Hi, everybody. My name is Gideon Stitt. I'm a pharmacist and a T32 postdoctoral fellow at the Center for Clinical Pharmacology at the Children's Hospital of Philadelphia, and today I'm going to be talking about five big things you need to know about pharmacology. There's probably a few more than five tucked into this lecture, but we'll make sure that we hit all the high points. My only disclosure today is that my fellowship is funded by a grant from the NICHD. A quick roadmap for what this talk includes is that we'll start with some objectives. We're then going to go over a couple of just baseline definitions to make sure we're all on the same page, then move on to a broad overview of pharmacokinetic principles, as well as integrate some changes in developmental pharmacology that happen over time, and then we'll finish with a few special considerations and some clinical application. Our first objective today is to discuss medication pharmacokinetic, or PK, properties, often summarized as ADME, as they relate to age and critical illness. So we'll go over absorption, distribution, metabolism, and elimination. Secondly, we're going to compare pharmacokinetic principles as they relate to first-order and zero-order kinetics. This is a big one that I think is very useful in the ICU when you're thinking about how quickly should I expect this drug to work, as well as maybe I'm getting either too much drug effect or not enough, and to sort of dial that effect in, how do I need to adjust this patient's dose most appropriately? We'll start by talking about pharmacology and what does this term mean. Broadly speaking, pharmacology can be defined as the science of drugs, including their origin, composition, genetics, therapeutic use, and toxicology. It can also really be used to talk about the properties and reactions of drugs, especially with relation to their therapeutic value. We'll then compare that to pharmacokinetics, which lives under the umbrella of pharmacology, by defining pharmacokinetics as the study of the time course of a drug and its metabolites. Again, going back to that absorption, distribution, metabolism, and elimination. You've probably heard this before, but it's broadly what the body does to a drug. Example parameters for pharmacokinetics are clearance, so how does the body eliminate the drug, the volume of distribution, where in the body does this drug go? Closely related to pharmacokinetics is the term pharmacodynamics, which can be defined as reactions between drugs and living systems. With this term, we're really talking about what the drug does to the body with things like exposure response relationships. If I give this much epinephrine, what's going to happen to this patient's blood pressure? Or a time above the minimum inhibitory concentration, or MIC, for a bacteria. If I give this dose or this exposure of an antibiotic, how long will that concentration remain above my minimum goal concentration? We'll now move to talking more specifically about these four big pillars of pharmacokinetics, absorption, distribution, metabolism, and elimination. We'll start with absorption, which is the rate and extent at which a drug leaves the site of administration and moves into the circulation. Now, closely related to absorption, but distinct, is bioavailability, which then is defined as the fraction of that administered dose that reaches the systemic circulation as intact drug. So, absorption is really the process of the drug going into the body, while bioavailability describes how much of that parent drug that I have administered actually makes it to the circulation. Absorption can be altered by a bunch of different factors. Starting with some drug-specific factors, particle size matters. So, broadly speaking, smaller particles are easier to absorb. Solubility, and specifically the site in which the drug is being administered, which may alter its solubility, is very important. Things like lipophilicity, ionization of the drug, all of these are going to affect how easily a drug can cross a cell membrane. There are also some important patient-specific factors. Things like gastric pH, which we'll talk about in a minute, but it can be affected by age or the use of acid-suppressing medications. Gastric motility and regional blood flow change based on age, as well as critical illness. Things like exocrine and biliary function may change how well a patient is able to enterally absorb lipophilic drugs. Surface area and the patient's age, as well as how much surface area are recovering with the drug, matter. And then I've brought up age a whole bunch of times already, but it has a big factor in the PK of children. Gastric pH changes, both based on age as well as what we're doing to a patient in the ICU. So generally speaking, gastric pH is neutral to maybe slightly alkaline at birth. And what this means is that a patient will have increased absorption of acid labile drugs, aka drugs that are broken down by acid. So the classic example here is penicillins. If you give an equivalent dose of penicillin G, for example, to a newborn and a 10-year-old, the newborn is going to have much higher concentrations of penicillin in their system because less of it is broken down, because they have less stomach acid, and