Hello, and welcome to the first of a two-part series of discussions of local anesthetic pharmacology for central interaxial techniques with a specific focus on obstetrics and obstetric anesthesia or analgesia. I'm going to spend the first bit or part 1 at least of this talking about the clinical pharmacology, the science, so to speak, behind the local anesthetics. In the second part, I'll talk about the clinical application of how we use these medications in clinical practice. I have no disclosures. You will see that in all of my lectures, I have the same slide. I'll say the same thing. Here are the learning objectives. I won't insult your intelligence. You have access to these through the slide set and you can read them there. When we start talking about local anesthetics, we know that local anesthetics are drugs that block sodium channels. In particular, the sodium channels on nerve tissue, particularly either peripheral nerves or nerves as they exit the central nervous system. Or we inject them into the CSF in the central nervous system, and then they can actually block those sodium channels right at the level of the spinal cord. Interestingly, we know that there are actually nine different subtypes of sodium channels in the body, and this was discovered a while ago actually in the lab. This is a fairly recent article that talks about the characterization of these specific ones. Just the cliff notes version of all of that is that of those nine different types of sodium channels, these were all figured out in the lab or deduced in the lab, related to the use of teratotoxin, which is a neurotoxin excreted by puffer fish actually. They excreted on their scales so that it deters predators from eating them because it is a neurotoxic, and most predators are adverse to that particular exposure. We were able to group the sodium channels into two groups, either teratotoxin-resistant or teratotoxin-susceptible. Further, then they've looked at these and classified where these actually live in the body. Sodium channel subtype 1.1, 1.2, 1.3, and 1.6 live in the central nervous system. 1.7, 1.8, and 1.9 live in the peripheral nervous system, and then 1.4 and 1.5 live in the muscle. It doesn't really matter because our local anesthetics work on all of these different subtypes. However, there is some suggestion in the current literature that we might be able to develop local anesthetics or use currently available local anesthetics to target very specific sodium channel subtypes. Here's an article that talks about the sodium channel 1.5. I will come back to this article when we talk about toxicity, we'll revisit this. That's all I'm going to say for right now, but just know that there's some really interesting things coming on the horizon for us in the use of local anesthetics in ways that we probably never envisioned using them in clinical practice. Interestingly, the pufferfish I said excretes teratotoxin, it's a neurotoxin, it's a protective mechanism for them. It turns out that dolphins are immune to it. As a matter of fact, dolphins get high when they ingest the teratotoxin. It's interesting if you have any insomnia and you want to get deep into YouTube, there are actually some YouTube videos that show dolphins passing around a pufferfish getting high on it. It's just a big dolphin party. There's some useless information for you and let's move on. I like this particular image for a couple of reasons. First of all, here's that teratotoxin molecule. This is actually at least acknowledging the fact that we were using teratotoxin in the lab to help discern these sodium channels and their function. The other reason I like this is because when we look at the difference between what's happening extracellularly and what's happening intracellularly, on the outside or the extracellular membrane when we introduce, so we're taking a needle and we're injecting a big blob of local anesthetic out here. What we want is we want this uncharged base form of the local anesthetic to be the predominant form because it's this uncharged base form that will cross the phospholipid bilayer and diffuse intracellularly. Now, in addition to that, as you can see, some of this uncharged base form will actually hang out in that phospholipid bilayer. Remember that the sodium channel is a transmembrane channel that's a pore. It's also a protein channel. These local anesthetics have high protein binding, and so some of them will bind on the outside portion of the sodium channel. What happens is that they can actually cause a mass effect and deform the channel, which will deform the pore, and just the physical presence of the local anesthetic here can actually block sodium from entering the open channel because of that mass effect. That's pretty esoteric. It's pretty much the discussions in the labs. We don't have any evidence of that clinically, nor do we really care because we inject these drugs and they typically work. How do we typically talk about it? We typically talk about what's happening intracellularly and that's the dissociation reaction from the uncharged base form to the charged cation form. It's the charged cation form here that finds its way into the open pore of the sodium channel and blocks the sodium channel, and that's how we see our clinical effect. Outside, we want high concentration of uncharged. Inside, we want high concentration of charged or the cation. Now, we've also known for a very long time, this is 2003, that the local anesthetics not only block sodium channels, but they block calcium channels as well, and again, they block potassium channels. When we get into local anesthetic systemic toxicity, this becomes important to remember, and I'm going