost overshoots slightly. Phase one happens and there's a slight rebound repolarisation, i.e. a drop in the positivity of that cell, only slightly, and this is due to briefly opened potassium channels, letting some potassium out.

Then you have phase two. This is the phase that you don't see in other neuronal action potentials, and it is the plateau phase. This is facilitated by calcium channels, and these are L-type calcium channels. I don't know if the L stands for long, but they open, they let calcium into the cell. This calcium was obviously quite useful for sarcoplasmic reticulum to contract, but calcium influx provides a prolonged period of positive cell membrane compared to good old-fashioned nerve.

Phase three is our dip back towards electronegativity. Phase three is repolarisation. Calcium channels that have been open close. Potassium channels wide open here, allowing shift of potassium out of the cell, dropping it back towards electronegativity. And we get phase four, this is the resting state, which is confusing really, because I would say that the resting state should be like first thing but who knows anyway phase four resting state negative 90 millivolts and this is facilitated by those potassium channels being open and a loss of whatever sodium and calcium channels remain trying to be open they're gone five phases 0 1 2 3 4 2 is the plateau phase that's where you're getting all that calcium ingress courtesy of our L-type calcium channels let's remember that these L-type calcium channels are a drug target, folks. That's where your dihydropyridines and non-dihydropyridines come into play.

Pharmacokinetics

19:00-21:24

Right, quite a bit of talking thus far, but let's just touch on the pharmacokinetics of these drugs. Remember, pharmacokinetics is absorption, distribution, metabolism, and elimination. I mentioned earlier that the absorption behaviour of bupivacaine depends on where it is injected and the vascularity of that site. The range from most absorption to least absorption, we say intercostal most, then caudal, then epidural, and then brachial plexus, and then subcutaneous administration. There is a linear dose response relationship between peak plasma concentration you will see and the amount of drug you've put in.

Vasoconstrictors in the world of bupivacaine do not influence this terribly much because bupivacaine has a local vasodilatory effect, which is bothersome. It's probably that the surgeons stick adrenaline in to make themselves feel better and actually it probably doesn't change very much. This bears out in reality because we know it doesn't change how long the drug lasts for because the bupivacaine causes dilation which means there's clearance from that site. That same dilation is not altered by administering adrenaline. The time it lasts is the same therefore who really knows. But if it makes them happy it doesn't matter although you might see a little bit of that beta-1 beta-2 response that you get by administering adrenaline into subcutaneous tissues and you might get a bit of hypertension and then hypotension, very interesting.

Distribution. Its pKa as mentioned above is 8.1. At physiological pH you have 15% unionised. It is 95% protein bound which is mega and in plasma it is mostly bound to alpha-1 acid glycoprotein. It has a volume of distribution of 21 to 103 litres but I don't really think it is terribly relevant for this drug and it also binds to albumin.

Metabolism. How does the body get rid of it? Bupivacaine undergoes N-dealkylation, remember that's a phase one metabolism liver thing, into pipecoloxylidide. I don't think you need to know that, but it is inactive. It gets through the liver, phase one metabolism, N-dealkylation, inactive metabolite. Clearance of 0.47 litres per minute and the elimination half-life after intravenous administration is 0.3 to 0.6 hours, i.e. 20 to 40 minutes. It does get out reasonably quickly.

Allergies and Interesting Facts

21:24-22:08

Other things of note, remember that patients can be allergic to local anaesthetic agents, although classically more likely to be allergic to ester local anaesthetic agents than amide local anaesthetic agents. And interestingly, some vets administered up to 8 milligrams per kilo of bupivacaine when they were trying to do interscalene blocks on ducks, and none of the ducks died. However, we need to think that maybe it's quite hard to inject into the brachial plexus of a mallard duck. And maybe if they're squirting bupivacaine into a tendon or other fairly avascular structures, the odds are that it couldn't absorb quick enough to cause harm. Not that I'm recommending that as a dose, but I thought that was an interesting aside and reflects how easy it is to get very lost on the internet reading about things.

Levobupivacaine (Chirocaine)

22:10-24:04

Just to close out the show, guys, and I hope you've managed to get here thus far, levobupivacaine, otherwise known as chirocaine, and chiro because it's all about chiral molecules and enantiomers, which we're going to touch on later. Levobupivacaine is the S enantiomer of the racemic bupivacaine mixture. Why are we interested in levobupivacaine? Well, it does seem to cause a bit less of a motor block, interestingly. It seems to yield sensory blocks more, especially in lower doses. There is a notion that it is slightly less potent than its racemic mixture which might make you think that if you were to take the other enantiomer R-bupivacaine you might have a more potent local anaesthetic agent.

