hey this is Dr busty and we're going to be doing a uh focused uh kind of topic on special populations in the consideration of pharmacocinetic and pharmacodnamic related properties this kind of builds off of some of the other lectures and topics related to pharmacocinetics and dynamics um there's a number of objectives that we'll you can read on your own but I want to jump into the different patient populations that we're going to be discussing the first is the pediatric patient then we'll kind of move on to pregnancy um and then the last one will be the geriatric patient um where we may see I guess variations from the norm from the typical u average adult and so let's focus our attention on the uh pediatric patient so when their child is first born their gastric pH so as we think about absorption of a medication the pH can influence that especially for the depending on if it if the drug is a weak acid or a weak base because obviously a weak acid in the presence of a more alkaline environment is going to be more um ionized and so as it's ionized it's more hydrophilic we see that um in the first few hours of life basically the gastric fluid is pretty much neutral where the pH is somewhere between 6 to 8 and then with a matter of of a couple of uh 1 to two days you'll see that the pH goes back to pretty much normal where it is throughout the rest of their life when you look at gastric emptying it's not really significantly changed um though it may not reach full potential um until they're about 6 to 8 weeks and the gastric emptying is going to be influenced by drugs that are going to be um obviously absorbed in the small intestine so the longer it takes to get into the small intestine the delayed onset of action um that will occur so the time to peak concentration or the the rate to achieve the CAX is going to be a little slower and delayed based on that um depending on you know uh when you are managing this patient how old they are as it relates to the volume of distribution there is a big difference early on in life where uh ma mainly hydrophilic um molecules uh tend to have a harder time staying in adequate concentrations in the plasma and so you actually actually give larger doses with uh certain medications like genttomyosin for example uh than you might actually give to an adult and the reason for that is because it goes into the tissue and doesn't stay in the right concentrations in the blood so if you have a uh bacterial infection involving the blood then you're going to need a little bit of a bigger dose earlier on maybe in a pediatric patient plasma protein binding is a little less uh than compared to adults the albamin um concentrations and level of binding is about 80% of that of the adult and the relevance of that is that the free fraction is what exerts the pharmacologic effect that's our pharmacodnamic property right the effect on the body and so when we have greater amount of drug free it's more likely to exert its biologic effect now the al alpha 1 acid glyoprotein which typically binds to basic drugs is about the same as that of an adult so not really seeing much change there when we talk about protein binding there are obviously a number of molecules and things that can displace drugs off of protein binding sites one of those being Billy Rubin especially early on in life and so they can compete with binding sites on albiman for some medications which would then result in an increase in the free fraction when we look at you know so that was all absorption when we start thinking about and some some distribution when we start thinking about metabolism so the ADME uh really there's uh this this does mature uh pretty rapidly in the first uh year of life and there are some drugs that are going to be impacted because it may not be fully at capacity and certainly drugs with a more narrow therapeutic sort of index uh you know window of uh safety and efficacy might be a little bit more effective uh affected um those where phase two where these are glucaronidation pathways conjugative pathways things like drugs like um morphine and um specifically acetaminophen may not be as efficiently um glucaronidated or um have glutathione attachments uh depending on their nutrition status um that that makes those conjugates available when we go to the EDM elimination we tend to think of again kidney function predominantly most drugs are going to be renally eliminated when you look at the GFR or contribution of the kidneys to secrete drugs in the proximal renal tubule um that may take several weeks to the full year to develop and as a result may may not see the same degree of renal dose adjustments that might be seen in adult with a more functioning uh kidney function so there are a number of methods to analyze kids outside of doing a 24-hour urine um the Schwarz method and and the Tro method or some of the historical uh formulas that are used to determine or kind of estimate the grat and clearance but recognize that if their kidney function is changing it's not going to be very accurate you may have to then go to a 24-hour urine collection um obviously drugs can cross the the into the placenta and and I Yep sorry this slide is off in one order but um when we get into pregnancy um the pregnant patient now uh we go through the again some of the principles of pharmaccoinetics adme um so the hormones that change during pregnancy are pretty significant actually they do a lot of things and they kind of prepare the body uh not only for carrying an extra you know ch you know human right the they're going to peruse a placenta so the plasma volume changes the the the cardiac output is going to change the profusion to the kidney is going to change all these things are partially being influenced by the hormone