to revisit this when I talk about toxicity, but just to plant the seed in your mind, if you go back to neurophysiology 101 and you think about the Nernst equation and that's the equation, the equilibrium across those membranes related to the charge on all of these cations and anions in the extracellular and intracellular spaces, the local anesthetics essentially block all of the cations, sodium, potassium, and calcium. We'll revisit that when we talk about toxicity. They exist as weak bases. The uncharged form is the form that penetrates the phospholipid bilayer, and then it goes through its dissociation reaction, and it's the charged form or the cation that actually finds its way into the open pore of the sodium channel. Now, pH plays a role in this because ionization increases as pH decreases. This is important because this is related to pKa. pKa is the pH at which 50 percent of the local anesthetic is ionized and 50 percent is unionized. This is a constant for each of the local anesthetics. The important thing to remember is that the pKa is of all of the available local anesthetics that we use in clinical practice is greater than physiologic pH. pH here is less than the pKa, and I'm sorry, it's really hard to write with a mouse. That means ionization is increasing, which is really counter to what we would like. If we could design the perfect local anesthetic, it would be completely unionized or in the base form in solution so that when we inject it next to a nerve tissue, 100 percent of it would be available to cross, and then once it crossed into the intracellular space, it would completely dissociate into its cation form and therefore block the channel, but that's actually not what happens. pKa affects onset. As I mentioned, the pKa of all of the local anesthetics that we're going to use in clinical practice is higher than physiologic pH, and what we're going to use for physiologic pH is 7.4. Because it's higher, that means that the ionized form is higher in concentration than the unionized form in its solution when we draw it up from the bottom. Now, what we're going to talk about mostly in the clinical application are these three local anesthetics, because these are really the three workhorses for obstetric anesthesia. I'm going to mention lidocaine briefly, because it is the gold standard and what everything is measured against. I'm not going to talk a lot about mipivacaine. I've developed this chart for a lecture that I give in our program and I talk a lot about mipivacaine because I use a lot of mipivacaine in my clinical practice, but there's really not a lot of crossover for obstetrics, so we're really going to focus on these three. If you look, you can clearly see that the pKa of these three is much higher than the physiologic pH that we're injecting in, which means that the ionized form is the predominant form in the bottle. That's why you can see when we talk about onset, we can see that ropivacaine and bupivacaine have relatively slow onsets and that's all related to pKa. Now, those of you that are awake and have had coffee, you will tell me that, hey, McShane, you must have been smoking dope because we know that 2-chloroprocaine is by far the fastest onset for a local anesthetic that we have, and that is indeed true. There are two things that are unique about 2-chloroprocaine that actually make it so that the pKa is not what we worry about for onset. The first is that the 2-chloroprocaine is a very small molecule, and so it crosses that phospholipid bilayer easily because it's such a small molecule. The second reason is it's a concentration effect. We use 2 percent or 3 percent 2-chloroprocaine, whereas we're using half percent, 0.5 percent bupivacaine, or 0.5 percent ropivacaine. These are actually several orders of magnitude higher than the concentration of the bupivacaine and ropivacaine, and because of that, this is a much faster onset. It has to do with the size of the molecule and a concentration effect and simply the mass of molecules that we're surrounding that nerve tissue with, and that's why this clearly has the fastest onset. Now, lipid solubility is always related to potency. That hasn't changed. This is true with the local anesthetics. But actually, lipid solubility actually can slow down a little bit of your onset. The reason is because we're typically injecting these things into tissues that are surrounded by either fat or myelin, which is a form of fatty tissue. All of these fatty tissues will take up molecules of the local anesthetic and therefore there are less molecules available to cross that membrane. It's a double-edged sword. Yeah, we want it to be relatively lipid soluble, so it'll cross those membranes so that it's relatively potent, but it does tend to slow down the onset a touch. Protein binding, I mentioned that these sodium channels are protein channels. They're transmembrane channels, pore channels that allow the cation to penetrate or cross those membranes. The higher the protein binding, the higher the affinity for the channel. The higher the protein binding, the longer it's going to stick at that channel, and that's how we get into the duration. When we talk about the molecular pharmacology, we talk about three areas of the local anesthetic molecule that are important to us. We've got a lipophilic head, we've got this intermediate chain, and then we've got a hydrophilic tail. That makes sense. The lipophilic head is important for us to penetrate the phospholipid bilayer. The hydrophilic tail, this is the charged part. This is the tail that goes up and blocks the open sodium channel. Then this intermediate chain here is related to metabolism. When we look at the local anesthetics, again, we