Why on earth did they bother trying to divvy this out and use one half of bupivacaine? And the answer is levobupivacaine is less cardiotoxic. If you were to pick which toxicity you would like, CNS toxicity, i.e. your brain turns off until you clear the local anaesthetic out, is probably less harmful than ventricular fibrillation. One, you just need to wait. The other one, you might not be able to undo. Hence why levobupivacaine is more readily favoured.

What is the dose? The max dose is generally quoted as 150 milligrams in one go with a total of 400 milligrams over 24 hours. This would work out at about 30 ml of 0.5% in an appropriately sized adult or about 200 ml of 0.5% over 24 hours. In some literature, the max dose of levobupivacaine is quoted as 2.5 milligrams per kilo instead of the 2 milligrams per kilo of standard bupivacaine. This is why it tends to be favoured. It really confused me when I first started. Which one's levo? Which one's bupivacaine? Which one's chirocaine? Which one's marcaine? Chirocaine is levobupivacaine. Standard bupivacaine is marcaine. Heavy marcaine is when it's mixed with glucose for intrathecal administration so it sinks down.

Closing Remarks

24:04-24:57

And that's your lot folks, you've listened to the end, you've done brilliantly well. That was bupivacaine with a touch on cardiac action potential, neuronal action potential and additives you could mix in and their approximate likelihood of having clinical benefit. I think the jury is approximately out on most of it, there's no robust consistent, everyone does one thing, I think I'd be tempted to say that steroids probably help and most other things might help but it's less clear at this point in time.

Thanks for listening guys, I hope you've 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 is 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 un modified Show Transcript - Courtesy of Whisper LLM

00:00-00:00
Please listen carefully.

00:30-00:31
and let's get on with the show.

00:35-00:37
Hi everyone, this is James at Gas, Gas, Gas.

00:38-00:40
Today we are getting stuck into bupivacaine,

00:41-00:44
thinking about friends that you might mix with bupivacaine,

00:44-00:48
going to touch on action potentials in cardiac and neuronal tissues,

00:49-00:52
break down all the additives that you might want to introduce

00:52-00:52
alongside

00:52-00:53
your

00:53-00:54
local anaesthetic agent,

00:54-00:58
and then touch on Levo bupivacaine, why it's different, why we seem to like it.

00:58-01:02
Since the last episode, I have managed to set up a donation system that's using PayPal.

01:03-01:05
If you think you want to support the show, there's a link in the show notes for it.

01:06-01:07
Any sort of donation is appreciated.

01:08-01:10
Or if you don't fancy that, just leave me a review.

01:10-01:13
Tell me if you like it or not, because that'll keep me going.

01:13-01:17
Because sometimes it does sound and feel like you're sort of shouting into the ether.

01:17-01:21
Although I know the stats for the podcast are always on the upward trend.

01:21-01:23
It always helps to know if I can do

01:23-01:23
anything better.

01:24-01:24
Anyway,

01:24-01:26
on to bupivocaine.

01:26-01:30
So this is a local anaesthetic agent, but it's an amide local anaesthetic agent.

01:31-01:32
We touched on it in the introduction episode.

01:32-01:35
Remember, the other local anaesthetic agent is esters.

01:35-01:38
So it's colour, its appearance, how you might want to introduce it.

01:38-01:47
So it's a clear colourless solution, and it contains a racemic mixture of R and S enantiomers of bupivacaine.

01:47-01:55
Classically, it is provided in concentrations of 0.25% and 0.5% solution, although there are 0.75% preparations as well.

01:55-02:00
There are a number of preparations also combined with adrenaline in a 1 in 200,000 solution,

02:00-02:06
noting guys that this doesn't improve the length of block, but improves the surgical field for the

02:06-02:12
surgeons, so there's less blood sloshing around. Bupivacaine is also supplied as a hyperbaric

02:12-02:18
mixture, aka heavy bupivacaine, and this is mixed with 80 milligrams per mil of glucose,

02:19-02:24
creating that higher specific gravity that means that we can manipulate how local anesthetic works

02:24-02:26
in people's CSF spaces. Cool. It's a

02:26-02:27
molecular weight for

02:27-02:29
those who are deeply excited by such

02:29-02:38
a thing is 288 grams per mole. So pharmacodynamics of bupificane. So it works by sodium channel

02:38-02:42
blockade. Let's remember that there's sodium channels in a number of places in the human.