therefore it has a higher bioavailability. The flip side of this is that neonates generally have decreased absorption of weakly acidic drugs. Things like phenobarbital and phenytoin are classic examples. The good thing is that by around two years of age, gastric pH basically reaches adult levels. Gastric emptying is another really important thing to think about any time we're administering any enteral medications, whether your patient is taking them by mouth or they have an NG tube versus some kind of post-pyloric tube. So overall, gastric emptying is quite slow in neonates, delayed by anywhere from six to eight hours, and reaching adult values by about six months of age. However, we also need to think about what drugs are we giving these patients. So anytime we're giving patients opioids, for example, we're going to slow down their gastric emptying as well as intestinal transit. Additionally, gastric enzymes change over time. So up to about four months of age, infants will have lower activity of pancreatic enzymes, making absorption of lipophilic drugs a little bit slower. Surface area is an important thing to think about anytime we're applying a topical medication. So the body surface area to weight ratio or the BSA to weight ratio is greater in neonates and infants compared to an adult. And the way that I like to think about this is if I covered an entire newborn in hydrocortisone and an entire adult in hydrocortisone, the newborn would receive a higher milligram per kilogram dose of hydrocortisone. We need to be thoughtful about how much of the child we're covering with a topical medication. On top of that, neonates have an immature epidermal layer and largely increased skin hydration, which can lead to improved absorption of topical medications. And this can cause a number of toxicities. So overuse of betadine can lead to something like hypoparathyroidism because of all the iodine in it. Small amounts for procedural use, not a problem. Overuse of steroids can lead to HPA axis suppression. Products with a lot of alcohol in them can cause something called gasping syndrome because neonates can't metabolize alcohol very well. And salicylic acid products can cause salicylism. Thinking about percutaneous absorption, there are a number of factors that affect how well a drug will be absorbed, how lipophilic it is. So generally more lipophilic drugs will be absorbed topically a little bit better. Surface area, which we just touched down, and how much of this patient am I covering with the drug, as well as how hydrated is this patient's skin. Overall, we'll have increased systemic exposure in children. Again, going back to that BSA to body mass ratio, the thinner stratum corneum in infants, as well as increased cutaneous hydration and blood flow. Additionally, we want to think about burned, abraded, or denuded skin. So maybe in a burn patient or a trauma patient, someone who's got a bunch of road rash, for example, have to be very cautious about what we apply topically because that is a direct port of entry into the systemic circulation. And finally, inflammation and changes in cutaneous blood flow can alter absorption. So if I've got a severely hypotensive patient who's cranked up on high doses of norepinephrine and vasopressin, for example, their really peripheral cutaneous blood flow is going to be very low. And so if for some reason they have some topical medication or maybe they have some kind of a patch on, that absorption is likely going to be much lower than it would be if they were not in the ICU at the time. Thinking next about subcutaneous and intramuscular IM absorption, because they can be very convenient ways to administer certain drugs. Broadly speaking, absorption is slower, and this provides a more sustained effect, right? So we think about sort of a localized depot effect, whether it's a long-acting antipsychotic that's given intramuscularly, or even something like anoxaparin given once or twice a day subcutaneously. It's creating this depot that slowly releases drug. Overall, obese or emaciated patients may experience some unusual absorption patterns because they either have maybe more than expected or less than expected subcutaneous tissue. And alterations in absorption likely occur with critical illness, but data are really limited in this space. So really, I try to think about in the ICU, limiting subcutaneous and IM absorption to either things that are emergent, for example, you have to intubate a patient and you have no IV and just like can't get a line, or things that you can measure, right? So we'll use a lot more insulin drips, but if a patient needs to be on sub-q insulin, we can measure blood glucose. Or if they're going to be on anoxaparin, we can measure antitannase and adjust accordingly. Next, we'll talk about distribution of drugs and how they get around the body. Distribution can be defined as the movement of drug from the site of administration through the body. There's a number of physiologic factors that are going to affect this. So cardiac output is probably the number one thing. So drugs are getting into the bloodstream, and if they're not being pumped around throughout the body, they aren't going to be delivered to distal sites. Similar with regional blood flow. So