Ep.30 – Local Anaesthetics, the Fundamentals

00:00-00:00
Please listen carefully.

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

00:39-00:39
Hello, everyone.

00:40-00:41
This is James at Gas, Gas, Gas.

00:42-00:43
As you know, and I know,

00:43-00:47
we’ve finally, finally finished the opioids chapter,

00:47-00:48
Gas, Gas, Gas.

00:48-00:50
I’ve decided it was a chapter in retrospect.

00:51-00:55
And now we’re going to move into a chapter on local anesthetics.

00:56-00:58
Now, it’s going to cover today’s episode,

00:58-01:04
obviously introduction, which is going to try and hit the nail on the head for how they work,

01:05-01:11
some of the concepts of onset offset, and a bit of an overview, with then episodes focusing on

01:11-01:16
all the main local anaesthetic agents. We’re going to go from levobupivacaine to cocaine

01:17-01:23
and everything in between. There’s going to be a robust episode on local anaesthetic toxicity,

01:24-01:26
and that’s going to go into reasonable detail.

01:27-01:31
We’re going to touch on local anaesthetic systemic toxicity last today

01:32-01:34
because it’s just something you need to know well,

01:35-01:38
but then we’ll have a look at a bit of a deep dive into the physiology

01:38-01:40
just for some interest and fun

01:40-01:45
and to understand its purported mechanisms in a bit more detail.

01:45-01:49
That’s probably going to come in an episode towards the end of the chapter,

01:49-01:51
so we need to get through some of the nitty-gritty first.

01:52-01:56
we can’t just indulge our deep physiological joys, of which I’m sure we all have many.

01:57-02:02
Putting myself in your shoes, when I first came into anaesthesia, I could name a bunch of local

02:03-02:09
anaesthetic agents and understood that levopipivacaine was different to lidocaine, but that was really

02:09-02:15
the extent of my knowledge. I didn’t appreciate any of the nuances which dictated how the mechanism

02:15-02:22
of action works and what agents might be better in what certain situations. I certainly didn’t know

02:22-02:28
there were two classes of local anaesthetics and as I was studying for the FRCA primary many moons

02:28-02:35
ago I came to realise that there is expectation of having a in-depth and robust knowledge of local

02:35-02:41
anaesthetic agents. This is because a we use them daily in practice from being kind when we’re

02:41-02:47
sticking in that grey cannula, to near axial anaesthesia in emergency caesarean sections,

02:49-02:53
and wound infiltration guiding the dose the surgeons should use. I imagine if you turned

02:53-02:58
around and asked a surgeon who hadn’t just sat their exams how a local anaesthetic really worked

02:58-03:03
and what the doses were, and they’d be like, no, ask the anaesthetist. And that means that we hold

03:03-03:08
a position in the hospital whereby people look at us for robust knowledge on local anaesthetics.

03:09-03:13
So you might not have much of a Scooby-Doo at the start of this chapter,

03:13-03:18
but by the end of it, you are going to be singing from an extensive hymn sheet of knowledge,

03:18-03:22
and then you’ll just be like, 20 mils of 0.5, 40 mils of 0.25, be all right.

03:23-03:28
Obvious with the natural caveats that if they’re really tiny, maybe don’t give them that much.

03:29-03:35
So bringing it into this episode, by the end of it, I’m hoping we will have reminded ourselves about the anatomy of a nerve,

03:36-03:42
how it functions on a physiological level, nerve classification, and then exploring local

03:42-03:47
anaesthetic mechanism of action, classification of those local anaesthetics and factors that

03:48-03:54
influence onset and offset, as well as dipping our toes into local anaesthetic systemic toxicity

03:55-03:59
and what that really means and why you need to be on top of it if it is an emergency.

04:00-04:03
If by the end of this episode you’ve had a listener thought, damn, that was great,

04:04-04:08
Everyone should know this. Then, you know, crack on, share it with your mates. That would be great.

04:09-04:14
So before we get into the nitty gritty of how local anaesthetics work, we need to just remind

04:14-04:19
ourselves about nerves. So remember, we have a central and a peripheral nervous system. We’ve got

04:19-04:24
an autonomic nervous system, which also breaks down into your sympathetic and parasympathetic

04:24-04:32
nervous systems. And a somatic nervous system, i.e. the bit that senses things. When I say things,

04:32-04:38
I mean like external stimuli, and delivers motion by telling your muscles where to go

04:38-04:42
and receiving data from your muscles as to where they are in space.