02:42-02:47
We're interested in the sodium channels you will find on neuronal membranes, at least initially.

02:48-02:53
But first, let's think about the details of this mechanism. So we know that the PKA influences

02:53-03:00
onset time because the unionised fraction is the one we're interested in when it comes to drug

03:00-03:01
getting in the right place to

03:01-03:01
work.

03:01-03:05
We also know that its lipid solubility plays a role in this

03:05-03:10
and let's recall that protein binding plays a role in how prolonged the action of the local

03:10-03:16
anaesthetic is. The more protein bound generally the longer it lasts. We need to bear in mind that

03:16-03:21
this unionised fraction gets into the nerve but then it's going to re-dissociate because everything

03:21-03:28
is in a dynamic equilibrium isn't it? It's the ionized fraction of the re-disassociated molecule

03:28-03:33
that's got into the nerve that is the one that actually does the sodium channel blockade. So

03:33-03:39
you can imagine that the amount of agent you give, the amount that actually makes it to the effect

03:40-03:45
site is quite a small fraction and we know that this plays out in most drugs we administer to

03:45-03:50
humans. Go back and listen to any of those other episodes if you don't have a scuba do what I'm on

03:50-03:56
about, maybe start with the polycompartmental model episodes or the TCI propofol episode.

03:56-04:00
So let's focus back in on local anesthetics and this sodium

04:00-04:00
channel they

04:00-04:02
act on. So this sodium

04:02-04:07
channel, you'll find it in your neuron, generally speaking in those nodes of Ranvier, and it has

04:07-04:15
three states, two natural human-y type states, i.e. open, it's litting sodium in, or closed,

04:15-04:21
It's not letting sodium in, but then also a local anesthetic bound state, because we know that if

04:21-04:27
you have a protein and then you stick something to that protein, it causes a conformational change

04:27-04:32
to that thing. That's why all these drugs have influences on all these proteins,

04:33-04:39
protein coupled receptors, channels, tyrosine kinase receptors, etc, etc, etc. Something binds

04:39-04:45
to something changing the shape of the thing and altering its activity. Now interestingly

04:45-04:46
local

04:46-04:53
anaesthetic agents prefer the open state i.e. that open state enables a higher affinity of local

04:54-05:00
anaesthetic to sodium channel. This is called use dependent or phasic block if you want to apply a

05:01-05:06
buzzword to it. So before I get back into the depths of bupivacaine let's just quickly touch

05:06-05:11
on these neuronal action potential phases because we're going to do it properly in perhaps three and

05:11-05:16
a half decades when we finally get onto physiology. The curriculum is massive, but remember this is

05:16-05:22
something you might be asked to draw in the exam. So for a neuron, i.e. a nerve that is conducting

05:23-05:23
something

05:23-05:23
in your peripheral

05:23-05:29
nervous system, there are four phases and the graph is a graph of a line

05:29-05:34
running at a sort of basal electronegative state with then a rapid upshoot and then a rapid

05:34-05:41
down shoot. There's no middle ground, there's no plateau phase in a nerve action potential. So when

05:41-05:46
your action potential comes along, some volt-gated sodium channels open, because naturally there has

05:46-05:46
to

05:46-05:47
be a degree of conduction

05:47-05:51
at this point in time, doesn't there? However, once a sufficient number of

05:51-05:57
volt-gated sodium channels open, that you hit a shift in your neuronal electronegativity, deflecting

05:57-05:58
back towards positive,

05:59-05:59
i.e.

05:59-06:04
when you hit about minus 55 millivolts, you trigger widespread volt-gated

06:04-06:09
channel opening. So loads of sodium pours into the cell. Remember that there's lots of sodium

06:09-06:15
outside of a cell, not much in. There's loads of potassium inside a cell and there's not much out.