if a patient is peripherally very vasoconstricted, we shouldn't expect drug to get out to these peripheral sites, as well as capillary permeability. So if there's a lot of capillary leak, for example, maybe in a septic patient, drugs that normally would remain intravascular may leak out and become more extravascular than we would expect. There's some drug factors that play into this as well. So binding to plasma proteins is a big one. Broadly speaking, highly protein-bound drugs, things like ceftraxone or phenytoin, most of that drug is going to remain intravascular because those proteins are too big to get out of the vascular space. Lipid solubility. The more lipid soluble a drug is, the easier it's going to cross something like the blood-brain barrier. So when I think of what are good examples of generally lipophilic drugs, anything that affects the CNS, because it has to be in order to get there. And then things like transmembrane pH gradients and whether or not something is a weak acid or a weak base. And I'll give a couple examples of those coming up. We can't talk about drug distribution without talking about and understanding, at least broadly, volume of distribution. Volume of distribution is a hypothetical volume that a drug is dissolved in, relating the dose given to the concentration achieved in the blood or plasma. And I always think about it as a bucket. And all I'm trying to figure out is for this drug in this patient, how big is the bucket that relates the dose I gave them to the concentration achieved in the blood? The significance of volume of distribution is that it tells us where did this drug go? Is it all intravascular or is it broadly distributed into things like adipose tissue? It can help in determining dosage requirements. So if I know that I have a target concentration I want to achieve, and I know generally the volume of distribution, using that equation up top I can do a small rearrangement and figure out what dose I should give. And the larger the volume of distribution, the larger the dose must be to achieve the same target concentration. It's a bigger bucket, so to achieve the same concentration I have to put more drug in. There are a number of conditions that can affect the volume of distribution. So first is fluid accumulation. This is largely going to increase volume of distribution. So think about this in patients with things like renal failure, congestive heart failure, ascites, big inflammatory processes. So maybe those CAR T patients or a septic patient, patients who are burned or have lots of edema. So in this case we have a larger VD, our bucket is bigger, so if I give the same dose of drug we're going to achieve a lower peak serum concentration. The flip side of that is very fluid depleted patients. Broadly speaking they'll have a lower volume of distribution. So think about patients who are dehydrated, maybe they came in with heat stroke in the summer months. Fluid restricted patients or those who are on a lot of diuretics. These patients are going to have a smaller bucket, so if I give them the same dose of drug we'll achieve a higher peak concentration. Developmentally distribution changes over time. So neonates largely have increased total body water compared to older children or adults. Infants also have less fat and muscle mass than adults. So really hydrophilic drugs is what we're going to think about most here, that they're going to have increased volume of distribution for those hydrophilic drugs and need a larger dose to achieve the same concentration as an adult would. Then the flip side of that is that they're going to have a smaller volume of distribution for lipophilic drugs. A classic example for this change in volume of distribution are the immunoglycosides and we'll look at gentamicin dosing here. So in a neonate they have a volume of distribution of just under half of a liter per kilo and you can see that their dose is four milligrams per kilogram to achieve a target concentration. You can ignore the dosing frequency for a moment because we'll talk about clearance next. But let's compare that volume of distribution and that dose to what an adult would get. So you can see an adult has about half the volume of distribution for gentamicin. So to achieve the same target concentration as in the neonate they only need about half as much drug. So it's a great example of we have the same target in both of these populations but over time that volume of distribution has gotten smaller therefore to achieve the same concentration we can give less drug. Protein binding is another thing to think about when you're discussing volume of distribution mainly because protein bound drug is not pharmacologically active. Only free drug is. So the main proteins we're going to think about are albumin which mostly binds acidic drugs and alpha-1 acid glycoprotein which largely binds basic drugs. Now the extent of a drug binding to either of these proteins is affected by the affinity of the binding sites for that protein specifically, the number of binding sites, so less albumin in the patient means less binding sites for an albumin bound drug, as well as drug concentration. Drug concentration is an important one because this is a saturable process. So there are only