04:42-04:47
So in the context of local anaesthetics, you could say that we’re actually interested in all of those things

04:47-04:49
because local anaesthesia can influence all of those things.

04:50-04:57
But we’re just going to imagine a nerve that is running from your spinal cord out to a muscle

04:58-04:59
and what this nerve is made up of.

05:00-05:06
So at one end, you have a cell body, and sometimes cell bodies can be a little outpouching of a nerve,

05:06-05:09
and sometimes they are part of the proximal end.

05:09-05:14
And in this example, we’ll assume we’ve got a cell body at the proximal end of a nerve.

05:14-05:19
That’s where the nucleus is, and there are a bunch of dendrites, like little tendrils coming off that nerve,

05:20-05:21
that receive data from a few different places.

05:22-05:24
When I say data, I should say impulses.

05:25-05:31
There is then an axon between that cell body and the site at which that nerve is going to synapse

05:32-05:38
with either another nerve or, in our case, a muscle, our synaptic cleft neuromuscular junction realm.

05:39-05:41
There are a number of features on that axon.

05:41-05:46
This axon is the chief thing that’s going to influence speed of conduction,

05:47-05:49
depending on how well insulated it is.

05:50-05:53
These axons are wrapped in myelin, which is like a fatty material.

05:54-06:01
call it a myelin sheath courtesy of Schwann cells hence Schwannomas when you get them on your little

06:02-06:09
cranial nerve 8 and these Schwann cells wrap the axon however they don’t completely encase it there

06:09-06:18
are gaps these gaps between the insulated strips of wire are called nodes of Ranvier or

06:18-06:18
Ranvier

06:18-06:18
who

06:18-06:24
Who knows? The final interesting point is the distal end. This is the synaptic cleft. Sometimes

06:25-06:31
it’s called a terminal bouton. So now we can all imagine this nerve. Now we’ve got to think about

06:31-06:38
how does it work? So it works by saltatory conduction. Saltaire means to leap. And this is

06:38-06:45
because these convenient chunks of insulated nerve reduce the requirement of a continual

06:46-06:51
opening of sodium channels to achieve action potentials conducted down the cell because it

06:51-06:57
takes time to do that if your action potential can actually hop along gap because you achieve

06:57-07:03
electronegativity across a greater bit of the cell’s membrane then you speed up conduction

07:03-07:10
and it’s one of the direct influences on nerve conduction speed is how wrapped in myelin it is

07:10-07:15
as is the thickness of the axon amongst other things there’s some cool studies with squid

07:15-07:22
songs. So myelin sheaths speed up conduction through saltatory conduction where this action

07:22-07:28
potential jumped between the nodes of Ranvier courtesy of that insulation you get action

07:29-07:34
potentials triggering sodium channel opening at the nodes which then achieves sufficient

07:34-07:39
depolarization at that point of the nerve to facilitate conduction further down. Sometimes

07:39-07:46
this cell membrane of a nerve is called a neurolemma as well, just to avoid confusion with

07:46-07:53
extra words. Like plasma lemma might be a fancy way to discuss a cell membrane in a common cell,

07:54-07:59
although no cells are common really. So what does a nerve look like when it’s minding its own

08:00-08:05
business, having just discussed its action potential actions? So it has a resting state

08:05-08:09
when it’s just waiting for someone to come along and tell it what to do next.

08:10-08:15
And they have a resting negative potential of about minus 70 millivolts.

08:16-08:21
This is maintained by displacing potassium ions out of the cell,

08:22-08:24
alongside keeping sodium out of the cell.

08:25-08:32
The chief maintainer of intracellular electronegativity is the negatively charged.

08:32-08:34
Elements in that cell chiefly proteins.

08:34-08:40
So what is the cutoff for triggering these sodium channels to open,

08:41-08:43
letting a flood of sodium come into the cell?

08:43-08:45
Remember, there’s lots of sodium in your plasma.

08:45-08:46
There’s not much potassium.

08:47-08:49
There’s lots of potassium in your cells, not much in the plasma.

08:50-08:53
So you get a flood of sodium into the cell that depolarizes it.