06:15-06:16
So all that

06:16-06:16
sodium piles

06:16-06:21
on in and the neuronal membrane becomes positive. These sodium channels

06:21-06:27
don't stay open forever. However, once you hit that positive state, vault gated potassium channels

06:27-06:34
trigger open, allowing efflux of potassium, triggering a repolarization of that

06:34-06:34
nerve

06:34-06:41
into the world of electronegativity. Interestingly nerves of the peripheral nervous system type

06:41-06:46
flavour overshoot their electronegativity as they repolarise. So they dip down a little bit more

06:46-06:48
negative than they otherwise would rest at

06:48-06:50
before returning to that resting

06:50-06:51
negative neuronal

06:52-06:55
potential waiting for a new action potential to flow

06:55-06:55
along.

06:55-06:57
Four phases one two three and four

06:58-07:04
no plateau. So back to bupivacaine what do we use bupivacaine for? So I'm sure you're all kind of

07:04-07:08
thinking this is daft, but you might get asked it in the exam. So it is used for post-operative

07:08-07:13
pain control when you've administered a block at the end of surgery, i.e. you've done a tap block,

07:14-07:14
or the

07:14-07:17
surgeons have done an ilio-inguinal block for an inguinal

07:17-07:17
hernia.

07:17-07:19
You could utilize it for

07:19-07:24
intra-operative pain control. So this is the realms of your spinal anesthetic, or you're thinking you

07:24-07:30
want to actually cover the operative intervention with some form of local anesthesia, a spinal and

07:30-07:30
GA for

07:30-07:35
example. And then regional blockade either to facilitate surgery upper limb blocks lower limb

07:35-07:35
blocks

07:35-07:36
or regional

07:36-07:40
blockade following traumatic injury. So I think we're ending up using erector

07:41-07:47
spinate plane blocks and serratus anterior blocks and paravertibles much more frequently to provide

07:47-07:53
pain control. You could break this down further into anaesthesia that achieves sensory blockade

07:53-08:00
or sensory and motor blockade because we like to differentiate some limb blocks as motor sparing,

08:00-08:02
which the orthopods love for their knee replacements.

08:03-08:03
But that's more detail

08:03-08:04
than we're

08:04-08:08
going into today. So dosing, how do we dose bupivacaine? So it depends where you're putting

08:08-08:11
it, doesn't it? Because you could, in theory, do two milligrams per kilo

08:11-08:12
intrathecally.

08:13-08:13
That isn't

08:13-08:18
a toxic dose from the perspective of local anesthetic toxicity, but you would have a total

08:18-08:19
spinal and

08:19-08:26
a very cardiovascularly unstable patient. Generally speaking, most people go up to

08:26-08:34
15 milligrams of intrathecal bupivacaine, i.e. 3 mils of 0.5. You can go quite low and sometimes

08:34-08:40
people go a tad higher. I do know, having had a nosy about this for bilateral hip or knee

08:40-08:48
replacements, which they do in some sites in the United States, they put quite a bit more. They

08:48-08:52
they're going to do both hips at once. Not something that tends to happen so much in the

08:52-08:53
UK.

08:53-08:58
So other routes. Remember we have intrathecal, we have epidural, and in this site you can go up to

08:58-09:04
two milligrams per kilo. Infiltration, again two milligrams per kilo. That's injecting your

09:05-09:11
cesarean section incision site at the end of a case or rectus sheath catheters. Topical, I don't

09:11-09:13
really know how much topical bupipicane

09:13-09:15
anyone's using. If people are, let me know.

09:15-09:16
And intravenous

09:16-09:22
dosing. We don't tend to do that. You can use other local anaesthetics in intravenous manner,

09:22-09:27
lidocaine and prilocaine in beer's blocks, if I remember correctly. And I did because I've just

09:27-09:33
checked. Can you put it intra-arterially? No, it's going to be just as toxic. It's just going to take

09:33-09:38
slightly longer to work. And what I mean by work is slightly longer to cause a local anaesthetic

09:39-09:45
toxicity disaster. You might get a slightly mixed picture if you were to inject that into carotid

09:45-09:48
because you're going to get CNS symptoms very quickly and

09:48-09:49
then cardiac

09:49-09:50
symptoms a bit later

09:50-09:56
because it's got to go all through the brain and back down. So we've mentioned toxicity hard quite

09:56-10:00
a few times here. The toxic dose of bupivocaine is two milligrams per

10:00-10:01
kilo.

10:01-10:02
Now is that if you

10:03-10:08
stick two milligrams per kilo into someone's vein you will get away with it? And the answer is no

10:08-10:14
you won't. So two milligrams per kilo is your infiltrative safe dose. Bearing in mind we all

10:14-10:20
know that local anaesthetic uptake differs depending on the site you've injected it in.