so many binding sites on however much albumin is in that patient. That means that we can give some amount of drug that fills all of those binding sites up and from that point forward every extra milligram of drug that we give that patient will be free drug and therefore we would expect an exaggerated pharmacologic response. The other thing to think about is displacement can occur. Mentioned in the extent of binding section there that affinity matters. So if I give a drug with a higher affinity for the binding site it can kick another drug off. We'll next briefly touch on the blood-brain barrier because it's an important site when we think about volume of distribution and how do we get drugs there. The blood-brain barrier is formed by endothelial cells that line the cerebral micro vessels and they act as a physical barrier between the blood and the interstitial fluid in the brain with tight junctions that are between these cells that really force drugs to move transcellularly if they're going to cross the blood-brain barrier and similar for other endogenous substances. There are five primary mechanisms for substances that cross the blood-brain barrier and we won't go super into the weeds here but to know what they are. The first is the paracellular aqueous pathway. So water soluble agents here try to diffuse through these tight junctions and as you can see in letter A not very much gets through. Letter B is the transcellular lipophilic pathway and in this case lipid soluble agents are able to pass through the epithelial lining and move across the blood-brain barrier. This is the primary way that drugs get into the CNS is through this transcellular lipophilic pathway. The third mechanism is via transport proteins and so things like glucose, amino acids, nucleosides as well as drugs like the vinca alkaloids take advantage of these active transport proteins. The fourth is via receptor mediated transcytosis so things like insulin and transferrin cross the blood-brain barrier via this method and finally adsorptive transcytosis where things like albumin and other plasma proteins can cross the blood-brain barrier to some extent. Probably the most frequent time that we think about how well a drug crosses the blood-brain barrier in the PICU is really for the treatment of meningitis and so we have to think about the CNS penetration of antibiotics in children and really it's very dependent on two things. Number one is what drug are we giving and number two is how much inflammation is going on. So if we think about CNS infections broadly speaking there's going to be quite high local inflammation and therefore those tight junctions loosen up things are a little more leaky and it's easier to get drug in. So aminoglycosides traditionally not thought of as particularly great CNS penetration. They do okay in neonates because blood-brain barrier still is not quite as effective but generally speaking not great. We can compare that to something like a fluoroquinolone that has up to 90 percent penetration so great bioavailability into the CNS for this drug. Same for lenazolid, vancomycin sort of okay particularly with inflammation going on you can get acceptable levels there and metronidazole is sort of the go-to if we need anaerobic coverage in the CNS, great penetration. We'll next move on to drug metabolism. Metabolism can be defined as the biotransformation of a substance within the body to other molecular species. It largely occurs in the liver though it can take place in other sites as well. Another big one where it takes place is actually within the intestinal lining. There are a lot of phase one metabolic enzymes that live within the intestines and on that note the major factor in metabolism is enzymatic capacity largely broken down into phase one enzymes and phase two. Phase one metabolism is sort of what most people think of classically with drug metabolism. It's the CYP enzymes plus a few others things like alcohol dehydrogenase and there are three main phase one reactions. First is hydrolysis, reduction, as well as oxidation. Phase two metabolism largely consists of conjugation reactions in which a substrate is having something added on to it to make it more water soluble and therefore easier to eliminate from the body and the major processes here are glucuronidation, sulfation, methylation, and acetylation. Whether it's phase one enzymes or phase two enzymes, overall all that metabolism is really doing is largely making things more water soluble so that the body can get rid of them. Now this process generally deactivates drugs. Sometimes it may turn a parent drug into an active metabolite or it may turn some inactive parent drug, the prodrug, into its active form, but regardless really it's preparing drugs for elimination. Drug metabolism does change over time. Here we have listed a number of important metabolic enzymes. We have cytochrome P453A4, 1A2, and 2E1, as well as UGT 2B7 and 1A6, two of the phase two enzymes, and what you can see is that relative to adult function they increase over time. The sort of good number to keep in your head here is that by age 10, with the exception of 1A2, which is eight years of age, but by 10 years of age, metabolic capacity has really reached that of an adult. We still