Our next presenter is Dr. Thomas Moran, who is a PharmD and is the Director of Clinical Pharmacy at Lurie Children's. Thank you. Good afternoon, everybody. Thank you for having me. I feel the weight that pharmacists have been pumped up for the last two days. I'm going to let everybody down. But I will do my best. So this original talk was given by or written, made by Gideon Stitt. He was a fellow at CHOP when he did this. And so I'm not sure where he's at nowadays. But the extended version is over 60 slides. And I have condensed it a lot. And so we'll be talking like in big overviews about concepts. And I'm also the only person in this room who will not be taking their critical care exam for pediatrics. So I have that going for me. But I'll try to weigh in on exam content as I've heard it throughout the course if I think something might be relevant. So to begin, nothing disclosed. Abductives. So again, we're going to do an overview, discuss some indication of pharmacokinetic properties, whether those are ADME. I think you've seen those throughout this course. Absorption, distribution, metabolism, and excretion. Try to relate them to age and critical stages of illness. Look at pharmacokinetics and ontogeny. So I love ontogeny as a word. But it relates to how things develop over time. And then pharmacokinetic principles as they relate to first-order and zero-order kinetics. But we'll start with some broad definitions again. All the pharma words. So pharmacology, the science of drugs, including their origin, composition, therapeutic use, and toxicology. Pharmacokinetics, which is where we're going to be spending a lot of our talk, a study of the time course of a drug and its metabolites. Pharmacodynamics, the reactions between drugs and linux systems. And this was mentioned in a previous talk. But a different way of thinking about pharmacokinetics versus pharmacodynamics is that pharmacokinetics is what the body does to the drug. So absorbs, metabolizes, excretes. And pharmacodynamics is what the drug does to the body. So that's just a different way of thinking about it and try to help you differentiate between those two words. And then pharmacogenomics. Again, we don't spend a ton of time on pharmacogenomics because that is a very big topic. It's still burgeoning. It's been around for years. But how to apply it is still evolving. But I will mention some of the SIP enzymes when we get to metabolism. And maybe a drug or two that might pop up on your exams too. So to begin with an overview of absorption and bioavailability. And so these two are linked. Absorption, the rate and extent at which drugs leave site administration moves into circulation. So in simplest terms, you have a tablet of 100 milligrams. You swallow it. How long does it take for that tablet to go from your hand into your body? And then bioavailability is a fraction of administered dose reaching systemic circulation as intact drugs. So that 100 milligram tablet, if all 100 milligrams get inside your body, that's 100% bioavailable. If 50 milligrams get into your body, that's 50% bioavailability. And so very few oral drugs approach 100% bioavailability. As a further explanation, an IV drug, it's given directly into your body. So the bioavailability of it is 100%. So think of it that way as a way to differentiate between bioavailability and oral and IV. There are drug-specific factors which affect absorption bioavailability. And these factors will kind of fall into play a little bit throughout the presentation. So particle size, solubility, lipophilicity, ionization, these all play a role in how things are absorbed. So in general, the smaller the size, the more soluble, the more lipophilic, the easier things are to absorb. If you have a really large molecule, maybe a highly charged molecule, those things tend to be harder to kind of get into your body. There are also patient-specific factors. So gastric pH, there are actually drugs which need a high gastric pH because of the dosage form, because of the drug itself, to kind of transform it into a more absorbable form. I think iron would be a good example of that. High pH changes your charge, which allows for better absorption as it moves forward in the system. Gastric motility, patients who have very slow motility and have very slow motility, which we have several of those in the PICU, if you give them an oral tablet, that's going to take a while for that to get to a site where it will be absorbed fully. Regional blood flow, surface area, age, looking at body surface area to weight ratios is greater than it is in infants. So like a two-inch square in my hand is not that significant to me, but a two-inch square in an infant is going to be much more significant and could lead to a higher McBricker dose that could lead to toxicity, as Ed will talk about or has talked about in the past. Topical absorption, neonates have immature epidermal layer, increased skin hydration, subcutaneous absorption. And the idea of a critical care unit, subcutaneous absorption can be variable. So your patients have