08:53-08:55
It has to depolarize the cutoff.

08:55-09:00
If it was all minus 70, then your nerves would be very, very lively and very excitatory.

09:01-09:04
And maybe they wouldn’t get very much stuff done because they’re constantly

09:04-09:04
being

09:04-09:05
discharged in a

09:05-09:11
discoordinate manner. So the cutoff is approximately minus 55 millivolts for triggering opening of

09:12-09:19
sodium channels and full depolarization of that nerve cell. When the membrane fully depolarizes,

09:19-09:26
it can peak at approximately plus 40 millivolts. So I mentioned these sodium channels. These sodium

09:26-09:31
channels are the thing we’re mostly interested in from a local anesthetic perspective. That’s

09:31-09:36
our local anesthetics work and they are voltage gated sodium channels that are keeping an eye

09:36-09:43
out for this change to about minus 55 millivolts that make them open up and let sodium flood into

09:43-09:50
the cell. These channels can be in an open state, a closed state, and then an inactivated state

09:51-09:55
where they are closed in an inactivated position courtesy of local anesthetic agent.

09:56-10:01
How do these nerves repolarize? Otherwise they’re just going to be sat all depolarized

10:01-10:06
40 millivolts and then you’re just going to end up all floppy. Well these sodium channels don’t

10:06-10:12
stay open forever they inactivate this leads to a cessation of sodium flow into the neuron.

10:13-10:20
Sodium potassium ATPase pumps start well they’re probably constantly actually pumping out sodium

10:20-10:25
taking in potassium but then you think oh you just told me earlier that there wasn’t much potassium

10:25-10:31
in a nerve cell in some regards either because it relies mostly on electronegative proteins for its

10:30-10:35
internal charge. And you’re right, that’s because at the same time you’re opening up potassium

10:35-10:42
channels, allowing them to run down its concentration gradient. And whilst potassium has a role in

10:42-10:48
maintaining electronegativity in a nerve, we shouldn’t discount the role of the negatively

10:48-10:53
charged proteins inside that cell. You can’t pump a protein out very easily, they’re quite large

10:53-10:59
compared to a sodium ion. The last thing I’ll say is that there’s not just one type of sodium channel

10:59-11:05
in a human being because as you can imagine if you gave local anaesthetic it might lurk off and

11:05-11:10
cause havoc elsewhere because it would like that sort of sodium channel but that sodium channel

11:10-11:14
was everywhere. I’m not going to say that the sodium channels are tremendously different but

11:15-11:21
it’ll come about in the local anaesthetic toxicity episode that some local anaesthetic agents have a

11:21-11:27
greater affinity for cardiac sodium channels than others. This is important in differentiating

11:28-11:33
local anaesthetics that demonstrate early or late cardiovascular toxicity, but we’ll get into that

11:33-11:39
later. So now we have an understanding of the anatomy of a nerve, an approximate gist of the

11:40-11:46
structure of the nervous system, and hopefully we’ve reminded ourselves about the basic physiology

11:46-11:50
of how a nerve works, although you should definitely go away and do some reading also.

11:50-11:54
But here’s the money shot, like what about actual local anaesthetic agents, how do they really work?

11:54-11:55
because that’s why we’re all here, really.

11:56-12:01
So local anesthetic agents work by sodium channel blockade,

12:01-12:04
i.e. they stop those sodium channels working.

12:04-12:06
Now, they’re quite interesting drugs

12:06-12:08
in that it isn’t just it moseys along,

12:09-12:12
it binds to the outside aspect of those sodium channels

12:13-12:14
in the nose of Ranvier,

12:14-12:17
’cause no, that would be just too darn simple.

12:17-12:20
A local anesthetic agent will only work

12:20-12:24
on the internal element of that sodium channel

12:24-12:30
your nerve. Why do we care? Well that means that the drug has to get inside the nerve first and

12:30-12:37
there’s our first delay. It takes time to do that as we know. Stuff going across membranes takes time.

12:38-12:44
It has to diffuse. The other interesting element of a local anaesthetic agent is that it has a marked

12:44-12:50
preference for activated sodium channels. So if a nerve is sat there doing nothing and some local

12:50-12:56
anaesthetic has potted on its way through. It takes longer for the block to onset. Interesting.

