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And welcome to my talk today on pain management in the patient with deranged liver function. So this talk is aimed at medical students, foundation doctors. Um And there's plenty of other talks that we have in this series. There are Pain management series that you can find on medal so far has been broadcast uh general principles and our pain management ther use in these. We've got a few more exciting ones coming up which I'll talk about at the end. Um but stick around and you can see that. So we're gonna start now and we're gonna talk about the first of all, see all the different things that we're gonna cover, just make sure my slides are working. They are good. So today we're going to talk about how are drugs metabolized by the liver. What are the effects of the range of liver function on pharmacodynamics and pharmacokinetics? Um A brief consideration of what happens in coexisting renal impairment. I'm going to do, go through some specific medications that we're gonna talk about gonna present a case and then summarize some key learning points. Um and some things that we can refer to in the future So it starts off. I'm gonna get a pole just to see where everyone is at in their career stage. So you should see that coming up on medal that you can have a choice to answer. So go ahead. Should be in the message box or the poll box that you should see on your variety of your screen. Ok. We'll keep that out there. So we've got m mostly foundation um doctors, some medical students and some higher grades as well. Fantastic good. So now we're gonna talk about hepatic drug metabolism. So back to basics, back to medical school, a bit of preclinical science to understand where we're going with all of this today. So I'm using this image in a context of um oral medications. So we first go through, we have our medication up the top just over here. This goes through our digestive tract, makes its way into our intestines for instance, and then gets absorbed by our circulation. This then gets brought to our liver by a portal circulation and undergoes one or both of two phases of metabolism. So phase one is known as our of oxidation phase can also be a reduction or hydrolysis and this is mainly done by our liver enzymes. So an example of a class of enzyme that we always talk about are, are C YP 450 CP 450. Um This can either make a pro drug active or can make a drug inactive depending on the process that's going there. And then we have our phase two reaction. So again, this can happen independently of the phase one or it can happen as well as the phase one. And this is a conjugation reaction. So this is when you get an extra sort of little group that gets added on to the medication, again, can make it active or inactive, can make it soluble. Um So then it can move into the phases of excretion, which can be to our kidney can be to our gallbladder, um, or sometimes en reenters our circulation. So something to bear in mind here is, for instance, with an oral medication like this, this initial bit of metabolism is called our first pass metabolism. And so this is our first stage and then what all oral medications are based on that they're going to go through this little bit of metabolism first before they even reach our circulation. But this process is continuously happening with medications going through our bloodstream. So when we talk about liver impairment, um, can anyone put in the chat box, any kind of features of liver impairment that you think might affect? Um, our drug pharmacodynamics and kinetics to anything that you think can happen in an impaired liver that might mean that our drugs aren't gonna work the right way or something strange is gonna happen with how they're distributed or anything like that. Any guesses? No. Ok. That's all right. So we'll give some suggestions. So the liver produces lots of stuff, lots of stuff that's very important. One of them is albumin. So albumin is one of our main binding proteins in the body. And some drugs are bound by albumin as they flow through the body, this prevents them from going out of the kidney and also prevents them sometimes from interacting with receptors. So if we've got a lower albumin than normal, more of our drug is going to be filtered through the kidney. And more of our drugs are going to potentially be free to act on binding sites. So a bit of un unpredictable effect of action sometimes because of that. So as we spoke about before as well, um our liver is the site of processing for our phase one and phase two reactions. If we've got cirrhosis, we've got a decreased cell mass of our liver and therefore less space for these reactions to happen. And further on top of that, we have less liver enzymes. So less catalysts for our phase one reactions to happen. All of these can lead to less phase one processing of our drug. And depending on the drug, this can mean that it acts more or less than we intended to. So in someone with liver cirrhosis, they've often got portal hypertension. Now, what this means is you've got a backup of the blood flow going through the liver essentially. And what this causes sometimes is what's called portosystemic collateral. So this is collateral blood vessels that kind of bypass the liver. So with this happening is you'll have the drug absorbed by your gastrointestinal blood supply and then going straight into your systemic circulation while bypassing the liver, meaning you don't get that first pass metabolism again, depending on the medication. This can mean that more of the drug is active or more is inactive than you'd normally expect ascites. So for those who don't know, ascites is when you get a redistribution of fluid um in liver failure. Um and it often ends