different fluid status. They could be dry. They could be overloaded. This all affects how your subcutaneous absorption happens. So it's a very good route. It can help with getting drugs into patients, but it is something to pay attention to. If you have a fluid overloaded patient, sub-Q might not be the best way to go. I do use IM. We do use IM in our PICU a lot. A lot of vitamin K is being given IM post-liver transplant. I always feel a little bit cruel giving it to them when they're craggy like that, but it's an easier way to get the drug in, and it absorbs over time and generally very well absorbed. Distribution. So this is the movement of drug from the site of administration throughout the body. So again, we're kind of moving through the ADME, so now with the D. Physiological factors that could impact this. Cardiac output. So if your drug is absorbed and your heart isn't pumping blood very well, you're going to have that drug stagnate, not move very well. Regional blood flow, capillary permeability. Again, drug factors. If a drug is highly protein-bound, it might bind to the protein in your blood and get to your site of action. Lipid solubility, transmembrane, pH gradients. Again, they go into more depth in the full-length slides, but I didn't spend much time on them here. So after distribution, there's the volume distribution. This is a theoretical construct. So some drugs, like amiodarone, to give amiodarone, there could be volume distribution for amiodarone of 60 to 100 liters per kilo. That's way bigger than anybody's body. I'm one of the bigger people here, and I'm not even close to that. So that's a theoretical construct. That reflects the fact that amiodarone is going into different sites within the body, and you're measuring their concentration in the blood. So if it's getting into different tissue types, you're not measuring the concentration there. So it's a theoretical amount of dose over concentration leads to your theoretical volume distribution. The significance of this, as I said, indicates the extent of drug distribution, aids in determining dosage requirements. So generally, drugs have a really large volume distribution. It takes longer to get to a steady-state dose because those drugs are spreading out more and going into different areas of your body, and aids in determining dosage requirements. Conditions affecting volume distribution. So volume, as you might expect. Volume affects volume distribution. So fetal accumulation, patients with renal failure, CHF, ascites, burns, depleted fluid stores, patients with dehydrated fluid restricted around diuretics, and protein binding. Reduces free drug and is variable in needs and influence. These are all things that also change over time. So looking at this graph here, you can see that we can look at total body water, extracellular water, and body fat as you progress through age. So more water in needs means that they're absorbed differently than they would be in adults, and so your volume distribution can be affected by that too. Metabolism. So biotranspiration of substance within the body to other molecular species. There usually happens in the liver, and there are two major phases. And so this is where we get into our SIP enzymes a little bit. Phase one metabolism, hydrolysis, reduction, oxidation, all your favorite terms from chemistry back in the day. Phase two metabolism, conjugation of substituents and water soluble compound resulting in elimination from the body. So the phase one metabolism, these are primarily accomplished through the SIP enzyme system. And as I was listening to these talks over the last few days, and how there would be tricky drugs you might have to account for in SIP enzymes, fluconazole is something that happens a lot in real life. So patients are on fluconazole for many, many, many reasons, and that's a very active SIP drug. We actually use it for some of our transplant patients to increase the tacrolimus levels if we're having trouble getting to a therapeutic dose. So we'll start them on a low dose of fluconazole to help get to a therapeutic dose, which is a way to use that drug beneficially, but it can also cause things you don't necessarily want to cause. So if you're starting a patient on tacro, doing a high dose of fluconazole for whatever reason, it's gonna affect your levels. And hopefully your pharmacist will catch that before you do, or your electronic system will point out, hey, there's a drug interaction here, be careful. It's still something to bear in mind. So if you see fluconazole, maybe in the back of your questions, think about, oh, is there an action here I'm looking for, or have to be aware of, to help me answer some of these questions. Phase two metabolism, I like to think about acetaminophen. So glucuronidation is the way acetaminophen is metabolized, and it's the way you're attaching a glucuronid molecule onto the acetaminophen to kind of help the body handle it. All these are ways to help the body deal with the molecules of the drugs are, either by modifying the drug itself or adding