10:20-10:23
Mentioned that in the previous episode, you can go back and have a listen. But now we're thinking

10:24-10:28
we've chucked this dose of bupivacaine in around someone's brachial plexus. How long does it take

10:28-10:32
to work? I would generally quote patients 10 to 20 minutes, but sometimes it can

10:32-10:33
be even longer

10:33-10:34
than that.

10:34-10:36
Auxiliary blocks seem to take ages to cook.

10:37-10:37
Now, if you've

10:37-10:39
sold a regional anaesthetic

10:39-10:44
to a patient with excellent skill, having balanced their risks and benefits and consented them

10:44-10:44
appropriately,

10:45-10:48
but then you forgot to tell them it takes a while, you've stuck that injection in,

10:48-10:51
and then you've started pottering around and doing other things, and then looking at you with raised

10:52-10:56
eyebrows, you've lost your patient a little bit there. So open the door with how long it takes to

10:56-10:56
work,

10:57-10:58
but then, you know,

10:58-11:02
it does last for up to 16 hours, and sometimes a bit longer with additives.

11:02-11:03
So you might

11:03-11:09
have seen some folk mixing drugs together. Wouldn't it be dandy if we could use a

11:09-11:13
local anesthetic that acts really quickly, and then mix it with one that takes longer to work,

11:13-11:17
but lasts longer so that you get the best of both worlds fast fast acting and lasts a while

11:18-11:22
unfortunately it doesn't quite 100% work like that so say we take lidocaine and mix it with

11:22-11:27
bupivacaine seems like a great idea we've taken one mil of two percent lidocaine and we've mixed

11:27-11:33
it with one mil of 0.5 percent bupivacaine what this actually ends up giving you is a two milliliter

11:34-11:35
mixture that is itself

11:35-11:36
one percent

11:36-11:40
lidocaine and 0.25 percent bupivacaine and you probably

11:40-11:43
at Salen thinking right now, well that's not the end of the world is it? And technically no, but

11:43-11:44
there's another complicating

11:44-11:45
factor here in

11:45-11:49
that the pH of lidocaine in its natural form is different

11:50-11:55
to that of bupivacaine. And herein lies an issue. Now we're going to touch on bupivacaine pKa in a

11:55-12:03
minute, but the pKa is 8.1 and it is 15% unionized, whereas lidocaine 7.7, 25% unionized. However,

12:03-12:08
the pH of lidocaine is more acidic than the pH of the good old-fashioned ampoule of bupivacaine.

12:09-12:13
So actually you create a more acidic environment for the bupificane to work.

12:13-12:17
And as we all know, bupificane wants to be more alkali.

12:17-12:20
Therefore, you actually impair the function of your long acting agent.

12:20-12:23
So it fails on two counts of physicochemical reality.

12:24-12:24
So you just

12:24-12:24
don't do it.

12:24-12:32
Now, there's a great paper that I'm going to link in the show notes that explores pharmacological and clinical implications of local anaesthetic mixtures.

12:32-12:34
And it's a narrative review and it's really good.

12:34-12:36
So I would thoroughly recommend reading that.

12:36-12:38
but you might have heard about mixing bicarb in with things.

12:39-12:39
You know, you've got

12:39-12:40
that bum abscess,

12:41-12:46
it's grotty, it's angry, it's inflamed, the tissues are acidic around it, the local anesthetics just

12:46-12:50
barely work. Wouldn't it be dandy if we could make it more alkaline with bicarb?

12:50-12:51
And the answer is

12:51-12:51
yes

12:51-12:57
you can. So if you mix in bicarb you achieve a more alkaline environment and therefore improved

12:57-12:57
onset time.

12:57-12:58
Again we

12:58-13:03
hit another barrier here though in that unfortunately bupivacaine, levobupivacaine

13:03-13:09
and ropivacaine have a tendency to precipitate when mixed with bicarb, so that's kind of in the

13:09-13:14
bin. However, lidocaine behaves and therefore that is an option, mix your lidocaine with bupivacaine.

13:15-13:23
It's approximately 1 ml of 8.4% sodium bicarb per 10 ml of local anaesthetic. Some sites use a

13:23-13:31
lidocaine bicarb mix for rapid onset of surgical anaesthesia via the epidural route in sections.