have the aromatic ring or this is the lipophilic area. This is what crosses the membrane. This is what blocks the sodium channel. This intermediate chain, we classify based off of whether there's an ester or an amide bond in the intermediate chain. That's how we classify the local anesthetics, and that's how they are metabolized. When we look at metabolism, esters are hydrolyzed by plasma esterases. These are extensively available in the body. These drugs tend to have very short durations. Really, the only one we use in clinical practice is 2-chloropropane. We don't use any of these other in clinical practice for the most part. Tetracane is still around. Tetracane is a little bit different. Although it's hydrolyzed by plasma esterases, it has such high protein binding that once it binds to the sodium channel, it just doesn't come off. That's why tetracane of all of the local anesthetics has the longest duration of action. When we look at the amides, we actually have two families of amide local anesthetics. We have the lidocaine family and then the pivocaine family. When we talk about these individually, I'll show you there is a little bit of a difference in the hepatic metabolism of these. They're both P450 systems, but it's a slightly different mechanism. We don't use prilocaine or atitocaine in clinical practice. Lidocaine is still available, but pretty much nobody's using it. Really, the two amides that we're going to use are going to be bupivocaine and ropivocaine. Now, this is where we get into the difference in how we can talk about the difference between anesthesia and analgesia. It's all related to concentration and volume. Concentration is important because we need to deliver a mass of the molecules of local anesthetic to the nerve tissue so that they can penetrate the nerve tissue and block the open sodium channel. It makes sense if we have a higher concentration of local anesthetic, we've got more molecules that we're delivering, therefore, we get more penetration and we get a better effect. Concentration is absolutely true and absolutely important and absolutely probably the most important concept when we talk about the difference between analgesia and anesthesia. Now, there are some other things that make a difference. When we talk about rate of traffic, what we're talking about is how often is that nerve fiber stimulated? How often do those sodium channels cycle through open, resting, open, resting, open, closed, resting, open, closed, resting? They have to be open for the local anesthetics to be able to penetrate that pore. I already talked about concentration and volume. We'll talk a little bit more about volume in a second. Then where does that nerve tissue lie? Is it in a big fatty mass? Is it around a lot of blood vessels? Is there a lot of uptake of the local anesthetic away from the site of injection? Now, when we talk about length, we're going to start talking about having to block three nodes of Ranvier. Now, this is where the lab comes in when we put a nerve in a Petri dish and we drip a local anesthetic on it. Then we need three nodes of Ranvier for these myelinated fibers to block the stultatory conduction along that nerve. Now, I like this picture. It's a really simple way to talk about this, and it's a simple way to really cement it into your brain. If we have a big, large motor fiber, that's right here, versus a small pain fiber, saying A-Delta or a C-Fiber here, this would be an A-Alpha fiber, big, large motor fiber. These are pain, temperature, proprioception, and very small fibers. If we put a big drop of local anesthetic on these nerve fibers, you can see that we indeed catch three nodes of Ranvier on the small pain fiber, and this is going to block stultatory conduction. There is no conduction around this big blob of local anesthetic, which means we have no pain, and the patient is comfortable. However, laying right next to this pain fiber is this big motor fiber, and you can see we only block one node of Ranvier. Stultatory conduction can jump from here and then continue down here. This is how we can have analgesia here and still maintain motor here. Hence, we have just an analgesic block. Now, if we wanted anesthesia because we needed motor, we would simply increase volume, and now this bubble would cover out here. Now, we've got two, three nodes of Ranvier, and now we've blocked motor, and now we have anesthesia. Now, that's a very simplistic drawing. It makes the concept really easy to see. I would be disingenuous if I told you that's really what happened in the body. This is what Schwann cells and myelin look like in the body. But nonetheless, this is just a nice way of putting that all together in your mind. How is it that when we inject a local anesthetic, we get analgesia, and then we turn around and inject another local anesthetic and we get anesthesia? It's all related to concentration and volume. I think I have said all of those words. Now, we don't really add additives to our local anesthetics and obstetrics for the most part with one exception, and that's the testos. When you're doing an epidural and you do an epidural testos we always add epinephrine. It's a one to two hundred thousand concentration of epinephrine and we're using it as a vascular marker. What we want to do is we want to verify that the tip of the epidural catheter is not in an epidural vein. Now this is, I've seen a lot of people, I've talked to a lot of people and I've heard that some people will do a testos through the needle then thread their catheter and then tape it in place and they do that because they think it's faster and they can get the mom more comfortable. I absolutely do not do that in my clinical