levels and one of the things that the hormones can do to the gastrointestinal system as it relates to absorption is that they progesterone can relax some of these smooth muscle um and that can change the gastric emptying time and that obviously will affect the T-max kind of a little bit like we were saying with the pediatric patient um there is some degree of increased mucus production as well as decreased gastric acid that can create a more alkaline environment um and when we look at absorption the cardiac output generally is increased and the tital volume some drugs we can eliminate by exhalation or by removal by increasing the perfusion to tissue and so that may affect the little bit of the absorption and it's really hard to probably tell these difference clinically and you may be saying "Then why are you telling me this and why am I learning this?" Um again it's just important to recognize that when you might see variations in the clinical response in certain special patient populations because of physiologic differences and that's the point of this lecture is to point out some of the differences in the physiology that's happening that might change the expected or predicted pharmacologic response that you might be looking for so like I said in pregnancy the cardiac output is going to increase and that's going to increase actually renal blood flow so drugs that are highly dependent on renal elimination may actually be able to be excreted a little bit more efficiently um when you look at part of the contributions to increased cardiac output and the renal blood flow that has to do with plasma volume extension like I said before you have to peruse another organ and another person and so we need to bring nutrients to that that uh placenta and to the baby oxygen and um as well as nutrients to grow and so the plasma volume increases and that may affect our hydrophilic u molecules that um that are more likely going to stay in the water and compartment and so we can see the total body water um increase up to 8 L and with 60% of this being distributed to the placenta the fetus and amniotic fluid um and so this can change the CAX or the concentrations that are seen because it's basically going to be diluted um and so drugs with a small volume of distribution may see the greatest effect on that because they're more likely to reside in the plasma versus the tissue when we look at protein binding again um the amount of albammen present partly due to the dilutional properties that I just mentioned from the increase in plasma volumes can theoretically cause less binding opportunities um and increase the free fraction of the drug we don't see that as much with the alpha one acid glyoprotein but you see it with maybe a little bit of um albammen now you may say okay well I got an increase in free fraction which may increase my pharmacologic and biologic response but at the same time I have increase in cardiac output and profusion to the kid uh kidney so I may be increasing the elimination and so they kind of cancel each other out but again individually it depends on the drug and the physi physiology of that patient that's going on so it's kind of important to recognize when we look at hormones influence not only on smooth muscle in the GI system but it also can influence other pathways and and the metabolism can be affected a little bit when we start looking at microsal oxidases and and stuff like that which may affect the clearance of a of the drug but like I said clearance pathways um we predominantly thinking of the kidneys and because of the increase in cardiac output in renal blood flow and so that may lower the steadyst state concentrations that are are present now however you we have to keep in mind that member of drug metabolism h happens not only in the intestine at the level of the interosite but also obviously more importantly and most well recognized is the hpatosy uh cells of the liver but it can happen in the kidneys and it can also happen in the placenta as well as the developing fetus so then so now you got a whole another compartment so to speak right um that drugs can distribute into and can also be metabolized and so those need to be factored in there's there's two uh models there's the one compartment model where the the fetal maternal drug concentration you know what's the difference between those two now that drug can maybe distribute in through the placenta into that child um and then the two compartment model where we um this is more slowly accessible and it tends to be a more of a deep um sort of compartment where it can hold on to drugs and it tends to show up a little bit later uh than during the absorptive phase so once a drug gets absorbed in the body remember it's distributing and dist going to tissue and there's some play going inside and outside of those tissues to find that balance and equilibrium based on the volume of distribution of that drug um and also the um amount of plasma volume in that patient so you can see in the post distributive phase a little bit of a difference than what you might see in the absorptive phase as a result of these compartments that can form um obviously the fetus has its own protein concentration has its own uh enzymes for metabolism and has a different pH so for example if you look at the acid base equilibrium effect there may be a little bit of ionization depending on that drug because when you look at um ion trapping this is going to be influenced by the pH of the of the tissue um and so depending on the pKa um in relationship to the pH of where that drug is located it might get trapped inside of the fetus um as a result of that and so then it serves as a deep reservoir which not only may affect the fetus but may then leak back out infect the