12:56-13:04
We call that use-dependent block. So those nerves that are firing more actively, more frequently,

13:04-13:10
more busier, great grammar there James, are more susceptible from an onset time perspective.

13:11-13:18
So we all now can think of a number of things that might influence how local anaesthetics get

13:18-13:23
into this nerve because we’ve covered it all before. We’re interested in the lipid solubility

13:23-13:29
of the agent and the pKa of the agent. We’ll talk about lipid solubility a little bit later,

13:30-13:38
but pKa has a chief influence in onset time, and this is why lidocaine and bupivacaine have

13:38-13:43
different onset times, because the fraction of unionized molecule is different in these drugs,

13:44-13:45
and we’ll elaborate on that later.

13:45-13:46
The other important

13:46-13:49
factor to consider is that only the

13:50-13:57
ionized form of the local anesthetic agent will bind to that internal element of the sodium channel.

13:57-14:03
So it’s not like all that drug piles across the membrane, it’s all sat in the nerve unionized,

14:03-14:08
ready for action. Unfortunately the contrarion is that it needs to be the ionized element that works.

14:09-14:16
now if we had two buckets with a plasma membrane between the two and a ph different on each side

14:16-14:22
of the bucket and we chucked some local anesthetic in on one side we know that it would diffuse across

14:22-14:30
when its unionized form makes it over and we don’t end up with just unionized molecules on the other

14:30-14:35
side of that of that bucket because they’re in an equilibrium so actually some of those unionized

14:35-14:41
molecules shift back into their ionized form, dependent on the pH of the solution they’re in,

14:42-14:48
depends on the ratio of that balance between ionized and unionized. Let’s remember that pKa,

14:48-14:56
the number with which we label a drug, for example a pH of 8.1 in bupivacaine, means that if we put

14:56-15:03
that bupivacaine in a solution that had a pH of 8.1, then you would find yourself with a 50-50 split

15:03-15:13
of ionized and unionized drug. You change that pH to 7.35 or 7.45 or say 7.4 for simplicity,

15:14-15:23
then that ratio shifts and you end up with only 15% of those bupivacaine molecules in an unionized

15:24-15:28
state, i.e. not very much of it floating around that can cross a

15:28-15:28
membrane.

15:28-15:30
However, once it’s on

15:29-15:34
the other side, it’s probably quite a bit happier, and we’re quite a bit happier, that in fact most of

15:34-15:40
it is then ionized. Therefore you have a greater fraction of molecules that could be potentially

15:41-15:46
active, causing your desired effect. So it swings and roundabouts. That’s why when you stick some

15:46-15:53
bupivacaine in someone’s interscalene groove, you need to tell them it’s not going to be instant,

15:53-15:56
because otherwise they might be thinking that you’re crapping your job. So just say,

15:57-16:04
takes a while to work don’t you worry. So we’ve spashed through quite a lot of heavy stuff there

16:05-16:11
so just maybe take a moment to let that soak in, have a pause, have a breather, maybe go around that

16:11-16:18
roundabout. There you go you’ve had a rest. However I also just want to put it out there that if anyone

16:18-16:25
is thinking I need some viva practice and I fancy being famous, you won’t be that famous don’t worry

16:25-16:32
guys. Maybe I want to get on and do some vivacast action with Dr. Gas. And that can be arranged.

16:32-16:38
Drop me an email. We can think about time and place. We could do one. We could do several.

16:38-16:44
It’s up to you. Terror is a great way to learn. And if you can do it with me, then you can do it

16:44-16:50
with the examiners. And it’s all a bit of fun, isn’t it? You know, I think if you can stomach

16:50-16:55
that you can stomach most things. And hey Tom passed. N of 1. It must be great then guys.

16:56-17:02
Naturally I want to take credit for all his hard work. So I’ll let you mull over that. Back on with

17:02-17:09
the show. So I mentioned earlier that the onset time in some ways for local anesthetics is

17:09-17:17
determined by how heavily myelinated the nerve is and we could just say that you know motor

17:17-17:23
nerves are more myelinated than sympathetic nerves etc etc but everyone loves a classification and

17:23-17:29
it’s really confused me for quite some time when I was studying for the exam it didn’t really seem

17:29-17:33
to go in my head very well. I think that’s because there are lots of other classifications that sound

17:33-17:40
a bit like an A, a B and a C and therefore it is just like another thing in the brain soup that

17:40-17:46
you’re trying to absorb and hold in long enough to blurt it out in an exam. So we’ll go over it here.