some to the drug that the body can move it along with. Back to ontogeny, again, there's a lot on this slide, but what basically we have here is we have several CYP enzymes. We have ages on the left side there. So premature up to 10 years of age. And at 10 years of age, you're at the adult CYP capacity. And so what I would point out then here is that the variable rates of CYP enzymes, or enzymes in general, as patients age, and even at one year of age or six months for CYP3A4, you're actually above the adult activity for CYP3A4. And so what does this mean clinically? Not too much, honestly. A lot of these drugs are dosed kind of age group appropriate and so that's kind of taken into effect, but if for drugs that you're using like fentanyl perhaps, maybe you're seeing it like not work as long or faster in some of these younger kids, maybe that's one of the reasons why. But there are not a lot of recommendations for how to dose through these CYP activities. Again, knowing that pharmacogenomics is still a burgeoning field, there's a lot more to be discovered. And there's more recommendations coming forth every day, but it's hard to get a consensus knowing the diversity of our patients and the diversity of drugs that are used in this. But this is just to kind of show how, again, the CYP system changes over time. Elimination. Okay, so this is excretion of substance from the body, primarily hepatic, I'm sorry, primarily renal, but there is some biliary tract excretion from the liver. You can see the Schwartz equation here. Again, active tubular secretion, transported mediated renal drug clearance exceeds GFR and then passive tubular absorption there. Again, you can see the GFR, as you guys are all aware, changes over time and directly proportion to gestational age, dramatic increase of birth, and the primary mechanism of elimination of drugs that are hydrophilic with low protein binding. So again, we're talking about drugs that are hydrophilic going out of, excreted through a urine. That's easy because they're soluble if things move forward. If it's lipophilic, you're not gonna see a lot of things excreted through the urine. So that might be more biliary tract or stool. And ICUs do ICU things. Renal replacement therapy. We do this a lot. And so there's PD, there's HD, there's CRT. Raj would talk about this probably for days. But knowing that there's changes in drug clearance driven by modality. So a patient's got PD, do they have any renal function whatsoever? Are they getting PD because they have zero renal function? That's kind of easier because then you're only accounting for the PD modality. CRT again, it's not uncommon for a patient to have some residual renal function while they're on CRT. This makes dosing complicated. I was at an SCCM conference a few years ago and there was, I'm forgetting his name, but there was a professor of pediatric pharmacy from the University of Michigan. And he's a well-known author in my circles, but he's done a lot of the dosing for renal impairment. And he did a lot of lab work and he did a lot of clinical work. And in his talk he said the dosing is all crap. It's all made up and it's not really real life. And I was a little crestfallen to hear that because I'm like, this is how I do things. I look at the numbers, look at the book. What are you trying to tell me? But it's true. These are all theoretical situations these dosing recommendations are made off of. And real life is different. Real life is harder. This doesn't help you with your exam, but maybe in practice moving forward, when you have a patient on CRT and they have some residual function and you're wondering why you're not clearing an infection as quick as you might otherwise expect. Or your levels are a little lower than you might expect for a certain drug. It's maybe because their renal function, their inherent renal function, plus the mechanical renal function are clearing things at a rate that nobody's really expecting. And so we do try to calculate a mechanical GFR in my group. It helps, but it changes a lot. Kidney tends to walk in, make some changes, drop a note, and then leave. You never actually see it happen. So you do have to kind of look in, look at their flow rates and see how much things have changed over time and see if you need to make adjustments to your drug dosing. ECMO, again, I'll vary ICU modality. It's largely due to absorption. So you can see a lot of drug changes due to absorption to the oxygenator and to the tubing. You can increase inflammation using scuff. So removing fluid with drugs or proteins on it can also remove your drugs. But this is more of a, instead of eliminations, more of an increased volume distribution. So you often have a kid who's doubling their volume distribution. So you have a small child who has now got attached to the circuit that's got his own volume distribution. While that volume distribution is fixed, it may double the patient's. And so how does that affect things for dosing? You might take, it'll take longer to get steady state, which we'll talk about a