the mother if there was something you know potentially negative going on beyond what you would normally think and beyond even the administration of the medications um so there like I said drug metabolism can occur and it starts to work pretty early within the period of gestation and again part of that is protective mechanisms so that remember the developing fetus in that first really 8 to n weeks when organogenesis is going on and cells are differentiating and forming organs you don't want stuff messing around with that right and so the the there are protective mechanisms and they get started pretty early to try to facilitate the reduced exposure to that but like I said the the fetus and the placenta can serve as a compartment as well as drug metabolism and again that can influence the effect that you're seeing um obviously we have drugs that we use in pregnancy that have different risk categories and although the pregnancy risk category concept uh although historically has been used and what many clinicians are still used to this has migrated away from by the FDA um to uh pregnancy considerations because of confusions over what evidence and you know risk of harm and what what do we do with pregnancy category C drugs i mean it's pretty easy with pregnancy category D and X because they're typically considered contraindicated and there's some evidence to support that a and B uh makes it easy as well because there's some evidence to support that it seems to be safe there's no real evidence of harm um in that patient but the the gray zone where a lot of drugs kind of reside is in the pregnancy C because you know everything that we do in medicine has risks there's pros and there's cons it's everything has got a a sort of like a double-edged sword you know it does one benefit but then it creates a negative ramification sometimes and so we're always trying to balance those things and I think that that's the purpose for going in more from a pregnancy considerations versus a risk category where we become dogmatic and we say "Well if it's not an A and B I'm not going to use the drug." Well that may not be appropriate because the best thing that you can do to help that clinical situation or the mother and or the baby is by giving the medication recognizing that there are risks with everything that we do including even driving your car down the road right so um you know those risk uh categorizations have fallen out of favor um because of that reason but our ultimate goal to sort of apply this clinically that we want to be careful of is that drugs can pass through the placental barrier those those that do that are at greatest risk a good example warrin okay couadin or warphin can pass through that placenta and get to that child also increases the risk of bleeding that can cause a placental uh uh hemorrhage uh and separation obviously uh causing um a placental abruption that can end the pregnancy and compromise the safety to the child um drug exposure during that first 8 to 9 weeks as I mentioned is most critical we try to avoid at all cost drug exposure during that time because that's when organogenesis is occurring inside the fetus so cells are differentiating organs are forming and we do not want to interrupt or dis uh influence that process um there are obviously a number of medications that are listed here that have been shown and known to cause problems ace inhibitors angotensory receptor blockers renin inhibitors in particular we avoid as a good example and that's relevant because some women will develop hypertension during pregnancy i.e known as preeacclampsia some women go into pregnancy already having hypertension and it gets worse so you have to be careful on the an anti-hypertensive medication that you can use in that patient population for that reason obviously we've know about theomide and theomide babies and unfortunately learned the hard way from that uh and then cumin as I mentioned can cross through whereas low molecular weight hepins don't and they tend to be the drug of choice in patients who have a hypercoagable disorder and may be infaring their placenta and causing miscarriages so there are some clinically relevant applications to factor in recognizing the changes in the physiology but recognizing that there's another being in there that has ability to serve as a reservoir for drug but also metabolize and clear that drug now let's move on to the geriatric patient um so there's a number of body systems that are affected during the aging process you know many pe patients develop heart disease and so they don't peruse their kidneys as well so that may change renal blood flow and then renal elimination uh they may not get good cardiac output to their GI tract and so that may compromise the ability of the GI system in particular the stomach to maintain integrity and so they may be more prone to GI bleeds as a result of that uh many of these patients are also on other drugs so there's a lot of um concominant medication use and so that can compound those risks uh their respiratory status tends to decline a little bit their kidney function declines over their life and we're going to kind of point through some of these things so when we look at the uh concept of absorption in the gastrointestinal tract there's a number of things that can happen especially if they develop disease and as they develop neuropathies especially if they have underlying diabetes you can see changes in GI motility and emptying um on top of that many of these patients are already taking antacids or on PPIs for GIRD peptic ulcer disease whatever and again changing the pH especially for certain types of drugs like weak acids may uh change their ionization state and become more ionized in an alkaline environment and that