All right. Good morning, everyone. Today we'll be talking about the challenges of drug distribution in patients with high body mass index. I have no disclosures or conflicts of interest to report. And specifically, we will review the physiologic changes in obesity as well as weight equations for medication dosing. And we will evaluate obesity-induced alterations in our four pharmacokinetic principles of absorption, distribution, metabolism, and excretion. Most recent CDC data on the prevalence of obesity from 2017 to 2020 showed an incidence or prevalence of 41.9%. It's important to note that this has increased from the previous measurements in 1999 to 2000. And when comparing the same time frames, we can see that severe obesity has increased as well from 4.7% to 9.2%. And when we start talking about severe obesity, this is where we start to have extreme challenges in our drug dosing. Annual medical cost of obesity was estimated to be close to $173 billion in 2019 dollars. This graph, excuse me, this slide shows some key physiologic changes in obesity that we should keep in mind when we think about our medications. The first is that these patients have an increased adipose tissue. Likewise, they have an increase in lean muscle mass. But the biggest key thing in comparing these increases in tissue is the fact that the ratio of these two types of tissue does not increase in proportion to each other. So these patients have a higher ratio of fat to muscle mass. We have to consider these different types of tissues when we consider our drug dosing. Other key physiologic changes to keep in mind that we will revisit as we progress through the slides, increased blood volume, increased cardiac output, increased hepatic blood flow, and increased renal blood flow. Now with these organ systems, one of the other considerations on the flip side of assuming that these increased blood flows mean increased metabolism or clearance are the fact that with chronic disease states, liver disease, kidney disease, heart disease, we may expect that these disease states from chronic poor health to also decrease clearance or metabolism of drugs. The difficulty with dosing medications in obese patients comes from the fact that we have a simultaneous risk of decreased effectiveness if we're not identifying which drugs should be dosed based on a certain weight or taking into account that their increased weight means we need to give an increased dose of drug or simultaneous increased risk of toxicity. So maybe their increased weight actually would put them at risk of harm because the drug is not impacted by that increase in adipose tissue. The majority of our available literature when evaluating medication dosing utilizes pharmacokinetic endpoints and not clinical outcomes. And currently, the Food and Drug Administration does not have a standard requirement for obese patients to be represented in our preclinical studies. An example of that was a survey that Jane and colleagues performed in 2011. Between the FDA and the European Medicines Agency, they found few guidance documents to suggest that obese patients be included in preclinical studies. A few of these documents included things like diabetes and venous thromboembolism. In evaluating new molecular entity products from 2004 to 2010, they found that two out of 137 of these products included meaningful efficacy and safety information for obese patients. Furthermore, out of all the medications included in the physician's desk reference, only eight entries had meaningful information related to obese patients. So this is the type of information that we're dealing with as we evaluate this day-to-day. Choosing the optimal weight descriptor is vitally important in our medication dosing. We utilize BMI to classify severity levels of obesity. But it does not account for changes in lean muscle mass and adipose tissue and therefore is not routinely utilized in drug dosing. In clinical practice we're using our indirect measurements of body composition. These may include ideal body weight, a decision between adjusted body weight or lean body weight, noting that lean body weight is a more difficult calculation and potentially prone to transcription of numbers or errors, and then lastly total body weight. Intravenous administration is our gold standard for bioavailability where we would assume 100% bioavailability via this route. There is some literature suggesting there are physiologic changes in obesity with the oral route of administration, particularly delayed gastric emptying or changes like that. But there's no significant data to show us how this impacts oral medication absorption. Obese patients receiving subcutaneous administration of medications are at risk of incomplete or delayed absorption with their increased adipose tissue. And likewise, when intramuscular is necessary, these patients are at a risk of not actually achieving intramuscular administration and achieving deep subcutaneous administration. The volume of distribution, which is key in terms of our obese patients, is defined or can be described as how extensively a drug distributes into tissues. We consider the volume of distribution when we're calculating our loading doses. And overall, the properties of the specific drug are the main determinant of its distribution into tissue. There are two key physiologic factors to keep in mind with drug distribution. And that is the increase in cardiac output, which then translates to an increase in tissue blood flow or delivery of drug to the tissues for distribution. These are the five main properties that I would think of when I'm considering how extensively a drug may distribute into tissues. The first is the lipid solubility. Drugs that are lipophilic or more likely to distribute into adipose tissue may require consideration or extra consideration in your obese patient to make sure that you are achieving that efficacy marker that we had mentioned. But contrary to that, medications that are hydrophilic are the ones that we have to consider optimal weight descriptors or optimal dosing strategies because of that increased toxicity risk. Molecular weight, so size of the drug, its degree of ionization, as well as ability to cross biologic membranes are factors to consider with drug distribution. And lastly, protein binding as well. There's a small body of literature to suggest that obesity may not have significant impact on albumin drug binding. And to a greater extent, alpha-1-acid glycoprotein may be impacted. But once again, this literature is difficult to make concrete decisions or drug dosing changes on as to what extent it impacts clinical outcomes. Clearance is comprised of both metabolism and excretion in the various end organs for both of these pharmacokinetic processes. We mentioned patients have an increase of hepatic blood flow. So delivery of medications