practice. In my clinical practice I testos the catheter. I need to know where the tip of the catheter is because that's what's staying in the patient not the needle. I'm taking the needle out. I don't really care where the tip of the needle is. I mean to the to some extent. I mean it's got to be in the epidural space otherwise you're not going to thread the catheter. But I don't really care where the tip of the needle is. I need to know where the tip of the catheter is and so I always testos the catheter. So thread the catheter, get the needle out, put your adapter on and then give your testos. So we give three mils of one and a half percent lidocaine and one to two hundred thousand epinephrine. That's 15 mics of epi and we can use that as a vascular marker. That's really about the only time we use epinephrine in obstetrics. Epinephrine does increase the duration of local anesthetics. I added this chart just because people tend to ask that. If you've got an epidural who cares? You just re-dose. If you're doing a spinal we don't really do epi washes and spinals anymore. Epi wash doesn't really make a difference with bupivacaine and that's what we're going to use for most of our spinal anesthetics anyway. So it's really kind of a moot point. Now if we're doing peripheral blocks then yeah you can start talking about using epinephrine and some of those other things. But for the most part in current obstetric practice nobody's using epinephrine except for the epidural testos. Now bicarb, there is one area where you could use bicarb. We know that bicarb alkalizes the local anesthetic solution. It actually speeds onset. So where might you use this? I think in a true crash c-section. If you have an epidural in and you are sure that the epidural is working and it's working well, my go-to in that situation is I grab a vial. I always keep it up on top of the epidural cart. I just grab a bottle of the 3% 2-chloroprocaine. I'm drawing it up in a syringe as I'm running into the room and as soon as I get in the room I start giving the 3% 2-chloroprocaine through the epidural catheter. It is by far the fastest onset local anesthetic. By the time you get the patient into the c-section room over onto the table, if you've given 10 or 12 or 14 mils of 3% 2-chloroprocaine, you're going to have a T8 block. Certainly enough to get the procedure started and then you can continue to top it off to get up to T4 so that they're comfortable when they exteriorize the uterus. And that's what I do for a true c-section if I know my epidural is working. Now some people have told me they don't have access to 2-chloroprocaine. In that case you can use 2% lidocaine. If you add this concentration of bicarb to it, it almost approximates the onset of 2-chloroprocaine and you could use it in that situation. Again you have to mix it. Now you're wasting time so I'm not sure there's utility in it. My go-to is the 3% 2-chloroprocaine. All right let's talk a little bit about toxicity because these are volume blocks and we need to be careful of these and talk about this. This is a chart I developed for my students. I give this to them. I make them memorize this. We hammer them this about it. We ask them test questions about it. We make them do math on it and in the operating room if a surgeon knows there's a CRNA student in the room and they're about to inject local anesthetic invariably they're going to ask the student how much of this can I give and it's a great way to approximate what when we're using these larger volumes how much local anesthetic we've used whether or not we're getting close to toxicity and on and on and on. Having said that there is absolutely no clinical evidence for these numbers. This is pure anesthesia myth. There are no clinical studies. There are no animal studies. There are no concentration studies. Nothing has been done to validate these numbers. So how did we get here? I'm going to give you the CliffsNotes version. If you guys are interested in this it's kind of an interesting discussion. When we're at the workshop I'm happy to talk about it a little bit more. But there was a Swedish physician Tristan Gore who in the early 1940s came over to the United States actually went to the University of Wisconsin in Madison and did an anesthesia residency and then went back to Sweden and for about 25 years was the only board certified or board trained anesthesiologist in the entire country of Sweden. He had some good friends that were doing some clinical investigations. They were looking at a new drug. It wasn't doing what they needed it to do but when they got it on their hands they realized that their fingers started getting numb and they said hey I know this anesthesiologist maybe he wants it. So he took it he started playing with it and lo and behold in 1946 was the introduction of lidocaine and this is how we got lidocaine on into clinical practice. So AstraZeneca bought the rights to lidocaine and they went to Tristan and said hey what's the max dose and he said well you know when I give him about 300 milligrams they start to get twitchy and lo and behold guess what the toxic dose of lidocaine is. And that's literally how they came up with it. There are no human studies for this. Now there's some anecdotal evidence people have drawn you know blood samples and figured out what the plasma concentrations are for that but we have no way to deduce doses based off of those plasma concentrations. So we really still don't know at this point and it's interesting that we are using the exact same drugs manufactured by the exact same pharmacology or pharmaceutical companies and yet depending on what nation that you're practicing in we have different toxic ranges