up in your sort of peritoneal cavity. Um And what can happen here is a lot of the drugs can sometimes build up in that space, especially if it's water soluble. So therefore, you have drug in the wrong place essentially, again, affecting its um pro possibly decreasing its efficacy and moving on similar to decreased liver, liver enzymes, decreased cell mass, you've got decreased conjugates. So, decreased extra groups are going to add onto those drugs in the phase two metabolism. Again, a bit more of a variable effect of the drug depending on whether what its metabolism is in which direction that's gonna go and lastly decreased bile. So, bile is important for the excretion of medication. Um The once they're made soluble, the drugs move into that bile and get excreted that way. If you've got decreased bile, you've got decreased excret excretion essentially. So all of this entirely can do decrease or increase the effect of the drug that you're trying to do um increase the amount of toxic metabolites, cos stages of the processes that are normal are being held up or delayed. And for some drugs can increase the risk of hepatotoxicity and encephalopathy. So it can be quite dangerous to give the wrong drug or the wrong dose for a patient with liver impairment. So these are quite important things we need to consider. So when we're thinking about this and we think how to kind of risk stra stratify, um which patients have deranged liver function. Um Can anyone tell me how we would normally measure liver function? So if you can write in the chart, any ideas come on deep breath, any guesses? No. Ok. Well, some people might normally use our standard liver function test panel, commonly known as LFT S. There we are. However, this is not a good way to measure liver function. Uh ironically by the name of it. So our liver function tests often measure a bunch of liver enzymes, they don't accurately predict and they don't correlate well, with your overall liver function, they can show you lots of useful stuff but not your active liver function. The the gold standard to find out the liver function and to find out what degree of cirrhosis there is would be things like elastography. So stuff like fibroscan is the brand name sometimes that see in the UK here, radiology So you can sometimes see evidence on ultrasound or evidence on ct scan, things like that. But the best, best best is biopsy. So you can take a sample of the liver. Unfortunately, when you have a patient that's sitting in your emergency department or sitting on your ward, you can't always just go straight in, get a needle and stick it into the liver to test what, see what their um the quality of their synthetic process is. So instead we use a nice composite score called the child Pugh score. Um And this is a way that takes multiple aspects of the synthetic function of the liver. So, such as the bilirubin, the albumin, the I nr because the liver produces clotting factors. Um and then takes into account um peripheral signs of liver disease such as ascites and hepatic encephalopathy to determine the level of derangement in that liver function. So as you can see here, it's all fairly straightforward. Um each of these scores, you a certain amount of points depending on what your levels are. Um and something like this can be found on MD CALC where you can look it up and you type in on your phone, it's very quick or you can find plenty on the internet. Ok. So very useful little screen, but you do require a bunch of blood tests first. So before we go into specific medications, while it's not strictly um deranged liver function, um things like certain medications can alter your hepatic metabolism of medications. So, if we look at this little mnemonic for us, sick faces.com, this decreases your, um, activity of your liver enzymes. So all these medications, if you're taking them alongside, some other ones, they will decrease your metabolism and our scrap gp in the morning, that will increase our metabolism of those liver functions. So, again, these are our phase one reactions. So if you're giving anyone a medicine that is dependent on that phase one reaction alongside one of these medications, it's important to know what that might do to that metabolism of that medication. One important thing to note in this is alcohol. If you take it, if you have an acute ingestion of that like a binge drinking, um that's going to decrease the metabolism of your liver enzymes. However, if you have that over a long period of time, your body will eventually adapt and you will have increased metabolism of those. So bear these in mind. This is not the range of liver function necessarily, but this will cause altered metabolism of your medications. Great. So we will jump into some specific medications today. C let's talk about the first one, paracetamol. So this is the big scary one that everyone thinks of when we think about liver injury, often because of the toxic effects of of the metabolites in the liver. If you take an overdose. So as you can see from this little graph, most of it goes through that phase two reaction, 95% to be conjugated where a small amount goes through our phase one reaction and um turns into a toxic metabolite before then getting conjugated itself. Um And this is this stage of the process with our glutathione gets overloaded um in our paracetamol overdose leading to a big build up of this toxic metabolite. However, if you've got someone with liver disease that's not necessarily taken an overdose, what are you gonna do about it? Does anyone know does, is it something they might want to prescribe, not prescribe any guesses, feel free to message on the chat. No takers. That's OK. That's all right. Um So you can be safe with this one. So even in the