13:31-13:36
You bang it in and it works real quick. So there are a number of other additives that are used,

13:36-13:41
were used, could be used more in the future. Noting that you could mix clonidine in,

13:41-13:46
that's compatible with lidocaine and bupivacaine. The evidence is mixed, but it may improve block

13:47-13:52
duration. And again, dexmedetomidine, this is technically not compatible, but seemingly folks

13:52-13:58
do use it. And that appears to extend block effect in some studies so far. Ketamine has been used,

13:58-14:04
and it has a positive effect. Ketamine in itself has some local anaesthetic-like sodium channel

14:04-14:08
blocking properties. However, there is some evidence that it is injurious to those nerves

14:08-14:14
and the CNS. There's a degree of evidence that says that magnesium prolongs regional anaesthetic

14:14-14:19
blockade. You just need to make sure you don't accidentally put a humongous amount intrathecally.

14:19-14:24
Apparently that's happened. Steroids. There's mounting evidence that either co-administered

14:24-14:29
steroids or IV high-dose steroids prolongs the effect of your local anesthetic on nerve,

14:30-14:35
although it may actually be that intravenous steroids work just as well. With a lower risk

14:35-14:38
factor, you're putting less next to very important nerve structures, aren't

14:38-14:38
you? Now, we know

14:38-14:39
that

14:39-14:42
opioids seem to improve the quality of neuraxial

14:42-14:43
anesthesia. I don't know

14:43-14:45
about regional anesthesia

14:45-14:49
and if you stick some fentanyl in someone's interscalene, whether or not that has any value.

14:49-14:54
Obviously, these nerves have opiate receptors, but I wonder if anyone knows that, please

14:54-15:01
drop me an email. So we've dipped quite deep into pharmacodynamics there before we've even got to

15:01-15:04
side effects. These drugs do have a side effect profile, chiefly

15:04-15:06
ones arising

15:06-15:07
from toxicity,

15:07-15:12
so we know they're toxic. Bupificane tends to favour the cardiovascular system, binding to

15:12-15:19
myocardial proteins and blocking cardiac sodium channels. This impairs the phase zero of the

15:19-15:24
cardiac action potential, and we're going to touch on that in a second, but also can drop your

15:24-15:29
peripheral vascular resistance or your systemic vascular resistance, as well as dropping your

15:29-15:34
contractility and being arrhythmogenic. From a neuro perspective, we have sodium channels in

15:34-15:34
our

15:34-15:35
brains,

15:35-15:39
unsurprisingly, everyone. You get a spectrum of effect here depending on how much

15:40-15:45
agent has been absorbed and delivered to the brain. So these could come on very quickly if

15:45-15:50
you've accidentally squirted some into a vein and over a prolonged period of time if you've

15:50-15:57
inadvertently overdosed someone in a highly vascular bit of tissue. So early signs, patients get some

15:58-16:04
slightly excitatory effects. They get sensory disturbances like tinnitus, altered taste sensation,

16:04-16:11
metal taste in mouth, circumoral tingling. They can then progress on to seizure activity and coma.

16:11-16:16
Now you could perhaps make an argument that if someone's in a coma due to local anaesthetics,

16:16-16:21
then maybe they're going to not breathe very much. It's not really quite a side effect in some ways.

16:22-16:27
And as I understand, there are no real quoted GI, renal, metabolic or

16:27-16:28
endocrine

16:28-16:29
side effects of

16:29-16:32
local anaesthetics that you're going to be asked about in the exam. It's all about the toxicity.

16:32-16:38
And we touched on the action potentials of nerves. I just want to quickly differentiate the action

16:38-16:44
potentials you see in myocardium because this is something that interminably flummoxed me because

16:44-16:45
it all sounds exactly the same and it's

16:45-16:46
probably going to sound

16:46-16:47
exactly the same

16:47-16:48
to you but

16:48-16:48
consider

16:48-16:49
it cognitive

16:49-16:49
priming.

16:49-16:54
So there are actually five phases of the cardiac action potential compared to

16:54-17:00
a standard nerve with four. You have a phase zero and then a one, two, three and a four. Now phase

17:00-17:08
zero is the initial depolarization, that uptick. You get sodium shifting in and potassium being

17:08-17:09
able to shift

17:09-17:09
out.