little bit later. It could mean you have to use higher bolus doses, kind of see effect. In practice, I've seen patients go on plasmaphrasis, using albumin to bind toxins or other things in the blood, but it also binds drugs. So you often might see them become a little light in sedation. And the residents would be like, why is this patient waking up? I don't understand why they're so hard to deal with if they don't like the plasmaphrasis. I'm like, well, the plasmaphrasis is working really well because it's pulling off all that fentanyl you've been giving them. And now they're awake. And so you have to think about these things and account for these things as you're treating these patients. And when you talk about that, they're like, oh, that makes sense. I should think about that or have maybe a little dose or two ready to go when I'm starting this up so I know where I'm at. And you will kind of get to a steady state depending on how long it lasts, but it takes a little while for that free drug to kind of be replenished and the patient to get sedated better again. This concept is difficult. So the biggest thing I want you to take away from this is that zero order is the amount remains constant. So it's like one unit per one unit of time. And so it's a very linear thing. First order is like a percentage. So I don't know if anybody's heard of Zeno's paradox. So Zeno's paradox is like, one of Zeno's paradoxes is if you like, if you walk 50% away to the wall, are you ever gonna reach the wall? You're never gonna reach the wall. It's gonna be this constant, like always 50%, always 50%, always 50%. So like the first order curves kind of like they approach zero, but they never actually get to zero mathematically because you're removing a percentage at a fixed percentage versus a fixed amount. The sad thing is that most drugs follow that kind of pathway, which involves in half-life. So then how much time does it take for half of that drug to go away? Half-life, again, it's derived from the K elimination, so the elimination rate constant, and the time that it takes to do half of your drug. So for a first order drug, it's 0.693 over the K elimination is equal to your half-life. The other day, there was a question about warfarin, and warfarin dosing and changes, and it was one of the board questions. It looked, I don't like that as a stupid question. I don't like the question. As a pharmacist, I'm like, one, don't tell me how to dose this, and two, like the recommendations in there, some of them I thought were dangerous. And I've had conversations with physicians, none of you, obviously, about giving like huge doses of warfarin because they weren't happy with, it's actually surgeons, but they weren't happy with how fast they were getting their INR up. And I'm like, you can't give a 10 milligram load because you don't need that right now. You've only been like a day since you started this. You don't need to kind of like load this drug up. You're gonna go super therapeutic if you do that. So back to the question, several of the answers had recheck in one day. And so like half-life of warfarin is something you guys would look up when you're kind of faced with this in real life, but half-life of warfarin is variable, but it goes from 20 hours to like 60 hours. So checking in one day, you're not gonna really see anything different at all. And often when people do that, they want to increase their dose again or give another load. And so then you're on the path where in four days time, this stuff, they're gonna start showing up in the patient's system and their INR is gonna be eight. And they're gonna be wondering why this happened. And it's because you weren't thinking about, or they weren't thinking about how this drug is actually gonna affect the patient in the time course in which you're gonna see the changes take effect. So for that drug, increasing to six milligrams and checking in two, three days made the most sense, right? And so that was like knowing a little bit about the half-life of warfarin, in which I'm not expecting you guys to know that off the top of your head, but that was an easy answer for me, because I'm like, that's the only thing that even made sense based upon the other options available. So that's my hope. Go ahead. Things like, I know a lot of times when we're monitoring AACs for brain cancer, a lot of times the pharmacist will extrapolate the correct dosing and just draw it at a long time. Is that dependent on the elimination of the drug? Yeah. Is it dependent on certain drugs? Yes. So vancomycin is nice because it's generally linear. It follows those zero-order kinetics. And so, and nothing is, it's not actually linear, theoretically, if you measure, they ought to be like a little bit of a curve to it, but it's linear enough where you can take samples within that linear phase of it, so you can estimate the area under the curve. And so that's like the pharmacodynamics of this drug, right, the area on the curve is how vancomycin works. So AUC over MSU greater than 400 is the vancomycin like