most severe impairment, you can give paracetamol. However, something to consider is reducing the dose. So this would be something like giving a 500 mg dose as you would do with someone who's under 50 kg or giving an overall reduced dose in 24 hours such as 3 g. This is backed up with a lot of local guidance. Um but always make sure to check, check, check your trust guidance on this issue, cos they will specify what they might want you to do. For instance, in this case, whether it would be a reduced dose over 24 hours or reduced initial dose per interval. Ok. So, and this is just to specify as well. This is even in stage c of um, the child's Pugh score. So the most severe cirrhosis you can give paracetamol. So don't be too afraid of it when we talk about another medication. Uh, nsaids or Ibuprofen, naproxen, et cetera, these should be avoided. So, the big thing with these, despite the fact that they're not actually metabolized by the liver is that they are, um, they are quite bad in our, er, in, with, in, with the risk of er varices. So our liver patients, they often have, as we said, portal hypertension, they can get esophageal varices, nsaids increase your risk of gi bleeding. As you can look back in our general principles of pain management talk, it explains the whole mechanism. Um And therefore we want to avoid this risk additionally because they're renally excreted. We have a condition called hepato renal syndrome where due to hepatic damage, you can get liver impairment backing up secondary to that. And if you do have hepato renal syndrome, then this might not be the one for you. Also, for that reason, as you want to avoid it in severe um kidney problems as well. Topical use is a bit of a question. Some places advocate for it, some people are against it. Um The amount of systemic circulation is debated. Um However, if you're using a small amount in very, in moderate cirrhosis and moderate impairment, it might not cause a problem. But it's important to note how often people are using it and how wide surface area are they using it on as well? Ok. So moving on, we've got opioids. So this area is a bit more highly contested. There is no strong, strong, strong, strong, strong evidence to back up a lot of the guidelines that are in er, use for this. A lot of it is expert opinion. And so you will find varying guidance based on where you are. Again, I'd recommend to use your local guidance here because they will advocate for certain dosing and certain medications in certain situations. However, um what I've used to pro to produce this um presentation is a combination of some of the um most respected guidance out there. Um So again, take this with a bit of a pinch of salt. So they're mainly metabolized in the liver, but some have active or toxic metabolites which go through the kidneys. Um, you should use them with extreme caution with all patients with impaired renal function. Again, look at um, the talk on impaired eer knees um for more information about that. Um and a lot of them have pro drugs. So, um what I mean by this is they, they're given us pro drugs and then the liver metabolizes them into the active component. And if you have the range of liver function, as we said before, that might give you a variable effect of that medicine, um, now they also can worsen encephalopathy if you've already got it um due to their sedative effects and I wouldn't advise prescribing anything long acting or without senior advice. Uh due to, again the effects on metabolism, um we classify them into strong and weak um opioids. Um and we'll go through the strong ones first through with some examples. So, morphine, everyone's favorite. This is potentially one of the better strong opioids in liver cirrhosis. Um ideally you can use it if the EGFR is above 30 start at a lower dose than you normally would. So an example would be 2.5 mgs um or APR N 4 to 6 hourly. Of course, it does depend on the weight of the person. If they're much smaller, you'd give a lower dose. If they're a much larger person, you'd consider giving a higher dose. Um problems with liver impairment is it has much higher bioavailability. So we spoke about that first pass metabolism. If you're taking this medicine orally, it's very reliant on that first pass metabolism. Um So it's going to change your levels of serum drugs that you know, and if you have an increased risk of side effects, so it's always good to look out for. Again, hepatic encephalopathy due to the sedative effects, things like constipation, nausea as well. So some other ones we have on option. Um again, with reduced renal function are fentaNYL, HYDROmorphone and oxyCODONE. So, depending on where you go, some places will advocate for HYDROmorphone over fentaNYL or a fentaNYL. Um When we talk through fentaNYL itself, it's got no active or toxic metabolites. So it's often quite a nice option for this and you can use it in reduced renal function. You would have to reduce the dose. One downside of fentaNYL is that there's no oral option. So this is an IV or subcut option. So, not suitable for those ones that aren't in hospital HYDROmorphone. Um You don't get a, a changed half life in liver disease that's quite handy. However, in the B NF, the manufacturer says avoid, despite this, there are multiple guidelines that suggest the use of this medicine. Um I would reduce the dose, increase the interval that you normally give and notice it is much more potent than morphine. So you'd give a smaller dose. One example of a dose that you might give here would be 1.3 mgs, um eight hourly P RN. And this can be an oral option as well. So it's a nice kind of use for that oxyCODONE. So this is our next one. This can't be used in severe impairment. So it's limited to those possibly