17:46-17:54
so nerve classification it’s broken down by you could imagine fibres that conduct quickly

17:54-18:00
conduct somewhat quickly and conduct slowly and you could already imagine in your mind that

18:01-18:05
you could sort of logically work that one out a bit because there’s no point having a sensory

18:06-18:12
fibre that takes yonks to get from your toe to your head because then you’ve stood on that nail

18:12-18:18
and fully committed. And equally, there’s no point having fibres that tell your muscles to work and

18:19-18:23
throw that ball or catch that ball if it takes too long that the ball hits you in the face.

18:24-18:29
We’ve all noticed that if we pick up something that’s hot, sometimes it takes just a few moments

18:29-18:36
to realise. And those few moments can mean singeing of extremities, toes, fingers, noses,

18:36-18:44
or ears versus hair straighteners. So let’s break it down. So A fibres have four subdivisions,

18:45-18:52
alpha, beta, gamma, and delta. And the alpha fibres are the fastest, and the delta fibres are the

18:53-19:01
slowest in this subclassification. Alpha fibres innovate skeletal muscle and go right fast,

19:01-19:09
70 to 120 meters per second. That is really speedy. Beta fibers do tactile sensation, i.e. touch and

19:10-19:15
pressure at about 30 to 70 meters per second. You see there’s really broad ranges as well.

19:15-19:21
Now gamma fibers, it took my head a while to get around what a gamma fiber was. A gamma motor

19:22-19:28
neuron might be the label it gets, like that alpha fibers are alpha motor neuron. So gamma fibers,

19:29-19:38
gamma motor neurons, innovate the muscle spindles inside your muscle. And these are spindles that

19:38-19:44
provide a proprioceptive mechanism for how that muscle is positioned in space and time, length,

19:45-19:48
contractility. There’s loads of other stuff you’re going to have to learn about muscles, which we’ll

19:48-19:55
eventually do in the future in a muscle physiology podcast. But gamma fibers, muscle spindle,

19:56-19:59
proprioceptive mechanism, 15 to 30 metres per second.

20:00-20:05
So not that fast and quite a bit slower than the actual motor, alpha motor neurons.

20:06-20:07
And then delta fibres.

20:08-20:11
These are the ones we test day in and day out, guys,

20:12-20:18
when we are checking for cold sensation during neuraxial or regional,

20:18-20:20
but classically neuraxial anaesthesia.

20:21-20:24
Because if you can’t transmit cold, you can’t transmit pain

20:24-20:32
because your delta fibres do both. And they operate at 12 to 30 metres per second. So that’s our A

20:33-20:41
nerves. A alpha, A beta, A gamma, A delta. And they are heavily myelinated and they’re fast.

20:41-20:50
B fibres. So B fibres are also myelinated but they are less myelinated than our A fibre friends.

20:52-20:54
And these run at about 3 to 14 metres per second.

20:55-20:59
And if you’re being neurotic, there are subdivisions for this, but you don’t need to know that.

21:00-21:04
You just need to know B, still myelinated, slower than A.

21:05-21:10
And these are autonomic pre-ganglionic fibres.

21:10-21:12
Are you going to say, well, pre-ganglionic?

21:12-21:14
Eh, eh, for me too.

21:15-21:20
Think of it that these are a fibre that go from the central nervous system to an effect site.

21:21-21:27
So, for example, the parasympathetic crannoy nerve 3 going to the ciliary ganglion,

21:27-21:35
or, you know, the ootic ganglion, the pterygopalatine ganglion, the submandibular ganglion,

21:35-21:41
all these little ganglions that then provide parasympathetic to the rest of the face, you know, saliva, etc.

21:42-21:49
Or the vagus nerve that’s oodling its way from your noodle down to your esophagus or your stomach.