for the very same drug from the very same manufacturer. And you can see in Sweden you know bupivacaine with epi or excuse me plain bupivacaine is a little bit different than what it is in the United States. Sweden's a little bit more conservative which is kind of surprising they don't have an FDA. You can see many of ours are higher than what you would see in other countries. Some of them are the same. How did we end up here I have no idea. It doesn't make any damn sense to me. Having said that if you're at all interested in it I highly recommend this particular article. I have the reference at the end of this lecture. It's a I'll forewarn you it's a difficult read it's a technical read but you'll have a much much better understanding of local anesthetic toxicity and how we got where we are today and what the mechanism behind all of that is. So really what is it related to? There's a couple of things that it's related to. Where are we injecting it? Have we added anything to decrease the vascular uptake of the local anesthetic? And then there are some patient factors and don't forget pregnancy is one of those patient factors. When we get into a local anesthetic systemic toxicity event three of these processes happen in every cell in the body and then the fourth one happens in particular in the cardiac cells. So let's talk about the first three because this happens everywhere. So when we look at this section here in pink this is that Nernst equation that I was talking about right so these are all of the positive ions all of the cations that maintain equilibrium across the nerve that membrane and local anesthetics block all of these so they completely shut down membranes they shut down transmembrane pores and there are no there's no dissociation or no diffusion of the cations across their concentration gradient and it shuts the entire cell down. So that's the first and most important mechanism. Number two is kind of interesting and this relates back to that sodium channel subtype and when we look at it I'm talking about this green area here these are called pro-survival kinases we don't have to get into the actual ones it's not important what's important is that you realize that these are systems within each cell that are designed to keep the cell alive and what happens is the local anesthetics shut these down we stop these pro-survival kinases right which shuts down the architecture within the cell to stay alive and it induces apoptosis in other words cell death so the local anesthetics actually induce cell death by by poisoning the system of kinases that keep the cell alive that's important we'll come back to this in a second. Number three is that it uncouples oxidative phosphorylation and therefore the conversion of ADP to ATP it stops so we shut down the mitochondria we shut down the energy source for the cell so we block the Nernst equation there's no diffusion across concentration gradients we shut down we'd cause or induce apoptosis we shut down the energy supply for the cell that happens everywhere in the body and then as if that's not enough in the heart the local anesthetics bind over here by the ryanodine receptor and what they do is they block calcium as it exit this exits the sarcoplasmic reticulum it blocks calcium from binding to the actin myosin cross-linking and therefore the heart can't contract because it blocks calcium it blocks that contractile mechanism in the actin myosin cross-linking and that's how local anesthetic toxicity manifests itself in the body. Now I mentioned these pro-survival kinases are important and I'm coming back to this article now and it turns out that when we look at lidocaine levopivacaine is not in the clinical market anymore that's too bad I used to use levopivacaine it was chirocaine it was a great drug it worked really really well but unfortunately it couldn't penetrate the market because of ropivacaine anyway it the lidocaine preferentially targets sodium channel 1.5 why is that important because 1.5 is important here because it's part of the muscle where all of these pro-survival kinases are it's a actually it's in every cell but predominantly in muscle but in every cell and so there is a suggestion that for cancer surgeries particularly big debulking surgeries where they manipulate a tumor that we in anesthesia should probably run low-dose lidocaine infusions during the procedure and for 24 hours after the procedure so that any cancer cells that are shed by the manipulation of the tumor into either the lymphatics or into the blood when they then land somewhere distant to the tumor because they're so metabolically active and because they have such a rich blood supply the lidocaine would be preferentially delivered to those particular cell types and by blocking those pro-survival kinases we would actually induce apoptosis in those particular cells and we may actually increase the five-year or decrease the five-year recurrence rates may increase quality of life and those kinds of things it's really esoteric it's just being talked about in the literature but don't be surprised in the not too distant future if you start hearing people talk about this and people doing this in clinical practice particularly for cancer surgeries so what is the take-home message the take-home message in toxicity is it's absolutely the rate of rise of the plasma concentration that's the most important thing yes the dose is important but not as important yes biotransformation elimination so biotransformation metabolism and elimination is important but it's this it's the rate of rise of the plasma concentration that's the most important aspect of local anesthetic toxicity so here's the bottom line if as you