may affect the overall bioavailability and absorption if it's more hydrophilic molecule um obviously decreased blood flow to the GI tract as I mentioned before can compromise uh the integrity and the ability to maintain the function of that GI system especially when there's other drugs on board like NSAIDs warin uh other antiplay anti-coagulant medications and so we see or we tend to see more GI bleeds in our older patients for that reason epithelial if you're using topical um agents you got to be careful their skin is thinner so that again absorption characteristics are going to be uh different we talked about blood flow to different organs because of changes in cardiac output especially if they have known heart failure um because of their nutrition can sometimes decline then their drugs that are highly proteinbound to things like albammen may have an increase in free fraction um that can then cause again free fraction means it's going to be more pharmacologically um active and bind into cells and turn on their chemical reactions or modulate the activity of that that cell's biology and so therefore we can see exaggerated effects from the drugs and that's why we have lists like the beers list and things like that to help to recognize these are drugs that we want to avoid in patients that are older because they're more prone to the side effects of those medications and this is part of the reason why drugs that distribute in the tissue may also be affected because there's changes in the amount of fat to to muscle mass and we tend to see a lot more fat than we do muscle and so drugs that are high have a high volume of distribution or that tend to be more lipopilic are more likely to deposit and stay and have longer durations of action or half- livives because they're depositing in the tissue that's more readily available and as a result of that can have prolonged effects things like benzoazipines in an elderly patient can create many uh many hours if not days of confusion and changes in mental status that can compromise their safety because if they fall and break a hip or hit their head and they're on anti-coagulant now they're bleeding you see the problems that can sometimes happen in these patients when we factor in some of their changes in their physiology when we talk about drug metabolism probably the number one reason issues of concern is the other drugs that they're taking you know most older patients are going to be on three four up to 10 12 medications and the more medications you add obviously to the mix the greater the risk of drug drug interactions but in addition to that you have reduced blood flow to the GI um to the kidneys as well as the liver and so decreased hpatic um profusion um may not allow the drug to be metabolized on top of that the volume of the liver seems to change over time and so there the overall capacity of a a organ like that to be able to metabolize a drug while not getting perfused adequately is going to be compromised again that would change the overall area under the curve the amount of drug in the body it would change the half-life the duration of action that then increases the ability of that drug to exert its phicodnamic effects which is then why we sometimes see exaggerated or responses in these patients that are that are not something that we desire um and so I I've mentioned these these things already here kidney function also declines uh the mass of the kidneys also changes and if you look at patients as they approach F age 50 after that there's about a 1% reduction in GFR for every year and so you can have a quote unquote slightly elevated uh you know serum creatinin but their GFR is actually pretty low if you do the cockra g or you do um an assessments on their um GFR by doing a 24-hour urine and so renal blood flow changes on top of the fact that many of these patients also tend to have heart problems where there's reduced cardiac output on top of the fact that there's renal mass volume decreases they're just not going to clear drugs as readily and you need to keep that in mind so that you appropriately use the right medication in the right scenario um and so these patients can already have problems with as I mentioned the side effects of these medicines and when you add things like immobility incontinence already they're at high risk for infection and these patients can get septic and they get a simple even a urinary tract infection and they have significant changes in mental status um it can cause instability and um which can then cause them to fall and as I mentioned many of these patients are on blood thinners antiplatlet drugs i mean it's just a bad mix of things that go on with these patients and so the side effects are are basically compounded in this patient population which is why we try to avoid them so you know try to avoid therapeutic uh duplication of of medications try to avoid drug interactions to try to improve the drug selection so we avoid drugs that are known to stick around longer especially if they're dosed inappropriately or have side effects that are going to be more problematic um and I mean I think that just sort of just makes sense so what the goal of this special topics again hopefully you got appreciated this is just recognize there are changes in the physiology and the um anatomy even at some level and as a result of that the typical ADME absorption distribution metabolism elimination may be affected depending on the age of that child other coorbidities going on the patient and other coorbidities and the presence of other medications um that uh hopefully you see some degree of relevance why you might not always see the response that you're looking for uh when you typically use it in a standard age you know adult patient