need to think about other things like volume of distribution that might be different for a drug or the clearance mechanism of how we're gonna eliminate these metabolites, for example, but in terms of metabolic capacity, by 10 years, we're pretty much equal to that of an adult. Finally, we'll move to elimination, the fourth of our pharmacokinetic parameters. Elimination is simply defined as the excretion of a substance from the body, and two major organs are responsible for drug elimination. The first is the liver via the biliary tract, and the second, and one we probably think about more frequently that affects more drugs, is renal elimination via the kidneys, and the primary processes here are gonna be glomerular filtration, as well as active tubular secretion. I've mentioned passive tubular reabsorption here because it is gonna be important for a number of drugs, so while it's not necessarily an elimination pathway per se, it is involved in overall drug clearance through the kidneys. When we think about glomerular filtration and tubular secretion, it's important to know that they really develop at different rates. So glomerular filtration, while it's not zero before 30 days, it's quite low, and I have another graph on the next slide that we'll take a look at, but really, it's quite low before 30 days of age and increases after that, whereas tubular secretion takes even longer, up to six months, to really develop. Focusing in now on glomerular filtration, it's directly proportional to gestational age. It also has dramatic increases at birth. So now if we look at this graph over on the right-hand side and pay attention to the blue line, which represents glomerular filtration, along the x-axis, we have age, starting at birth and going up to 12 years of age, and on the right-hand y-axis, we have glomerular filtration rate. If we think about a patient at birth, or days one to two of life, they probably have a glomerular filtration rate, or a GFR, of somewhere in the 20 to 30 mls per minute per 1.73 meters squared range, whereas within a couple of weeks, their GFR has doubled. So now we're probably 50 to 60 mls per minute. And so this is gonna have important implications when we think about how do we dose these drugs, whether we have a newborn or a several-week-old infant in the PICU, or if you're going to a NICU, you're gonna have to change the drug dose frequently for these patients because their glomerular filtration is quickly ramping up. This is gonna be the primary mechanism of elimination for drugs that are hydrophilic with low-protein binding, which encapsulates quite a few drugs that we use, particularly things like antibiotics. Moving next to tubular function, we'll start with tubular secretion. It's a transporter-mediated process and is involved anytime renal drug clearance exceeds glomerular filtration rate. So anytime the kidney is able to clear more drug than can be explained by GFR, there has to be some tubular secretion going on. And some classic examples here, things like penicillins, methotrexate, furosemide, sedalfavir, and metformin. And we'll talk in a second about how we can change how much of these drugs is eliminated via tubular secretion. Tubular reabsorption, sort of the opposite, but it's a diffusive process in this case for most compounds. And it's influenced by tubular concentration, so how much drug is actually present, as well as how ionized is the drug. That's gonna be really the key driver of tubular reabsorption. And some examples of drugs that experience tubular reabsorption are salicylates, phenobarbital, and digoxin. We typically think about changes in renal clearance of a drug as being decreased clearance, things like AKI, for example. But we can actually increase the renal clearance of specific drugs in certain circumstances where that's advantageous. Using something like urinary alkalinization can decrease the reabsorption of weak acids by increasing their ionization in the urine and ion trapping them. So a great example here is aspirin overdose. Aspirin is a weak acid. So if we alkalinize the urine, as aspirin makes it into the urine, we now have a weak acid in a basic environment which is going to ionize whatever aspirin is there. And ionized molecules don't cross lipid membranes very well. It's gonna make it more difficult for the aspirin to be reabsorbed and therefore the patient will excrete extra acid, or excuse me, will excrete extra aspirin. We can also do the opposite of that, using urinary acidification to decrease the reabsorption of weak bases via the same mechanism. An example here is something like an amantadine overdose. More commonly thought about and more commonly experienced is decreased renal clearance. Primarily this is gonna be due to some form of renal hypoperfusion causing decreased GFR, but it can also be due to things like nephrotoxic medications. Competition at tubular secretion transporters also can decrease the renal clearance of drugs. So we talked about how penicillin and sodafovir have active tubular secretion, but we can give a drug like probenicid to prevent that and block that tubular secretions. NSAIDs do the same thing to methotrexate. Trimethoprim does it to brocainamide and verapamil to digoxin. Important to think about how do we estimate renal function in pediatrics? And most commonly we're gonna use an equation called the Bedside-Schwartz equation to estimate glomerular filtration rate vis-a-vis creatinine clearance. There's a whole bunch of caveats about creatinine clearance and why it may or may not be the best in specific situations, which could be its whole own lecture. But we'll start with what is the Bedside-Schwartz equation? And it's an easy one to remember. 