don't inject a significant dose of local anesthetic directly intravascularly even relatively high plasma concentrations are well tolerated by the body so this is for lidocaine this is something that everybody learns everybody knows this we actually do know the plasma concentrations for each of these things although we don't know what dose of lidocaine will actually induce these plasma concentrations but at least we do have some of this data and it's important that we understand the progression of these things we they certainly start with circumoral numbness or numbness of their tongue and their lips sometimes they'll start smacking their lips or they'll start chewing they'll get a little bit light-headed they'll have visual and auditory disturbances that's actually very very common and important you can pick that up pretty quickly if you have a meaningful conversation or meaningful interaction with your patients they'll get a little twitchy and then it goes seizure coma death and so we just have to be really careful about it just here's a table that does the same thing but what's important we know is that it's that rate of rise of plasma concentration so if we do a very fast injection you can see we have a very steep excuse me rate of rise of plasma concentration we get a much higher plasma concentration whereas if we do a slower injection we've got a much slower rate of rise and because of that we have a much lower plasma concentration so when we put the two of these together and we see this high rate this very fast rate of rise from a fast injection you can see we're over here and we're already almost at coma right and what's after coma death so we've already passed seizures we're at coma next is death right so if we do the same injection same drug same molecules same everything else but we slow the injection down you can see now we're down here and the patient's just getting twitchy so that's the difference right so death is here twitchy is here anytime i have a choice i want to be here at twitchy we can we can fix twitchy it's really hard to fix death so the rate of rise is really important take your time don't rush now the plasma concentrations are also important we can see this is bupivacaine here's ropivacaine in every single one of these instances there is a huge safety margin between bupivacaine which is blue and ropivacaine which is pink you can see there's a huge safety margin in convulsions even bigger safety margin for hypotension large again for apnea and big again for circulatory collapse so what's the upshot of all of this if you're running an infusion and you're running an infusion for a long time ropivacaine is the drug of choice that's what you should be using for your epidurals from a strictly safety profile and that's what we use in our clinical practice now if you get into a resuscitation event you can see that lidocaine is 100 reversible in other words we can resuscitate 100 of the patients that have a local anesthetic systemic toxicity event related to lidocaine it's only 50 in bupivacaine it's like 90 in ropivacaine again huge safety advantage in ropivacaine and levopipivacaine is slightly different again it's not in clinical practice anymore you don't have to worry about it so what do you do if you do get into an event obviously it's abc so airway management stop or control the seizures and here it is here's the lipid emulsions you have to use lipid it should be on your epidural trip cart you should know exactly where it is you should be able to give this very quickly it's the 20 interlipid it's the same thing that's in the tpn we give one and a half mils per kilogram we repeat it every three minutes or until the seizures stop and the patient becomes more stable and then we run an infusion for at least 24 hours they say until hemodynamically stable but we in our practice run it for 24 hours this is from azra it's the it essentially says the same thing here's all of your lipid infusion therapy and again basics right airway management suppress the seizures advanced cardiac life support and off you go now the there is an event or a secondary gain from using lipids everybody think it's kind of it's a lipid sink but the lipids actually do a couple of different things the first is from the heart standpoint by providing triglycerides you provide triglycerides as a energy source to the mitochondria if you can increase that concentration of triglycerides across that membrane in the mitochondria it will actually start the mitochondria back up it will start up the energy system within the cells and then it will also help to energize the calcium release and help pull that off of the local anesthetics off of that actin myosin by cross-linking so it will actually restart the heart now what it what it will also do is that these local anesthetics get picked up by the triglycerides once they're picked up by the triglycerides now everything's available in the cell to work but then the triglycerides then shuttle this over to the liver and the muscle why is that important liver because it's metabolized muscle because it's a huge mass of of tissue to deposit some of these local anesthetic molecules in we don't get toxicity in the muscle nearly as quickly as the small heart so much much larger volume of muscle to deposit them in and then deliver them to the liver so again it's a lipid shuttle so it's a sink and a shuttle and that is the end of part one and i will stop here i do have the references here for you and i will see you in part two thank you for your time

local anesthetics

central neuraxial techniques

obstetric anesthesia

sodium channel blockers

systemic toxicity

lipid emulsion therapy

nerve impulse transmission