stages A and B cirrhosis, it's twice as potent as morphine. So it's very strong. Um You'd consider a dose of maybe 1.25 mg, six hourly uh P RN. Again, you can space out those intervals even more if you'd like. Um And it's, it's an option for some if you're not tolerating oral morphine. Um and you have some element of renal impairment, something to think about. And of course, with all of these, consider your doses in light of the renal function and the renal distribution of that medication. Again, for more information about er, prescribing pain management in altered renal function. Look at our previous talk on deranged user knees. So, moving on to our weak opioids. So codeine's our first one, the best advice for this one. Avoid. Ok. So this is the codeine is a pro drug. It gets metabolized. If you don't have a great active phase one metabolism, this might get a bit messed up. You have an increased half life, increased plasma concentration, increased side effects with taking this with the liver disease. Um So do please try and avoid it. It's going to have an unpredictable therapeutic effect. TraMADol. This is a bit more of a grayer area. Um try and avoid if you can, but it's not a complete con contraindication. Um It will decrease your seizure threshold. Um You've got again, a very unpredictable analgesic effect, like most of the weak opioids here with liver disease and there's a risk of serotonin syndrome due due to its serotonergic uses. So avoid, especially if you're having other medicines that will increase that risk again. Yeah, avoid or increase a dosing interval. It's excreted by the kidneys metabolized by the liver. So think about your renal function and um you'd, I'd only really use it in moderate impairment if there are no other options available to me. So, adjuvant a brief touch on these ones. Pregabalin and gabapentin, they're all wonder drugs. Fantastic. All good. They're renally excreted. If you think about liver impairment, they're all good. But obviously, if they have got coexisting renal impairment, give that a think, uh, amitriptyline. Um, so this would be, uh, not so great. Um, try to use nortriptyline if you can. Um, again, you would avoid all of these though, in severe impairments, you have an increased risk of side effects, sedation. Um, also intestinal stasis and all of these can, um, induce hepatic encephalopathy, which we do not want. It's a very phaseal dependent, not the best. Um, so avoid it, basically. Cool. So that's all of our specific medications. We've been through a whistle stop tour. Now, we can talk a bit more about a case. Cyp. I'll read it out to you. You've got a lot of information here and there will be a question in one of the poles. Um, I will just release that poll now. So you can start answering if you feel ready. But a disheveled 58 year old gentleman limps into the emergency department and he's carrying an almost empty bottle of vodka. His presenting complaint is queary ankle fracture and you don't have access to any of his past medical history or his current medications. As normally goes, he's out of area. You have nothing on your system, his routine bloods from two weeks ago. However, cos he seemed to pop in or his GP requested, who knows? Um, his eeg fr was fine. It was 70. Um, Bilirubin was 40 Albumin 27 and I nr 1.8 the triage nurse comes to find you. You haven't picked him up yet. He is crying out in pain. Paracetamol hasn't helped and he's wearing lots of clothes. You can't really look at him properly and he won't let you examine him or take a proper history until he's had some analgesia. He wants some pain relief. He says he has no allergies. What are you gonna go for? So we have the options here of 200 mg of ibuprofen orally, 50 g of traMADol orally, 2.5 mg of morphine and 15 mg of codeine. Now, things you need to think about here is obviously estimating his um deranged liver function. And what, what, how, what his, what's his level? Um What different classification systems he gonna use to score it? Is it that bad? Um And from that, we can work out where we're going to go with this case. What we're gonna prescribe. So let's have a look. You've got five responses so far. So when I know there's more, more than five of you here, give us a nice answer. Your best guess. Got six sponsors. Good, good. A couple more. OK. We'll leave it at that. Oh, no, we just got another one as well. Fantastic. So, keep answering and we'll talk through how we're gonna work through this case. So, this gentleman has some pain paracetamol has not worked. So that normally would be our first shot for some pain killers for a, a little bit of pain. But obviously this guy's crying out in pain, he's got pretty bad pain. Um, and we need something else to give him. So what w what we'd use for? Um, our liver impairment is as we specified earlier in our presentation, we think about our child's Pugh score for this gentleman. So I've got it up on my phone here so we can talk through it. So our bilirubin is our first bit over there. His bilirubin is 40. Um This level would score him two points. Then we go down to our albumin. His albumin is 27. Um This would just meet him the requirement for three points there. Er I nr now 1.8 that was given another two points and we can't really answer if he's got ascites or encephalopathy. Cos he's not telling us anything. He's being a bit um annoying essentially. Um So we've got a total of nine points. So that would classify him as child class B obviously, if he had anything like um encephalopathy or ascites that would push him over into c so this guy is moderate or severe risk of um cirrhosis cirrhosis. Um And so we've got to think accordingly with that. Now, out of our, our, our options that automatically excludes our ibuprofen. So