0.413 times the patient's height in centimeters divided by their serum creatinine in milligrams per deciliter. And that's gonna estimate their creatinine clearance in milliliters per minute per 1.73 meters squared. So we're normalizing it for age and size in order to compare it to adult values. Is the calculation always helpful? No, it's not, but it often is. When might it be less helpful? So newborns is a great example where serum creatinine in a newborn for that first week or so of life isn't particularly reflective of the newborn's own creatinine production. Malnourished patients who have lower amounts of muscle mass, since creatinine is a byproduct of muscle turnover, they may have a falsely low serum creatinine. Similar with oncology patients or an ECMO patient, for example, who may be paralyzed for a couple of weeks at a time in certain circumstances. If they're not moving around much, they're not gonna have a lot of muscle turnover, much less creatinine production. And therefore, while their GFR may not be great, their creatinine won't necessarily reflect that. And likewise, their creatinine clearance won't reflect their decreased renal function. Dialysis is another one that can sometimes trip people up because you may have a patient with a really high serum creatinine, they get put on dialysis and their creatinine comes down. It's not because their kidney's magically recovered since yesterday, but creatinine is cleared by dialysis. So it's another one to think about that if your patient is on dialysis, kind of ignore their creatinine. It's good that it's getting better, but it is not reflective of their renal function. The other important thing to think about with clearance is that it doesn't scale linearly. We can't simply say this patient is half the size of an adult, therefore their clearance is half of an adult. We have to think about something called oelometry. And we won't get super into the weeds here, but overall oelometry is a description of how the characteristics of living creatures change with size. And the fun trivia fact on this slide is that it was actually developed by looking at the development of fiddler crabs. And why do they have one giant claw and how does its development relate to the rest of their body? So we can use the ideas of oelometry to perform allometric scaling using this generalized equation, which is that Y or any biologic characteristic we want to estimate has some relationship to body mass and then a couple of empirically derived constants. There are a few allometric scaling exponents that can really be grouped together. They've been predicted mathematically and then verified in various different species. And they can really be thought about in terms of characteristics that describe volume. So things like blood volume or tidal volume scale with an exponent of one. They're effectively linear. We can think about variables that involve rates. So metabolic rates, for example, oxygen consumption rates, they scale with an exponent of 0.75. And finally time or frequency variables, which scale with an exponent of 0.25. Applying that to a pharmacokinetics in children, clearance scales with an exponent of 0.75. So we can use this general equation in which the clearance of any individual equals some standardized clearance times the individual's weight over a standardized weight to the 0.75. Volume is easier because volume scales to an exponent of one and therefore is effectively linear. So the real question is, why does it matter? And how does this affect my patients? So on this slide, we're gonna look at how different is a clearance estimate depending on if we scale it linearly, sort of with a classic milligram per kilo scaling factor versus allometrically. You can ignore the red line, but the blue line is linearly scaled per kilo dosing. And the x-axis is the reference, which is allometric scaling. And so if we wanna use a cutoff of a 20% difference or less, really any patient under 30 kilos or so, their clearance is gonna be more than 20% different depending on how we scale it, either allometrically or linearly. If we lower that cutoff to 10% difference, really any patient under 45 kilos or so is gonna have a greater than 10% difference in clearance. So why does this matter in real life? Most of this is gonna be sort of cooked into the dosing that you look up in LexiComp or Micrometics, for example. But the more important takeaway is that clearance doesn't change linearly as patients get older. So we can't necessarily just think about this patient doubled in age from one month to two months, just assume that their clearance has doubled. Things don't change on quite a straight line. And so it's just important to think about any time that you may be using a drug that doesn't have great pediatric data and we're doing some