21:49-21:54
that’s preganglionic. Just to break this into something that makes a little bit more

21:54-22:02
logical sense, parasympathetic preganglionics go from either the brain or the sacrum and go on a

22:03-22:10
long journey to then a postganglionic neuron that’s co-located very much near that organ,

22:10-22:17
whereas sympathetic preganglionics, the preganglionics are in the CNS space almost,

22:18-22:25
and they quite rapidly synapse with a post-ganglionic neuron, of which you will find those

22:26-22:32
in your sympathetic chain of your paravertebral sympathetics. And the post-ganglionics of the

22:32-22:37
sympathetics tend to take a longer journey to their effect site. So you can imagine that

22:37-22:43
your parasympathetic nervous system is quite pleased to have B myelinated fibres because of

22:43-22:48
the length of those nerves, whereas your sympathetic nervous system might be a bit less fussed

22:48-22:57
is quite short. And last but not least, C-fibres. These are absolutely unmyelinated fibers and they

22:57-23:05
do three roles-ish. This is where you will find your sympathetic post-ganglionic nerves, i.e. those

23:05-23:11
ones that have synapsed in those paravertical sympathetic chain ganglia and then journeyed off

23:11-23:18
to their effects on heart, gut, etc etc. They also are involved in transmission of dull pain

23:18-23:25
from skin and viscera, and hot and cold sensation. This is why almost it takes you longer to realise

23:25-23:31
something is hot than something is cold. And they run about 0.5 to 2 metres per second, so

23:32-23:36
spectacularly slowly. And then you can think about this from a local anaesthetic perspective,

23:36-23:43
that they operate in an ascending order in that C fibres are the most influenced by local

23:43-23:49
anesthetics and A-alpha fibers are the least and that’s why when you stick some bupivacaine in

23:49-23:56
someone’s intrathecal space it takes a while for that cold sensation to go but then the patient’s

23:56-24:01
like oh I can still move my legs though and that’s because it’s going to take longer to achieve that

24:01-24:09
skeletal muscle block. As a cheeky little aside in the world of the art of anesthesia I have taken

24:09-24:15
to checking cold sensation almost immediately. Caveating to the patient, I’m expecting you to

24:15-24:21
feel this. This gives you some information. One, if they already can’t feel cold, then expect things

24:21-24:25
to work quite quickly. And you probably need to be a little bit more vigilant. You don’t want a

24:25-24:31
too high block if it’s all going swimmingly. But also it means that then when you come to recheck

24:31-24:36
the patient’s cold sensation, when you’re actually expecting them to have lost it, they really

24:36-24:42
believe you because they’re like wow I could feel that now I can’t amazing helping people feel safe

24:42-24:48
and that you know exactly what’s going on we’ve bounced between like deep-seated science and stuff

24:49-24:54
and actually the application of these things which is the joy of anaesthesia but now we’re going to

24:54-24:58
talk about the chemical structure of local anaesthetic agents and classifying them back into

24:58-25:06
the scientific delights I’m glad you’re as pleased as I am so we classify local anaesthetic agents

25:06-25:13
ester and amide local anesthetics. Now all local anesthetic agents have some similarities and some

25:13-25:21
differences. The similarities, they all have a lipophilic aromatic ring aka a benzene ring.

25:21-25:28
This offers up reasonably good lipid solubility for local anesthetic agents and you’ll find that

25:28-25:35
on one side of the local anesthetic molecule. On the other side of the local anesthetic molecule

25:35-25:41
you will find an amine group and this is the bit that does more of the local anesthetic side of

25:41-25:47
things i.e getting up to mischief and different molecules have different amine groups that offer

25:48-25:55
them up slightly different onset times etc etc. The bit that the classification alludes to

25:55-26:02
is the element that joins your lipophilic aromatic ring and your amine group and it’s this joining

26:02-26:09
element where the names come from. So it can either be joined by an amide or an ester. Now an

26:09-26:14
ester, as we know from remifentanyl land, means that it’s actually quite susceptible to breakdown

26:15-26:22
at the tissue site because we have plasma and tissue esterases and quite a lot of them floating

26:22-26:29
around. So ester local anaesthetic agents don’t last as long. They’re broken down at the site of

26:29-26:36
action but also in the liver whereas amide local anaesthetic agents classically only really broken

26:36-26:43
down in a distant site i.e the liver and they are often N-dealkylated by that virtue they last

26:43-26:47
longer. Now you’re probably trying to think yeah that’s great we’ve got classes but then what drugs

26:47-26:55
go in what class? A big long list the chief amides to know about bupivacaine, levobupivacaine which is

26:55-27:03
a stereoisomer of bupivacaine, which is an enochumeric mix, lidocaine, repivacaine, and

27:03-27:09
prilocaine. ESTA, local anaesthetic agents, we’re talking cocaine, emethocaine, procaine.