17:09-17:14
There's phase one and this is a very small uptick at the top of this. If you

17:14-17:19
imagine that initial depolarization phase almost overshoots slightly. Phase one

17:19-17:20
happens and

17:20-17:20
there's

17:20-17:28
a slight rebound repolarization, i.e. a drop in the positivity of that cell, only slightly, and this

17:28-17:33
is due to briefly opened potassium channels, letting some potassium in. Then you have phase two.

17:34-17:39
This is the phase that you don't see in other neuronal action potentials, and it is the plateau

17:39-17:45
phase. This is facilitated by calcium channels, and these are L-type calcium channels. I don't know

17:45-17:52
if the L stands for long, but they open, they let calcium into the cell. This calcium was obviously

17:52-17:58
quite useful for sarcoplasmic reticulum to contract, but calcium influx provides a prolonged

17:58-18:00
period of positive cell

18:00-18:01
membrane compared

18:01-18:02
to good old-fashioned

18:02-18:04
nerve. Phase three, so

18:04-18:05
this is our

18:05-18:11
dip back towards electronegativity. Phase three is repolarisation. Calcium channels that have been

18:11-18:15
open close. Potassium channels wide open

18:15-18:15
here,

18:15-18:18
allowing shift of potassium out of the cell,

18:19-18:23
dropping it back towards electronegativity. And we get phase four, this is the resting state,

18:23-18:28
which is confusing really, because I would say that the resting state should be like first thing

18:28-18:34
but who knows anyway phase four resting state negative 96 millivolts and this is facilitated

18:35-18:38
by those potassium channels being open and a loss

18:38-18:39
of whatever

18:39-18:41
sodium and calcium channels remain

18:41-18:41
trying to

18:41-18:43
be open they're gone so

18:43-18:48
five phases 0 1 2 3 4 2 is the plateau phase that's where you're

18:48-18:52
getting all that calcium ingress courtesy of our l-type calcium channels

18:52-18:53
let's

18:53-18:53
remember that these

18:53-19:00
L-type calcium channels are a drug target, folks. That's where your dihydropyridine and non-dihydropyridines

19:00-19:06
come into play. Right, so quite a bit of talking thus far, but let's just touch on the pharmacokinetics

19:06-19:12
of these drugs. Remember, pharmacokinetics is absorption, distribution, metabolism, and elimination.

19:12-19:13
Add me.

19:13-19:14
I mentioned earlier that the absorption

19:14-19:15
behaviour,

19:15-19:17
the pivacaine, depends on where it is

19:17-19:22
injected and the vascularity of that site. So the range from most absorption to least absorption,

19:23-19:28
we say intercostal most, then cordial, then epidural, and then brachial plexus, and then

19:28-19:34
subcutaneous administration. There is a linear dose response relationship between peak plasma

19:34-19:40
concentration you will see and the amount of drug you've put in. Vasoconstrictors in the world of

19:40-19:46
bupivacaine do not influence this terribly much because bupivacaine has a local vasodilatory

19:47-19:52
effect, which is bothersome. It's probably that the surgeons stick adrenaline in to make themselves

19:52-19:56
feel better and actually it probably doesn't change very much. This bears out in reality because we

19:56-20:01
know it doesn't change how long the drug lasts for because the bubificane causes dilation which

20:01-20:01
means

20:01-20:01
there's

20:01-20:06
clearance from that site. That same dilation is not altered by administering adrenaline. The

20:07-20:11
time it lasts is the same therefore who really knows. But if it makes them happy it doesn't matter

20:11-20:16
although you might see a little bit of that beta 1 beta 2 response that you get by administering

20:16-20:21
adrenaline into subcutaneous tissues and you might get a bit of hypotension and then hypotension.

20:21-20:28
very interesting. So distribution. Its pKa as mentioned above is 8.1. So at physiological pH

20:28-20:35
you have 15% unionized. It is 95% protein bound which is mega and in plasma it is mostly bound

20:36-20:38
to alpha-1 acid glycoprotein.

20:38-20:39
It has a volume

20:39-20:42
of distribution of 21 to 103 liters but I don't

20:42-20:48
really think it is terribly relevant for this drug and it also binds to albumin. Metabolism. How does

20:48-20:54
how does the body get rid of it? So bupivacaine undergoes N-dealkylation, remember that's a phase

20:54-21:01
two metabolism liver thing, into pipey coloxylide. I don't think you need to know that, but it is

21:01-21:06
inactive. So it gets through the liver, phase two metabolism, N-dealkylation, inactive metabolite.