to the liver does that increase clearance, excuse me, metabolism and drug removal from serum. Consequently, over time, do our obese patients develop fatty liver disease and what extent does that liver disease have on changing metabolism of drugs? When we talk about metabolism, we're considering both Phase 1 and Phase 2 metabolism. SIP enzymes make up 75% of all of our drug metabolism. There's a few small studies evaluating what impact SIP alterations, one, if they're present. But two, if they are present, what impact does that have on metabolism of drugs and obesity? There's no significant data from either to say that there are alterations or that these alterations translate into changes. Excretion is a renal process. We're using the function of the kidneys to help determine maintenance doses and medications that are renally excreted via the three possible pathways for clearance of drugs to the kidney, glomerular filtration, tubular secretion and tubular reabsorption. We mentioned that patients have an increased renal blood flow with obesity. But if they develop chronic kidney disease over time, what is the impact of the kidney disease on clearance as well? And lastly, one of the main predictors of renal function that we're using right now is keratinine clearance. Estimating our keratinine clearance in obese patients is problematic. Once again it gets back to that discussion about what is the optimal weight descriptor to include in our calculations of keratinine clearance. So overall, what I can tell you is that the impact of drug dosing, the impact on drug dosing from obesity alterations to hepatic and renal clearance is overall unclear. So to wrap up, a few key areas that we should think about occurring in our daily practice as we come across these patients that are critically ill. The first would be our sedation. So when I'm considering these medications with sedation, I'm considering what our indication is. And so that indication may vary if we're delivering a bolus modality or if we're just starting a continuous infusion. And then what is the particular adverse effect that I'm concerned about if we over or under dose these patients? So I'll just take boluses of dexmedetomidine off the conversation for today just because in my particular ICU we are not routinely utilizing these. It is important and it should be discussed when we think about if your facility is using dexmedetomidine boluses in procedural areas. For propofol and dexmedetomidine we're considering the risk of hemodynamic adverse effects with choosing a weight descriptor which ultimately translates into an initial dose that may be non-optimal for patients. When we label a patient as not able to tolerate propofol or not able to tolerate dexmedetomidine because of these hemodynamic adverse effects, we know where our minds go if the patient has an indication for sedation and we start to have to go down the cascade of less ideal sedative agents, the big bad benzodiazepines. And lastly ketamine, if your institution is using a lot of boluses or potentially certain areas are high utilizers of bolus doses versus continuous infusions. And so when we're talking about sedation as well as our neuromuscular blockade, I think one of the unique challenges is, especially in the bolus type of administration, is related to how often are boluses or single doses calculated without an order prospectively being in your electronic medical record. And so we can do a lot of things for continuous infusions with trying to drive the optimal dosing weight with our electronic medical records. But if the care team is not routinely shown in your electronic medical record or routinely thinking about alternative weight descriptors, it's difficult to calculate that bolus when you're doing RSI or you're doing a procedure at the bedside. And so we have to go back to our technology and try to help drive to optimal use. Neuromuscular blockade, once again I would consider the indication. Are we doing an intubation? Are we doing a bedside procedure where we could re-dose if we needed to? And then lastly sustained neuromuscular blockade. For sustained neuromuscular blockade the Society of Critical Care Medicine guidelines for utilization of sustained neuromuscular blockade would suggest that we don't use a total body weight dosing strategy in obese patients. Once again for continuous infusions we could drive that through our electronic medical record because in the case of an infusion we're going to prospectively have an order in the chart prior to administering. Finally enoxaparin. This is certainly something that is commonly occurring in almost every trauma patient in your ICU. The volume of distribution of enoxaparin approximates total blood volume. So that's important to consider. We mentioned at the beginning of the talk that obese patients have an increase in their blood volume. So there's a scenario where these patients, you can see it in some of the literature for prophylaxis, that at higher BMIs we are potentially giving inadequate doses of prophylaxis. But there's a point in time where when we're giving treatment doses and we are using Mg per kg weight-based dosing, that that increase in total blood volume could be offset by the increase in adipose tissue. Enoxaparin is not going to distribute into adipose tissue. And therefore we have this paradigm where at prophylaxis we may need higher doses to achieve adequate efficacy. And for treatment we actually need lower Mg per kg doses than a non-obese patient to back away from that toxicity or adverse effect scenario. A constant question is where does therapeutic drug monitoring come into play? How do our low molecular weight heparin anti-TENA levels translate to clinical outcomes? Which is something that each institution is going to utilize these levels a little bit differently. In conclusion, there's minimal literature available to guide our drug dosing in obesity. There's little data from the drug development process and I anticipate, at least for now, that to continue. Whereas the majority of our available literature is based in pharmacokinetics and not clinical outcomes in obese patients. Our drug properties are primarily impacting our drug distribution. An increase in adipose tissue is more likely to affect lipophilic drugs. Our physiologic properties are primarily impacting metabolism and excretion. And lastly, each medication must be separately evaluated when considering dosing in obese patients. So we cannot simply make a conclusion about all neuromuscular blocking agents knowing that based on the indication or based if you're utilizing succinylcholine we may have a difference. So this is the challenges that each drug has to be taken with each drug's literature and not applied as a class. »» Thank you.

drug distribution

high body mass index

obesity

medication dosing

physiological changes