27:10-27:16
And there’s a cheeky trick, if you’re not sure, in an exam which is which, is that cocaine,

27:16-27:23
emethocaine, and procaine all have one I, one letter I in them, whereas bupivacaine,

27:23-27:29
levopupifacaine, lidocaine, ripivacaine, prilocaine, two eyes therefore must be an amide. Science in

27:29-27:35
action guys. Wonderfully technical stuff. So we’re going to push into a little bit more about the

27:35-27:41
pharmacokinetics, pharmacodynamics. We mentioned earlier that pKa influences onset time, the

27:41-27:45
concentration of drug at site obviously influences onset time, more drug available, more action,

27:46-27:51
the lipid solubility influences onset time, and then the nature of the connective tissue around

27:51-27:56
that nerve. So we know that epidurals take longer because it’s got further to diffuse in, we know

27:56-28:03
that a spinal when it’s floating around smack bang next to that nerve, faster onset time but also in

28:03-28:08
your space there may be more or less distance for that local to travel and the nature of that tissue

28:09-28:14
might be different. In younger children fascia generally a bit thinner, generally slightly

28:14-28:19
faster onset of action of local anaesthetic around that nerve but because kidneys have a nice speedy

28:19-28:25
cardiac output more gets mopped up from the site and broken down so maybe faster on set but it’s

28:25-28:31
cleared quicker. So if we’re going to dip our toe into some pharmacokinetics there’s a number of

28:31-28:39
elements that influence absorption and distribution so the vascularity of the site, the dose you give

28:39-28:43
and whether or not you introduce vasoconstricting agents to that site as well, things that are going

28:43-28:49
going to reduce the perfusion of your target site in order to preserve the dose of local in that

28:50-28:55
site for longer. The nature of the drug’s protein binding, so bupificane 95% protein bound,

28:56-29:02
or idocaine 70% protein bound, creates more of a pool of local at the site. This is turning into

29:02-29:08
the extensive episode I imagined it might end up being. So now feel free to pause and make a cup of

29:08-29:14
tea guys or mow the lawn whilst listening you know be active be efficient and we’re just going to touch

29:14-29:20
on toxicity of local anaesthetic agents and I’m sure your brain immediately jumps to intralipid

29:20-29:26
last VF but also we need to think that actually if you accidentally inject your local anaesthetic

29:26-29:32
inside the spinal cord that’s bad news it is directly neurotoxic and you can cause bother

29:33-29:39
There’s something called conus medullaris syndrome. That’s the little tapering end of the spinal cord

29:39-29:44
that, if you jab, demonstrates a distinct set of pathology. It looks a bit like corda equina syndrome.

29:45-29:51
So that’s why you don’t inject unless you’re definitely getting some CSF dripping back,

29:51-29:57
or the patient goes, ow, when you inject. Reduce your odds of getting yourself in a pickle.

29:57-30:07
If you’re not getting CSF back, I would be hesitant to inject unless you were explicitly sure or there was some weird reason why you wouldn’t expect CSF to be coming back.

30:08-30:16
Maybe they’re led on their side and they’ve had a huge lumber drain of CSF because they’ve got high intracranial pressure.

30:16-30:20
These are niche things. If you’re not getting CSF dripping back, I’d say you’re probably not in the right place.

30:21-30:26
don’t make your life hell by injecting and then not having a spinal because you’ve just squirted it

30:26-30:32
in their paravirtebral muscles. Oops, may have been there myself. Fairly sure it was an epidural.

30:33-30:38
Anywho, we are interested in systemic toxicity though because it can be lethal. Now you’re

30:38-30:44
unlikely to cause it with your injection of spinal bupivacaine because your dose is quite low.