extrapolation. We need to account for these differences. We can also eliminate drugs using extracorporeal support. So renal replacement therapy, or RRT, is a great example. And it's got several modalities, whether it's peritoneal dialysis, intermittent hemodialysis, continuous hemodialysis, or some of the modalities more often used in adults, things like SLED or PERT, for example. But really there are changes in drug clearance that are gonna be driven by modality, what type of dialysis are we giving? If it involves a blood pump, how fast is that blood pump going? And then if we're using dialysate or replacement fluid rates, what are they? As well as the filter type and size. The main drug attributes that are going to affect how well or how poorly a drug is cleared by renal replacement therapy are hydrophilicity, so water-soluble drugs tend to be cleared better than lipophilic drugs. How protein-bound is this drug? Most proteins are too large to fit through a dialysis filter so the higher the protein binding of a drug, the less you're gonna clear via dialysis. What's the volume of distribution of this drug? Dialysis only clears drugs that are in the bloodstream, so anything that's out of the bloodstream is gonna stay in the patient. Therefore, the lower the volume of distribution, the more dialysis clearance we can expect, as well as molecular size. So small and middle molecules, which encompass the majority of the non-biologics that we use, are generally going to be within these two categories and fit through the dialysis filter very, very easily. Large molecules, it gets a little muddier. They don't fit through the filters quite as well. However, high-flux dialysis filters these days have filter sizes or pore sizes of anywhere from 35 to 50,000 Daltons. So large drugs certainly can still fit through, but once we get up to proteins, things like monoclonal antibodies, broadly speaking, there's gonna be minimal to no dialytic clearance in these drugs. We also need to think about extracorporeal membrane oxygenation, or ECMO. Largely drug clearance, at least initially, early in an ECMO run, is going to look decreased because a lot of drugs stick to the oxygenator and the tubing. There's adsorption that goes on. And so we put a bunch of drug into the patient, and as their blood goes through the ECMO circuit, the drug sticks to the circuit, and it looks like they're clearing drug. We can also directly increase elimination, for example, if we're scuffing a patient to remove fluid. ECMO mostly is going to affect volume of distribution rather than clearance. However, there are a number of studies that do show decreased drug clearance in patients on ECMO. Additionally, as you know, we don't put healthy patients on ECMO. And so these patients have a very high rate of AKI. Some of that is likely just due to being on ECMO, but some of it is also due to their critical illness and the known high rates of AKI in critically ill patients. So if a patient is on ECMO, regardless of the mechanism, they're likely to have some decrease in drug clearance. We're now gonna take a few slides and look at the pharmacokinetics of alternative routes of administration. Aerosolization is a great way to deliver drugs. There's rapid absorption through the lungs due to the high surface area, and it has high bioavailability. Here we have a table from a paper that looked at the bioavailability of a couple drugs, albuterol and budesonide, and really look at how much of it got to the lungs, as well as what was the lung availability to their systemic availability ratio. And overall, we can see that lung disposition really depends on how it was delivered. And so that's the most difficult part of giving a drug that we wanna aerosolize is, can we get the particles small enough and can we get them deep enough into the lungs so that they're well absorbed? Once they're there, absorption is quite good. Closely related is administering drugs via the endotracheal route. Overall bioavailability is going to be very similar to an aerosolized medication. It's getting to the same location. However, the efficiency of delivery, rather than being driven by an atomizer in this case, is now largely being driven by the diluent volume. So when you think about PALS medications, for example, you wanna make sure that if you're delivering a dose of epinephrine, that it's diluted in a large enough volume so that when you bag the patient after administration via either endotracheal tube or through a tracheostomy tube, that you're actually gonna be able to flush the drug down deep enough using, depending on the size of the patient anywhere from one to three to 10 milliliters of diluent to make sure that it gets all the way down into their lungs. Once it's there, like I said, great bioavailability. There are studies that show epinephrine peak effects occur within 15 seconds of endotracheal administration. Intraosseous or IO administration is another great route for patients with limited or difficult access, particularly in emergencies. And overall, we can think of it as being similar to administering something via central venous catheter. This chart is a bit small, but really the big takeaway is that particularly for emergency drugs, there are good data in both pediatric