we know this guy has liver cirrhosis, possibly severe liver cirrhosis. We definitely don't want to be giving that due to our risk of gi bleeding. Um, although his kidney function is ok. Um Our traMADol again, we want to avoid, we only really think about if there's no other option in our moderate impairment. So I would probably avoid that. Um I'm glad all of you haven't picked codeine as well. Fantastic. We don't want to do that. The, it's a prodrug and we don't know how many of the effects are actually gonna get in terms of the analgesia, but we know he's gonna get side effects from it. And a lot of you, 70% of you have picked our morphine, which is our correct answer starting on a nice small dose and seeing how it goes and titr to effect. So fantastic. Very good. So moving on from this case are key learning points that we've got vitamin P or paracetamol people can have it even if you have liver impairment. I've seen lots of cases um throughout early, you know, medical school and foundation years where colleagues are quite hesitant to prescribe paracetamol in someone with a raised ast or something like that, unless they've had a paracetamol overdose or unless they're, they basically do not have a liver, you can give paracetamol again. Look at local guidance um to specify your dosing strategy or what, you know, whether it's decreased dosage or er, spread out over wider intervals or a decreased overall 24 hour dosage, but you can give it. So also your LFT S, um your, you know, your blood panel does not necessarily equal the range liver function, use your child's Pugh score. Save it as a favorite on MD CALC on your phone. You've got it handy if you need it. Nsaids and weak opioids just avoid uh it's not worth it. There are some people who say dihydrocodeine might be a good option. Um But again, it does have a bit more of an unpredictable therapeutic effect. So easy way is just try to avoid it really strong opioids. Think about your morphine and HYDROmorphone. Think about your fentaNYL. Again, look at your local guidance, guidance guidance. Some will specify they want you to use fentaNYL, some will specify they want you to use HYDROmorphone potentially. Um It again, you can't give HYDROmorphone IV from what I remember and you can't give fentaNYL oral. So it depends on, I guess of the route that you're giving it. And lastly, pharmacists in hepatology, they are your best friends. If you are in doubt. If you're a bit stuck, if you don't know what to prescribe, give them a call, they're on the end of the phone. Um Some places won't have Hepatology, but you'll have gastroenterology. Um or you'll always have your seniors on hand to help you. But this should give you a nice solid basis of things to think about in your cases with deranged liver function. So some good resource to look at the B NF has got some a nice summary on some of the different problems and issues that might come about when you're prescribing a liver impairment. Generally, the B NF is quite cautious with lots of medicines in terms of what to give them. Definitely check it before you give them medicine. Um However, for instance, in the case of HYDROmorphone, I think it was uh the BNF says the manufacturer says a void, however, it is used widely. So um take it with a pinch of salt, use some of these other guidelines as well. Um So the British Association of the study of the liver um released a whole nice analgesia guideline um for the people with advanced liver disease, it's just dosages, intervals, et cetera um for these things. And we've also got some great summaries from the West Midlands palliative care. Um They've got again, some suggestions on opioids. Again, a lot of these are from um expert opinion rather than a lot of evidence. So you will find a different in the guidelines and the research papers you use e as always if there is local guidelines use that first. So that brings the end of our session. Um just to summarize, we have already had a session on the general principles of pain management. Fantastic in depth. Talk about different medications, how they work. Um, a real good grounding and basis understanding. So, I'd recommend having a look at this if you haven't already. Um, and then our pain management with the range E and E is quite relevant to our one today as well because there are a lot of patients that have coexisting renal impairment with liver impairment. We have a couple coming up over the next few months, the dates will be released soon. Hopefully, uh We've got pain management in palliative care, chronic pain and non pharmacological methods of pain management. And then we've got pain management in the trauma patient as our final one. So look out for these. Um we, we'd hope to see a lot of you there. Um And now we've got some time for questions. If anyone has any, you can feel free to put them in the chat or feel free to unmute your microphone if that's possible. Um But go ahead for it. If you've got any questions, I don't think we've got any questions so far. Well, in the meantime, while you're thinking of any questions, if you do have one, we've got a feedback link um which I would greatly appreciate if you could answer if you've got any um positive negative feedback ways we can improve this series ways we can improve this talk, feel free to shoot us a little bit of a message on there. Um Tell us how we've done. Um We want to make this er, series as engaging and as fun um and as interesting as possible. But otherwise, um if you've got no questions and you've filled in the feedback, feel free to leave, otherwise stick around, you can ask any questions you have. Oh, and thanks also Maria for posting the little link down there um where you can fill in the feedback as well as scanning the QR code.