gold standard. That's what it works, where it works best. And that's great for pediatrics because you can actually get away with less vancomycin because adults that, and I'm probably talking too much about this, side to side, thanks for your question, but for adults, the troughs represent the AUC better because they're like adult PKs are very similar. But pediatrics, since we're so different, pediatrics are different, so the AUC of MSU can be represented by a much lower trough, which is like, why can't I choose a lower trough goal? You can't because every kid is a little different, so you have to make sure you measure the AUC that you're getting to a therapeutic place with that. And so in short, it works for some drugs which are linear, or where you can take samples in a linear portion of that curve. So they probably did like a peak in a trough for that drug. And so they wanna do it like maybe an hour and a half, 90 minutes after the administration, and then like an hour or two before the next dose is due, which kind of like, so you're missing that IV, where you kind of like spike up, and then kind of come down, you're missing that first part, and kind of getting this like linear rate of alienation before it kind of like mellows out and it's more of a curve. So getting those two points allows you to kind of get a rough estimate for the AUC, and then make a good guesstimate on what the dose should be. And to be clear, like we don't always calculate these things by hand, there are apps and there are programs that do a lot of this stuff for us, but knowing that the inputs are correct is important, right? So knowing that the time, things are drawn at the right time, and they were drawn with the right intention is important for us. So always conversations with the nursing staff. I'm actually getting towards the end, but so this again is like the changes. So this is a little bit relevant to what you're saying. So study state, so you need to get, we'll go back here. Half-life determines dosing interval, takes about five half-lives to achieve a study state. So again, for that warfarin question, like you wouldn't wanna start warfarin and check it in two days, you're not gonna see a change. Checking in three to four days, five days, then you maybe see some bumps. There are other factors at play with that because you have half-lives of the factors that's affecting, which are still circulating in your body, which you have to go away to. And then two to the half-life represent 75 to 80% of study state. So these little loops you see on this picture, these are kind of like you're starting to metabolize. So you kind of like this little bolus, quote-unquote bolus when you take your dose, and it goes up and then it starts to curve down. That's kind of how it really looks. And so you end up in your study state, you're just this little peaks and valleys, but they're in this therapeutic range is what you want. But there's a way to get there quicker. For a lot of drugs, not all drugs, you can give a loading dose. And so I think the easiest example, most practical example of this is opioids. So if you're starting an opioid infusion, how many people in the room would just start a fentanyl infusion and walk away? Probably nobody. Because it's not gonna do anything. You're gonna be sitting there for, the nurse is gonna be yelling at you because your patient is running around and not behaving because they're still approaching that therapeutic window. But what do you do? You give a couple of fentanyl boluses, and then you start the infusion. And now they're snowed, maybe not snowed, but they're sedated with those boluses. Then the infusion catches up as the boluses coming down, and you kind of travel along that study state, which hopefully for that is a very narrow window. You don't wanna be overstated, don't wanna be understated, but you walk that line, giving the boluses first to kind of get that study state quicker versus just starting to drip and crossing your fingers and the nurse won't complain. I went through that quickly because I talk fast. I talk faster than that, I think. But that is generally what I had to talk about. So hopefully we discussed a little bit of the ADME, and again, broad concepts. These broad concepts can help you narrow questions down, I think, if you understand broad concepts about these things. Ontogeny, there's very specific things with that. I think I would focus more on, in my personal opinion, focus more on some highlight drugs. So gluconazole, googling a table with some CYPVA4 drugs that are common. I think tacrofluconazole, those are, boriconazole, those are ICU drugs, a lot of azoles, which might affect your questions, kind of like help you think through answers and narrow some things down. And then first-order, second-order, or zero-order curves. So again, the zero-order is linear, first-order's got that percentage over time. That's all I got. Hopefully it helps you guys. Thank you.

Pediatric Pharmacokinetics

Pharmacodynamics

Drug Absorption

Metabolism

Renal Excretion

Pharmacogenomics