and adult patients that show that most emergency drugs we would need to use are safe to administer, they're well absorbed, and that the dosing is effectively no different than if we were giving it via an IV. We're gonna spend the last few slides thinking about first order and zero order elimination and really how to conceptualize them in the context of patient care. Let's start by defining these. First order elimination occurs when the fraction of drug eliminated remains constant. For example, 10% of however much drug is in that patient will be eliminated every hour. This is the classic linear kinetics in which concentration and elimination are proportional. And some examples are vancomycin and aminoglycosides. We'll contrast this with zero order elimination or Michaelis-Menten kinetics, you might also hear it called that, where the amount of drug removed remains constant. This is also called nonlinear kinetics. So we're in first order elimination, I said 10% may be removed every hour as an example. For a nonlinear drug, it may be 10 milligrams per hour are removed. So concentration and elimination are not proportional. And the classic example here, particularly in children, is phenytoin. Here's a graphical representation of first order on the left versus zero order on the right. So on the left, concentration and dose are proportional. If I double my dose, generally speaking, I will double my concentration. If I zoomed out on this graph enough, there probably is a point at which this would become zero order. But for most drugs that we see in clinical practice within normal dosing ranges, they'll remain with first order relationship here, double my dose, double my concentration. The zero order drug over on the right hand side, this is a great example like phenytoin. Here you can see that at very low doses, they may act relatively linear. However, at a certain point, if I double my dose, my concentration might increase by fivefold. And so dose adjustments in these drugs becomes a little more tricky. We're next gonna touch on half-life. It's a term that gets used a lot and it's an important concept when we wanna think about how long is this drug gonna stick around for? Or when can I expect to see the peak effects of this drug at steady state? So half-life is aptly named as the time necessary for the concentration of drug in the plasma to decrease by half. And to calculate it, there's two steps. If you ever wanted to hand calculate a half-life. The first is to derive the elimination rate constant or the KE, which we do by calculating a slope of a time concentration curve with the natural log of concentration one over concentration two, divided by the difference in time between them. We then take that KE and we use it in the denominator of this equation, 0.693, which is the natural log of two and divide that by KE. That gives us our half-life. So how long it will take for half of this drug to be eliminated. Why is half-life important? Because it tells us how long it's gonna take to either reach steady state or to eliminate all of this drug from a patient's body once I've stopped giving it to them. So steady state really just represents this point at which for a given dosing regimen, the amount of drug being administered and the amount of drug being eliminated are equal. You've probably heard the three to five half-lives to achieve steady state. And that is accurate. At five half-lives, we're at about 97% of steady state. However, the sort of clinical pearl to take away from this is that if you're thinking about, okay, I just went up on this patient's fentanyl, for example, when should I see an effect and when can I make the next dose increase and not sort of overdo it? Well, two to three half-lives, you're anywhere from 75 to almost 90% of steady state. So really think about, am I seeing 80 to 90% of the effect that I expect? If I'm not, and I'm two to three half-lives in, it's reasonable to make some dosage adjustment. The last thing we're gonna talk about is a loading dose, which really is just a shortcut way to get to steady state. Best example that I can think of here is a patient who's seizing and we're gonna give them some phenobarbital. Phenobarbital has an extremely long half-life and I don't wanna wait five days for this patient to achieve therapeutic concentrations on whatever maintenance regimen that I'm giving them. So we'll give a loading dose. Ultimately, we're gonna give them a big dose up front to achieve this high concentration. We're then gonna start their maintenance dose. And what you can see is that as the loading dose is cleared over time and their maintenance dose reaches steady state, overall, we can achieve therapeutic concentrations very, very quickly and then maintain them using that maintenance dosing regimen. That concludes my talk on pharmacology and the five things you need to know. I think there were probably more than five in there, so there's a few bonuses. But I'd like to thank everyone for their attention today as well as the Society of Critical Care Medicine for the opportunity to give this talk.

pharmacology

Gideon Stitt

pharmacokinetic principles

developmental pharmacology

critical illness considerations

first-order kinetics

zero-order kinetics

loading doses