21:07-21:13
Clearance of 0.47 litres per minute and the elimination half-life after intravenous

21:13-21:19
administration is 0.3 to 0.6 hours, i.e. 20 to 40 minutes. So it does get out reasonably quickly.

21:19-21:24
Other things of note, remember that patients can be allergic to local anaesthetic agents,

21:24-21:30
although classically more likely to be allergic to ester local anaesthetic agents than amide local

21:30-21:36
anaesthetic agents. And interestingly, some vets administered up to 8 milligrams per kilo of

21:36-21:43
bupivacaine when they were trying to do interscalene blocks on ducts, and none of the ducts died

21:43-21:48
However, we need to think that maybe it's quite hard to inject into the brachial plexus of a

21:49-21:53
mallard duck. And maybe if they're squirting bupivacaine into a tendon or other fairly

21:54-21:58
avascular structures, the odds are that it couldn't absorb quick enough to cause harm.

21:58-22:01
Not that I'm recommending that as a dose, but I thought that was an interesting side

22:02-22:06
and reflects how easy it is to get very lost on the internet reading about things.

22:06-22:07
So just to

22:07-22:08
close out

22:08-22:10
the show, guys, and I hope you've managed to get here thus far,

22:10-22:16
Levo-bupivacaine, otherwise known as chirocaine, and chiro because it's all about chiral molecules

22:16-22:22
and enantiomers, which we're going to touch on later. Levo-bupivacaine is the S enantiomer of the

22:22-22:29
racemic-bupivacaine mixture. Why are we interested in levo-bupivacaine? Well, it does seem to cause

22:29-22:34
a bit less of a motor block, interestingly. It seems to yield sensory blocks more so,

22:35-22:40
especially in lower doses. There is a notion that it is slightly less potent than its racemic

22:40-22:45
mixture which might make you think that if you were to take the other enantiomate R-bupivacaine

22:45-22:50
you might have a more potent local anesthetic agent. So why on earth did they bother trying to

22:50-22:55
divvy this out and use one half of bupivacaine? And the answer is levobupivacaine is less

22:56-23:01
cardiotoxic. If you were to pick which toxicity you would like, CNS toxicity, i.e. your brain

23:02-23:03
turns off until you clear the local

23:03-23:04
out,

23:04-23:07
is probably less harmful than ventricular fibrillation.

23:08-23:12
One, you just need to wait. The other one, you might not be able to undo. Hence why

23:13-23:19
levobupivacaine is more readily favoured. What is the dose? So the max dose is generally quoted as

23:19-23:27
150 milligrams in one go with a total of 400 milligrams over 24 hours. So this would work out

23:27-23:36
at about 30 mils of 0.5% in an appropriately sized adult or about 200 mils of 0.5% over 24 hours.

23:36-23:47
In some literature, the max dose of levobupificane is quoted as 2.5 milligrams per kilo instead of the 2 milligrams per kilo of standard bupificane.

23:47-23:49
This is why it tends to be favoured.

23:50-23:51
It really confused me when I first started.

23:51-23:55
Which one's levo? Which one's bupificane? Which one's kyrocane? Which one's marcane?

23:55-23:57
Kyrocane is levobupificane.

23:57-23:59
Standard bupificane is marcane.

23:59-24:04
Heavy marcane is when it's mixed with glucose for intrathecal administration so it sinks

24:04-24:04
down.

24:04-24:07
Oh and that's your lot folks, you've listened to the end, you've done brilliantly well. That was

24:07-24:12
bupivacaine with a touch on cardiac action potential, neuronal action potential and additives

24:13-24:17
you could mix in and their approximate likelihood of having clinical benefit. I think the jury is

24:18-24:23
approximately out on most of it, there's no robust consistent, everyone does one thing,

24:23-24:28
I think I'd be tempted to say that steroids probably help and most other things might help

24:28-24:34
but it's less clear at this point in time. Thanks for listening guys, I hope you've

24:34-24:39
found it useful but if you found it awful do let me know. Please like and subscribe, register with

24:39-24:43
whichever podcast platform you find yourself using and leave a comment if you think I need to square

24:44-24:48
something away. I just want to make sure that you guys know that every day you are getting better at

24:48-24:52
this. There is a bucket of content to try and consume and it is like drinking from a fire hose.

24:53-24:57
Take it day by day, don't overcook yourself, don't freak out and keep studying.