30:45-30:53
The danger zone is repeated epidural top-ups in labour, for example, or someone with an

30:53-30:59
rectospinate playing catheter in who’s been having some extra doses or someone puts too much of a

30:59-31:04
drug down there, or when we are conducting regional anaesthetic blockade in theatre and we

31:04-31:13
inadvertently cause an injection intravenously of local anaesthetic. You will get a spectrum of

31:13-31:20
symptoms, early and late. Early symptoms are CNS excitatory. You get perioral tingling,

31:21-31:28
tinnitus, agitation, weird taste in your mouth. And then you have a CNS depressed phase. They get

31:28-31:35
drowsy. They become unconscious. Seizure activity. And then from a cardiac perspective, you get a

31:35-31:43
hypertension followed by a drop in myocardial contractility and subsequent arrhythmias and

31:43-31:51
these arrhythmias could be acystole, VT, VF, weird bradycardias and then cardiac arrest. Then you can

31:51-31:57
obviously presume that if you manage to anesthetize your CNS with local anesthetic you’re gonna become

31:57-32:04
apneic. So this is a disaster and it is an emergency and you can’t deal with it by yourself

32:04-32:11
So you’re going to do the obvious things, declare an emergency, call for help, oxygen on the patient, and get out your quick reference handbook.

32:12-32:13
The QRH is your friend.

32:13-32:26
Get someone who’s competent in theatre to start reading out the steps, i.e. sister, because they will know exactly where the stuff is, who to send for what kit, allowing you to focus on the patient.

32:27-32:33
You don’t care where the intralipid is, you just want someone getting the intralipid, because you’re not going to go and run and get it yourself.

32:33-32:40
Trilipid is the treatment of choice other than managing your ABCDEs and going down the ALS

32:40-32:47
algorithm alongside intralipid if you have a cardiac arrhythmia. The dose is 1.5 millilitres

32:47-32:54
per kilo as a bolus and then you start an infusion at 15 millilitres per kilo per hour.

32:55-32:59
But read the handbook because it’ll tell you exactly what to do. The mechanism, if you put

32:59-33:06
loads of fat in someone’s plasma space then you partition off that local anesthetic that is zooming

33:06-33:10
around the plasma so that it becomes inactive because it’s quite happily sat in a little

33:11-33:17
molecule of lipid. So folks that was extensive but I hope that contextualizes local anesthetics

33:17-33:23
and gives you some structure to hang your study off of and it will inform the rest of this local

33:23-33:30
anaesthetic chapter of Gas Gas Gas. So where should you go for some reading? Check out the AAGBI

33:30-33:35
guidelines on local anaesthetic systemic toxicity. Really useful. There’s a bunch of great BJA

33:36-33:44
articles on local anaesthetics. And Dr. Erskine, Robbie Erskine of Royal Derby Hospital is a bit of

33:44-33:49
a local anaesthetics boffin. He’s been recently featured in the Block It Like It’s Hot podcast.

33:50-33:55
great podcast series. The episode I’m thinking of is all about neuroaxial blockade and local

33:56-34:02
anaesthetic choice for brief blockade, i.e. prilocaine and chloroprocaine. Have a look.

34:02-34:07
I’ll link it in the show notes. Anywho, thanks for listening. See you next time when we’re gonna

34:08-34:13
do bupivacaine and levobupivacaine. Cheers, guys. Hey, folks, you might have realised that this

34:13-34:20
episode sounds a bit different. Well that’s because my 90-day free trial of Logic Pro has

34:20-34:26
run out and I’ve had to resort to other inferior technologies. It makes me come to realise that

34:26-34:29
actually if you want to do a good job you have to spend a bit of money on a podcast.

34:30-34:36
I’ve already coughed up for hosting a relatively decent microphone and then now some editing

34:36-34:42
software. It makes me realise why folks set up systems for donations when they do podcasts.

34:43-34:44
So I might try and figure that out.

34:44-34:45
I don’t really know how.

34:46-34:48
Anyway, I apologise if it sounds a bit squirrely.

34:49-34:50
I’m trying to sort things out.

34:52-34:53
Thanks for listening, guys.

34:53-34:56
I hope you found it useful, but if you found it awful, do let me know.

34:56-35:00
Please like and subscribe, register with whichever podcast platform you find yourself using,

35:01-35:03
and leave a comment if you think I need to square something away.

35:03-35:04
I just want to make

35:04-35:07
sure that you guys know that every day you are getting better at this.

35:07-35:11
There is a bucket of content to try and consume, and it is like drinking from a fire hose.

35:12-35:16
Take it day by day, don’t overcook yourself, don’t freak out, and keep studying.